from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import cm, mm
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, PageBreak, KeepTogether
)
from reportlab.lib.enums import TA_LEFT, TA_CENTER, TA_JUSTIFY
from reportlab.platypus import BaseDocTemplate, Frame, PageTemplate
from reportlab.lib.colors import HexColor

OUTPUT = "/home/daytona/workspace/named-effects-guide/Named_Effects_in_Medicine.pdf"

# ── Colour palette ──────────────────────────────────────────────────────────
C_NAVY    = HexColor("#1a3a5c")   # deep navy – title / system headers
C_TEAL    = HexColor("#0d7c8c")   # teal – effect name labels
C_STEEL   = HexColor("#3d7ab5")   # mid-blue – sub-headings
C_LIGHT   = HexColor("#e8f4f8")   # pale blue – row shading
C_PALE    = HexColor("#f4f9fc")   # near-white – page bg tint effect
C_ACCENT  = HexColor("#e05e2a")   # warm orange – "Clinical pearl" accent
C_GRAY    = HexColor("#6b7c93")   # gray – body text complement
C_LGRAY   = HexColor("#dce7f0")   # light gray – table borders
C_WHITE   = colors.white
C_BLACK   = colors.black

PAGE_W, PAGE_H = A4

# ── Styles ───────────────────────────────────────────────────────────────────
base = getSampleStyleSheet()

def S(name, **kw):
    """Create a ParagraphStyle from base Normal + overrides."""
    s = ParagraphStyle(name, parent=base["Normal"], **kw)
    return s

sTitle = S("sTitle",
    fontSize=28, fontName="Helvetica-Bold", textColor=C_WHITE,
    alignment=TA_CENTER, leading=34, spaceAfter=4)

sSubtitle = S("sSubtitle",
    fontSize=13, fontName="Helvetica", textColor=HexColor("#cce0f0"),
    alignment=TA_CENTER, leading=18, spaceAfter=2)

sTocHead = S("sTocHead",
    fontSize=14, fontName="Helvetica-Bold", textColor=C_NAVY,
    spaceAfter=6, spaceBefore=4)

sTocItem = S("sTocItem",
    fontSize=11, fontName="Helvetica", textColor=C_NAVY,
    leftIndent=14, spaceAfter=3)

sSysHeader = S("sSysHeader",
    fontSize=16, fontName="Helvetica-Bold", textColor=C_WHITE,
    alignment=TA_LEFT, leading=20, spaceBefore=6, spaceAfter=2)

sEffectName = S("sEffectName",
    fontSize=12, fontName="Helvetica-Bold", textColor=C_TEAL,
    spaceBefore=8, spaceAfter=2, leading=15)

sAltName = S("sAltName",
    fontSize=10, fontName="Helvetica-Oblique", textColor=C_GRAY,
    spaceBefore=0, spaceAfter=2, leading=13)

sBody = S("sBody",
    fontSize=10, fontName="Helvetica", textColor=HexColor("#1e2a38"),
    leading=14, spaceAfter=4, alignment=TA_JUSTIFY)

sPearl = S("sPearl",
    fontSize=9.5, fontName="Helvetica-Oblique", textColor=C_ACCENT,
    leading=13, leftIndent=12, spaceAfter=6)

sFooter = S("sFooter",
    fontSize=8, fontName="Helvetica", textColor=C_GRAY,
    alignment=TA_CENTER)

# ── Data ─────────────────────────────────────────────────────────────────────
SYSTEMS = [
    {
        "name": "Respiratory",
        "color": HexColor("#1a6b7a"),
        "effects": [
            {
                "name": "Macklin Effect",
                "alt": "Also called: Macklin pathway",
                "desc": (
                    "Air dissects from ruptured alveoli along bronchovascular sheaths "
                    "toward the mediastinum, causing pneumomediastinum. Occurs in blunt "
                    "chest trauma, severe asthma, mechanical ventilation barotrauma, and "
                    "COVID-19 pneumonia. The air follows the path of least resistance "
                    "centrally rather than escaping to the pleural space."
                ),
                "pearl": "Clinical pearl: Look for streaky perihilar air on CT following blunt chest trauma — classic Macklin appearance.",
            },
            {
                "name": "Bohr Effect",
                "alt": "Described by Christian Bohr, 1904",
                "desc": (
                    "Increased CO₂ and H⁺ (lower pH) shift the oxyhemoglobin dissociation "
                    "curve to the RIGHT, reducing hemoglobin's affinity for O₂. This "
                    "facilitates O₂ unloading at metabolically active, acidic tissues "
                    "(e.g., exercising muscle). The reverse occurs in the lungs (lower "
                    "PCO₂, higher pH → left shift → O₂ loading)."
                ),
                "pearl": "Clinical pearl: The Bohr effect is why fever and acidosis promote O₂ tissue delivery. Conversely, stored bank blood (low 2,3-BPG, low CO₂) has a left-shifted curve — poor O₂ unloading.",
            },
            {
                "name": "Haldane Effect",
                "alt": "Described by John Scott Haldane",
                "desc": (
                    "Deoxygenated hemoglobin carries significantly more CO₂ than "
                    "oxygenated hemoglobin at the same PCO₂. Deoxy-Hb more readily "
                    "accepts protons (H⁺), driving the carbonate buffer toward "
                    "HCO₃⁻ formation and carbamino-Hb binding. In the lungs, "
                    "O₂ binding displaces CO₂, facilitating CO₂ excretion."
                ),
                "pearl": "Clinical pearl: The Haldane effect explains why giving high-flow O₂ to COPD patients (raising O₂-Hb saturation) can paradoxically increase PaCO₂ — O₂-Hb releases CO₂ from Hb, raising dissolved CO₂.",
            },
            {
                "name": "Euler-Liljestrand Mechanism",
                "alt": "Also: Hypoxic Pulmonary Vasoconstriction (HPV)",
                "desc": (
                    "Alveolar hypoxia causes local pulmonary arteriolar vasoconstriction, "
                    "diverting blood away from poorly ventilated lung segments to better-"
                    "ventilated ones. This optimizes V/Q matching. The mechanism involves "
                    "inhibition of K⁺ channels in pulmonary vascular smooth muscle → "
                    "membrane depolarization → Ca²⁺ influx → vasoconstriction."
                ),
                "pearl": "Clinical pearl: Inhibited by volatile anaesthetics, Ca²⁺ channel blockers, and vasodilators. Chronically activated in COPD/high altitude → pulmonary hypertension.",
            },
            {
                "name": "Pendelluft",
                "alt": "German: 'swinging air'",
                "desc": (
                    "Gas oscillates between lung units with different time constants "
                    "during spontaneous breathing in ARDS. Regional over-distension "
                    "occurs even with low tidal volumes. A key mechanism of patient "
                    "self-inflicted lung injury (P-SILI) — particularly dangerous with "
                    "strong inspiratory efforts against non-uniform lung compliance."
                ),
                "pearl": "Clinical pearl: Neuromuscular blockade in severe ARDS partly works by eliminating pendelluft.",
            },
            {
                "name": "Oxygen Toxicity (Paul Bert Effect)",
                "alt": "Paul Bert, 1878 — CNS O₂ toxicity",
                "desc": (
                    "Breathing high-pressure O₂ (hyperbaric, >1.6 ATA) causes CNS "
                    "toxicity — visual disturbances, tinnitus, nausea, and tonic-clonic "
                    "seizures. Due to excess ROS overwhelming antioxidant defenses in "
                    "neuronal tissue. Distinct from Lorrain Smith effect (pulmonary O₂ "
                    "toxicity from prolonged normobaric high FiO₂ > 0.6)."
                ),
                "pearl": "Clinical pearl: Lorrain Smith effect in ICU — avoid FiO₂ >0.6 for >24–48 hours; causes alveolar inflammation and diffuse alveolar damage.",
            },
            {
                "name": "Bernoulli / Venturi Effect",
                "alt": "Basis of Venturi masks and nebulisers",
                "desc": (
                    "In a flowing fluid, increased velocity through a constriction "
                    "produces decreased lateral (side-wall) pressure (Bernoulli principle). "
                    "Applied in Venturi masks: high-velocity O₂ jet entrains room air "
                    "through side ports in a fixed ratio, delivering a precise FiO₂ "
                    "regardless of patient's breathing pattern."
                ),
                "pearl": "Clinical pearl: Dynamic airway collapse in COPD during forced expiration is also explained by Bernoulli — intraluminal pressure drops at high flow, and atmospheric pressure crushes the airway.",
            },
        ],
    },
    {
        "name": "Cardiovascular",
        "color": HexColor("#8b1a2e"),
        "effects": [
            {
                "name": "Frank-Starling Law",
                "alt": "Otto Frank (1895) & Ernest Starling (1914)",
                "desc": (
                    "Within physiological limits, stroke volume increases proportionally "
                    "with end-diastolic volume (preload). Greater sarcomere stretch → "
                    "greater overlap of actin-myosin cross-bridges → stronger contraction. "
                    "This intrinsic autoregulation allows the heart to match output to "
                    "venous return beat-to-beat without neural input."
                ),
                "pearl": "Clinical pearl: In heart failure, the Starling curve is depressed and flattened — increasing preload produces little increase in stroke volume but causes pulmonary congestion.",
            },
            {
                "name": "Bowditch Effect (Treppe / Staircase)",
                "alt": "Henry Pickering Bowditch, 1871",
                "desc": (
                    "Increasing heart rate leads to a stepwise increase in myocardial "
                    "contractility (positive force-frequency relationship). More frequent "
                    "action potentials → less time for Na⁺/Ca²⁺ exchanger to extrude Ca²⁺ "
                    "→ greater intracellular Ca²⁺ accumulation → greater force per beat. "
                    "Important during exercise-induced tachycardia."
                ),
                "pearl": "Clinical pearl: Exploited pharmacologically — cardiac glycosides (digoxin) raise intracellular Ca²⁺ by blocking Na/K-ATPase, mimicking this effect to increase contractility.",
            },
            {
                "name": "Anrep Effect",
                "alt": "Von Anrep, 1912",
                "desc": (
                    "When aortic pressure (afterload) is abruptly increased, stroke volume "
                    "initially falls but then slowly recovers over 1–2 minutes back toward "
                    "baseline. Attributed to stretch-induced autocrine/paracrine release of "
                    "angiotensin II and endothelin from cardiac myocytes, increasing "
                    "contractility. A form of slow-response autoregulation."
                ),
                "pearl": "Clinical pearl: Contrasted with the immediate Frank-Starling response to preload. The Anrep effect is an intrinsic response to afterload changes — relevant in sudden hypertensive crises.",
            },
            {
                "name": "Cushing Reflex (Cushing Response)",
                "alt": "Harvey Cushing, 1901 — also: CNS ischemic response",
                "desc": (
                    "Acute rise in intracranial pressure (ICP) → brainstem ischemia → "
                    "massive sympathetic discharge → systemic hypertension. The hypertension "
                    "reflexly causes bradycardia (baroreceptor-mediated) and the brainstem "
                    "compression causes irregular (Cheyne-Stokes) respiration. "
                    "Cushing's triad: hypertension + bradycardia + irregular breathing = "
                    "sign of imminent herniation."
                ),
                "pearl": "Clinical pearl: A late and ominous sign — when you see the Cushing triad, the patient is minutes from herniation. Requires immediate neurosurgical intervention.",
            },
            {
                "name": "Bainbridge Reflex",
                "alt": "Francis Bainbridge, 1915",
                "desc": (
                    "Increased right atrial pressure (from volume loading or increased "
                    "venous return) stretches atrial mechanoreceptors, triggering a reflex "
                    "tachycardia via vagal afferents to medullary cardiovascular centers. "
                    "This helps increase cardiac output to clear venous overload. Opposes "
                    "the baroreflex-mediated bradycardia at high pressures."
                ),
                "pearl": "Clinical pearl: The net heart rate response to volume loading depends on the balance between the Bainbridge reflex (tachycardia) and baroreceptor reflex (bradycardia).",
            },
            {
                "name": "Bezold-Jarisch Reflex",
                "alt": "Albert von Bezold & Adolf Jarisch",
                "desc": (
                    "Stimulation of cardiac C-fiber afferents (vagal) in the inferoposterior "
                    "left ventricle by chemical irritants or ischemia causes the triad of: "
                    "bradycardia, hypotension, and apnea. Seen in inferior STEMI (RCA "
                    "occlusion), spinal anaesthesia, and vasovagal syncope. The reflex "
                    "arises from receptor activation in ischemic myocardium."
                ),
                "pearl": "Clinical pearl: Inferior STEMI patients often have paradoxical bradycardia and hypotension — Bezold-Jarisch reflex. Treat with atropine (not more fluids alone).",
            },
            {
                "name": "Windkessel Effect",
                "alt": "German: 'air chamber'; concept by Stephen Hales, formalized by Otto Frank",
                "desc": (
                    "The aorta and large elastic arteries behave like a pressure reservoir: "
                    "they expand (storing energy) during systole and recoil during diastole, "
                    "maintaining continuous flow to the periphery. This converts the pulsatile "
                    "cardiac output into a more continuous flow, sustaining diastolic pressure."
                ),
                "pearl": "Clinical pearl: Arteriosclerosis (stiff aorta) loses the Windkessel effect → widened pulse pressure, systolic hypertension, low diastolic pressure — common in the elderly.",
            },
            {
                "name": "Fick Principle",
                "alt": "Adolf Fick, 1870",
                "desc": (
                    "Cardiac output = O₂ consumption ÷ arteriovenous O₂ difference. "
                    "The amount of substance taken up by an organ per unit time equals "
                    "the blood flow × the arteriovenous concentration difference. "
                    "Gold standard for measuring cardiac output via right heart catheterisation."
                ),
                "pearl": "Clinical pearl: Thermodilution (PA catheter) and echo methods are used clinically; the Fick method remains the reference standard for research and complex cases.",
            },
        ],
    },
    {
        "name": "Renal & Fluid",
        "color": HexColor("#1a5c3a"),
        "effects": [
            {
                "name": "Starling Forces",
                "alt": "Ernest Starling, 1896",
                "desc": (
                    "Four forces determine transcapillary fluid movement: (1) capillary "
                    "hydrostatic pressure (Pc) — pushes fluid OUT; (2) interstitial "
                    "hydrostatic pressure (Pi) — pushes fluid IN; (3) capillary oncotic "
                    "pressure (πc) — pulls fluid IN; (4) interstitial oncotic pressure "
                    "(πi) — pulls fluid OUT. Net filtration = Kf × [(Pc − Pi) − σ(πc − πi)]."
                ),
                "pearl": "Clinical pearl: Hypoalbuminaemia (low πc) → oedema. Increased capillary hydrostatic pressure (heart failure, portal hypertension) → oedema / ascites.",
            },
            {
                "name": "Tubuloglomerular Feedback (Macula Densa Effect)",
                "alt": "TGF — renal autoregulation",
                "desc": (
                    "Increased NaCl delivery to the macula densa cells of the distal tubule "
                    "→ release of adenosine → afferent arteriolar constriction → reduced "
                    "GFR. This negative feedback loop maintains constant single-nephron GFR "
                    "despite changes in perfusion pressure. NaCl entry via NKCC2 in macula "
                    "densa cells is the sensor — blocked by loop diuretics."
                ),
                "pearl": "Clinical pearl: NSAIDs impair renal autoregulation (block prostaglandin-mediated afferent dilation), causing acute kidney injury especially with co-existing dehydration or RAAS activation.",
            },
            {
                "name": "Gibbs-Donnan Effect",
                "alt": "Josiah Gibbs & Frederick Donnan",
                "desc": (
                    "When a charged, non-diffusible molecule (e.g., plasma proteins) is "
                    "confined to one side of a semipermeable membrane, diffusible ions "
                    "distribute unequally to maintain electrical neutrality, generating a "
                    "Donnan equilibrium potential. Plasma proteins (negative) cause [Cl⁻] "
                    "to be lower and [Na⁺] to be higher in plasma vs. interstitium."
                ),
                "pearl": "Clinical pearl: Explains why plasma [Cl⁻] is slightly lower than interstitial fluid — relevant in anion gap calculations and ICU electrolyte interpretation.",
            },
            {
                "name": "Countercurrent Multiplication (Henle's Loop Effect)",
                "alt": "Mechanism of urinary concentration",
                "desc": (
                    "The hairpin structure of the loop of Henle allows the descending limb "
                    "(water-permeable) and ascending limb (water-impermeable, ion-transporting) "
                    "to amplify a small transverse osmotic gradient into a large axial gradient "
                    "in the medullary interstitium (up to 1200 mOsm/kg). ADH then allows the "
                    "collecting duct to equilibrate with this hyperosmotic environment."
                ),
                "pearl": "Clinical pearl: Loop diuretics (block NKCC2 in TAL) wash out the medullary gradient → inability to concentrate urine — therapeutic and also the mechanism of polyuria with furosemide.",
            },
        ],
    },
    {
        "name": "Haematology",
        "color": HexColor("#6b1a1a"),
        "effects": [
            {
                "name": "2,3-BPG (Bisphosphoglycerate) Effect",
                "alt": "Also: Rapoport-Luebering shunt product",
                "desc": (
                    "2,3-BPG is produced in red blood cells via the Rapoport-Luebering "
                    "shunt. It binds to the central cavity of deoxy-Hb (T state), stabilising "
                    "it and reducing O₂ affinity — right-shifting the ODC. Levels increase "
                    "in chronic hypoxia, high altitude, anaemia, and chronic lung disease, "
                    "enhancing O₂ delivery to tissues."
                ),
                "pearl": "Clinical pearl: Stored bank blood loses 2,3-BPG over days (left shift, poor O₂ unloading). Massive transfusion of old blood may temporarily impair tissue O₂ delivery despite normal SpO₂.",
            },
            {
                "name": "Prozone Effect (Hook Effect)",
                "alt": "Antigen excess phenomenon",
                "desc": (
                    "At very high antigen concentrations, an immunoassay gives a falsely "
                    "low or negative result because antigen excess saturates all antibody "
                    "binding sites individually, preventing the cross-linking needed for "
                    "precipitation or agglutination. A dilution of the sample restores "
                    "a positive result."
                ),
                "pearl": "Clinical pearl: Classic example — RPR/VDRL may be falsely negative in secondary syphilis (very high antigen load). Always dilute the sample if syphilis is strongly suspected despite a negative RPR.",
            },
            {
                "name": "Rouleaux Formation",
                "alt": "French: 'roll of coins'",
                "desc": (
                    "Red blood cells stack like coins due to elevated plasma proteins "
                    "(fibrinogen, immunoglobulins) that bridge between adjacent RBCs, "
                    "reducing the normal negative surface charge (zeta potential) that "
                    "keeps RBCs apart. Elevates ESR. Seen in multiple myeloma, infection, "
                    "pregnancy, and chronic inflammatory states."
                ),
                "pearl": "Clinical pearl: Rouleaux on a peripheral blood film in a patient with bone pain, hypercalcaemia, and anaemia — think multiple myeloma.",
            },
        ],
    },
    {
        "name": "Neurology",
        "color": HexColor("#4a1a6b"),
        "effects": [
            {
                "name": "Spreading Cortical Depression (Leão Effect)",
                "alt": "Aristides Leão, 1944",
                "desc": (
                    "A self-propagating wave of neuronal and glial depolarisation that "
                    "travels across the cortex at ~3–5 mm/min, followed by prolonged "
                    "neuronal suppression. Involves massive redistribution of ions (K⁺ "
                    "efflux, Na⁺/Ca²⁺ influx). The established neurobiological basis of "
                    "the migraine aura — the aura 'march' corresponds to the wave front."
                ),
                "pearl": "Clinical pearl: Triptans work partly by preventing spreading depression initiation and by causing trigeminovascular vasoconstriction — do not give in hemiplegic migraine (risk of true infarction).",
            },
            {
                "name": "Kindling Effect",
                "alt": "Graham Goddard, 1967",
                "desc": (
                    "Repeated sub-threshold electrical or chemical stimulation of limbic "
                    "brain structures progressively lowers the seizure threshold, eventually "
                    "producing spontaneous seizures. Permanent synaptic reorganisation occurs "
                    "(long-term potentiation-like mechanisms). Also proposed as a model for "
                    "recurrent mood episodes in bipolar disorder becoming progressively "
                    "easier to trigger over time."
                ),
                "pearl": "Clinical pearl: Clinical implication — early aggressive treatment of seizures may prevent kindling-induced epileptogenesis. Carbamazepine (anti-kindling properties) preferred in some epilepsy types.",
            },
            {
                "name": "Mass Effect (Cerebral)",
                "alt": "Radiological / clinical term",
                "desc": (
                    "An intracranial space-occupying lesion (tumour, haematoma, abscess, "
                    "infarct with oedema) displaces and compresses adjacent brain structures. "
                    "Causes midline shift, effacement of sulci, ventricular compression, "
                    "and ultimately transtentorial or tonsillar herniation syndromes."
                ),
                "pearl": "Clinical pearl: >5 mm midline shift on CT is a surgical emergency. Early signs: ipsilateral CN III palsy (blown pupil) from uncal herniation against the tentorial edge.",
            },
            {
                "name": "Doppler Effect",
                "alt": "Christian Doppler, 1842",
                "desc": (
                    "The apparent frequency of a wave changes when source and observer "
                    "are in relative motion. Applied in transcranial Doppler (TCD) to "
                    "measure cerebral blood flow velocity. Also widely used in "
                    "echocardiography and vascular ultrasound to assess blood flow "
                    "direction and velocity."
                ),
                "pearl": "Clinical pearl: TCD-detected microemboli in the middle cerebral artery predict stroke risk in carotid stenosis and patent foramen ovale.",
            },
        ],
    },
    {
        "name": "Pharmacology & Toxicology",
        "color": HexColor("#5c4a1a"),
        "effects": [
            {
                "name": "First-Pass Effect",
                "alt": "Pre-systemic hepatic metabolism",
                "desc": (
                    "Orally administered drugs are absorbed via gut into the portal vein "
                    "and pass through the liver before reaching systemic circulation. "
                    "Hepatic enzymes (CYP450) may substantially metabolise the drug, "
                    "dramatically reducing bioavailability. Drugs with high first-pass "
                    "effect require much higher oral vs. IV doses (e.g., morphine 30:10, "
                    "glyceryl trinitrate essentially 100% first-pass)."
                ),
                "pearl": "Clinical pearl: GTN given sublingually or transdermally bypasses first-pass. Propranolol, verapamil, and lignocaine all have significant first-pass — IV doses are much smaller than oral.",
            },
            {
                "name": "Tachyphylaxis",
                "alt": "Greek: 'rapid protection'",
                "desc": (
                    "Rapid diminution of a drug's effect with closely repeated doses — "
                    "distinct from tolerance (slower, develops over days-weeks). "
                    "Mechanisms: receptor downregulation/desensitisation, depletion of "
                    "neurotransmitter stores, or ion channel inactivation. Classic "
                    "examples: ephedrine (indirect sympathomimetic — depletes NE stores), "
                    "desensitisation of β₂ receptors with frequent SABA use."
                ),
                "pearl": "Clinical pearl: Patients who overuse salbutamol inhalers develop tachyphylaxis — paradoxical worsening of asthma control. Requires stepping up to ICS rather than increasing SABA frequency.",
            },
            {
                "name": "Warburg Effect",
                "alt": "Otto Warburg, 1924",
                "desc": (
                    "Cancer cells preferentially use aerobic glycolysis (fermenting glucose "
                    "to lactate even in the presence of oxygen) rather than oxidative "
                    "phosphorylation. This provides biosynthetic precursors for rapid "
                    "proliferation. The resulting massively upregulated glucose uptake "
                    "is the basis of ¹⁸F-FDG PET scanning — tumours 'light up' due to "
                    "high glucose transporter expression."
                ),
                "pearl": "Clinical pearl: FDG-PET is most useful for staging high-grade tumours (high Warburg activity). Low-grade or mucinous tumours may be FDG-cold — false negatives.",
            },
            {
                "name": "Crabtree Effect",
                "alt": "Herbert Grace Crabtree, 1929",
                "desc": (
                    "In the presence of high glucose concentrations, cells (especially "
                    "yeast and cancer cells) suppress mitochondrial respiration and shift "
                    "to fermentation/glycolysis — the reverse of the Pasteur effect. "
                    "Contributes to the Warburg phenomenon in cancer metabolism."
                ),
                "pearl": "Clinical pearl: Relevant in understanding cancer cell metabolism and the rationale for ketogenic diet trials in oncology (reducing glucose availability to exploit Warburg dependency).",
            },
        ],
    },
    {
        "name": "Endocrine & Metabolic",
        "color": HexColor("#1a4a5c"),
        "effects": [
            {
                "name": "Somogyi Effect",
                "alt": "Michael Somogyi, 1938 — 'rebound hyperglycaemia'",
                "desc": (
                    "Excessive insulin (typically nocturnal) → hypoglycaemia → counter-"
                    "regulatory hormone release (glucagon, cortisol, adrenaline, GH) → "
                    "rebound morning hyperglycaemia. The response overshoots, making "
                    "it appear as though insulin is insufficient when actually too much "
                    "was given. Management: reduce evening/bedtime insulin dose."
                ),
                "pearl": "Clinical pearl: Distinguished from Dawn phenomenon by CGM — Somogyi shows a mid-night glucose nadir before morning rise; Dawn phenomenon shows a smooth early-morning rise without prior hypoglycaemia.",
            },
            {
                "name": "Dawn Phenomenon",
                "alt": "Physiological early-morning hyperglycaemia",
                "desc": (
                    "Physiological surge of growth hormone and cortisol between 4–8 AM "
                    "increases hepatic glucose output and reduces peripheral insulin "
                    "sensitivity, causing morning hyperglycaemia. Occurs in both Type 1 "
                    "and Type 2 diabetes. Not preceded by nocturnal hypoglycaemia "
                    "(distinguishes from Somogyi). Managed by adjusting basal insulin "
                    "timing or using insulin pump with pre-dawn basal increase."
                ),
                "pearl": "Clinical pearl: The most common cause of unexplained fasting hyperglycaemia in well-controlled diabetics — check 3 AM glucose to differentiate from Somogyi.",
            },
            {
                "name": "Staub-Traugott Effect",
                "alt": "H. Staub & K. Traugott, 1922",
                "desc": (
                    "Successive oral glucose loads produce progressively smaller and shorter "
                    "rises in blood glucose. The first glucose load primes insulin-secreting "
                    "β cells, enhancing the secretory response to subsequent loads. Reflects "
                    "the dynamic glucose-stimulated insulin secretion capacity of the "
                    "endocrine pancreas."
                ),
                "pearl": "Clinical pearl: This is the physiological principle behind the 2-hour glucose tolerance test — the 'challenge' nature of sequential loading unmasks impaired insulin secretion in pre-diabetes.",
            },
        ],
    },
    {
        "name": "Gastroenterology & Surgery",
        "color": HexColor("#3a5c1a"),
        "effects": [
            {
                "name": "Courvoisier's Law",
                "alt": "Ludwig Courvoisier, 1890",
                "desc": (
                    "A palpable, non-tender, distended gallbladder in a jaundiced patient "
                    "is unlikely to be due to gallstones — it suggests malignant biliary "
                    "obstruction (most commonly pancreatic head cancer). Chronic cholelithiasis "
                    "causes scarring and fibrosis of the gallbladder wall, preventing it from "
                    "distending. Therefore, a palpable gallbladder implies a newly obstructed, "
                    "previously normal gallbladder."
                ),
                "pearl": "Clinical pearl: 'Law' is a misnomer — exceptions exist. Gallbladder may be palpable in Mirizzi syndrome (stone in Hartmann's pouch). Always investigate with US/CT/MRCP.",
            },
            {
                "name": "Pringle Manoeuvre",
                "alt": "James Hogarth Pringle, 1908",
                "desc": (
                    "Manual compression or clamping of the hepatoduodenal ligament (portal "
                    "triad — portal vein, hepatic artery, bile duct) to temporarily arrest "
                    "hepatic inflow during liver surgery, reducing haemorrhage. The 'Pringle "
                    "effect' refers to the ischaemia-reperfusion injury that follows clamp "
                    "release — managed with antioxidants and controlled reperfusion."
                ),
                "pearl": "Clinical pearl: Safe warm ischaemia time for the liver is approximately 15–20 minutes. Cirrhotic livers tolerate less — increased sensitivity to ischaemia-reperfusion injury.",
            },
        ],
    },
    {
        "name": "Immunology & Oncology",
        "color": HexColor("#5c1a3a"),
        "effects": [
            {
                "name": "Abscopal Effect",
                "alt": "Latin: 'ab scopus' — away from target; R.H. Mole, 1953",
                "desc": (
                    "Local radiotherapy to a tumour causes regression of distant, "
                    "non-irradiated metastases, mediated by systemic immune activation. "
                    "Radiation induces immunogenic tumour cell death → releases tumour "
                    "antigens → dendritic cell activation → systemic cytotoxic T-cell "
                    "response targeting metastases. Rare spontaneously but dramatically "
                    "enhanced by combination with immune checkpoint inhibitors."
                ),
                "pearl": "Clinical pearl: The abscopal effect is the scientific rationale for combining radiotherapy with anti-PD1/anti-CTLA4 immunotherapy — now an active clinical trial area.",
            },
            {
                "name": "Radiation Bystander Effect",
                "alt": "Non-targeted radiation effect",
                "desc": (
                    "Cells not directly irradiated but adjacent to irradiated cells "
                    "exhibit DNA damage, chromosomal instability, and increased cell "
                    "death. Mediated by gap junction communication, ROS diffusion, "
                    "and secreted cytokines from irradiated cells. Relevant for "
                    "understanding low-dose radiation risk and targeted radiotherapy "
                    "side effects."
                ),
                "pearl": "Clinical pearl: The bystander effect means radiation damage is not purely cell-autonomous — neighbouring normal tissue may be injured by signals from irradiated tumour cells.",
            },
            {
                "name": "Epitope Spreading",
                "alt": "Determinant spreading — autoimmunity amplification",
                "desc": (
                    "In autoimmune disease, the immune response initially directed at one "
                    "specific antigen (epitope) progressively diversifies to target additional "
                    "epitopes on the same protein (intramolecular) or different proteins "
                    "(intermolecular). Driven by bystander cell damage releasing new antigens. "
                    "Explains why autoimmune diseases progressively worsen and diversify over time."
                ),
                "pearl": "Clinical pearl: Seen in lupus (initially anti-dsDNA → spreads to anti-Sm, anti-Ro), MS, and Type 1 diabetes — explains why disease broadens despite initial partial response to therapy.",
            },
        ],
    },
]

# ── Helpers ──────────────────────────────────────────────────────────────────

def make_system_header(name, color):
    """Coloured banner with system name."""
    data = [[Paragraph(f"● {name}", sSysHeader)]]
    t = Table(data, colWidths=[PAGE_W - 4*cm])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0, 0), (-1, -1), color),
        ("TOPPADDING",    (0, 0), (-1, -1), 7),
        ("BOTTOMPADDING", (0, 0), (-1, -1), 7),
        ("LEFTPADDING",   (0, 0), (-1, -1), 12),
        ("RIGHTPADDING",  (0, 0), (-1, -1), 12),
        ("ROUNDEDCORNERS", [4]),
    ]))
    return t


def make_effect_block(effect):
    """Compound flowable block for one effect."""
    items = []
    items.append(Paragraph(effect["name"], sEffectName))
    if effect.get("alt"):
        items.append(Paragraph(effect["alt"], sAltName))
    items.append(Paragraph(effect["desc"], sBody))
    if effect.get("pearl"):
        items.append(Paragraph(f"🔑 {effect['pearl']}", sPearl))
    items.append(HRFlowable(width="100%", thickness=0.5,
                             color=C_LGRAY, spaceAfter=4))
    return KeepTogether(items)


def header_footer(canvas, doc):
    canvas.saveState()
    w, h = PAGE_W, PAGE_H
    # header bar
    canvas.setFillColor(C_NAVY)
    canvas.rect(0, h - 1.1*cm, w, 1.1*cm, fill=1, stroke=0)
    canvas.setFillColor(C_WHITE)
    canvas.setFont("Helvetica-Bold", 9)
    canvas.drawString(1.5*cm, h - 0.72*cm, "Named Effects in Medicine — Study Guide")
    canvas.setFont("Helvetica", 9)
    canvas.drawRightString(w - 1.5*cm, h - 0.72*cm, "Orris Medical Reference")
    # footer
    canvas.setFillColor(C_NAVY)
    canvas.rect(0, 0, w, 0.9*cm, fill=1, stroke=0)
    canvas.setFillColor(C_WHITE)
    canvas.setFont("Helvetica", 8)
    canvas.drawCentredString(w/2, 0.32*cm, f"Page {doc.page}")
    canvas.restoreState()


# ── Cover page builder ───────────────────────────────────────────────────────

def build_cover():
    items = []
    # big colour block
    cover_data = [[Paragraph("Named Effects<br/>in Medicine", sTitle)]]
    cover_tbl = Table(cover_data, colWidths=[PAGE_W - 4*cm], rowHeights=[6*cm])
    cover_tbl.setStyle(TableStyle([
        ("BACKGROUND", (0, 0), (-1, -1), C_NAVY),
        ("VALIGN",     (0, 0), (-1, -1), "MIDDLE"),
        ("TOPPADDING", (0, 0), (-1, -1), 20),
        ("BOTTOMPADDING", (0, 0), (-1, -1), 20),
        ("LEFTPADDING",   (0, 0), (-1, -1), 20),
    ]))
    items.append(cover_tbl)
    items.append(Spacer(1, 0.6*cm))
    items.append(Paragraph(
        "A Comprehensive Study Guide for Medical Students & Clinicians",
        sSubtitle))
    items.append(Spacer(1, 0.3*cm))
    items.append(Paragraph(
        "Organised by Body System · Mechanisms · Clinical Pearls",
        S("cov2", fontSize=11, textColor=C_STEEL, alignment=TA_CENTER)))
    items.append(Spacer(1, 1*cm))
    # system list as a 2-col table
    sys_names = [s["name"] for s in SYSTEMS]
    half = (len(sys_names) + 1) // 2
    rows = list(zip(sys_names[:half], sys_names[half:] + [""]))
    dot_style = S("dot", fontSize=10.5, fontName="Helvetica",
                  textColor=C_NAVY, leading=16)
    tdata = [[Paragraph(f"▸  {a}", dot_style), Paragraph(f"▸  {b}" if b else "", dot_style)]
             for a, b in rows]
    sys_tbl = Table(tdata, colWidths=[(PAGE_W - 4*cm)/2]*2)
    sys_tbl.setStyle(TableStyle([
        ("BACKGROUND", (0, 0), (-1, -1), C_LIGHT),
        ("TOPPADDING",    (0, 0), (-1, -1), 5),
        ("BOTTOMPADDING", (0, 0), (-1, -1), 5),
        ("LEFTPADDING",   (0, 0), (-1, -1), 14),
        ("LINEBELOW", (0, 0), (-1, -2), 0.3, C_LGRAY),
    ]))
    items.append(sys_tbl)
    items.append(Spacer(1, 1*cm))
    # stats
    total = sum(len(s["effects"]) for s in SYSTEMS)
    items.append(Paragraph(
        f"{total} named effects across {len(SYSTEMS)} body systems",
        S("stat", fontSize=12, textColor=C_TEAL, alignment=TA_CENTER,
          fontName="Helvetica-Bold")))
    items.append(PageBreak())
    return items


# ── TOC ──────────────────────────────────────────────────────────────────────

def build_toc():
    items = []
    items.append(Paragraph("Contents", sTocHead))
    items.append(HRFlowable(width="100%", thickness=1, color=C_TEAL, spaceAfter=8))
    for s in SYSTEMS:
        count = len(s["effects"])
        items.append(Paragraph(
            f"<b>{s['name']}</b>  <font color='#6b7c93'>({count} effects)</font>",
            sTocItem))
        for e in s["effects"]:
            items.append(Paragraph(
                f"<font color='#0d7c8c'>  ·  {e['name']}</font>",
                S("toci2", fontSize=9.5, leftIndent=28, spaceAfter=2,
                  textColor=C_TEAL, fontName="Helvetica")))
    items.append(PageBreak())
    return items


# ── Quick-reference table ────────────────────────────────────────────────────

def build_quick_ref():
    items = []
    items.append(Paragraph("Quick Reference Table", sTocHead))
    items.append(HRFlowable(width="100%", thickness=1, color=C_TEAL, spaceAfter=6))
    hdr_style = S("th", fontSize=9, fontName="Helvetica-Bold", textColor=C_WHITE)
    cell_style = S("td", fontSize=8.5, fontName="Helvetica", textColor=HexColor("#1e2a38"), leading=12)
    sys_style  = S("ts", fontSize=8.5, fontName="Helvetica-Bold", textColor=C_NAVY, leading=12)

    header_row = [
        Paragraph("Effect", hdr_style),
        Paragraph("System", hdr_style),
        Paragraph("One-Line Summary", hdr_style),
    ]
    rows = [header_row]
    one_liners = {
        "Macklin Effect":               "Alveolar rupture → pneumomediastinum via bronchovascular sheath",
        "Bohr Effect":                  "↑CO₂ / ↑H⁺ → right-shift ODC → O₂ unloading at tissues",
        "Haldane Effect":               "Deoxy-Hb carries more CO₂ than oxy-Hb",
        "Euler-Liljestrand Mechanism":  "Alveolar hypoxia → local pulmonary vasoconstriction → V/Q match",
        "Pendelluft":                   "Inter-unit gas oscillation in ARDS → regional lung overdistension",
        "Oxygen Toxicity (Paul Bert Effect)": "Hyperbaric O₂ → CNS seizures; normobaric high FiO₂ → lung injury",
        "Bernoulli / Venturi Effect":   "High-velocity flow → ↓ lateral pressure; basis of Venturi masks",
        "Frank-Starling Law":           "↑ Preload → ↑ Stroke volume (sarcomere stretch → ↑ force)",
        "Bowditch Effect (Treppe / Staircase)": "↑ Heart rate → ↑ Contractility (Ca²⁺ accumulation)",
        "Anrep Effect":                 "↑ Afterload → slow intrinsic recovery of contractility",
        "Cushing Reflex (Cushing Response)": "↑ ICP → hypertension + bradycardia + irregular breathing",
        "Bainbridge Reflex":            "↑ Atrial pressure → reflex tachycardia",
        "Bezold-Jarisch Reflex":        "Cardiac C-fiber stimulation → bradycardia + hypotension + apnoea",
        "Windkessel Effect":            "Aortic elastic recoil maintains diastolic pressure",
        "Fick Principle":               "Cardiac output = O₂ consumption ÷ A-V O₂ difference",
        "Starling Forces":              "4 forces govern transcapillary fluid: Pc, Pi, πc, πi",
        "Tubuloglomerular Feedback (Macula Densa Effect)": "↑ NaCl at macula densa → afferent arteriole constriction → ↓ GFR",
        "Gibbs-Donnan Effect":          "Non-diffusible proteins → unequal ion distribution across membrane",
        "Countercurrent Multiplication (Henle's Loop Effect)": "Loop of Henle builds medullary osmotic gradient for urine concentration",
        "2,3-BPG (Bisphosphoglycerate) Effect": "↑ 2,3-BPG → right-shift ODC → better O₂ delivery in hypoxia",
        "Prozone Effect (Hook Effect)": "Antigen excess → false-negative serology (e.g., RPR in 2° syphilis)",
        "Rouleaux Formation":           "↑ Plasma proteins → RBC stacking → ↑ ESR",
        "Spreading Cortical Depression (Leão Effect)": "Wave of cortical depolarisation → migraine aura",
        "Kindling Effect":              "Repeated sub-threshold stimuli → spontaneous seizures",
        "Mass Effect (Cerebral)":       "SOL displaces brain → midline shift → herniation syndromes",
        "Doppler Effect":               "Wave frequency shift → measure blood flow velocity (US/TCD)",
        "First-Pass Effect":            "Hepatic pre-systemic drug metabolism → reduced bioavailability",
        "Tachyphylaxis":                "Rapid drug desensitisation with repeated close doses",
        "Warburg Effect":               "Cancer aerobic glycolysis → ↑ glucose uptake → basis of FDG-PET",
        "Crabtree Effect":              "High glucose → suppression of mitochondrial respiration",
        "Somogyi Effect":               "Nocturnal hypoglycaemia → counter-regulatory rebound morning hyperglycaemia",
        "Dawn Phenomenon":              "GH/cortisol surge 4-8 AM → morning hyperglycaemia (no prior hypo)",
        "Staub-Traugott Effect":        "Successive glucose loads → progressively smaller glycaemic rises",
        "Courvoisier's Law":            "Palpable painless gallbladder + jaundice = malignant obstruction",
        "Pringle Manoeuvre":            "Portal triad clamping → arrest hepatic inflow during surgery",
        "Abscopal Effect":              "Local RT → systemic immune-mediated distant tumour regression",
        "Radiation Bystander Effect":   "Irradiated cells signal neighbouring cells → DNA damage",
        "Epitope Spreading":            "Autoimmune response diversifies to new epitopes over time",
    }
    for s in SYSTEMS:
        for e in s["effects"]:
            summary = one_liners.get(e["name"], "")
            rows.append([
                Paragraph(e["name"], cell_style),
                Paragraph(s["name"], sys_style),
                Paragraph(summary, cell_style),
            ])

    col_w = PAGE_W - 4*cm
    tbl = Table(rows, colWidths=[col_w*0.28, col_w*0.18, col_w*0.54])
    style = TableStyle([
        ("BACKGROUND", (0, 0), (-1, 0), C_NAVY),
        ("ROWBACKGROUNDS", (0, 1), (-1, -1), [C_WHITE, C_LIGHT]),
        ("GRID",       (0, 0), (-1, -1), 0.4, C_LGRAY),
        ("TOPPADDING",    (0, 0), (-1, -1), 4),
        ("BOTTOMPADDING", (0, 0), (-1, -1), 4),
        ("LEFTPADDING",   (0, 0), (-1, -1), 5),
        ("RIGHTPADDING",  (0, 0), (-1, -1), 5),
        ("VALIGN",     (0, 0), (-1, -1), "TOP"),
    ])
    tbl.setStyle(style)
    items.append(tbl)
    items.append(PageBreak())
    return items


# ── Main build ───────────────────────────────────────────────────────────────

def build():
    doc = SimpleDocTemplate(
        OUTPUT,
        pagesize=A4,
        leftMargin=2*cm, rightMargin=2*cm,
        topMargin=1.6*cm, bottomMargin=1.4*cm,
        title="Named Effects in Medicine — Study Guide",
        author="Orris Medical Reference",
    )

    story = []
    story += build_cover()
    story += build_toc()

    for sys in SYSTEMS:
        story.append(make_system_header(sys["name"], sys["color"]))
        story.append(Spacer(1, 0.25*cm))
        for effect in sys["effects"]:
            story.append(make_effect_block(effect))
        story.append(PageBreak())

    story += build_quick_ref()

    doc.build(story, onFirstPage=header_footer, onLaterPages=header_footer)
    print(f"PDF written to {OUTPUT}")


if __name__ == "__main__":
    build()