In the early stages of CHF, you most likely won’t notice any changes in your health. If your condition progresses, you’ll experience gradual changes in your body.

Chest pain that radiates through the upper body can also be a sign of heart attack. If you experience this or any other symptoms that may point to a severe heart condition, seek immediate medical attention.

Symptoms of heart failure in children and infants

It can be difficult to recognize heart failure in infants and young children. Symptoms may include:

These symptoms can easily be misunderstood as colic or a respiratory infection. Poor growth and low blood pressure can also be signs of heart failure in children.

In some cases, you may be able to feel a resting baby’s rapid heart rate through their chest wall

An echocardiogram, often called a cardiac echo, is a non-invasive ultrasound imaging test used to observe the heart. Your healthcare provider may order this test to help diagnose various heart conditions.

A cardiac echo is used to identify abnormalities in the heart's structure and function. A handheld device sends out sound waves that bounce off your heart and create a moving image of it on a screen. This allows your healthcare provider to look at the anatomy of the heart from many different angles and to observe your heart rhythm.

If you have symptoms of fatigue, shortness of breath, or fainting, you may need a cardiac echo. This is especially true if a stethoscope or an electrocardiogram (a test that charts the electrical activity of your heart) suggests that you have a structural heart proble

A cardiac echo is considered the best way to visualize the movement and function of the heart muscle and heart valves. You may need a cardiac echo if you have heart valve disease, heart rhythm irregularities, or cardiac muscle diseases such as dilated cardiomyopathy or hypertrophic cardiomyopathy.

b)Thyroid Gland:

Diagnosis:

Thyroid cancer is an unusual form of cancer or growth of abnormal cells in the thyroid gland.

The thyroid gland is a butterfly-shaped endocrine gland, which is situated at the anterior of the neck just beneath Adam’s apple. The major responsibility of this gland is to produce triiodothyronine (T3) and thyroxine (T4) hormones.

Thyroid cancer is an abnormal form of cancer. In most cases, women appear to be more vulnerable to this disease than men and it is more common in people among the higher age groups. In most cases, thyroid cancer causes a lump in the gland known as the thyroid nodule. Most of these nodules are non-malignant (or) noncancerous but about 10% of them are malignant.

Types of Thyroid Cancer

The thyroid cancer could be broadly divided into 3 groups namely:

Differentiated (includes papillary, follicular and Hurthle cell)
Medullary
Anaplastic

Papillary Thyroid Cancer

Papillary carcinomas or papillary adenocarcinomas are the most common form of thyroid cancer accounting for around 80-85% of all reported cases. Papillary cancer affects the follicular cells in the gland. It is generally found in either of the two lobes of the gland that spread quite slowly. In certain cases, it would spread to the lymph nodes in the neck.

Medullary Thyroid Cancer

It is a form of thyroid cancer that originates from the C cells, which are present within the Thyroid Cancer. The C cells are mainly responsible for the secretion of the calcitonin hormone. Thyroid cancer is very hard to locate as they spread to the lymph, the liver or to the lungs. Medullary thyroid cancer is sub-categorized into sporadic medullary thyroid cancer(non-genetic, not inherited) and familial medullary thyroid cancer(genetic, inherited across generations).

Anaplastic Thyroid Cancer

Anaplastic carcinoma or undifferentiated carcinoma is one of the rarest forms of thyroid cancer and is virtually undetectable as these cancer cells are completely different from normal thyroid cells when examined under the microscope. This cancer spreads quickly to other organs which are extremely difficult to diagnose and treat.

There are other forms of thyroid disease such as thyroid sarcoma, thyroid lymphoma, and other tumours which are extremely rare.

Physical examination. The doctor will feel the neck, thyroid gland, throat, and lymph nodes (the small, bean-shaped organs that help fight infection) in the neck for unusual growths or swelling. If surgery is recommended, the larynx may be examined at the same time with a laryngoscope, which is a thin, flexible tube with a light.
Blood tests. There are several types of blood tests that may be done during diagnosis and to monitor the patient during and after treatment. This includes tests called tumor marker tests. Tumor markers are substances found at higher-than-normal levels in the blood, urine, or body tissues of some people with cancer. Blood testing may include:
- Thyroid hormone levels. As explained in the Introduction, thyroid hormones regulate a person’s metabolism. The doctor will use this test to find out the current levels of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) in the body.
- Thyroid-stimulating hormone (TSH). This blood test measures the level of TSH, a hormone produced by the pituitary gland near the brain. If the body is in need of thyroid hormone, the pituitary gland releases TSH to stimulate production.
- Tg and TgAb. Thyroglobulin (Tg) is a protein made naturally by the thyroid as well as by differentiated thyroid cancer. After treatment, there should be very low levels of thyroglobulin in the blood since the goal of treatment is to remove all thyroid cells. If Tg is rising after surgery and/or radioactive iodine, it may be a sign of more cancer. A tumor marker test may be done to measure the body’s Tg level before, during, and/or after treatment. There is also a test for thyroglobulin antibodies (TgAb), which are proteins produced by the body to attack thyroglobulin that occur in some patients. If TgAb is found, it is known to interfere with the results of the Tg level test.
- Medullary type-specific tests. If MTC is a possibility, the doctor will order tumor marker tests to check for high calcitonin and carcinoembryonic antigen (CEA) levels. The doctor should also recommend a blood test to look for the presence of RET proto-oncogenes (see Risk Factors), particularly if there is a family history of MTC.
Ultrasound. An ultrasound uses sound waves to create a picture of the internal organs. An ultrasound wand or probe is guided over the skin of the neck area. High-frequency sound waves create a pattern of echoes that show the doctor the size of the thyroid gland and specific information about any nodules, including whether a nodule is solid or a fluid-filled sac called a cyst.
Biopsy. A biopsy is the removal of a small amount of tissue for examination under a microscope. Other tests can suggest that cancer is present, but only a biopsy can make a definite diagnosis. The way to determine whether a nodule is cancerous or benign is through a biopsy. During this procedure, the doctor removes cells from the nodule that are then examined by a cytopathologist. A cytopathologist is a doctor who specializes in analyzing cells and tissue to diagnose disease. This test is often done with the help of an ultrasound (see above).

A biopsy for thyroid nodules will be done in 1 of 2 ways:
- Fine needle aspiration. This procedure is usually performed in a doctor’s office or clinic. It is an important diagnostic step to find out if a thyroid nodule is benign or cancerous. A local anesthetic may be injected into the skin to numb the area before the biopsy. The doctor inserts a thin needle into the nodule and removes cells and some fluid. The procedure may be repeated 2 or 3 times to get samples from different areas of the nodule. A report of the results of this test is created by the cytopathologist. The test can be positive, meaning there are cancerous cells, or negative, meaning there are no cancerous cells. The test can also be undetermined, meaning it is not clear whether cancer is there.
- Surgical biopsy. If the needle aspiration biopsy is not clear, the doctor may suggest a biopsy in which the nodule and possibly the affected lobe of the thyroid will be removed using surgery. Removal of the nodule alone is usually not recommended due to the potential to incompletely remove the potentially cancerous tumor without enough margins, which is an area of tissue around the nodule. This procedure is usually done under general anesthesia. It may also require a hospital stay.
Molecular testing of the nodule sample. Your doctor may recommend running laboratory tests on a tumor sample to identify specific genes, proteins, and other factors unique to the tumor. Genetic analysis of your thyroid nodule may allow you to understand the risk of the thyroid nodule being cancerous. Other genetic, protein, and molecular analysis of thyroid cancers can help determine your treatment options, including types of treatments called targeted therapy.
Radionuclide scanning. This test may also be called a whole-body scan. This scan will either be done using a very small, harmless amount of radioactive iodine I-131 or I-123, called a tracer. It is used most often to learn more about a thyroid nodule. In this test, the patient swallows the tracer, which is absorbed by thyroid cells. This makes the thyroid cells appear on the scan image, allowing the doctor to see differences between those cells and other body structures.
X-ray. An x-ray is a way to create a picture of the structures inside of the body, using a small amount of radiation. For instance, a chest x-ray can help doctors determine if the cancer has spread to the lungs.
Computed tomography (CT or CAT) scan. A CT scan creates a 3-dimensional picture of the inside of the body using x-rays taken from different angles. A computer combines these pictures into a detailed, cross-sectional view that shows any abnormalities or tumors. A CT scan can be used to measure the tumor’s size. Sometimes, a special dye called a contrast medium is given before the scan to provide better detail on the image. This dye can be injected into a patient’s vein or given as a pill to swallow.

CT scans are often used in people with thyroid cancer to examine parts of the neck that cannot be seen with ultrasound (see above). Also, CT scans of the chest may be needed to look to see if thyroid cancer has spread to that area of the body. CT scans of the abdomen may be used to see if thyroid cancer has spread to the liver or other sites. Patients with the hereditary form (see Risk Factors) of MTC may be at risk for developing other types of endocrine tumors in the abdomen; these patients may also have a CT scan of the abdomen.
Positron emission tomography (PET) or PET-CT scan. A PET scan is usually combined with a CT scan (see above), called a PET-CT Scan. But you may hear your doctor refer to this procedure just as a PET scan. A PET scan is a way to create pictures of organs and tissues inside the body. A small amount of a radioactive sugar substance is injected into the patient’s body. This sugar substance is taken up by cells that use the most energy. Because cancer tends to use energy actively, it absorbs more of the radioactive substance. However, the amount of radiation in the substance is too low to be harmful. A scanner then detects this substance to produce images of the inside of the body.

X RAY:

An X-ray is a common imaging test that’s been used for decades. It can help your doctor view the inside of your body without having to make an incision. This can help them diagnose, monitor, and treat many medical conditions.

Different types of X-rays are used for different purposes. For example, your doctor may order a mammogram to examine your breasts. Or they may order an X-ray with a barium enma to get a closer look at your gastrointestinal tract.

There are some risks involved in getting an X-ray. But for most people, the potential benefits outweigh the risks.

c)URINARY TRACT INFECTION

A urinary tract infection (UTI) is an infection in any part of your urinary system — your kidneys, ureters, bladder and urethra. Most infections involve the lower urinary tract — the bladder and the urethra.

Women are at greater risk of developing a UTI than are men. Infection limited to your bladder can be painful and annoying. However, serious consequences can occur if a UTI spreads to your kidneys.

Doctors typically treat urinary tract infections with antibiotics. But you can take steps to reduce your chances of getting a UTI in the first place.

Symptoms

Urinary tract infections don't always cause signs and symptoms, but when they do they may include:

A strong, persistent urge to urinate
A burning sensation when urinating
Passing frequent, small amounts of urine
Urine that appears cloudy
Urine that appears red, bright pink or cola-colored — a sign of blood in the urine
Strong-smelling urine
Pelvic pain, in women — especially in the center of the pelvis and around the area of the pubic bone

Diagnosis:

Analyzing a urine sample. Your doctor may ask for a urine sample for lab analysis to look for white blood cells, red blood cells or bacteria. To avoid potential contamination of the sample, you may be instructed to first wipe your genital area with an antiseptic pad and to collect the urine midstream.
Growing urinary tract bacteria in a lab. Lab analysis of the urine is sometimes followed by a urine culture. This test tells your doctor what bacteria are causing your infection and which medications will be most effective.
Creating images of your urinary tract. If you are having frequent infections that your doctor thinks may be caused by an abnormality in your urinary tract, you may have an ultrasound, a computerized tomography (CT) scan or magnetic resonance imaging (MRI). Your doctor may also use a contrast dye to highlight structures in your urinary tract
Using a scope to see inside your bladder. If you have recurrent UTIs, your doctor may perform a cystoscopy, using a long, thin tube with a lens (cystoscope) to see inside your urethra and bladder. The cystoscope is inserted in your urethra and passed through to your bladder
Using a scope to see inside your bladder. If you have recurrent UTIs, your doctor may perform a cystoscopy, using a long, thin tube with a lens (cystoscope) to see inside your urethra and bladder. The cystoscope is inserted in your urethra and passed through to your bladder
MRI
MRI stands for magnetic resonance imaging. An MRI scan uses a strong magnetic field and radio waves to create pictures on a computer screen. It can show tissues, organs and other structures inside your body.

Your body contains millions of hydrogen atoms. When you are in an MRI scanner:

A strong magnetic field aligns particles called protons which are within the hydrogen atoms. All the protons line up in parallel to the magnetic field, like tiny magnets. (Normally the millions of protons all lie in random directions.)
Then short bursts of radio waves are sent from the scanner into your body. The radio waves knock the protons from their position.
When the burst of radio waves stop, the protons realign back into place. As they do so they emit radio signals. The protons in different tissues of the body realign at different speeds. Therefore, the signal emitted from different body tissues varies. So, for example, softer tissues can be distinguished from harder tissues on the basis of the signals sent.
These signals are detected by a receiving device in the scanner.
The receiving device transmits the signals to a computer. The computer creates a picture based on the radio signals emitted from the body.

3.a)Cognisive Heart Failure:Treatment:

You and your doctor may consider different treatments depending on your overall health and how far your condition has progressed.

Congestive heart failure drugs

There are several medications that can be used to treat CHF, including ACE inhibitors, beta-blockers, and more.

ACE inhibitors

Angiotensin-converting enzyme (ACE) inhibitors open up narrowed blood vessels to improve blood flow. Vasodilators are another option if you can’t tolerate ACE inhibitors.

You may be prescribed one of the following:

benazepril (Lotensin)
captopril (Capoten)
enalapril (Vasotec)
fosinopril (Monopril)
lisinopril (Zestril)
quinapril (Accupril).
ramipril(Altace)
moexipril (Univasc)
perindopril (Aceon)
trandolapril (Mavik)

ACE Inhibitors shouldn’t be taken with the following medications without consulting a doctor, because they may cause an adverse reaction:

Potassium-sparing diuretics and potassium supplements. These diuretics can cause potassium buildup in the blood, which may lead to abnormal heart rhythms. Examples include: riamterene (Dyrenium), eplerenone (Inspra), and spironolactone (Aldactone).
Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAID's such as ibuprofen, aspirin, and naproxen, can cause sodium and water retention. This may reduce the ACE inhibitor’s effect on your blood pressure.

This is an abbreviated list, so always speak with your doctor before taking any new medications.

Beta-blockers

Beta Blockers decrease the work the heart has to do and can reduce blood pressure and slow a rapid heart rhythm.

This may be achieved with:

atenolol (Tenormin)
bisoprolol (Zebeta)
carvelol (Coreg)
esmolol (Brevibloc)
metaprolol (Lopressor)
nadolol(Corgard)
nebivolol (Bystolic)

Beta-blockers should be taken with caution with the following medications, as they may cause an adverse reaction:

Medications that slow the heart rate. These can increase cardiovascular effects, including slowed heart rate. Some examples include amiodarone (Nexterone), verapamil, diltiazem, and digoxin.
Albuterol (AccuNeb). The effects of albuterol on bronchodilation may be canceled out by beta-blockers.
Antipsychotics. Certain antipsychotics, such as thioridazine (Mellaril), may also cause low blood pressure in some people.
Fentora (Fentanyl). This may cause low blood pressure.
Clonidine (Catapres). clonidine may increase risk of slow heart rate.

b)Throid Gland Cancer:

Your thyroid cancer treatment options depend on the type and stage of your thyroid cancer, your overall health, and your preferences.

Most people diagnosed with thyroid cancer have an excellent prognosis, as most thyroid cancers can be cured with treatment.

Treatment may not be needed right away

Treatment might not be needed right away for very small papillary thyroid cancers (papillary microcarcinomas) because these cancers have a low risk of growing or spreading. As an alternative to surgery or other treatments, you might consider active surveillance with frequent monitoring of the cancer. Your health care provider might recommend blood tests and an ultrasound exam of your neck once or twice a year.

In some people, the cancer might never grow and never require treatment. In others, growth may eventually be detected and treatment can begin.

c)UTI''s

Treatment of Bladder Urinary Tract Infections

The specific intervention depends on the severity of the symptoms. In many instances, healthy patients who have a urinary tract infection but have no symptoms require no treatment at all. Such asymptomatic UTIs typically resolve within two to three days.

If urinary tract infection symptoms are present—such as a burning sensation during urination or an increased need to urinate—treatment usually consists of antibiotic medications, which are prescribed for three to 14 days. They include:

Trimethoprim: Trimethoprim is the standard treatment for urinary tract infections in otherwise-healthy adults. It is one of the more potent UTI antibiotics, so most patients only require a three-day course. Trimethoprim is generally well-tolerated with few side effects, which generally include nausea, vomiting, diarrhea/constipation or stomach pain.

Nitrofurantoin: Nitrofurantoin is the second most commonly prescribed antibiotic for bladder UTIs. It usually requires a longer course than trimethroprim (7 days), and is usually well tolerated but should not be taken by anyone with kidney disease. Side effects include nausea and vomiting.

Cephalosporins: Cephalosporins are often used as a first-line of treatment in patients that have upper urinary tract infections involving the ureters or kidneys. It is usually taken for seven to 10 days. Side effects include nausea, vomiting, upset stomach and diarrhea.

Penicillin or amoxicillin: These antibiotics are usually only prescribed if other antibiotics have proven ineffective. Bacteria, particularly E. coli, have become resistant to penicillin and amoxicillin and only respond about 50 percent of the time. Side effects include diarrhea, nausea, vomiting and vaginal itching or discharge.

4.a)SURGICAL PROCEDURE FOR CORRECTING HEART FALIURE:

A percutaneous coronary intervention (PCI) is a minimally invasive procedure to open blocked coronary (heart) arteries. An older name for PCI is coronary angioplasty with stenting or angioplasty for short.

Arteries are the blood vessels that carry oxygen-rich blood from your heart throughout your body. A PCI procedure uses a small balloon to reopen a blocked artery to increase blood flow.

Usually, your interventional cardiologist then places a small, permanent tube (stent) to keep the artery open long term. The stent usually contains medication that releases directly into your artery (drug-eluting stent) to reduce the risk of re-narrowing within the stent.

Your healthcare provider gives you specific instructions to prepare for a PCI. In a non-emergency situation, you will likely need to not eat or drink (fast) for several hours before the surgery.

If you take blood-thinning medications (anticoagulants), you may need to stop taking them temporarily. These medicines can increase your bleeding risks during a procedure. Be sure to follow your provider’s instructions.

An interventional cardiologist (doctor specializing in the heart, blood vessels and circulatory system) performs the PCI. You receive a sedative (anestesia) to help you remain calm and relaxed. You are usually awake but can’t feel anything during the procedure.

During a PCI, your cardiologist:

Inserts a small hollow tube (sheath) through a blood vessel in your arm or at the top of your thigh.
Guides a small, hollow tube (catheter) through the sheath and to your heart.
Injects a contrast dye and uses X-rays to view the catheter in real time.
Opens the blocked artery by inflating a balloon at the tip of the catheter.
Places a stent, if needed, to help the artery stay open.
Removes the catheter and closes the insertion site with a compression bandage (arm), a small stitch (thigh) or collagen plug (thigh).

The procedure usually lasts between 30 minutes and two hours. The exact treatment time depends on several factors, including the extent of plaque buildup.

Usually, you stay in a recovery area for several hours after a PCI. You may have bruising or soreness where the doctor inserted the catheter. You might return home that day or stay in the hospital overnight.

Usually, you can resume usual activities within a week after a PCI. If you have a job that requires physical activity or heavy lifting, you may need to wait longer to return to work.

During recovery from a PCI, your cardiologist may prescribe blood-thinning medicines. These drugs, such as clopidogrel (Plavix®), prasugrel (Effient), or ticagrelor (Brilinta®), lower your risk of blood clots. You should take these medications according to the recommendations of your healthcare provider.

b)SURGICAL PROCEDURES TO REMOVE THYROID CANCER:

Lymphadenectomy:

Although the specific surgical procedure may differ according to which lymph nodes are to be removed, some steps are common among all lymphadenectomies. General anesthesia is usually administered for the duration of surgery; this ensures that the patient remain unconscious and relaxed, and awaken with no memory of the procedure.

First, an incision is made into the skin and through the subcutaneous layers in the area where the lymph nodes are to be removed. The lymph nodes are identified and isolated. They are then carefully taken out from surrounding tissues (that is, muscles, blood vessels, and nerves). In the case of axillary node dissection, the pad of fat under the skin of the armpit is removed; generally, about 10 to 20 lymph nodes are embedded in the fat and separately removed. The incision is sutured (stitched) closed with a drain left in place to remove excess fluid from the surgical site.

Alternatively, laproscopy may be used as a less invasive method of removing lymph nodes. The laparoscope is a thin, lighted tube that is inserted into the abdominal cavity through a small incision. Images taken by the laparoscope may be seen on a video monitor connected to the scope. Certain lymph nodes, such as the pelvic and aortic lymph nodes, may be removed using this technology.

Lymph nodes may become swollen or enlarged as result of invasion by cancer cells. Swollen lymph nodes may be palpated (felt) during a physical exam. Before lymph nodes are removed, a small amount of tissue is usually removed. A biopsy will be performed on it to check for the presence of abnormal cells.

The patient will be asked to stop taking aspirin or aspirin-containing drugs for a period of time prior to surgery, as these can interfere with the blood's ability to clot. Such drugs may include prescription blood thinners (for example, Coumadin—generically known as warfarin and heparin). However, patients should discuss their medications with regard to their upcoming surgery with their doctors, and not make any adjustments or prescription changes on their own. No food or drink after midnight the night before surgery will be allowed

Aftercare

Directly following surgery, the patient will be taken to the recovery room for constant monitoring and to recover from the effects of anesthesia. The patient may then be transferred to a regular room. If axillary nodes have been removed, the patient's arm will be elevated to help prevent postsurgical swelling. Likewise, the legs will be elevated if an inguinal lymphadenectomy had been performed. A drain placed during surgery to remove excess fluids from the surgical site will remain until the amount of fluid collected in the drain decreases significantly. The patient will generally remain in the hospital for one day.

Specific steps should be taken to minimize the risk of developing lymphedema, a condition in which excess fluid is not properly drained from body tissues, resulting in swelling. This swelling can sometimes become severe enough to interfere with daily activity. Common sites where lymphedema can develop are the arm or leg. Prior to being discharged, the patient will receive the following instructions for care of areas of the body that may be affected by lymph node removal:

All cuts to the area should be properly cleaned, treated with an antibiotic ointment, and covered with a bandage.
Heavy lifting should be avoided; bags should be carried on the unaffected arm.
Tight jewelry and clothing with tight elastic bands should be avoided.
Injections, blood draws, and blood pressure measurements should be done on the unaffected arm.
Sunblock should be worn on the affected area to minimize the risk of sunburn.
Steps should be taken to avoid cuts to the skin. For example, an electric razor should be used to shave the affected area; protective gloves should be worn when working with abrasive items.

c)SURGICAL PROCEDURE TO CURE URINARY TRACT INFECTION:

A UTI is an infection, usually caused by one of many bacteria, that enter into the urethra and cause inflammation and other related conditions in the bladder, tract, or even the kidneys. While they are most typically contained to the bladder or upper urinary tract, they can also spread to any part of the system and, once reaching the kidneys, lead to several complications.

In patients with recurring UTIs, the infection keeps coming back. While that may mean that the initial UTI didn’t completely go away or that another type of bacteria has entered the system, the result is the same, and the patient can’t seem to get rid of the infection, meaning that symptoms are suffered regularly.

Causes of UTIs

Women are more likely to have UTIs for several reasons, and these are also causes of recurring UTIs, especially in females.

Kidney and bladder stones can lead to a urinary tract infection.
Bacteria can enter into the urethra during intercourse.
The urethra in women is shorter than in men, giving bacteria a shorter entrance point before taking root.
Menopause can cause changes to estrogen levels, which can lead to the sort of imbalance that helps bacteria thrive in the urinary tract.
Use of spermicides, and especially related to diaphragms, increases the risk of developing a UTI.
Problems with incontinence, sometimes related to pregnancy, can lead to development of a UTI.
Prolonged bedrest and reduced mobility, whether due to another medical condition or an injury, promotes the spread of bacteria, especially in the urinary tract.
An abnormality of the kidneys, bladder, or uterus at birth can lead to issues with the urinary tract that maximize risk of chronic and recurring UTIs.
A history of cancer in any part of the abdomen or pelvis increases the chance of recurring UTIs.
Neurological conditions that reduce bladder and kidney functionality can cause recurring UTIs.

These are just a few of the more common causes of the issue, with several other risk factors and causes possible. A doctor will want to take an extensive medical history to help determine what could be the culprit.

Identifying recurrent UTIs

Two tests in particular can help lead to a diagnosis of recurrent UTIs, aside from the general pelvic exams and medical history. First, the physician will request a urine sample and take a culture, in which any bacteria present will be allowed to grow (for identification purposes). This must be documented twice before a recurrent condition can be diagnosed. On top of that, most physicians will want to do a post-void residual check, which means evaluating the amount of urine left in the bladder after urination. Those with high amounts of urine remaining may have other underlying issues.

Treatment for recurrent UTIs

Several treatments may be suggested prior to determining surgery is the right solution, depending on the circumstances. For example:

Many women find that recurring UTIs occur after sexual intercourse. One way to help reduce the likelihood of developing an infection is to urinate directly after intercourse. This helps dispel any bacteria that has entered the urethra. A doctor may also offer an advanced prescription to be turned in that can be taken immediately after intercourse to assure an infection doesn’t ensue.
Others may find that they aren’t sure of the inciting incident but recognize the symptoms early on. In this case, the patient may choose to use the same preemptive method, having a recurring prescription for the physician to fill at the earliest signs of a UTI, typically a low dose antibiotic on a three day course.
An additional option is to take low dose antibiotics over a long period of time – up to six months – to reduce the susceptibility to infection.
If the cause seems to be linked to inability to empty the bladder, it may be important to change certain habits, including eliminating certain medications or even learning self catheterization in order to completely void urine from the bladder.

In some cases, the frequency and recurring of a UTI could be due to some sort of obstruction or abnormality of the urinary system. For example, the presence of a kidney stone, a fistula (abnormal connection), or even damage from previous surgeries (such as improper healing from stitches and the build up of scar tissue) could be behind the problem. In these instances, it is quite common for a doctor to recommend corrective surgery, which typically remedies the issue. Of course, certain medications and practices can still cause a UTI, but avoiding triggers once the surgery is complete should significantly reduce the occurrence of infection.

Conclusion

Working with a physician to uncover the root issue behind a recurring UTI can help find the right solution, which will then enhance quality of life overall.

A patient will experience less pain and daily disturbance, allowing them to function normally at work, at home, and at public social events. In addition, it might help solve other unknown issues that the patient hadn’t even noticed. Reducing the chances of a UTI also helps reduce the possibility of complications, such as developing kidney disease or even getting sepsis, since a constant battle with an infection can weaken the immune system, leave the kidney exposed to infection, and (with reduced kidney function) cause waste to leak into the bloodstream. Taking care of the body includes addressing health of all organs, and assuring that the bladder and urinary tract work properly is crucial to overall wellness.

a)Introduction and context

Heart failure (HF) is a major public health concern that affects as many as 23 million people worldwide¹. Furthermore, hospitalization rate and costs of care for HF are enormous, and recent years have provided few indications of improvement in these trends². There has been substantial progress in the management of chronic HF with the availability of drugs such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonist (MRA). However, community-based outcomes for patients with HF remain suboptimal. One ongoing challenge is to ensure that proven HF therapies are used at tolerated target doses in appropriate patient populations. Because of high morbidity and mortality, there is an overwhelming need for new therapies that are safe and that can improve outcomes in patients with HF.

In 2015, the US Food and Drug Administration (FDA) approved two promising new drugs to treat HF: ivabradine and sacubitril/valsartan. In addition, some of the newer agents in testing offer the potential for significant progress. In this article, we provide a brief description of novel agents in acute and chronic HF, highlighting their mechanism of action and the clinical experience, where applicable.

LCZ696 (sacubitril/valsartan)

Background

Currently, blockade of the renin-angiotensin-aldosterone system (RAAS) is the cornerstone of treatment of HF. However, the combination of RAAS blockade with inhibition of neprilysin, an enzyme that degrades natriuretic peptides (NPs), has recently emerged as a potentially superior treatment strategy³. In July 2015, the FDA approved sacubitril/valsartan (previously known as LCZ696) for use in patients who have chronic and stable but symptomatic HF and who have a left ventricular ejection fraction (LVEF) of less than 40%. The labeling states that the agent should be used in conjunction with other HF therapies but in place of ACE inhibitors or ARBs and is contraindicated in patients with a history of ACE inhibitor or ARB-induced angioedema.

Mechanism of action

LCZ696 combines a neprilysin inhibitor (sacubitril) and an ARB (valsartan). Neprilysin is a zinc-dependent neutral endopeptidase that is responsible for the degradation of several vasoactive peptides such as NPs, bradykinin, and adrenomedullin and contributes to the breakdown of angiotensin II⁴. As NPs act to promote natriuresis, diuresis, and vasodilation, neprilysin inhibition is thought to be the therapeutic target for counteracting the neurohormonal activation and complementary inhibiting the RAAS.

Clinical efficacy

The PARAMOUNT trial. The PARAMOUNT (Prospective Comparison of ARNi [angiotensin receptor-neprilysin inhibitor] with ARB on Management of Heart Failure with Preserved Ejection Fraction) trial was the first randomized controlled trial (RCT) that compared LCZ696 with valsartan in patients (n = 301) that have HF with preserved ejection fraction (HFpEF)⁵. There was a significant decrease in NT-proBNP (N-terminal of the prohormone brain natriuretic peptide) levels in the LCZ696 group at 12 weeks; however, the difference was no longer significant at 36 weeks. Furthermore, there was no change in LV size, function, or mass; diastolic function; New York Heart Association (NYHA) class; or quality-of-life scores at 12 weeks⁵. The trial was not designed or powered to detect clinical outcomes but has provided the rationale for the larger ongoing PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial (ClinicalTrials.gov identifier: NCT01920711), examining the long-term outcome of LCZ696 compared with valsartan in patients with HFpEF.

The PARADIGM trial. The PARADIGM-HF (Prospective Comparison of ARNi with ACE Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) Trial was conducted in 8,399 patients who had NYHA class II–IV HF and an LVEF of not more than 40% and who were randomly assigned to LCZ696 or enalapril³. The trial was stopped early because of an overwhelming benefit with LCZ696 therapy. The composite primary endpoint, including cardiovascular mortality and hospitalization for HF, occurred significantly more often in patients receiving LCZ696 compared with those receiving enalapril (hazard ratio 0.80, 95% confidence interval [CI] 0.73–0.87, P <0.001). LCZ696 was also associated with significant reductions in all-cause mortality, cardiovascular mortality, and hospitalization for worsening HF. Furthermore, those patients who received LCZ696 had lower levels of the biomarkers NT-proBNP and troponin compared with those receiving enalapril. These differences were apparent within 4 weeks of treatment and were maintained when patients were assessed again 8 months later. Interestingly, levels of B-type natriuretic peptide (BNP) actually increased and this is consistent with the mechanisms of action of neprilysin inhibition⁶. This trial provided strong evidence for superiority of the ARNi in patients with HF with reduced ejection fraction (HFrEF)³.

Mineralocorticoid receptor antagonist

Background

In the activity of RAAS, aldosterone is one of the most important neurohormones in the pathophysiology of HF affecting salt and water retention, endothelial dysfunction, ventricular hypertrophy, and myocardial fibrosis⁷. Based on the results of RALES (Randomized Aldactone Evaluation Study)⁸ and EPHESUS (Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study)⁹, the guidelines recommended that the addition of low-dose MRA to optimal therapy be considered in all patients with moderate to severe chronic HF in the absence of hyperkalemia or significant renal dysfunction or both^10,11. Therefore, inhibition of RAAS by MRAs, such as spironolactone and eplerenone, has become a milestone in the current HF treatment in symptomatic (NYHA class III and IV) patients with HFrEF in addition to ACE inhibitors or ARBs.

Clinical efficacy

The EMPHASIS trial. The EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure)¹² was a randomized, placebo-controlled study that enrolled 2,737 patients with NYHA class II with decreased LVEF under optimal recommended therapy. Patients with serum potassium of more than 5.0 mEq/l were excluded. In this study, eplerenone reduced significantly (by 37%) the primary composite outcome of risk of death from cardiovascular causes and first hospitalization for HF in comparison with placebo. The most frequent adverse event in patients receiving eplerenone was hyperkalemia.

The TOPCAT trial. Thus, MRAs are highly efficacious in patients with HFrEF^8,12. However, the management of HFpEF represents an ongoing challenge because therapies of proven benefit in HFrEF have repeatedly been shown to add little benefit in HFpEF^13–17. The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial was designed to test the clinical benefit of spironolactone in patients with HFpEF¹⁸. In all, 3,445 patients with HFpEF were randomly assigned to receive spironolactone or placebo. In this trial, spironolactone failed to reduce the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for HF compared with placebo (hazard ratio 0.89, 95% CI 0.77 to 1.04, P = 0.14). However, it did reduce the rate of HF hospitalizations (hazard ratio 0.83, 95% CI 0.69 to 0.99, P = 0.042)¹⁹. Of interest, those enrolled in the Americas have higher event rates and followed the NP entry criteria more closely than those from Russia/Georgia and seemed to have more consistent benefits²⁰. Meanwhile, hyperkalemia was again more common in patients receiving spironolactone versus placebo (18.7% versus 9.1%, P <0.001). Thus, further research with a more efficient protocol is warranted to assess the efficacy of this agent in patients with HFpEF. In addition, adequate monitoring for potential side effects (mainly hyperkalemia and worsening of renal function) is needed in the addition of eplerenone to standard therapy as the current guidelines stated.

Patiromer and zirconium cyclosilicate

Background

As the use of RAAS inhibitors and MRAs in patients with HF increases, hyperkalemia has become a more common electrolyte disturbance in clinical practice, especially in patients with chronic kidney disease (CKD). Moreover, hyperkalemia is a major limiting factor to fully titrate these drugs in these patients who are most likely to benefit from treatment. In fact, recent clinical trials that tested the efficacy of intensive RAAS blockade had to be stopped prematurely or showed unexpected outcomes. One of the frequent adverse events was hyperkalemia^21–23. Currently, non-invasive treatment of hyperkalemia is limited by a lack of safety, efficacy, and tolerability. Thus, agents to control reliably the plasma concentration of potassium while maintaining the use of RAAS inhibitors or MRAs are needed. Now, there are two novel potassium absorbents, patiromer calcium and zirconium silicate (ZS-9), that are designed to increase potassium loss via the gastrointestinal tract. Although they have not yet been approved by the FDA, both have demonstrated efficacy and safety in recent trials.

Patiromer

Mechanism of action. Patiromer is a non-absorbable polymer that binds potassium in exchange for calcium throughout the gastrointestinal tract. This agent, which is an orally administered drug, increases fecal excretion of potassium and consequently decreases plasma potassium levels²⁴. Prior patiromer clinical trials have also demonstrated the drug’s utility in treating hyperkalemia in at-risk populations for periods ranging from a few days to up to 12 weeks²⁴.

Clinical trials. The PEARL-HF study: The PEARL-HF study tested the combined use of patiromer with spironolactone in 105 HF patients receiving standard care but with previous documented hyperkalemia or CKD. Patiromer significantly lowered serum potassium levels from baseline relative to placebo and prevented the development of hyperkalemia for more than 4 weeks in normokalemic patients with HF²⁵.

The OPAL-HK trial: The OPAL-HK (A Two-Part, Single-Blind, Phase 3 Study Evaluating the Efficacy and Safety of Patiromer for the Treatment of Hyperkalemia) assessed the efficacy and safety of patiromer in 243 patients with CKD on RAAS inhibitors with high levels of serum potassium. In this study, a mean reduction in plasma potassium levels was 1.0 mEq/l after the initial 4 weeks of active treatment. When patiromer treatment was stopped at the end of the active treatment period, hyperkalemia rapidly recurred over 8 weeks. The recurrence of hyperkalemia during this period was significantly higher in the placebo group than in the patiromer group (60% versus 15%, P <0.001), indicating the need for persistent treatment to maintain normokalemia²⁴. The most common adverse effect of patiromer therapy was constipation.

ZS-9

Mechanism of action. ZS-9 is a high-specificity inorganic crystal that entraps potassium in the intestinal tract²⁶. Instead of exchanging calcium, ZS-9 exchanges sodium and hydrogen ions for potassium. Dose-dependent excretion of potassium occurs in the feces, whereas urinary excretion decreased with dose.

Clinical trials. The efficacy of ZS-9 was assessed in a multicenter RCT including 753 patients with hyperkalemia associated with a variety of diseases, including CKD, HF, and diabetes. Patients were randomly assigned to one of four doses of ZS-9 (1.25, 2.5, 5, or 10 g) or placebo for 2 days. The reduction of serum potassium with ZS-9 started acutely, and there was a dose-dependent reduction in serum potassium from baseline to 2 days, with absolute mean reductions of 0.73 and 0.53 mEq/l in the 10- and 5-g dose groups, respectively (P <0.001). Reductions in serum potassium were significantly greater with ZS-9 than placebo at all time points on study day 2. Notably, 98% of patients were normalized on the 10-g dose within 2 days. The most frequent adverse effect of ZS-9 was diarrhea.

The HARMONIZE study: The HARMONIZE study was an RCT evaluating long-term efficacy and safety of ZS-9 in 258 patients with hyperkalemia^29,30. Patients achieving normokalemia (3.5 to 5.0 mEq/l) were randomly assigned to different doses of ZS-9 (5, 10, or 15 g) or placebo for 28 days in the maintenance phase. Mean baseline potassium was 5.6 mEq/l and declined to 4.5 mEq/l after 48 hours of 10-g ZS-9 treatment in the acute phase. Significant reduction in potassium was observed within 1 hour of ZS-9 administration, and 84% of patients achieved normokalemia at 24 hours and 98% at 48 hours³⁰. Furthermore, studies assessing the long-term efficacy and safety profile of this novel drug are ongoing (ClinicalTrials.gov identifier: NCT02163499).

These recent trials of patiromer and ZS-9 represented short-term safety and efficacy of these attractive therapeutic strategies in patients who develop hyperkalemia during RAAS inhibition. However, the durability of the beneficial effects and the long-term safety of these agents still have to be elucidated. In addition, there are no prospective data answering whether intensive RAAS inhibition with the use of patiromer or ZS-9 would improve the efficacy of RAAS inhibition and cardiovascular outcomes. Further study is needed to address these issues.

Diseases of the thyroid gland are common, and most are of a metabolic or immunologic nature. Malignancies of the thyroid are uncommon, and there is probably no organ where there is a greater range of biologic behavior of the malignant phenotypes. Papillary thyroid carcinoma, the most common thyroid malignancy, is one of the least aggressive cancers in humans. However, the giant cell variety of undifferentiated thyroid carcinoma, the least common thyroid carcinoma, is highly lethal, and few patients with this cancer survive three years from the time of diagnosis. Overall, few patients with thyroid malignancy die from their disease.

Given the relatively well-defined histologic types of malignancy of the thyroid gland and the sound understanding of the natural history of the specific histologic types of tumors, one would think that the management of patients afflicted with these malignancies would be relatively straightforward. However, this is not the case. The main reason for the controversy is that there has never been a prospective, randomized, controlled trial evaluating the operative management of patients with any type of thyroid cancer. Considering the small number of patients who develop the disease and the relatively slow growth patterns characteristic of the more common types of thyroid malignancy (i.e., papillary carcinoma and follicular carcinoma), such trials may never be done. Nevertheless, we can learn a great deal from retrospective evaluation of data about these patients, and such is provided in the excellent review written by Drs. Robert Gagel, Helmuth Goepfert, and David Callender in this issue of CA-A Cancer Journal for Clinicians.¹

In discussing thyroid carcinomas, it is best to divide them into the differentiated and undifferentiated types. Differentiated thyroid carcinomas account for 80 percent of all thyroid malignancies and are of either a papillary or follicular type. Medullary thyroid carcinoma, while in the thyroid gland, is not of the thyroid gland. The progenitor “C-cells” derive from the neural crest. In birds and fishes, the C-cells are located in a separate site called the ultimobranchial body. Undif-ferentiated thyroid carcinomas are either of the small cell (B-cell lymphomas) or the giant cell type.

With differentiated and medullary thyroid carcinomas, early diagnosis and treatment are important. Improved prognosis is directly related to the following: young age at the time of diagnosis, small tumor size, absence of local tissue invasion, absence of regional lymph node or distant metastasis, and favorable histologic type. Therefore, it is important to diagnose thyroid malignancy at an early stage when operative therapy is associated with a good prognosis.

In considering patients who present with a thyroid nodule, it is important to determine if there is any history of exposure to external-beam radiotherapy, especially in childhood. It is known that at least one third of patients with such exposure will develop thyroid nodules, and about one third of these patients will develop a thyroid malignancy, almost always of the papillary or follicular type.² There is thought to be little, if any, increased risk of thyroid carcinoma in patients treated with radioactive iodine for generalized toxic goiter. However, a very high incidence of a virulent form of papillary thyroid carcinoma occurred in children in the Ukraine and Belarus who were under the umbrella of the fallout from the Chernobyl nuclear accident.³ An increased risk of thyroid carcinoma in survivors of the nuclear explosions in Japan at the close of World War II has also been documented.⁴

It is also important to ask a patient with a thyroid nodule if there is any family history of thyroid malignancy. Medullary thyroid carcinoma often occurs in a hereditary pattern as either multiple endocrine neoplasia type 2A (MEN 2A),⁵ multiple endocrine neoplasia type 2B (MEN 2B),⁶ or familial medullary thyroid carcinoma (FMTC).⁷

The large majority of papillary, fol-licular, or medullary types of thyroid carcinomas grow slowly and metastasize to regional lymph nodes and distant sites after the primary tumor has been present for several years. Some patients with papillary carcinoma present with local invasion of the trachea, but at the time of en bloc resection of the thyroid carcinoma and the trachea, there is minimal regional or distant spread of disease. Some of these patients are cured by this aggressive resection. It is difficult to tell which patients with differentiated thyroid carcinoma need a total thyroidectomy and which will benefit from a lesser resection.^8, 9 Therefore, because a total thyroidectomy can be performed relatively easily and with minimal morbidity, this procedure is most often performed for all patients with papillary, follicular, or medullary thyroid carcinoma.

Over the last five years, we have learned a great deal about the molecular biology of thyroid carcinoma. The most clearly defined molecular events involve the RET proto-oncogene and its relationship to papillary carcinoma and medullary carcinoma. At least 40 percent of papillary thyroid carcinomas are associated with a pericentromeric inversion on chromosome 10.¹⁰ A portion of the chromosome containing the RET protooncogene is inverted, and the RET proto-oncogene is cleaved at the site of the breakpoint and repositioned close to a promotor that leads to its expression. The etiologic significance of this event is unknown at present.

Another important molecular event occurs in patients with MEN 2A,^11, 12 MEN 2B,^13-15 and FMTC. It has been shown that these diseases result from specific and inheritable mutations in RET. In MEN 2A and FMTC, several mutations have been described, all of which occur either in the external ligand binding segment of the proto-oncogene or just inside its transmembrane portion. In all cases of MEN 2B, a single mutation occurs at codon 918 in the internal catalytic core. At present, little is known about the function of RET. However, the identification of these discrete mutations has provided the opportunity for prophylactic therapy of patients with the type 2 MEN syndromes. The mutations can be demonstrated by direct DNA testing of the white blood cells of kindred members with MEN 2A, MEN 2B, or FMTC. Because the mutations are present at the time of conception and can be demonstrated either in utero or soon after birth, a therapeutic strategy can be designed that would prevent the onset of the disease. This amounts to prophylactic removal of the thyroid gland in youngsters before they manifest biochemical or clinical evidence of medullary thyroid carcinoma, the most common cause of death in patients with these syndromes.¹⁶ This strategy, which is highly effective in patients with these familial thyroid diseases, will doubtless be employed for patients with other forms of hereditary solid organ malignancies and in some patients with sporadic cancers as well.

We are certain to learn much more about the etiology and biologic behavior of thyroid malignancies as molecular and genetic medicine continue to unlock the secrets of cell biology. As the metabolic pathways and the mechanisms of cell growth are elucidated, it is likely that we will treat patients with thyroid malignancies by yet to be designed pharmacologic therapies rather than the operative techniques that we employ today.

Stop the overuse and misuse of antibiotics

Asymptomatic pyuria and bacteriuria are very common in the elderly, especially in women residing in long-term care facilities or in patients who use a urinary catheter, with a prevalence of 25–50%^7,8. In older residents of long-term care facilities, diagnostic testing and the initiation of antibiotics should be reserved for residents with fever, dysuria, gross hematuria, worsening urinary frequency and incontinence, costovertebral angle tenderness, or suspected bacteremia. Non-specific symptoms and altered mental status are no longer part of the recommended evaluation for a possible UTI^9,10. Asymptomatic bacteriuria also occurs in an estimated 1–5% of healthy pre-menopausal females, increasing to 0.7–27% of patients with diabetes, 2–10% of pregnant women, and 23–89% of patients with spinal cord injuries^11,12. Asymptomatic bacteriuria does not cause systemic disorders, such as renal damage¹³. Thus, the treatment of asymptomatic bacteriuria is not recommended in patients without risk factors¹¹. Avoiding antibiotic administration in cases where the urine culture does not indicate UTI may be the first step to decreasing antibiotic misuse¹⁴.

For patients with non-febrile uncomplicated UTIs, active pain control and minimal use of antibiotics should be prioritized. Uncomplicated cystitis can be a self-limiting disease in some cases. Pain in acute cystitis is a natural consequence of the inflammatory response, and pain-mediated urinary frequency or urgency is the chief complaint of patients. Therefore, for this self-limited disease, painkillers, including NSAIDs, may be a good option for symptomatic care as well as reducing the consumption of antibiotics^15,16. Delaying antibiotic treatment with a back-up prescription to see if symptoms will resolve without antibiotic treatment, or delaying the antibiotic until microbiological results are available, may be an option for antibiotic sparing¹⁷.

Recently, multiplex PCR assays for the detection of sexually transmitted infection (STI) agents became commonplace in Eastern Europe, Western Europe, South America, and Asia^18–20. However, the use of unnecessary antibiotics has increased by including strains other than “true” STIs such as Mycoplasma hominis, Ureaplasma urealyticum (previously U. urealyticum biovar 2), and Ureaplasma parvum (earlier U. urealyticum biovar 1)²¹. M. hominis, U. urealyticum, and U. parvum are commonly detected in the urogenital tract of both healthy and symptomatic individuals^22,23. Testing for M. hominis and U. parvum and subsequent antimicrobial treatment of positive men or women are currently not recommended. Instead, “true” STIs and bacterial vaginosis in symptomatic women should be diagnosed and treated²¹. Bacterial vaginosis, sexually transmitted diseases (STDs), and pelvic inflammatory disease can mimic symptoms of UTIs. In fact, a recent study showed that approximately one-third of STD cases were misdiagnosed as UTIs²⁴.

The era of antimicrobial resistance

There are limited oral options for the treatment of antibiotic-resistant uropathogens associated with lower UTIs (acute cystitis). Co-trimoxazole was a typical antibiotic used to treat UTIs, but the resistance of Escherichia coli to this drug has markedly increased. According to the literature published in the past decade, the resistance rates of E. coli to co-trimoxazole varied but were usually over 15–30%^25–28. However, there was an interesting report wherein the authors emphasized the role of co-trimoxazole in empirical antibiotics because of the recent decrease in the resistance rate to co-trimoxazole in several European countries owing to its low prescription rate²⁹. Nevertheless, it may not be possible to reuse the drug worldwide within the next few years, and close observation of surveillance data will be required.

With respect to fluoroquinolones, the increase of resistance in uropathogens has occurred at an alarming rate in relation to increased prescribing practices^27,28. Fluoroquinolones are no longer recommended as first-line therapy for uncomplicated UTIs¹¹. Similar to what was seen with co-trimoxazole, there is evidence that escape from exposure to this antibiotic will increase antimicrobial susceptibility in UTIs. According to Lee et al., the susceptibility of Gram-negative bacteria to ciprofloxacin was much higher in patients younger than 20 years old than in patients older than 20 years old. The reason for this observation may be the lower exposure to fluoroquinolones in young individuals because these drugs are not recommended for use in those under 20 years old³⁰.

One recent issue of importance is the increasing prevalence of extended spectrum beta lactamase (ESBL)-producing uropathogens. Before 2010, the vast majority of countries showed less than a 5–10% prevalence of ESBL-producing E. coli, whereas the prevalence exceeded 10% in the local communities of many countries after 2010^31–35. Therefore, the increase in ESBL-producing E. coli is no different to that of co-trimoxazole-resistant E. coli or fluoroquinolone-resistant E. coli, and the prevalence of ESBL-producing E. coli is likely to increase soon.

Use of re-emerging older antibiotics

Fosfomycin is an oral antibiotic agent that has broad activity against MDR uropathogens including ESBL-producing E. coli. Fosfomycin prevents peptidoglycan synthesis earlier than do beta-lactam or glycopeptide antibiotics and is broadly active against several Gram-positive and Gram-negative organisms, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp.. Fosfomycin has been shown to have advantages in the treatment of UTIs owing to its high concentration in the urinary tract, which exceeds 2,000 mg/L after the initial administration and remains at high levels for a prolonged period, over 24 hours. However, oral fosfomycin should not be used for pyelonephritis or in patients with bacteremia because of inadequate concentrations within the bloodstream^36,37. Fosfomycin susceptibility in uropathogens, including E. coli, is currently greater than 90%, even in ESBL-producing E. coli^38–40. It is safe to use in pregnancy⁴¹. The drug is likely to be excreted in low levels in breast milk, but would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than two months.⁴².

Another oral antimicrobial agent that can be considered for the treatment of ESBL-producing E. coli cystitis is nitrofurantoin. Nitrofurantoin is a drug that has been used since the 1950s to treat uncomplicated UTIs and works by damaging bacterial DNA in its highly active reduced form. Now, and even in earlier eras of widespread use, the baseline resistance to nitrofurantoin is low (0–10%)^43,44. Nitrofurantoin should be used only for lower UTIs, and its use should be avoided in patients with a creatinine clearance of less than 60 mL/minute, as reduced renal function results in decreased active drug within the urine⁴⁵. Nitrofurantoin is one of the few drugs that can be used during pregnancy⁴⁶. A recent retrospective, matched-cohort study in older adults concluded that long-term use of nitrofurantoin is associated with greater risk of lung injury than acute exposure⁴⁷.

Role for non-antimicrobial prophylaxis

The active use of non-antimicrobial prophylaxis is often indicated and does not result in an increase in antimicrobial resistance of the commensal flora. Immunoactive agents, probiotics (Lactobacillus spp.), cranberry-based products, D-mannose, methenamine hippurate, hormonal replacement (in post-menopausal women), and other options have been studied as non-antimicrobial prophylaxis^48–53. Evidence for the use of non-antimicrobial prophylaxis is hampered by considerable heterogeneity, and further placebo-controlled randomized trials of these agents are needed. However, trials investigating these options have produced promising results and combining these agents may offer the best route to lowering the rate of recurrent UTIs without needing to use antimicrobials⁵⁴.

Among these modalities, the urinary immunopotentiator is now well documented and strongly recommended in the guidelines¹¹. The oral immunostimulant OM-89 (Uro-Vaxom^®), an extract of 18 different serotypes of heat-killed uropathogenic E. coli, stimulates innate immunity by increasing non-specific and specific humoral and cellular immune responses via the induction of interferon-γ and tumor necrosis factor-γ production as well as the activities of lymphocytes and macrophages^55–57. Uro-Vaxom^® is a safe and effective medicine that can reduce recurrent UTI episodes^48,58–60 and can effectively reduce the repeated use of antibiotics⁶¹. Uromune^® is a sublingual spray consisting of equal amounts of four common UTI-causing bacteria in a suspension of 10⁹ inactivated whole bacteria/mL: E. coli; Klebsiella pneumoniae, Proteus vulgaris, and Enterococcus faecalis⁵⁴. The data from European prospective and retrospective studies suggest that Uromune^® is a viable alternative therapy for treating recurrent UTIs in women^62,63.

The lower estrogen state found in postmenopausal women is linked with decreased innate immunity via the loss of the commensal bacteria Lactobacillus and the loss of the acidic pH microenvironment within the vagina. Although specific mechanisms are still poorly understood, estrogen plays a key role in modulating the natural defense of the lower urinary tract against UTIs⁶⁴. The role for topical (intravaginal cream, vaginal rings, impregnated pessary rings, vaginal pessaries, and vaginal tablets) estrogen in averting recurrent UTIs in postmenopausal women compared with placebo is clear, and guidelines for this population recommend their use^11,65,66. Currently, there is evidence that CO₂ ablative vaginal lasers may help rejuvenate this microenvironment, much like topical estrogen therapy, restoring the lactic acid synthesis of commensal bacteria and the innate vaginal defense against UTIs^67–69. For postmenopausal women, vaginal estrogen therapy has been considered often as an adjunct to antimicrobial-based prophylaxis⁷⁰. However, combination therapy with both immunostimulants and vaginal therapy (laser rejuvenation or estrogen) may provide better effectiveness at preventing UTI recurrence in postmenopausal women and is a potentially novel avenue for further research.

Paradigm shifting in the era of the microbiome

The microbiota is defined as the microorganisms in a particular environment. The microbiome refers to their genomes that are revealed using molecular techniques such as 16S ribosomal RNA (rRNA) sequencing⁷¹. Recently, more sensitive diagnostic tests demonstrated that urine is not sterile⁷². The urinary tract is inhabited by a unique urinary microbiota, and standard bacteriuria represents a fraction of the diverse microbiota hosted by the urinary tract⁷³. In the past, the notion that UTI was the detection of organisms as a standard culture in sterile urine has changed in the era of the microbiome. The fact that we diagnosed UTIs through standard culture and antibiotic susceptibility ignored the dozens of bacterial species and intracellular bacterial colonies known to reside in the urinary tract⁷². As expected, in the era of the microbiome, stable bacterial communities are generally beneficial and this condition is referred to as symbiosis. In this sense, patients with urinary tract symptoms would be more likely to be classified as having urinary tract dysbiosis rather than a UTI⁷³. If the full array of microbes resident in the human urinary tract is identified in the near future, some treatment of UTIs by antibiotics may turn into a correction of dysbiosis. In the gut microbiome, treatments of Clostridium difficile infections through fecal transplants have been investigated^74,75. In the urinary tract, the instillation of non-pathogenic E. coli safely reduced the risk of symptomatic UTI in patients with spinal cord injury. All of these efforts are ultimately related to preventing the overuse and misuse of antibiotics. The paradigm of managing UTIs has shifted from diagnosing UTIs and antibiotic treatment to screening for patients who really need antibiotics.

Conclusions

A clear achievement in recent oncology is the emergence of immunotherapy, a type of treatment that helps our immune system fight cancer and that marks an entirely different way of treating cancer by targeting the immune system, not the tumor itself. If the immune system also helps our body fight infections, why not use our body’s immune system instead of antibiotics to treat UTIs? This paradigm shift seems to be beginning in the management of UTIs. Further understanding of the microbiome in the urogenital system is expected to stimulate this shift. Eventually, the spread of antibiotic resistance can be reduced if antibiotics are used only when they are needed.

PART B

In the vertebrates skull is the bony structure that forms the head. Moreover, it offers a protective cavity for the brain and supports the structure of the face. Besides, the skull consists of two parts namely the cranium (top part of the skull) and the mandible (the lower part of the skull).

Besides, in humans, the two parts are viscerocranium (facial skeleton) and neurocranium that has the mandible as its largest bone.

Moreover, the skull forms the anterior-most portion of the skeleton and is the product of cephalization- brain housing and several sensory structures like the eyes, nose, mouth, and ears. Also, these sensory structures are part of the human facial skeleton.

MICROSCOPIC ANATOMY OF THE SKULL:

Microscopic Anatomy (Bone Cells)

The five major types of bone cells are osteogenic cells, osteoblasts, osteocytes, bone lining cells , and osteoclasts. All except osteoblasts originate from mesenchymal cells. Each is basically a specialized form of the certain cell type that becomes mature or functions in a certain process involved in bone growth. Like various connective tissue cells, bone cells are also surrounded by their own self-made extracellular matrix. The five types are explained in detail as:

Osteogenic cells: Also known as osteoprogenitor cells, these mitotically active stem cells are found in the periosteum and endosteum. They are squamous or flattened cells when bones are growing. Stimulation of these cells causes them to often differentiate into osteoblasts or bone lin-ing cells; others may remain as osteogenic cells

Osteoblasts: These cells produce bone matrix and are related to osteoprogenitor cells, osteocytes,fibroblasts, and chondroblasts. They are mitotic and become active with connective tissue layers, depositing bony matrix around them. Spongy bone tissue forms in all directions within the layers of connective tissues. They secrete an unmineralized bone matrix that includes colla-gen (which makes up the majority of bone pro-tein) and calcium-binding proteins that form the original unmineralized bone ( osteoid). They also aid in matrix calcification. Osteoblasts are cube-shaped when they are depositing matrix, but appear similar to flattened osteogenic cells when inactive. They may also differentiate into bone lining cells. Osteoblasts become osteocytes when they are totally surrounded by the matrix they are secreting.

Osteocytes: These are mature osteoblasts that have become embedded in the bone matrix. They occupy small cavities (lacunae) in the bone and have protoplasmic projections con-nected with the same structure of other osteo-cytes. The osteocytes conform to the shapes of the lacunae. These connections form a system of tiny canals within the bone matrix and act to maintain it as needed. When osteocytes die, the matrix surrounding them is resorbed. They also react to strain or stress and respond to stimuli such as bone deformation, bone loading, and weightlessness. The osteocytes alert the osteo-blasts and osteoclasts to build up or degrade the bone matrix as needed. This preserves calcium homeostasis.

Bone lining cells: These are flat cells on bone sur-faces where bone remodeling does not occur and are believed to also help maintain the bone matrix. On external bone surfaces, they are called periosteal cells , and when they line internal sur-faces, they are called endosteal cells.

Osteoclasts: These are large, multinucleated bone cells found at sites of bone resorption, which is called osteolysis. They form from the hema-topoietic stem cells that also differentiate into macrophages. During fractures and bone heal-ing and certain disease processes, osteoclasts use enzymes to excavate passages (resorption bays) through the surrounding tissue, breaking down the calcified extracellular matrix. At this point, they have an irregular border that con-tacts bone directly. This border has deep plasma membrane infoldings that greatly increase the surface area for bone degradation via enzyme activity. The infoldings close off the surface area from the matrix surrounding it. Osteoclasts are also known as osteophages. They secrete an acid that dissolves the matrix. They resorb bone matrix throughout life, replacing it with osteoblasts. These opposing processes (resorp-tion and deposition) are regulated by hormones that control blood calcium.

Compact Bone

Bone cells called osteocytes occupy small chambers (lacunae) that create concentric circles around cen-tral canals in bones . Cellular processes passing through canaliculi allow osteocytes to com-municate with other cells. Bone tissue is mostly made up of collagen and inorganic salts such as calcium phosphate. Calcium phosphate interacts with calcium hydroxide to form crystals of hydroxyapatite. These crystals incorporate various calcium salts as well as ions such as fluoride, magnesium, and sodium. Com-pact bones have a central canal that helps to make up cylinder-shaped osteons or Haversian systems. The osteons are parallel to the bone’s long axis, aid in weight bearing, and are the structural units of compact bone. Each osteon consists of a group of hol-low tubes of bone matrix that appear like the rings in a tree trunk. Each lamella (matrix tube) lends its name to the other description of compact bone, which is lamellar bone.

The collagen fibers of each lamella run in one direction, whereas those in nearby lamellae run in different directions. This alteration of collagen fiber placement strengthens compact bone and resists twisting motions. Between collagen fibrils, bone salt crystals also are aligned with directional alterations. Each central canal contains nerve fibers, blood vessels and the surrounding connective tissue. The central canals are connected by perforating Volkmann’s canals, which contain larger nerves and blood ves-sels. The Volkmann’s canals lie at right angles to the long axis of the bone. They are not surrounded by con-centric lamellae, but are lined with endosteum. At the junctions of the lamellae are spider-shaped osteocytes occupying the lacunae. Thin, hair-like canaliculi con-nect lacunae to each other and to the central canal. During bone formation, the osteoblasts that secrete bone matrix surround blood vessels and stay in con-tact with each other, as well as nearby osteocytes, via projections that extend outward. Each of these exten-sions contains gap junctions. As the matrix hardens, a system of canaliculi is formed, containing tissue fluid and the osteocytes’ extensions. A mature osteon is then bound together, and both nutrients and wastes can move from one osteocyte to the next. The bone matrix, therefore, allows bone cells to receive nour-ishment while it still remains hard and impermeable. However, some lamellae in compact bone are not part of complete osteons. Between osteons are incomplete interstitial lamellae that either fill gaps or are leftover structures of previous osteons that experienced bone remodeling. Deep to the periosteum, just superficial to the endosteum, are circumferential lamellae, which extend completely around the diaphysis, help-ing the long bone to resist twisting.

Spongy Bone

Spongy bone is similarly composed as compact bone, but its cells do not aggregate around the central canals. The cells in spongy bone lie inside the trabeculae (supporting structures of dense tissue) and take their nutrients from diffused substances that enter the can-aliculi. The trabeculae are only a few cells thick. They have irregular lamellae and osteocytes, interconnected by canaliculi, and no osteons are present. Nutrients reach spongy bone osteocytes via diffusion through the canaliculi from capillaries in the endosteum that surround the trabeculae.

BLOOD SUPPLY FOR THE BONE

Anatomy and physiology of the blood supply to bone

The channels and vessels in bone were observed by Van Leeuwenhoek and Havers in the late 17th century and were confirmed to be linked to blood supply by Albinus in the mid-18th century. The importance of the blood supply for bone was clearly recognized by surgeons in the 19th century . In the 20th century advances in orthopedics gave strong impetus to detailed functional studies of the bone vasculature, with pioneering contributions from Trueta and colleagues . Key studies by Brookes and colleagues demonstrated that the main blood supply of healthy long bones was derived from the principal nutrient arteries, which penetrate the cortex and perfuse the medullary sinusoids, then exit via multiple small veins. The cortical bone is perfused by a mixture of arterial blood originating from the main nutrient arteries as well as from the separate, smaller periosteal arteries. Thus, the flood flow in the long bones, at least from young adults, is largely centrifugal (ie, radiating outward after delivery to the marrow cavity)

ealthy bone requires a substantial blood flow to supply the requisite oxygen and nutrients, and to eliminate carbon dioxide, acid and other metabolic waste products. Estimates of the proportion of the cardiac output received directly by the skeleton range from about 5.5% to 11% . The rich perfusion of bone reflects not only the requirements of the bone cells (osteoblasts, osteocytes and osteoclasts), but also of the marrow (hematopoietic lineage cells, stromal cells and adipocytes), as well as endothelial cells. The long bones form from embryonic cartilage rudiments that are invaded by blood vessels and bone cells. The vascular supply of bone enables rapid growth, remodelling (including mechanical responsiveness) that is not possible in cartilage, which is essentially avascular. For a detailed consideration of the functional anatomy of the blood supply to bone during growth, maturity and regeneration, readers are referred to the comprehensive review of Wilson

Bone formation and remodeling

Bone formation takes place to support mechanical forces, growth and reparative process. Bone remodeling is a process of constantly resorbing bone by osteoclasts and replace it by osteoblast. Osteocytes act as mechanosensors and instruct the osteoclast where to resorb bone, and osteoblast when and where to form new bone.^1,14 Bone remodeling consists of four phases. First the activation phase, this phase involves detection of a remodeling signal due to changes in physical forces recognized by the osteocytes or damage to the bone matrix due to osteocyte apoptosis, these are signals for the osteoclast. The second phase is the resorption phase, osteoclast breaks down the bone matrix. Third is the reversal phase, the mononuclear cell removes the undigested demineralized collagen matrix in the lacunae and prepare the bone surface for bone formation. The last phase is the bone formation by osteoblast. Mechanical stimulation stimulates bone formation and inhibits bone resorption. Resting conditions inhibit bone formation. The remodeling cycle concludes when an equal amount of resorbed bone has been replaced. Remodeling are most of the time develop randomly but also occur in areas that need repair. According to the Wolff’s law, bone architecture is determined by the mechanical stress on the bone.^{9, 14-17}

Bone is a living tissue capable of self-repair

Bone only forms when mechanical loading is present (Wolff’s law)
Bone is continuous being renewed; balance between osteoblasts forming bone and osteoclasts resorbing bone
This process of constant bone resorption and bone formation is called bone remodeling
This process is also called “creeping substitution” ¹⁷
- The osteoclastic resorption of dead bone from the allograft and its replacement by new living bone made by osteoblasts from the host.
- Gradual penetration across a fracture site by osteogenic tissue followed by bone formation

Endochondral bone formation

Endochondral ossification ²⁵is the process by which growing cartilage is systematically replaced by bone to form long bones during growth. This process occurs at two predominant main sites in the bone: physis, epiphysis. Furthermore this process is also occurring in the cuboidal bones of the carpus and tarsus. Endochondral bone formation involves mesenchymal progenitor cells differentiating into chondrocytes. Chondrocytes are responsible for depositing a cartilaginous template that is later mineralized and replaced by bone. Chondrocytes in the physis can be divided into various layers or zones. The most distal zone (farthest from the metaphysis) is called the resting or reserve zone. Direct adjacent to this zone is the proliferative zone, in which chondrocytes divide. These cells progress further to the hypertrophic zone, in which they enlarge and form ordered columns. During this stage the chondrocytes become surrounded by extracellular matrix that gradually becomes mineralized in the zone of provisional calcification. The chondrocyte columns are supplied with angiogenesis (invasion of blood vessels) and bone forms on the residual columns of calcified cartilage. This mixture of calcified cartilage and immature bone is over time remodeled to produce the mature bone of the metaphysis.

Anatomic Region of the Heart	Associated Coronary Artery
Anteroseptal	Left anterior descending
Inferior	Right coronary
Anterolateral	Circumflex artery
Anteroapical	The left anterior descending distal part
Posterior	Right coronary artery

Symptoms you may notice first	Symptoms that indicate your condition has worsened	Symptoms that indicate a severe heart condition
fatigue	irregular heartbeat	chest pain that radiates through the upper body
swelling in the ankles,legs and hands	a cough that develops from congested lungs	rapid breathing
weight gain	wheezing	skin that appears blue, which is due to lack of oxygen in your lungs
increased need to urinate , especially at night	shortness of breath, which may indicate pulmonary edma	fainting

Symptoms you may notice first	Symptoms that indicate your condition has worsened	Symptoms that indicate a severe heart condition
fatigue	irregular heartbeat	chest pain that radiates through the upper body
swelling in the ankles,legs and hands	a cough that develops from congested lungs	rapid breathing
weight gain	wheezing	skin that appears blue, which is due to lack of oxygen in your lungs
increased need to urinate , especially at night	shortness of breath, which may indicate pulmonary edma	fainting

Cardiac afferents

Symptoms of heart failure in children and infants

a)Introduction and context

LCZ696 (sacubitril/valsartan)

Background

Mechanism of action

Clinical efficacy

Mineralocorticoid receptor antagonist

Background

Clinical efficacy

Patiromer and zirconium cyclosilicate

Background

Patiromer

ZS-9

Stop the overuse and misuse of antibiotics

The era of antimicrobial resistance

Use of re-emerging older antibiotics

Role for non-antimicrobial prophylaxis

Paradigm shifting in the era of the microbiome

Conclusions

Compact Bone

Spongy Bone

Anatomy and physiology of the blood supply to bone

Bone formation and remodeling