Biguanides (Metformin):
People who take metformin alone should be able to fast safely given that the possibility of hypoglycaemia is minimal. However, patients should modify its dose and administration timing to provide two-thirds of the total daily dose, which should be taken immediately with the sunset meal, while the other third is taken before the predawn meal.

Thiazolidinediones: No change needed.

Sulfonylurea:
Once-daily sulfonylurea (such as glimepiride or gliclazide MR): the total daily dose should be taken with the sunset meal.
Shorter-acting sulfonylurea (such as gliclazide twice daily): the same daily dose remains unchanged, and one dose should be taken at the sunset meal and the other at the predawn meal.
Long-acting sulfonylurea (such as glibenclamide): these agents should be avoided.

It is important that diabetic patients to eat a healthy balanced diet and choose foods with a low glycaemic index (such as complex carbohydrates), which can help to maintain blood glucose levels during fasting. Moreover, it is crucial to consume adequate fluids to prevent dehydration. Physical activity is encouraged, especially during non-fasting periods.

The most likely diagnosis is chronic tophaceous gout, which is classically associated with chronic renal impairment or long term diuretic therapy. There is tophus formation due to urate crystal deposition in and around the joint. These tophi can also form in the bones and soft tissues. Renal manifestations with uric acid include nephrolithiasis and uric acid nephropathy. Whenever there is an acute on chronic attack of gout, the inciting cause must be established and in case of diuretic use, they should be immediately replaced with another medication. Allopurinol is never started during an acute episode. it is first allowed to settle before administration of allopurinol. Although dietary restriction must be observed in people with a propensity of gout, this scenario clearly presents diuretics as the cause.

Clubbing of the fingers can be present in many clinical conditions like CLD, bronchiectasis, lung abscess, Ulcerative colitis and Crohn’s Disease. Koilonychia or spoon shaped nails are a typical finding in iron deficiency anaemia. Splinter haemorrhages are pin point haemorrhages found in infective endocarditis and secondary to trauma. Yellow nails are present in pulmonary and renal diseases.

Finasteride is often prescribed for patients with Benign Prostatic Hyperplasia (BPH) or enlarged prostate. However, it has been known to cause a decrease in Prostatic Specific Antigen (PSA) levels in patients with BPH, which may lead to false negatives in a case like this, where a palpable mass has been detected and malignancy is suspected.

Aprepitant is an anti-emetic which blocks the neurokinin 1 (NK1) receptor and acts as a substance P antagonist. It is licensed for chemotherapy-induced nausea and vomiting (CINV) and for prevention of postoperative nausea and vomiting.

Nausea and vomiting are the common side effects of chemotherapy. Risk factors for the development of these symptoms include age<50 years, anxiety, concurrent use of opioids, and the type of chemotherapy administered.

Because Charcot-Marie-Tooth disease (type 1) is an autosomal dominant condition; therefore, there is a 50% chance that the children of this patient will be affected.

Cataract is a condition characterized by clouding of the lens of the eye. This condition most frequently occurs due to age-related degenerative processes in the lens, but can also be associated with ocular trauma, metabolic disorders, side-effects of drugs, or congenital infections. The clouding causes distortion of light, as it passes through the lens, resulting in visual impairment and glare. Initially, a cataract presents discretely and may even go unnoticed, but the visual impairment worsens as the cataract grows larger.

Diagnosis is typically established on the basis of a thorough history and direct visualization of the cataract (by means of slit-lamp microscopy). Surgery is indicated with significant visual impairment and involves lens extraction and implantation of an artificial lens. Untreated cataracts eventually lead to complete blindness.

The patient most likely suffers from antiphospholipid syndrome. The clinical criteria consist of vascular thrombosis and pregnancy morbidity. Vascular thrombosis is defined as one or more clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ confirmed by findings from imaging studies, Doppler studies, or histopathology. ASD, VSDs would cause paradoxical emboli and stroke, however the recurrent pregnancy loss in this case is strongly suggestive of antiphospholipid syndrome. The ECG would be normal in most cases associated with anti phospholipid syndrome.

The major delayed problem with radiotherapy is the development of secondary cancers. This risk begins to appear ten years after therapy.

This is most likely describing irritable bowel syndrome (IBS). Symptoms are either diarrhoea, constipation, or both, abdominal pain, bloating, with various durations. It is a functional, not organic, problem, as far as research shows at this point. It is essentially a diagnosis of exclusion. Treatment is a high fibre diet with fluids. Caffeine should be avoided as this can worsen symptoms. Full colonoscopy is not warranted at this time, neither is a barium enema. A wheat-free diet is not likely to help as there is no evidence they have an allergy to this.

The classic history in this high risk patient is suggestive of a dissecting aortic aneurysm. His transoesophageal echocardiogram confirms the diagnosis. ST elevation in ECG is probably due to the extension of the dissection of the aorta which results in compromised coronary blood supply.

Charles Bonnet syndrome (CBS) involves visual hallucinations due to eye disease, usually associated with a sharp decline in vision. The phenomenon is seen in patients with moderate or severe visual impairment. It can occur spontaneously as the vision declines or it may be precipitated, in predisposed individuals, by concurrent illness such as infections elsewhere in the body.

It is not clear why CBS develops or why some individuals appear to be predisposed to it. It is particularly noted in patients with advanced macular degeneration. It has been suggested that reduced or absent stimulation of the visual system leads to increased excitability of the visual cortex (deafferentation hypothesis). This release phenomenon is compared to phantom limb symptoms after amputation.

CBS is much more common in older patients because conditions causing marked visual loss are more common in older people. However, it can occur at any age and has been described in children.
The prevalence is hard to assess due to considerable under-reporting, perhaps because patients frequently fear that it is a sign of mental illness or dementia. However, it is thought to occur in:
About 10-15% of patients with moderate visual loss.
Possibly up to 50% of people with severe visual loss.
Presentation:
The nature of the hallucination depends on the part of the brain that is activated. The hallucinations may be black and white or in colour. They may involve grids/brickwork/lattice patterns but are typically much more complex:

The hallucinations are always outside the body.
The hallucinations are purely visual – other senses are not involved.
The hallucinations have no personal meaning to the patient.
Hallucinations may last seconds, minutes or hours.
CBS tends to occur in a ‘state of quiet restfulness’. This may be after a meal or when listening to the radio (but not when dozing off).
Symptoms also have a tendency to occur in dim lighting conditions.
Patients may report high levels of distress, with some patients reporting anger, anxiety and even fear associated with the hallucinations.

The most probable diagnosis considering hypochloraemia and the mild metabolic alkalosis as well as the history of GERD (requiring a high dose of PPI to control) would be bulimia.

Other options:
Diuretic abuse tends to give a hypochloraemic acidosis.
Gitelman syndrome also fits the diagnosis but, it is very rare compared to bulimia.
Inhaled steroid use and stress would not be responsible for such marked electrolyte derangement.

Other potential signs of bulimia nervosa would be parotid gland swelling and dental enamel erosion induced by regular vomiting.

Bivalirudin is a competitive, direct thrombin inhibitor. It inhibits both free and clot-bound thrombin and thrombin-induced platelet aggregation. Thrombin enables fibrinogen conversion to fibrin during the coagulation cascade. So inhibition of fibrinogen conversion to fibrin inhibits thrombus development.

The farmer has most likely ingested an organophosphate insecticide.
Organophosphorus compounds are used widely as:
• Insecticides – Malathion, parathion, diazinon, dichlorvos
• Nerve gases – Soman, sarin, tabun, VX
• Ophthalmic agents – Echothiophate
• Antihelmintics – Trichlorfon
• Herbicides – merphos
• Industrial chemical (plasticizer) – Tricresyl phosphate
Signs and symptoms of Organophosphorus Poisoning (OPP) can be classified as:
• Muscarinic effects:
o Cardiovascular – Bradycardia, hypotension
o Respiratory – Rhinorrhoea, bronchorrhea, bronchospasm, cough, severe respiratory distress
o Gastrointestinal – Hypersalivation, nausea and vomiting, abdominal pain, diarrhoea, faecal incontinence
o Genitourinary – Incontinence
o Ocular – Blurred vision, miosis
o Glands – Increased lacrimation, diaphoresis
• Nicotinic effects:
o Muscle fasciculation, weakness, cramping, diaphragmatic failure, and autonomic side effects include: hypertension, tachycardia, and mydriasis.
• Central nervous system (CNS) effects:
o Anxiety, emotional lability, restlessness, confusion, ataxia, tremors, seizures, coma, apnoea
Mainstay Treatment:
• Decontamination
• Securing Airway, Breathing and Circulation
• Atropine
• Pralidoxime
• Benzodiazepines

Historically, high rates of maternal and fetal death have been reported for pregnant women with pulmonary hypertension (30–56% and 11–28%, respectively). The causes of poor maternal outcomes are varied and include risk of death from right heart failure and stroke from intracardiac shunting. Furthermore, there is a high peri-/post-partum risk due to haemodynamic stress, bleeding complications and the use of general anaesthesia, which can all lead to right heart failure.
The most common risk to the foetus is death, with premature birth and growth retardation being reported in successfully delivered children.
CXR is not contraindicated in pregnancy. D-dimers are not used as a diagnostic aid as they are almost always elevated in pregnancy. Nifedipine, although contraindicated in pregnant women may be used judiciously if the need arises.

Chvostek and Trousseau signs can be elicited in patients with hypocalcaemia. Chvostek sign is the twitching of the upper lip with tapping on the cheek 2 cm anterior to the earlobe, below the zygomatic process overlying the facial nerve. Trousseau sign (a more reliable sign present in 94% of hypokalaemic individuals and only 1% to 4% of healthy people) is the presence of carpopedal spasm observed following application of an inflated blood pressure cuff over systolic pressure for 3 minutes in hypokalaemic patients.

Urobiligen is produced by the action of bacteria on bilirubin in the intestine. As a reminder, unconjugated bilirubin becomes conjugated in the hepatocyte. Conjugated bilirubin goes through enterohepatic circulation. About half of the urobiligen is reabsorbed and excreted by the kidneys in the urine. The rest is converted to stercobilinogen –> stercobilin, which is excreted in stool, giving it its brown colour.

Gram-staining of the blood cultures of this patient will show gram-positive cocci. Gram-negative bacilli used to be the most common pathogen isolated in neutropenic sepsis, but currently, the most common pathogens are gram-positive organisms. Staphylococcus epidermidis is the most frequent causative agent, and following this are other staphylococci and streptococci species.

Neutropenic sepsis is a relatively common complication of cancer therapy—usually chemotherapy. It most commonly occurs 7-14 days after the treatment and is usually defined as a neutrophil count of <0.5 x 10^9/L in a patient undergoing anticancer treatment and who has either a temperature higher than 38°C or has other features consistent with clinically significant sepsis. Management approach includes starting empirical antibiotic therapy (piperacillin with tazobactam—Tazocin) immediately. Following this initial treatment, the patient is usually assessed by a specialist and risk-stratified to see if outpatient treatment may be possible. However, if the patient remains febrile and unwell after 48 hours, an alternative antibiotic such as meropenem is often prescribed with or without vancomycin. If patient is still not responding after 4-6 days, then an antifungal, such as amphotericin B, is started after carrying out investigations (e.g. HRCT and Aspergillus PCR) to determine the likelihood of systemic fungal infection.

Downbeat nystagmus (DBN) suggests a lesion in the lower part of the medulla. Arnold-Chiari malformation usually presents with symptoms due to brainstem and lower cranial nerve dysfunction such as DBN.

Oestrogen therapy reduces plasma levels of LDL cholesterol and increases levels of HDL cholesterol. It can improve endothelial vascular function, however, it also has adverse physiological effects, including increasing the plasma levels of triglycerides (small dense LDL particles). Therefore, although HRT may have direct beneficial effects on cardiovascular outcomes, these effects may be reduced or balanced by the adverse physiological effects.

Patients with diabetes often develop ophthalmic complications, the most common and potentially most blinding of these complications is diabetic retinopathy.
The following are the 5 stages in the progression of diabetic retinopathy:
1. Dilation of the retinal venules and formation of retinal capillary microaneurysms.
2. Increased vascular permeability.
3. Vascular occlusion and retinal ischemia.
4. Proliferation of new blood vessels on the surface of the retina.
5. Vitreous haemorrhage and contraction of the fibrovascular proliferation.
The first 2 stages of diabetic retinopathy are known as background or nonproliferative retinopathy. Initially, the retinal venules dilate, then microaneurysms (tiny red dots on the retina that cause no visual impairment) appear. As the microaneurysms or retinal capillaries become more permeable, hard exudates appear, reflecting the leakage of plasma.

Mild nonproliferative diabetic retinopathy (NPDR) or background diabetic retinopathy is indicated by the presence of at least 1 microaneurysm, while neovascularization is the hallmark of Proliferative Diabetic Retinopathy (PDR).

The presence of a third heart sound is the most sensitive indicator of heart failure. All of the other signs can be found in heart failure with varying degrees.

This case has hypercalcaemia most likely associated with the bony metastases from her pre-existing breast carcinoma. The most appropriate next step is to give Pamidronate 60mg intravenously, a bisphosphonate, to immediately inhibit bone resorption and formation.

Drugs causing torsades de pointes are Amiodarone, Chlorpromazine, Clarithromycin, Disopyramide, Dofetilide, Erythromycin, Haloperidol, Methadone, Procainamide, Quinidine, Sotalol, Levofloxacin, Moxifloxacin, Nilotinib, Ondansetron, Ranolazine, Sunitinib, Ziprasidone, Amitriptyline, Ciprofloxacin, Imipramine, Chlorthalidone, Dasatinib, Hydrochlorothiazide, Furosemide.

The main cardiovascular manifestations associated with Marfan’s syndrome are aortic dilatation and mitral valve prolapse.

Increased WBC count and CRP suggest infection. But with the fluctuating hard neurological signs, there is suspicion of the presence of a cerebral mass, which is an indication for requesting for a CT scan with contrast, to rule out an abscess or haematoma. The lumbar puncture can be considered after the CT scan.

Cisplatin is a cytotoxic agent that acts by causing cross-linking in DNA. Its adverse effects include ototoxicity, peripheral neuropathy, hypomagnesaemia, etc.

The causative cytotoxic agents acting through the other aforementioned MOAs are as follows:

1. Doxorubicin: Stabilizes DNA topoisomerase II complex and inhibits DNA and RNA synthesis.

2. Hydroxyurea (hydroxycarbamide): Inhibits ribonucleotide reductase, decreasing DNA synthesis.

3. Mercaptopurine (6-MP): Purine analogue that is activated by HGPRTase, decreasing purine synthesis.

4. Vincristine, vinblastine: Inhibits formation of microtubules.

The patient has a recent history of bleeding peptic ulcer disease, which is an absolute contraindication for thrombolysis. So he should be offered primary angioplasty.

A cohort study is a particular form of longitudinal study that samples a cohort (a group of people who share a defining characteristic, typically those who experienced a common event in a selected period, such as birth or graduation), performing a cross-section at intervals through time.
The relative risk (RR) or risk ratio is the ratio of the probability of an outcome in an exposed group to the probability of an outcome in an unexposed group. Relative risk is used in the statistical analysis of the data of experimental, cohort and cross-sectional studies, to estimate the strength of the association between treatments or risk factors, and outcomes.