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      // ─── COVER ───
      new Paragraph({
        children: [new TextRun({ text: 'ANSWER SHEET', bold: true, size: 40, color: '1F3864' })],
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      // ══════════════════════════════════════════════════════
      // Q1 – OLIGURIA
      // ══════════════════════════════════════════════════════
      sectionHeader('Q.1', 'Evaluate and Manage the Patient Admitted with Oliguria', '20'),

      heading2('Definition'),
      para('Oliguria is defined as urine output < 400 mL/24 hours (or < 0.5 mL/kg/hour in adults). Anuria is defined as < 100 mL/24 hours. It is a key clinical indicator of acute kidney injury (AKI) and demands urgent evaluation.'),

      heading2('Pathophysiological Classification'),
      para('Oliguria is broadly classified into three categories based on the site of the underlying problem:'),

      heading3('1. Pre-renal Oliguria'),
      para('Cause: Decreased effective circulating volume or renal perfusion.'),
      bullet('Absolute hypovolaemia: haemorrhage, diarrhoea/vomiting, burns, diuretic excess'),
      bullet('Distributive: sepsis, anaphylaxis, hepatic failure (hepatorenal syndrome)'),
      bullet('Cardiogenic: heart failure, MI, tamponade'),
      bullet('Renal artery stenosis / renal vein thrombosis'),

      heading3('2. Intrinsic (Renal) Oliguria'),
      para('Cause: Parenchymal kidney damage.'),
      bullet('Tubular: Acute Tubular Necrosis (ATN) – ischaemic or nephrotoxic (drugs, contrast, myoglobin)'),
      bullet('Glomerular: Rapidly Progressive Glomerulonephritis (RPGN), Acute nephritic syndrome'),
      bullet('Interstitial: Acute Interstitial Nephritis (AIN) – drugs (NSAIDs, antibiotics), infection'),
      bullet('Vascular: Thrombotic microangiopathy (HUS/TTP), renal artery occlusion'),

      heading3('3. Post-renal Oliguria'),
      para('Cause: Obstruction to urine outflow.'),
      bullet('Ureteric: bilateral calculi, retroperitoneal fibrosis, malignancy'),
      bullet('Bladder outlet: BPH, urethral stricture, neurogenic bladder'),

      heading2('History'),
      bullet('Duration of reduced urine output; any preceding prodrome'),
      bullet('Fluid intake and losses (vomiting, diarrhoea, bleeding)'),
      bullet('Drug history: NSAIDs, aminoglycosides, contrast agents, ACEi, ARBs'),
      bullet('Past medical history: DM, HTN, CKD, heart failure, malignancy'),
      bullet('Symptoms of obstruction: hesitancy, poor stream, suprapubic pain'),
      bullet('Symptoms of glomerular disease: haematuria, frothy urine, oedema'),
      bullet('Systemic features: rash, arthralgia, haemoptysis (vasculitis), purpura (HUS/TTP)'),

      heading2('Examination'),
      bullet('Vitals: BP (hypotension → pre-renal; hypertension → GN/volume overload), HR, temperature'),
      bullet('Volume status: JVP, mucous membranes, skin turgor, oedema'),
      bullet('Cardiovascular: heart failure signs (S3, crackles)'),
      bullet('Abdominal: distended bladder (post-renal), palpable kidneys, bruits'),
      bullet('Skin: rash, purpura (vasculitis, TTP), jaundice (hepatorenal syndrome)'),

      heading2('Investigations'),

      heading3('Urine Tests'),
      para('These are the single most useful initial tests to differentiate pre-renal from renal AKI:'),
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              new TableCell({ children: [para('Pre-renal', true)], shading: { type: ShadingType.CLEAR, fill: 'BDD7EE' } }),
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      para(''),
      para('FENa = (UNa × PCr) / (PNa × UCr) × 100%  [Note: FENa < 1% may be seen in contrast nephropathy and myoglobinuria despite intrinsic AKI – use FEUrea in this setting]'),

      heading3('Blood Tests'),
      bullet('Serum creatinine, BUN, electrolytes (K+, Na+, HCO3-, Cl-)'),
      bullet('CBC, LFTs, coagulation profile'),
      bullet('CK (rhabdomyolysis), LDH, peripheral smear (TTP/HUS)'),
      bullet('Serology if GN suspected: ANA, ANCA (c & p), anti-GBM, ASO titre, C3/C4, hepatitis B/C, HIV'),
      bullet('ABG: metabolic acidosis (increased anion gap in AKI)'),

      heading3('Imaging'),
      bullet('Renal ultrasonography (FIRST LINE): assess kidney size, echogenicity, bilateral obstruction; hydronephrosis suggests post-renal'),
      bullet('Bladder scan: residual volume > 300 mL suggests outlet obstruction'),
      bullet('Doppler ultrasound: renal artery/vein thrombosis'),
      bullet('CT KUB: calculi, retroperitoneal mass'),

      heading3('Renal Biopsy'),
      para('Indicated when intrinsic renal disease (GN, AIN, TMA) is suspected and pre- and post-renal causes are excluded. Urgent biopsy in suspected RPGN.'),

      heading2('Management'),

      heading3('General Measures'),
      bullet('Strict intake-output monitoring (hourly urine catheterization)'),
      bullet('Daily weights'),
      bullet('Avoid nephrotoxic agents: NSAIDs, aminoglycosides, contrast media, ACEi/ARBs'),
      bullet('Nutritional support: restrict protein (0.8 g/kg/day if not on dialysis), high-calorie intake'),

      heading3('Pre-renal Oliguria'),
      bullet('Volume resuscitation: crystalloids (0.9% NS or balanced solutions like Plasmalyte) – 500 mL bolus, reassess JVP and urine output'),
      bullet('Treat underlying cause: sepsis (antibiotics), heart failure (diuretics + inotropes), haemorrhage (blood products)'),
      bullet('Avoid over-resuscitation in cardiogenic shock'),

      heading3('Intrinsic Renal Oliguria (ATN)'),
      bullet('Optimize haemodynamics; maintain MAP > 65 mmHg with vasopressors if needed'),
      bullet('Avoid diuretics to "convert" oliguric to non-oliguric AKI (no mortality benefit)'),
      bullet('Specific therapy: discontinue offending drug, treat rhabdomyolysis with aggressive fluids, treat infections'),
      bullet('For GN/RPGN: pulse methylprednisolone ± cyclophosphamide ± plasmapheresis (see Q5a)'),

      heading3('Post-renal Oliguria'),
      bullet('Relieve obstruction: bladder catheter (outlet obstruction), nephrostomy or ureteric stent (ureteric obstruction)'),
      bullet('Watch for post-obstructive diuresis: replace urine output with 0.45% NS at ~75% volume'),

      heading3('Fluid and Electrolyte Management'),
      bullet('Hyperkalaemia: restrict dietary K+; calcium gluconate (stabilize membrane), insulin-dextrose, sodium bicarbonate, salbutamol (shift); kayexalate/patiromer (eliminate); dialysis if refractory'),
      bullet('Metabolic acidosis: bicarbonate if pH < 7.2 or HCO3- < 15 mEq/L'),
      bullet('Hyponatraemia: fluid restriction if dilutional'),
      bullet('Fluid restriction: input = insensible losses (500 mL) + previous day's urine output'),

      heading3('Renal Replacement Therapy (RRT) – Indications (AEIOU)'),
      bullet('A – Acidosis refractory to medical management (pH < 7.1)'),
      bullet('E – Electrolyte abnormalities (K+ > 6.5 mEq/L refractory)'),
      bullet('I – Intoxication (dialysable toxins: ethylene glycol, methanol, salicylates, lithium)'),
      bullet('O – Overload (fluid; pulmonary oedema not responding to diuretics)'),
      bullet('U – Uraemic complications (encephalopathy, pericarditis, platelet dysfunction)'),
      para('Modalities: Intermittent haemodialysis (IHD) or Continuous Renal Replacement Therapy (CRRT) – CRRT preferred in haemodynamically unstable patients.'),

      heading2('Prognosis'),
      para('AKI carries significant short-term mortality (40–60% in ICU patients). Recovery depends on cause and severity. Pre-renal AKI is fully reversible with early treatment. ATN usually recovers in 1–3 weeks (may require temporary dialysis). RPGN carries high risk of permanent renal failure without urgent immunosuppression.'),

      new Paragraph({ children: [new PageBreak()] }),

      // ══════════════════════════════════════════════════════
      // Q2 – HEART FAILURE
      // ══════════════════════════════════════════════════════
      sectionHeader('Q.2', 'Discuss in Detail Heart Failure', '20'),

      heading2('Definition'),
      para('Heart failure (HF) is a clinical syndrome in which the heart is unable to pump sufficient blood to meet the metabolic demands of the body, or can do so only at elevated filling pressures. It is not a single disease but a syndrome resulting from any structural or functional cardiac disorder.'),

      heading2('Classification'),

      heading3('By Ejection Fraction (ESC 2021)'),
      bullet('HFrEF (Heart Failure with Reduced EF): EF < 40%'),
      bullet('HFmrEF (Heart Failure with Mildly Reduced EF): EF 41–49%'),
      bullet('HFpEF (Heart Failure with Preserved EF): EF ≥ 50% with elevated filling pressures'),

      heading3('By Onset'),
      bullet('Acute HF: de novo or acute decompensation of chronic HF'),
      bullet('Chronic HF: stable, compensated, slow progression'),

      heading3('By Side'),
      bullet('Left-sided HF: pulmonary congestion (dyspnoea, orthopnoea, PND, pulmonary oedema)'),
      bullet('Right-sided HF: systemic venous congestion (JVP elevation, peripheral oedema, hepatomegaly, ascites)'),
      bullet('Biventricular/Congestive HF: both sides'),

      heading3('NYHA Functional Classification'),
      bullet('Class I: No limitation; ordinary activity causes no symptoms'),
      bullet('Class II: Slight limitation; comfortable at rest; ordinary activity causes symptoms'),
      bullet('Class III: Marked limitation; comfortable at rest; less-than-ordinary activity causes symptoms'),
      bullet('Class IV: Unable to carry out any activity without symptoms; symptoms present at rest'),

      heading2('Aetiology'),

      heading3('Common Causes'),
      bullet('Ischaemic heart disease (most common in developed countries): MI, hibernating myocardium'),
      bullet('Hypertension: pressure overload → concentric LVH → diastolic dysfunction → HFpEF'),
      bullet('Dilated cardiomyopathy (idiopathic, alcoholic, viral myocarditis)'),
      bullet('Valvular heart disease: MR, AR (volume overload); AS, MS (pressure overload)'),
      bullet('Arrhythmias: atrial fibrillation, tachycardia-mediated cardiomyopathy'),

      heading3('Less Common Causes'),
      bullet('Hypertrophic cardiomyopathy (HCM)'),
      bullet('Restrictive cardiomyopathy (amyloidosis, haemochromatosis, sarcoidosis)'),
      bullet('Congenital heart disease'),
      bullet('High-output HF: anaemia, thyrotoxicosis, AV fistula, Paget disease, beriberi'),
      bullet('Peripartum cardiomyopathy'),
      bullet('Chemotherapy-induced (anthracyclines, trastuzumab)'),

      heading2('Pathophysiology'),
      para('The hallmark pathophysiological mechanisms are:'),
      bullet('Initial myocardial injury → decreased CO → activation of neurohormonal systems'),
      bullet('Sympathetic nervous system (SNS) activation: tachycardia, vasoconstriction, ↑contractility (short-term compensatory but long-term detrimental)'),
      bullet('RAAS activation: angiotensin II → vasoconstriction, aldosterone → Na+ and water retention → increased preload → congestion'),
      bullet('ADH/vasopressin: water retention → hyponatraemia (poor prognostic marker)'),
      bullet('Ventricular remodelling: cardiomyocyte hypertrophy, fibrosis, chamber dilatation → progressive dysfunction'),
      bullet('Natriuretic peptides (BNP, NT-proBNP): released in response to wall stress → compensatory vasodilation and natriuresis; used as biomarkers'),
      bullet('Inflammatory cytokines (TNF-alpha, IL-6): contribute to myocardial depression and cachexia'),

      heading2('Clinical Features'),

      heading3('Symptoms'),
      bullet('Dyspnoea on exertion (earliest symptom)'),
      bullet('Orthopnoea: dyspnoea on lying flat (relieved by sitting) → quantify by number of pillows'),
      bullet('Paroxysmal Nocturnal Dyspnoea (PND): awakening 1–2 hours after sleep with dyspnoea'),
      bullet('Fatigue, exercise intolerance'),
      bullet('Ankle swelling (bilateral pitting oedema)'),
      bullet('Nocturia (redistribution of dependent oedema when supine)'),
      bullet('Cardiac cachexia (late, severe HF)'),
      bullet('Right HF: nausea, abdominal discomfort (hepatic congestion), early satiety'),

      heading3('Signs'),
      bullet('Tachycardia (compensatory), may be irregular (AF)'),
      bullet('Pulsus alternans (severe LV dysfunction)'),
      bullet('Elevated JVP with hepatojugular reflux'),
      bullet('Displaced apex beat (volume-overloaded dilated heart)'),
      bullet('S3 gallop (pathological, indicates elevated filling pressures - most specific)'),
      bullet('S4 gallop (stiff ventricle, diastolic dysfunction)'),
      bullet('Pansystolic murmur (functional MR from annular dilatation)'),
      bullet('Bilateral fine basal crepitations (pulmonary oedema)'),
      bullet('Pleural effusion (bilateral or R > L)'),
      bullet('Hepatomegaly (tender in acute HF), ascites'),
      bullet('Bilateral pitting oedema (sacral oedema in bedbound patients)'),

      heading2('Investigations'),

      heading3('Blood Tests'),
      bullet('BNP > 100 pg/mL or NT-proBNP > 300 pg/mL: supports HF diagnosis (NICE-recommended cut-offs)'),
      bullet('CBC (anaemia as precipitant), RFTs, LFTs, electrolytes (hyponatraemia = poor prognosis)'),
      bullet('Thyroid function tests (exclude thyrotoxicosis or hypothyroidism)'),
      bullet('Iron studies, ferritin (iron deficiency common and treatable in HFrEF)'),
      bullet('Cardiac troponin (myocardial injury/ACS as cause)'),
      bullet('HbA1c, lipid profile (risk factors)'),

      heading3('Electrocardiogram (ECG)'),
      bullet('LVH, LBBB (new LBBB strongly suggests ischaemic or dilated CM), AF, Q waves (prior MI)'),
      bullet('Normal ECG has high negative predictive value for HFrEF'),

      heading3('Chest X-ray'),
      bullet('Cardiomegaly (CTR > 50%)'),
      bullet('Upper lobe venous diversion (pulmonary venous HTN)'),
      bullet('Kerley B lines (interstitial oedema)'),
      bullet('Bat-wing/perihilar haziness (alveolar oedema)'),
      bullet('Bilateral pleural effusions'),

      heading3('Echocardiography (Key Investigation)'),
      bullet('Confirms diagnosis and classifies HFrEF vs HFpEF'),
      bullet('LV dimensions, EF (Simpson method), wall motion abnormalities'),
      bullet('Diastolic dysfunction grading (E/A ratio, E/e\' ratio, TR velocity, LA volume index)'),
      bullet('Valvular assessment, pericardial effusion'),
      bullet('Estimated PASP (pulmonary hypertension)'),

      heading3('Additional Tests'),
      bullet('Coronary angiography: if ischaemic aetiology suspected'),
      bullet('Cardiac MRI: gold standard for myocardial tissue characterisation (fibrosis, infiltration, inflammation)'),
      bullet('Exercise stress testing: functional capacity, prognosis'),
      bullet('Endomyocardial biopsy: suspected myocarditis, infiltrative cardiomyopathy'),

      heading2('Management'),

      heading3('Non-Pharmacological'),
      bullet('Fluid restriction: 1.5–2 L/day if symptomatic/hyponatraemic'),
      bullet('Sodium restriction: < 2 g/day'),
      bullet('Daily weight monitoring: report if weight gain > 2 kg in 3 days'),
      bullet('Exercise rehabilitation: supervised cardiac rehabilitation in stable HFrEF (reduces hospitalisation)'),
      bullet('Vaccination: annual influenza and pneumococcal vaccines'),
      bullet('Optimise cardiovascular risk factors; avoid NSAIDs, thiazolidinediones (worsen HF)'),

      heading3('Pharmacological – HFrEF (The "Fantastic Four")'),
      para('Evidence-based therapies that reduce mortality in HFrEF:'),

      para('1. ACE Inhibitor (or ARB/ARNi)', true),
      bullet('ACEi (ramipril, enalapril): first-line; reduces mortality by 20–25% (CONSENSUS, SOLVD trials)'),
      bullet('ARB (candesartan, valsartan): alternative if ACEi not tolerated (cough)'),
      bullet('ARNi: Sacubitril/valsartan (Entresto) – superior to enalapril in HFrEF (PARADIGM-HF trial); replaces ACEi/ARB; dose: 97/103 mg BD after washout period'),

      para('2. Beta-blocker', true),
      bullet('Carvedilol, metoprolol succinate, bisoprolol: reduce mortality by 30–35%'),
      bullet('Start at low dose, titrate slowly (MERIT-HF, COPERNICUS, CIBIS-II trials)'),
      bullet('Avoid in acute decompensated HF; use only in stable patients'),

      para('3. Mineralocorticoid Receptor Antagonist (MRA)', true),
      bullet('Spironolactone or eplerenone: mortality benefit in NYHA Class II–IV (RALES, EMPHASIS trials)'),
      bullet('Avoid if K+ > 5.0 mEq/L or GFR < 30 mL/min'),

      para('4. SGLT2 Inhibitor', true),
      bullet('Dapagliflozin (DAPA-HF), empagliflozin (EMPEROR-Reduced): reduce HF hospitalisation and CV mortality regardless of diabetic status'),
      bullet('Now recommended for ALL patients with HFrEF (2021 ESC guidelines)'),

      heading3('Additional Pharmacotherapy'),
      bullet('Diuretics: loop diuretics (furosemide, torasemide) – for symptom relief of congestion; no mortality benefit'),
      bullet('Ivabradine: for sinus rhythm, HR ≥ 70 bpm, EF ≤ 35% on max beta-blocker; reduces hospitalisation (SHIFT trial)'),
      bullet('Hydralazine + isosorbide dinitrate: alternative for patients intolerant of both ACEi and ARB (particularly in Black patients – A-HeFT trial)'),
      bullet('Digoxin: reduces hospitalisation; no mortality benefit; useful in AF with HF; narrow therapeutic index'),
      bullet('Vericiguat: soluble guanylate cyclase stimulator for high-risk worsening HFrEF (VICTORIA trial)'),
      bullet('Omecamtiv mecarbil (cardiac myosin activator): modest benefit in GALACTIC-HF trial'),

      heading3('Device Therapy'),
      bullet('ICD (Implantable Cardioverter Defibrillator): EF ≤ 35% on optimal medical therapy ≥ 3 months, NYHA Class II-III, life expectancy > 1 year'),
      bullet('CRT (Cardiac Resynchronisation Therapy): EF ≤ 35%, LBBB, QRS ≥ 150 ms, NYHA Class II–IV; improves EF, symptoms, mortality'),
      bullet('CRT-D: combined device'),

      heading3('Acute Decompensated Heart Failure (ADHF)'),
      bullet('Sit upright, oxygen supplementation (target SpO2 ≥ 95%)'),
      bullet('NIV (CPAP/BiPAP): if severe pulmonary oedema; reduces need for intubation (3CPO trial)'),
      bullet('IV loop diuretics: furosemide 40–80 mg IV bolus or infusion (DOSE trial: high-dose preferred)'),
      bullet('Vasodilators (IV GTN): if SBP > 100 mmHg; reduces preload and afterload'),
      bullet('Inotropes (dobutamine, milrinone): if cardiogenic shock, SBP < 90 mmHg'),
      bullet('Vasopressors (norepinephrine): if refractory hypotension'),
      bullet('Tolvaptan: V2 receptor antagonist for refractory hyponatraemia and fluid overload'),
      bullet('Identify and treat precipitating cause: ACS (PCI), AF (rate/rhythm control), hypertensive emergency (IV antihypertensives), infection'),

      heading3('Advanced HF / Refractory HF'),
      bullet('Left Ventricular Assist Device (LVAD): bridge to transplant or destination therapy'),
      bullet('Heart transplantation: gold standard; 5-year survival ~75%'),
      bullet('Palliative care: symptom management in end-stage HF'),

      heading2('Prognosis'),
      para('1-year mortality for ADHF is ~20–30%. LVEF < 25%, NYHA Class IV, hyponatraemia (Na < 135), markedly elevated BNP/NT-proBNP, anaemia, and CKD indicate poor prognosis.'),

      new Paragraph({ children: [new PageBreak()] }),

      // ══════════════════════════════════════════════════════
      // Q3 – G-PROTEIN RECEPTOR + HYPERTHYROIDISM
      // ══════════════════════════════════════════════════════
      sectionHeader('Q.3', 'G-Protein Receptor Disorders (Genetic Causes) + Approach to Hyperthyroidism', '20'),

      heading2('Part A: Genetic Causes of G-Protein Receptor Disorders'),

      heading3('Overview of G-Protein Coupled Receptor (GPCR) Signalling'),
      para('GPCRs are transmembrane receptors that transduce extracellular signals via heterotrimeric G-proteins (Gs, Gi, Gq, G12). Mutations can be loss-of-function (LOF) or gain-of-function (GOF), each producing distinct clinical syndromes.'),

      heading3('Classification of GPCR Genetic Disorders'),

      para('A. Loss-of-Function (LOF) Mutations – Resistance Syndromes', true),
      new Table({
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          }),
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          new TableRow({ children: [new TableCell({ children: [para('V2 vasopressin receptor')] }), new TableCell({ children: [para('AVPR2 (X-linked)')] }), new TableCell({ children: [para('Nephrogenic Diabetes Insipidus (NDI) Type I')] }), new TableCell({ children: [para('Polyuria, polydipsia, hypernatraemia; unresponsive to ADH')] })] }),
          new TableRow({ children: [new TableCell({ children: [para('Rhodopsin')] }), new TableCell({ children: [para('RHO')] }), new TableCell({ children: [para('Retinitis Pigmentosa')] }), new TableCell({ children: [para('Progressive visual loss, nyctalopia, tunnel vision; most common cause of hereditary blindness')] })] }),
          new TableRow({ children: [new TableCell({ children: [para('Melanocortin 4 receptor (MC4R)')] }), new TableCell({ children: [para('MC4R')] }), new TableCell({ children: [para('Monogenic obesity')] }), new TableCell({ children: [para('Most common monogenic form of obesity; hyperinsulinaemia; hyperphagia')] })] }),
          new TableRow({ children: [new TableCell({ children: [para('ACTH receptor (MC2R)')] }), new TableCell({ children: [para('MC2R')] }), new TableCell({ children: [para('Familial glucocorticoid deficiency (ACTH resistance)')] }), new TableCell({ children: [para('Hypoglycaemia, hyperpigmentation, tall stature; ACTH high; cortisol low')] })] }),
        ],
      }),
      para(''),

      para('B. Gain-of-Function (GOF) Mutations – Constitutive Activation', true),
      new Table({
        width: { size: 100, type: WidthType.PERCENTAGE },
        rows: [
          new TableRow({
            tableHeader: true,
            children: [
              new TableCell({ children: [para('Receptor/Protein', true)], shading: { type: ShadingType.CLEAR, fill: 'FFC000' } }),
              new TableCell({ children: [para('Gene', true)], shading: { type: ShadingType.CLEAR, fill: 'FFC000' } }),
              new TableCell({ children: [para('Disease', true)], shading: { type: ShadingType.CLEAR, fill: 'FFC000' } }),
              new TableCell({ children: [para('Key Features', true)], shading: { type: ShadingType.CLEAR, fill: 'FFC000' } }),
            ],
          }),
          new TableRow({ children: [new TableCell({ children: [para('TSHR')] }), new TableCell({ children: [para('TSHR (germline)')] }), new TableCell({ children: [para('Familial non-autoimmune hyperthyroidism')] }), new TableCell({ children: [para('Autosomal dominant; hyperthyroidism without goitre; low/absent TSH; negative thyroid antibodies')] })] }),
          new TableRow({ children: [new TableCell({ children: [para('TSHR')] }), new TableCell({ children: [para('TSHR (somatic)')] }), new TableCell({ children: [para('Toxic adenoma / Toxic multinodular goitre')] }), new TableCell({ children: [para('Autonomous thyroid function; hot nodule on scan; accounts for ~50% of toxic adenomas')] })] }),
          new TableRow({ children: [new TableCell({ children: [para('Gsa')] }), new TableCell({ children: [para('GNAS1 (somatic R201C/H)')] }), new TableCell({ children: [para('McCune-Albright Syndrome')] }), new TableCell({ children: [para('Triad: polyostotic fibrous dysplasia + café-au-lait spots + precocious puberty; also hyperthyroidism, GH excess, Cushing syndrome')] })] }),
          new TableRow({ children: [new TableCell({ children: [para('LH receptor (LHCGR)')] }), new TableCell({ children: [para('LHCGR (germline)')] }), new TableCell({ children: [para('Familial male-limited precocious puberty (testotoxicosis)')] }), new TableCell({ children: [para('Males: precocious puberty with low LH/FSH; Leydig cell activation independent of gonadotropin')] })] }),
          new TableRow({ children: [new TableCell({ children: [para('PTHR1')] }), new TableCell({ children: [para('PTHR1')] }), new TableCell({ children: [para('Jansen metaphyseal chondrodysplasia')] }), new TableCell({ children: [para('Autosomal dominant; hypercalcaemia + hypophosphataemia without elevated PTH; short-limbed dwarfism')] })] }),
          new TableRow({ children: [new TableCell({ children: [para('Ca-sensing receptor (CaSR)')] }), new TableCell({ children: [para('CASR')] }), new TableCell({ children: [para('Autosomal dominant hypocalcaemia (ADH type 1)')] }), new TableCell({ children: [para('Hypocalcaemia + inappropriately low PTH; hypomagnesaemia; nephrocalcinosis risk with treatment')] })] }),
        ],
      }),
      para(''),
      para('Key concept: In GNAS1 mutations (Gs-alpha), the same gene can produce opposing phenotypes depending on which parental allele is mutated (genomic imprinting), illustrating the complexity of GPCR signalling disorders.'),

      heading2('Part B: Approach to Patient with Hyperthyroidism'),

      heading3('Definition'),
      para('Hyperthyroidism refers to excess thyroid hormone synthesis by the thyroid gland, whereas thyrotoxicosis refers to excess thyroid hormone from any source (including exogenous). All hyperthyroidism is thyrotoxicosis but not vice versa.'),

      heading3('Causes'),
      para('Classified by radioiodine uptake:'),
      bullet('HIGH uptake: Graves disease (autoimmune – most common cause overall; TRAb-positive), Toxic multinodular goitre (Plummer disease), Toxic adenoma, TSH-secreting pituitary adenoma, Familial non-autoimmune hyperthyroidism (TSHR GOF mutation), HCG-mediated (gestational thyrotoxicosis, hydatidiform mole, choriocarcinoma)'),
      bullet('LOW/ABSENT uptake: Subacute (De Quervain) thyroiditis – painful, post-viral; Hashimoto thyroiditis (hashitoxicosis phase); Painless/postpartum thyroiditis; Iodine-induced (Jod-Basedow); Amiodarone-induced thyrotoxicosis (Type I & II); Exogenous thyroid hormone (factitious); Struma ovarii; Metastatic follicular thyroid cancer'),

      heading3('Clinical Features'),

      para('Symptoms:'),
      bullet('Hypermetabolic: heat intolerance, weight loss despite increased appetite, sweating, fatigue, weakness'),
      bullet('Cardiovascular: palpitations, exertional dyspnoea, AF (in elderly)'),
      bullet('Neuropsychiatric: anxiety, irritability, emotional lability, fine tremor, insomnia'),
      bullet('GI: diarrhoea, increased bowel movements, nausea'),
      bullet('Reproductive: oligo/amenorrhoea, ↓ fertility, gynaecomastia'),
      bullet('Musculoskeletal: proximal myopathy, osteoporosis'),

      para('Signs:'),
      bullet('General: agitated, thin, warm moist skin, fine tremor of outstretched hands'),
      bullet('Pulse: tachycardia, irregularly irregular (AF), bounding pulse, wide pulse pressure'),
      bullet('Eye signs (Graves specific): exophthalmos (proptosis), lid lag (von Graefe sign), lid retraction (Dalrymple sign), periorbital oedema, chemosis, ophthalmoplegia'),
      bullet('Neck: diffuse smooth goitre (Graves) + bruit; nodular goitre (TMNG or toxic adenoma); thyroid bruit'),
      bullet('Skin (Graves specific): pretibial myxoedema (bilateral non-pitting oedema, shins), thyroid acropachy'),
      bullet('Reflexes: brisk, with short relaxation time'),

      heading3('Investigations'),

      para('Step 1 – Confirm biochemical thyrotoxicosis:'),
      bullet('TSH: suppressed (< 0.1 mIU/L) – most sensitive initial test'),
      bullet('Free T4 (FT4): elevated in overt hyperthyroidism'),
      bullet('Free T3 (FT3): helpful if FT4 normal but TSH suppressed (T3 toxicosis)'),

      para('Step 2 – Determine aetiology:'),
      bullet('TSH receptor antibody (TRAb / TSI): elevated in Graves disease (90–95% sensitivity)'),
      bullet('Anti-TPO and anti-thyroglobulin antibodies: elevated in Hashimoto and Graves'),
      bullet('Radionuclide thyroid scan (Tc-99m or I-123):'),
      bullet('   - Diffuse homogeneous uptake: Graves disease', 1),
      bullet('   - Multiple hot nodules with suppression of remainder: TMNG', 1),
      bullet('   - Single hot nodule: toxic adenoma', 1),
      bullet('   - Absent/minimal uptake: thyroiditis, exogenous thyroid hormone, struma ovarii', 1),
      bullet('Thyroid ultrasound with Doppler: thyroid vascularity (increased in Graves, decreased in thyroiditis)'),
      bullet('Serum thyroglobulin: elevated in thyroiditis; suppressed with exogenous ingestion (factitious)'),
      bullet('CXR, ECG (AF, SVT), bone density (DEXA)'),
      bullet('Serum calcium (elevated in severe thyrotoxicosis)'),

      heading3('Management'),

      para('1. Symptomatic Treatment (ALL causes):'),
      bullet('Beta-blockers (propranolol 40 mg TDS or atenolol 50–100 mg OD): rapid relief of adrenergic symptoms (tachycardia, tremor, anxiety); propranolol also inhibits peripheral T4→T3 conversion'),

      para('2. Antithyroid Drugs (ATDs) – for Graves, TMNG, Toxic Adenoma:'),
      bullet('Carbimazole (10–30 mg BD) or Methimazole (preferred; less hepatotoxic): block thyroid peroxidase; first-line in most centres'),
      bullet('Propylthiouracil (PTU): preferred in first trimester of pregnancy and thyroid storm (additional inhibition of T4→T3 conversion); use carbimazole in 2nd/3rd trimester'),
      bullet('Titration regimen: reduce dose as thyroid function normalises; maintain on low dose for 12–18 months in Graves'),
      bullet('Block-and-replace regimen: full-dose ATD + T4 replacement; alternative approach'),
      bullet('Side effects: agranulocytosis (0.3% – warn patient to seek CBC if fever/sore throat), hepatotoxicity (PTU >> carbimazole), rash, vasculitis (PTU)'),

      para('3. Radioiodine (I-131) Therapy:'),
      bullet('Preferred definitive treatment in Graves disease (USA) and TMNG / Toxic Adenoma (worldwide)'),
      bullet('Contraindicated in: pregnancy, breastfeeding, active Graves ophthalmopathy (may worsen), child-bearing age (relative)'),
      bullet('Pre-treat with ATD to prevent thyroid storm post-RAI in elderly/cardiac patients'),
      bullet('Hypothyroidism occurs in majority within 6–12 months; patient must be counselled and placed on lifelong thyroxine'),

      para('4. Thyroid Surgery (Thyroidectomy):'),
      bullet('Indications: large goitre with compressive symptoms, suspected malignancy, failed medical/RAI, patient preference, severe ophthalmopathy, pregnancy (2nd trimester if needed)'),
      bullet('Subtotal thyroidectomy for TMNG; total/near-total thyroidectomy for Graves'),
      bullet('Render euthyroid pre-operatively with ATDs (4–6 weeks) + iodine (Lugol\'s iodine for 10 days) to reduce vascularity'),
      bullet('Complications: recurrent laryngeal nerve palsy (hoarseness), hypoparathyroidism (hypocalcaemia), hypothyroidism, thyroid storm (rare)'),

      para('5. Thyroid Storm (Thyrotoxic Crisis) – Medical Emergency:'),
      bullet('Burch-Wartofsky score ≥ 45: suggests thyroid storm'),
      bullet('Treatment: PTU (500–1000 mg loading, then 250 mg Q4H), beta-blocker IV (propranolol), iodine (SSKI/Lugol – 1 hour AFTER PTU to avoid organification), corticosteroids (hydrocortisone 100 mg TDS – block conversion + possible adrenal insufficiency), cooling, fluid support, treat precipitant'),

      heading3('Special Situations'),
      bullet('Graves Ophthalmopathy: selenium supplementation (mild); IV pulse methylprednisolone (moderate); orbital decompression, radiotherapy (severe). Assess with CAS (Clinical Activity Score) and EUGOGO classification.'),
      bullet('Graves in pregnancy: PTU in 1st trimester; carbimazole in 2nd/3rd; target FT4 at upper limit of normal; monitor foetal thyroid function'),
      bullet('Amiodarone-induced thyrotoxicosis: Type I (iodine-induced excess synthesis) → ATDs; Type II (destructive thyroiditis) → prednisolone'),
      bullet('Subclinical hyperthyroidism: TSH < 0.1 with normal T3/T4; treat if age > 65, AF, osteoporosis, or symptomatic'),

      new Paragraph({ children: [new PageBreak()] }),

      // ══════════════════════════════════════════════════════
      // Q4 – LYMPHADENOPATHY + SPLENOMEGALY
      // ══════════════════════════════════════════════════════
      sectionHeader('Q.4', 'Lymphadenopathy (Causes) + Approach to Patient with Splenomegaly', '20'),

      heading2('Part A: Causes of Lymphadenopathy'),
      para('Lymphadenopathy refers to lymph nodes that are abnormal in size (> 1 cm in most regions, > 1.5 cm inguinal), consistency, or number. It may be localised (single region) or generalised (two or more non-contiguous regions).'),

      heading3('1. Infectious Causes (Most Common)'),
      bullet('Viral: EBV (infectious mononucleosis), CMV, HIV (acute seroconversion), adenovirus, rubella, measles, hepatitis A/B'),
      bullet('Bacterial: Streptococcal pharyngitis, Staphylococcal skin infections (cervical/axillary), TB (scrofula – cervical), atypical mycobacteria, brucellosis, cat-scratch disease (Bartonella henselae), tularaemia, plague, syphilis (secondary – generalised)'),
      bullet('Protozoal: Toxoplasmosis, leishmaniasis (kala-azar)'),
      bullet('Fungal: Histoplasmosis, coccidioidomycosis'),
      bullet('Helminthic: Filariasis (lymphatic obstruction → lymphoedema)'),

      heading3('2. Neoplastic Causes'),
      bullet('Primary lymphoid malignancies:'),
      bullet('   - Hodgkin lymphoma (HL): bimodal age distribution; Reed-Sternberg cells; constitutional B symptoms (fever, night sweats, weight loss > 10%)', 1),
      bullet('   - Non-Hodgkin lymphoma (NHL): diverse; B-cell (most) or T-cell; systemic involvement common', 1),
      bullet('   - Acute/Chronic leukaemias: ALL, CLL (generalised rubbery lymphadenopathy + splenomegaly), CML', 1),
      bullet('Secondary (metastatic):'),
      bullet('   - Cervical: oral, nasopharyngeal, thyroid cancers', 1),
      bullet('   - Axillary: breast, lung, melanoma', 1),
      bullet('   - Inguinal: genital, anorectal, lower limb melanoma', 1),
      bullet('   - Supraclavicular (Virchow\'s node, left): GI/lung/testicular malignancy (Troisier sign)', 1),

      heading3('3. Inflammatory / Autoimmune Causes'),
      bullet('Systemic Lupus Erythematosus (SLE)'),
      bullet('Rheumatoid arthritis (RA)'),
      bullet('Sarcoidosis: bilateral hilar adenopathy ± paratracheal; erythema nodosum, hypercalcaemia'),
      bullet('Kikuchi-Fujimoto disease: self-limiting necrotising histiocytic lymphadenitis; young Asian women; cervical; fever'),
      bullet('Kawasaki disease: in children; cervical lymphadenopathy + fever + rash + conjunctivitis'),
      bullet('Adult-onset Still\'s disease: generalised lymphadenopathy + quotidian fever + salmon rash'),

      heading3('4. Drug-Induced'),
      bullet('Phenytoin (pseudolymphoma), carbamazepine, hydralazine, allopurinol, sulphonamides'),

      heading3('5. Storage / Infiltrative Diseases'),
      bullet('Gaucher disease, Niemann-Pick disease, Amyloidosis'),

      heading3('6. Miscellaneous'),
      bullet('Castleman disease: angiofollicular lymph node hyperplasia; unicentric (localised, good prognosis) or multicentric (systemic, may be HHV-8 or HIV-associated)'),
      bullet('Dermatopathic lymphadenitis: associated with generalised skin disease'),
      bullet('Hyperthyroidism, Addison disease (rare)'),

      heading3('Approach to Lymphadenopathy'),
      para('Key history points: duration, location, associated symptoms (fever, night sweats, weight loss – B symptoms), exposure history (travel, animals, sick contacts), medications, prior malignancy.'),
      para('Key exam: size, consistency (firm-rubbery = lymphoma; hard = metastatic; fluctuant/tender = infection), matted/fixed, skin changes (erythema, sinus), organomegaly.'),
      para('Investigations: FBC + differential + smear, ESR/CRP, LDH (lymphoma marker), uric acid, serology (EBV, CMV, HIV, toxoplasma, syphilis), CXR, CT chest-abdomen-pelvis (staging), FNAC or excisional lymph node biopsy (gold standard).'),

      heading2('Part B: Approach to Patient with Splenomegaly'),

      heading3('Grading of Splenomegaly'),
      bullet('Splenomegaly: spleen enlarged beyond its normal size (> 12 cm on USS)'),
      bullet('Mild splenomegaly: < 4 cm below costal margin'),
      bullet('Moderate splenomegaly: 4–8 cm below costal margin'),
      bullet('Massive splenomegaly: > 8 cm below costal margin (or crossing midline)'),
      para('Massive splenomegaly: mnemonic "CCML" – Chronic malaria, CML, Myelofibrosis, Leishmaniasis (Kala-azar); also polycythaemia vera, thalassaemia major, Gaucher disease'),

      heading3('Causes of Splenomegaly'),

      para('A. Infective'),
      bullet('Acute: malaria (Plasmodium vivax/malariae; P. falciparum may cause acute enlargement), EBV, CMV, typhoid, bacterial endocarditis'),
      bullet('Chronic: malaria (tropical splenomegaly syndrome), visceral leishmaniasis (massive splenomegaly), TB, brucellosis, histoplasmosis, schistosomiasis'),

      para('B. Haematological'),
      bullet('Haemolytic anaemias: hereditary spherocytosis, thalassaemia, sickle cell (early; autosplenectomy in adults), G6PD deficiency (acute haemolysis)'),
      bullet('Myeloproliferative neoplasms: CML (hallmark – massive splenomegaly), polycythaemia vera, primary myelofibrosis (massive), essential thrombocythaemia'),
      bullet('Lymphoproliferative: CLL, NHL (splenic marginal zone lymphoma), hairy cell leukaemia (massive splenomegaly)'),
      bullet('Acute leukaemias (mild to moderate)'),

      para('C. Congestive'),
      bullet('Portal hypertension: liver cirrhosis (most common cause in clinical practice), Budd-Chiari syndrome, portal vein thrombosis'),
      bullet('Right heart failure (congestive hepatosplenomegaly)'),

      para('D. Inflammatory / Autoimmune'),
      bullet('Felty syndrome (RA + neutropenia + splenomegaly)'),
      bullet('SLE, adult-onset Still\'s disease, sarcoidosis'),
      bullet('Autoimmune haemolytic anaemia'),

      para('E. Infiltrative / Storage'),
      bullet('Amyloidosis, Gaucher disease (massive splenomegaly), Niemann-Pick'),
      bullet('Extramedullary haematopoiesis (myelofibrosis, thalassaemia)'),

      para('F. Neoplastic'),
      bullet('Primary: haemangioma (most common benign), lymphoma, angiosarcoma'),
      bullet('Secondary: metastases (rare), direct invasion'),

      para('G. Miscellaneous'),
      bullet('Splenic vein thrombosis, splenic abscess, splenic cyst (post-traumatic/hydatid)'),

      heading3('Clinical Approach'),

      para('History:'),
      bullet('Acute vs. chronic onset; fever (infection, lymphoma); weight loss, B symptoms (lymphoma)'),
      bullet('Jaundice, dark urine (haemolysis); alcohol history, liver disease (portal HTN)'),
      bullet('Travel (malaria, leishmaniasis); transfusions (haematological disease)'),
      bullet('Joint pains, rash (autoimmune); prior abdominal surgery/trauma'),
      bullet('Family history (hereditary haemolytic disorders, storage diseases)'),

      para('Examination:'),
      bullet('Confirm splenomegaly (percussion + palpation; confirm with USS – spleen moves with respiration, has medial notch)'),
      bullet('Size and characteristics: tenderness (acute enlargement, infarct, abscess), surface (nodular = haematological malignancy)'),
      bullet('Lymphadenopathy: generalised → haematological malignancy, infection'),
      bullet('Liver: hepatosplenomegaly → portal HTN, lymphoma, infiltrative, storage disease'),
      bullet('Stigmata of chronic liver disease: jaundice, palmar erythema, spider naevi, caput medusae, varices, ascites'),
      bullet('Anaemia, purpura, bleeding: haematological disorders'),
      bullet('Bone marrow tenderness (leukaemia)'),

      heading3('Investigations'),

      para('First-line:'),
      bullet('FBC + differential + peripheral smear: key investigation – reveals cytopenias (hypersplenism), leukaemia cells (CML – leukocytosis with left shift, basophilia), target cells (thalassaemia), parasites (malaria)'),
      bullet('LFTs, PT/INR (liver disease)'),
      bullet('USS abdomen: confirm splenomegaly, assess liver, portal vein, lymph nodes'),
      bullet('Blood cultures, blood film for malaria (if febrile), serology'),

      para('Second-line:'),
      bullet('Bone marrow biopsy: for suspected haematological malignancy, leishmaniasis (amastigotes), myelofibrosis'),
      bullet('CT chest-abdomen-pelvis: lymphadenopathy, splenic architecture, portal vein'),
      bullet('LDH, uric acid, beta-2 microglobulin (lymphoma markers)'),
      bullet('Liver biopsy (if hepatosplenomegaly with suspected infiltrative/storage disease)'),
      bullet('Serum protein electrophoresis + immunofixation (amyloid, myeloma)'),
      bullet('Glucocerebrosidase enzyme assay (Gaucher disease)'),
      bullet('JAK2 V617F mutation (myeloproliferative neoplasms)'),
      bullet('Echocardiography (cardiac causes)'),

      heading3('Management Principles'),
      para('Management is entirely directed at the underlying cause. Hypersplenism (pancytopenia from splenic sequestration) may require:'),
      bullet('Splenectomy (or splenic embolisation): for massive symptomatic splenomegaly, haematological indications (hereditary spherocytosis, ITP refractory), Felty syndrome'),
      bullet('Pre-splenectomy: vaccinations against encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis) at least 2 weeks pre-operatively'),
      bullet('Post-splenectomy: prophylactic penicillin V, carry medic-alert card, early treatment of febrile episodes (OPSI – Overwhelming Post-Splenectomy Infection)'),

      new Paragraph({ children: [new PageBreak()] }),

      // ══════════════════════════════════════════════════════
      // Q5 – SHORT NOTES
      // ══════════════════════════════════════════════════════
      sectionHeader('Q.5', 'Short Notes (2 × 10 = 20 Marks)', '20'),

      heading2('Q.5a. RPGN: Classification by Immunofluorescence + Immediate Therapeutic Interventions'),

      heading3('Definition'),
      para('Rapidly Progressive Glomerulonephritis (RPGN) is a clinical syndrome characterised by rapid deterioration of renal function (loss of ≥ 50% GFR over days to weeks) with pathological finding of crescents in ≥ 50% of glomeruli on renal biopsy (crescentic glomerulonephritis). Without treatment, it progresses to ESRD within weeks to months.'),

      heading3('Classification Based on Immunofluorescence Pattern (IF)'),
      new Table({
        width: { size: 100, type: WidthType.PERCENTAGE },
        rows: [
          new TableRow({
            tableHeader: true,
            children: [
              new TableCell({ children: [para('Type', true)], shading: { type: ShadingType.CLEAR, fill: 'BDD7EE' } }),
              new TableCell({ children: [para('IF Pattern', true)], shading: { type: ShadingType.CLEAR, fill: 'BDD7EE' } }),
              new TableCell({ children: [para('Pathology / Antibody', true)], shading: { type: ShadingType.CLEAR, fill: 'BDD7EE' } }),
              new TableCell({ children: [para('Diseases', true)], shading: { type: ShadingType.CLEAR, fill: 'BDD7EE' } }),
              new TableCell({ children: [para('% of RPGN', true)], shading: { type: ShadingType.CLEAR, fill: 'BDD7EE' } }),
            ],
          }),
          new TableRow({ children: [
            new TableCell({ children: [para('Type I')] }),
            new TableCell({ children: [para('LINEAR IgG deposits along GBM')] }),
            new TableCell({ children: [para('Anti-GBM antibodies; anti-GBM targets α3 chain of type IV collagen')] }),
            new TableCell({ children: [para('Goodpasture syndrome (anti-GBM GN + pulmonary haemorrhage); isolated anti-GBM nephritis')] }),
            new TableCell({ children: [para('10–15%')] }),
          ] }),
          new TableRow({ children: [
            new TableCell({ children: [para('Type II')] }),
            new TableCell({ children: [para('GRANULAR (lumpy-bumpy) deposits – IgG, IgA, IgM, C3')] }),
            new TableCell({ children: [para('Immune complex deposition; complement activation')] }),
            new TableCell({ children: [para('Post-streptococcal GN, IgA nephropathy (IgA vasculitis), Lupus nephritis (Class IV), MPGN, endocarditis-related GN, cryoglobulinaemia')] }),
            new TableCell({ children: [para('40%')] }),
          ] }),
          new TableRow({ children: [
            new TableCell({ children: [para('Type III')] }),
            new TableCell({ children: [para('PAUCI-IMMUNE (negative/near-absent IF)')] }),
            new TableCell({ children: [para('ANCA-associated vasculitis; pauci-immune because ANCAs circulate in blood and mediate neutrophil-driven injury without significant Ig deposition')] }),
            new TableCell({ children: [para('GPA (Granulomatosis with Polyangiitis, formerly Wegener\'s) – c-ANCA/PR3\nMPA (Microscopic Polyangiitis) – p-ANCA/MPO\nEGPA (Eosinophilic GPA) – p-ANCA/MPO\nRenal-limited vasculitis – p-ANCA')] }),
            new TableCell({ children: [para('45–50%')] }),
          ] }),
        ],
      }),
      para(''),
      para('Type IV: Combined anti-GBM and ANCA positivity (double positive) – particularly aggressive, ~10% of anti-GBM cases.'),

      heading3('Pathological Features on Renal Biopsy'),
      bullet('Cellular crescents (early): proliferating parietal epithelial cells + macrophages filling Bowman space'),
      bullet('Fibrocellular crescents (intermediate)'),
      bullet('Fibrous crescents (late/irreversible): extensive fibrosis – renal recovery unlikely'),
      bullet('Glomerular necrosis (fibrinoid necrosis – especially in Type III)'),
      bullet('Associated findings: segmental sclerosis, mesangial proliferation (Type II)'),

      heading3('Clinical Features'),
      bullet('Oliguria/anuria with rapid rise in creatinine (doubling of creatinine in days–weeks)'),
      bullet('Nephritic syndrome: haematuria, RBC casts, hypertension, proteinuria (usually non-nephrotic)'),
      bullet('Type I: haemoptysis (Goodpasture syndrome); pulmonary haemorrhage can be life-threatening'),
      bullet('Type III ANCA: systemic vasculitis features – sinusitis, bloody nasal discharge, haemoptysis, mononeuritis multiplex, skin purpura, saddle-nose deformity (GPA)'),
      bullet('Constitutional: fever, weight loss, arthralgia (especially Type III)'),

      heading3('Diagnosis'),
      bullet('Urinalysis + microscopy: haematuria, dysmorphic RBCs, RBC casts (pathognomonic of GN), proteinuria'),
      bullet('Serum: creatinine (rapidly rising), CBC, C3/C4 (low in Type II immune complex GN), ANA/anti-dsDNA (SLE), ANCA (c-ANCA PR3 and p-ANCA MPO), anti-GBM antibody (ELISA), ASO titre, hepatitis B/C, cryoglobulins, blood cultures'),
      bullet('Imaging: CXR (pulmonary haemorrhage, effusion), renal USS (early – kidneys may be normal size or enlarged)'),
      bullet('Renal biopsy: MANDATORY for definitive diagnosis, typing, and assessment of reversibility (proportion of fibrous vs. cellular crescents)'),

      heading3('Immediate Therapeutic Interventions to Salvage Renal Function'),

      para('RPGN is a medical emergency. Treatment must be initiated IMMEDIATELY – delays worsen prognosis.'),

      para('1. Pulse Methylprednisolone (ALL types)', true),
      bullet('IV methylprednisolone 500–1000 mg/day for 3 consecutive days'),
      bullet('Followed by oral prednisolone 1 mg/kg/day (max 60 mg); taper over 6 months'),
      bullet('Rationale: reduce glomerular inflammation, inhibit crescent formation, anti-inflammatory'),

      para('2. Cyclophosphamide (primarily Type III – ANCA; also Type II)', true),
      bullet('IV cyclophosphamide 15 mg/kg (max 1.2 g) every 2 weeks for 3 doses, then every 3 weeks (CYCLOPS regimen); OR oral cyclophosphamide 2 mg/kg/day'),
      bullet('Duration: 3–6 months for induction, then switched to azathioprine or rituximab for maintenance'),
      bullet('Rituximab: anti-CD20 monoclonal antibody; non-inferior to cyclophosphamide for ANCA vasculitis (RAVE and RITUXVAS trials); preferred in young women (to preserve fertility) and relapsing disease'),

      para('3. Plasmapheresis / Therapeutic Plasma Exchange (TPE)', true),
      bullet('MANDATORY for Type I (anti-GBM / Goodpasture syndrome): removes circulating anti-GBM antibodies; daily sessions × 14 days (or until anti-GBM becomes negative)'),
      bullet('For ANCA vasculitis with pulmonary haemorrhage (MEPEX criteria) or severe AKI requiring dialysis: benefit in specific subgroups (PEXIVAS trial 2020 showed no benefit on composite renal/death outcome for all ANCA, but TPE remains standard for Goodpasture and severe pulmonary haemorrhage)'),
      bullet('Volume: 60 mL/kg per session; replacement with FFP (if coagulopathy/pulmonary haemorrhage) or albumin'),

      para('4. Additional Measures', true),
      bullet('AVOID nephrotoxins, NSAIDs, contrast media'),
      bullet('Dialysis: initiate if severe AKI (K+ > 6.5, fluid overload, uraemia, severe acidosis)'),
      bullet('PCP prophylaxis: co-trimoxazole (TMP-SMX) 960 mg three times per week (due to high-dose steroids + cyclophosphamide)'),
      bullet('Gastric protection: PPI during high-dose steroid therapy'),
      bullet('Antihypertensives: control BP; ACEi/ARB should be used cautiously in acute setting (may reduce GFR)'),
      bullet('Maintenance therapy: azathioprine 2 mg/kg/day or rituximab for 18–24 months in ANCA vasculitis to prevent relapse'),
      bullet('Monitor: creatinine, urinalysis (RBC casts), ANCA titres (Type III), anti-GBM levels (Type I), CBC (cyclophosphamide toxicity)'),

      heading3('Prognosis'),
      para('Best outcomes with early biopsy and treatment. Renal survival at 5 years: Type I (~50–70% if treated early), Type II (~50–70%), Type III (~70–80% with ANCA treatment). Poor prognostic factors: creatinine > 600 µmol/L at presentation, > 70% fibrous crescents, dialysis dependence at diagnosis.'),

      divider(),

      heading2('Q.5b. Physiological Bases and Clinical Evidence for Lung Protective Ventilation, Prone Positioning, and Neuromuscular Blockade in Severe ARDS'),

      heading3('Definition of ARDS'),
      para('ARDS is an acute inflammatory lung syndrome defined by the Berlin Definition (2012):'),
      bullet('Acute onset within 1 week of a clinical insult or new/worsening respiratory symptoms'),
      bullet('Bilateral opacities on CXR/CT not fully explained by effusions, collapse, or nodules'),
      bullet('Respiratory failure not fully explained by cardiac failure/fluid overload'),
      bullet('Oxygenation: PaO2/FiO2 ratio ≤ 200 mmHg with PEEP ≥ 5 cmH2O (severe ARDS = PF ratio ≤ 100)'),

      heading3('A. Lung Protective Ventilation (LPV)'),

      para('Physiological Basis:'),
      bullet('In ARDS, the lung is heterogeneous: ~1/3 of lung is recruitable but collapsed ("baby lung" concept – only 200–400 g of aerated lung)'),
      bullet('Conventional large tidal volumes (10–15 mL/kg) cause:'),
      bullet('   Volutrauma: overdistension of open alveoli', 1),
      bullet('   Barotrauma: high airway pressure → pneumothorax, pneumomediastinum', 1),
      bullet('   Atelectrauma: repeated opening-closing of unstable alveoli', 1),
      bullet('   Biotrauma: mechanical stretch → pro-inflammatory cytokine release (IL-1β, IL-6, TNF-α) → VILI (ventilator-induced lung injury) and MSOF', 1),
      bullet('LPV principle: ventilate with LOW tidal volumes to prevent overdistension; use PEEP to prevent atelectrauma'),

      para('Strategy:'),
      bullet('Tidal Volume (VT): 6 mL/kg predicted body weight (PBW)'),
      bullet('Plateau Pressure: ≤ 30 cmH2O (maintain by reducing VT further if needed)'),
      bullet('Driving Pressure: ≤ 15 cmH2O (DP = Pplat − PEEP; independent predictor of mortality)'),
      bullet('PEEP: titrated to FiO2 requirements; use ARDSNet PEEP-FiO2 table; higher PEEP strategies beneficial in moderate-severe ARDS (ALVEOLI, LOVS, ExPress trials – no individual mortality benefit but meta-analysis favours higher PEEP in P/F < 200)'),
      bullet('FiO2: titrate to maintain SpO2 88–95% (hyperoxia harmful)'),
      bullet('Rate: 12–35 breaths/min to maintain pH 7.30–7.45'),
      bullet('Permissive hypercapnia: allow PaCO2 to rise up to 60 mmHg (accept "safe" hypercapnia) to avoid injurious tidal volumes; avoid in elevated ICP'),

      para('Clinical Evidence:'),
      bullet('ARMA Trial (ARDS Network, NEJM 2000): landmark RCT; VT 6 vs. 12 mL/kg PBW; 28-day mortality 31% vs. 40% (p = 0.007); absolute risk reduction 9%; NNT = 11. This established 6 mL/kg PBW as standard of care.'),
      bullet('Driving pressure analysis (Amato et al., NEJM 2015): driving pressure ≤ 15 cmH2O most strongly associated with survival; VT and PEEP independently associated with outcome only via driving pressure'),
      bullet('ExPress Trial (Mercat et al., JAMA 2008): higher PEEP (titrated to Pplat 28–30 cmH2O) improved oxygenation and organ failure score; no mortality benefit'),

      heading3('B. Prone Positioning'),

      para('Physiological Basis:'),
      bullet('In supine ARDS, the posterior/dependent lung is most severely affected (oedema, atelectasis, compression by heart/abdominal organs)'),
      bullet('Prone positioning improves:'),
      bullet('   V/Q mismatch: dependent lung zones (now anterior) receive less perfusion but more ventilation', 1),
      bullet('   Lung recruitment: posterior (formerly dependent) lung opens → more homogeneous distribution of VT', 1),
      bullet('   Reduction in driving pressure: more uniform stress distribution', 1),
      bullet('   Secretion drainage: gravity assists posterior bronchi', 1),
      bullet('   Cardiac compression: reduced on left lower lobe', 1),
      bullet('   Diaphragm: less compressed by abdominal contents', 1),

      para('Protocol:'),
      bullet('Indication: Severe ARDS: PaO2/FiO2 ≤ 150 mmHg (or ≤ 100 mmHg per PROSEVA) with FiO2 ≥ 0.6, PEEP ≥ 5'),
      bullet('Timing: within 36–48 hours of ARDS onset; early use is key'),
      bullet('Duration: 16 or more hours per day (continuous sessions); PROSEVA used 16 h/day; longer sessions associated with greater benefit'),
      bullet('Continue until PF ratio > 150 on FiO2 ≤ 0.6, PEEP ≤ 10 for ≥ 4 hours in supine (criteria for discontinuation)'),

      para('Clinical Evidence:'),
      bullet('PROSEVA Trial (Guérin et al., NEJM 2013): the pivotal trial; 466 patients with severe ARDS (P/F ≤ 150); prone ≥ 16 h/day vs. supine; 28-day mortality 16% vs. 32.8% (absolute reduction 16.8%, NNT = 6); statistically significant. The most impactful ARDS trial since ARMA.'),
      bullet('Meta-analyses (including trials before PROSEVA): benefit mainly in patients with P/F ≤ 150 and when sessions ≥ 12 h; short proning sessions showed no benefit'),
      bullet('PROSEVA subgroup: 90-day mortality also significantly reduced (23.6% vs. 41%); no increase in complications (extubation, pressure sores – prevented by careful nursing)'),

      para('Complications to Manage:'),
      bullet('Pressure sores (face, chest, knees) – foam padding, frequent repositioning'),
      bullet('Endotracheal tube displacement/kinking'),
      bullet('Haemodynamic instability during turning (brief)'),
      bullet('Vascular catheter dislodgement'),
      bullet('Oedema of face, conjunctiva'),
      bullet('Contraindications: spinal instability, open chest/abdomen, raised ICP, recent tracheoesophageal surgery, unstable arrhythmia'),

      heading3('C. Neuromuscular Blockade (NMB) in Severe ARDS'),

      para('Physiological Basis:'),
      bullet('In severe ARDS, spontaneous breathing effort generates high transpulmonary pressures (patient self-inflicted lung injury – P-SILI)'),
      bullet('NMB eliminates spontaneous breathing → reduces P-SILI and patient-ventilator dyssynchrony'),
      bullet('Benefits:'),
      bullet('   Improved lung mechanics: complete elimination of auto-PEEP, prevention of breath-stacking', 1),
      bullet('   Improved oxygenation: more homogeneous distribution of ventilation', 1),
      bullet('   Anti-inflammatory effect: cisatracurium shown to reduce systemic inflammatory cytokines (IL-8, IL-6) in some studies', 1),
      bullet('   Facilitation of prone positioning and deep sedation protocols', 1),

      para('Regimen:'),
      bullet('Agent of choice: Cisatracurium (Nimbex) – preferred because of Hofmann elimination (organ-independent); does not accumulate in renal/hepatic failure; reduced risk of ICU-acquired weakness compared to pancuronium/vecuronium'),
      bullet('Dose: IV infusion 37.5 mg/hour (cisatracurium) for 48 hours'),
      bullet('Deep sedation required when NMB used (RASS -4 to -5); ensure adequate analgesia'),
      bullet('Monitor with train-of-four (TOF) – target 1–2 twitches'),

      para('Clinical Evidence:'),
      bullet('ACURASYS Trial (Papazian et al., NEJM 2010): 340 patients; cisatracurium 48 h vs. placebo; 90-day adjusted mortality 31.6% vs. 40.7% (P = 0.08 unadjusted but significant after adjustment); improved P/F ratio; reduced barotrauma; landmark trial that established NMB practice'),
      bullet('ROSE Trial (PETAL Network, NEJM 2019): 1006 patients; cisatracurium 48 h vs. light sedation; no difference in 90-day mortality (42.5% vs. 42.8%); challenged ACURASYS findings. Importantly, control arm received lighter sedation (not deep sedation as ACURASYS control), so the comparison may have been NMB vs. effective light sedation rather than NMB vs. placebo-equivalent'),
      bullet('Current practice (2024): NMB is NOT routinely recommended for all ARDS; reserved for:'),
      bullet('   Severe refractory hypoxaemia (P/F < 120 or ≤ 150 on high PEEP)', 1),
      bullet('   Refractory patient-ventilator dyssynchrony despite adequate sedation', 1),
      bullet('   Severe hypercapnia/acidosis unresponsive to ventilator adjustments', 1),
      bullet('   As an adjunct to facilitate prone positioning', 1),
      bullet('Meta-analyses (2021): NMB associated with improved oxygenation and may reduce mortality in the subgroup with P/F < 120; evidence stronger in early severe ARDS'),

      heading3('Summary Table: LPV + Prone + NMB in Severe ARDS'),
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