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

OUTPUT = "/home/daytona/workspace/medical-notes/Infectious_Diseases_Notes.pdf"

doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    rightMargin=2*cm, leftMargin=2*cm,
    topMargin=2.5*cm, bottomMargin=2.5*cm,
    title="Infectious Diseases: Cholera, Malaria, Viral Hepatitis A & E",
    author="Orris Medical"
)

styles = getSampleStyleSheet()

# Custom styles
title_style = ParagraphStyle(
    'MainTitle', parent=styles['Title'],
    fontSize=20, textColor=colors.HexColor('#1a3a5c'),
    spaceAfter=6, fontName='Helvetica-Bold', alignment=TA_CENTER
)
h1_style = ParagraphStyle(
    'H1', parent=styles['Heading1'],
    fontSize=15, textColor=colors.white,
    backColor=colors.HexColor('#1a3a5c'),
    spaceBefore=14, spaceAfter=6,
    fontName='Helvetica-Bold',
    leftIndent=-0.3*cm, rightIndent=-0.3*cm,
    borderPad=5
)
h2_style = ParagraphStyle(
    'H2', parent=styles['Heading2'],
    fontSize=12, textColor=colors.HexColor('#1a3a5c'),
    spaceBefore=10, spaceAfter=4,
    fontName='Helvetica-Bold',
    borderPad=2
)
h3_style = ParagraphStyle(
    'H3', parent=styles['Heading3'],
    fontSize=10.5, textColor=colors.HexColor('#2c5f8a'),
    spaceBefore=8, spaceAfter=3,
    fontName='Helvetica-Bold',
)
body_style = ParagraphStyle(
    'Body', parent=styles['Normal'],
    fontSize=9.5, leading=14,
    spaceAfter=4, alignment=TA_JUSTIFY,
    fontName='Helvetica'
)
bullet_style = ParagraphStyle(
    'Bullet', parent=styles['Normal'],
    fontSize=9.5, leading=13,
    leftIndent=14, firstLineIndent=-10,
    spaceAfter=2, fontName='Helvetica',
    bulletText='•'
)
sub_bullet_style = ParagraphStyle(
    'SubBullet', parent=styles['Normal'],
    fontSize=9, leading=12,
    leftIndent=28, firstLineIndent=-10,
    spaceAfter=2, fontName='Helvetica',
    bulletText='–'
)
caption_style = ParagraphStyle(
    'Caption', parent=styles['Normal'],
    fontSize=8, textColor=colors.HexColor('#555555'),
    spaceAfter=6, fontName='Helvetica-Oblique', alignment=TA_CENTER
)
source_style = ParagraphStyle(
    'Source', parent=styles['Normal'],
    fontSize=7.5, textColor=colors.HexColor('#777777'),
    spaceAfter=2, fontName='Helvetica-Oblique'
)

def h1(text):
    return Paragraph(f"  {text}", h1_style)

def h2(text):
    return Paragraph(text, h2_style)

def h3(text):
    return Paragraph(text, h3_style)

def p(text):
    return Paragraph(text, body_style)

def b(text):
    return Paragraph(f"<bullet>•</bullet>{text}", bullet_style)

def sb(text):
    return Paragraph(f"<bullet>–</bullet>{text}", sub_bullet_style)

def hr():
    return HRFlowable(width="100%", thickness=0.5, color=colors.HexColor('#cccccc'), spaceAfter=4, spaceBefore=4)

def spacer(h=6):
    return Spacer(1, h)

def make_table(headers, rows, col_widths=None):
    data = [headers] + rows
    if col_widths is None:
        n = len(headers)
        col_widths = [16*cm/n] * n
    tbl = Table(data, colWidths=col_widths, repeatRows=1)
    style = TableStyle([
        ('BACKGROUND', (0,0), (-1,0), colors.HexColor('#1a3a5c')),
        ('TEXTCOLOR', (0,0), (-1,0), colors.white),
        ('FONTNAME', (0,0), (-1,0), 'Helvetica-Bold'),
        ('FONTSIZE', (0,0), (-1,0), 8.5),
        ('ROWBACKGROUNDS', (0,1), (-1,-1), [colors.white, colors.HexColor('#eef3fa')]),
        ('FONTNAME', (0,1), (-1,-1), 'Helvetica'),
        ('FONTSIZE', (0,1), (-1,-1), 8),
        ('ALIGN', (0,0), (-1,-1), 'LEFT'),
        ('VALIGN', (0,0), (-1,-1), 'TOP'),
        ('GRID', (0,0), (-1,-1), 0.4, colors.HexColor('#aaaaaa')),
        ('LEFTPADDING', (0,0), (-1,-1), 5),
        ('RIGHTPADDING', (0,0), (-1,-1), 5),
        ('TOPPADDING', (0,0), (-1,-1), 4),
        ('BOTTOMPADDING', (0,0), (-1,-1), 4),
    ])
    tbl.setStyle(style)
    return tbl

story = []

# ─── COVER ──────────────────────────────────────────────────────────────────
story.append(spacer(40))
story.append(Paragraph("Infectious Diseases", title_style))
story.append(Paragraph("Study Notes", ParagraphStyle('sub', parent=styles['Normal'],
    fontSize=14, alignment=TA_CENTER, textColor=colors.HexColor('#2c5f8a'),
    fontName='Helvetica', spaceAfter=4)))
story.append(spacer(8))
story.append(HRFlowable(width="60%", thickness=2, color=colors.HexColor('#1a3a5c'), spaceAfter=12))
story.append(Paragraph("Cholera &nbsp;|&nbsp; Malaria &nbsp;|&nbsp; Viral Hepatitis A &amp; E",
    ParagraphStyle('topics', parent=styles['Normal'], fontSize=11, alignment=TA_CENTER,
    textColor=colors.HexColor('#444444'), fontName='Helvetica-Oblique', spaceAfter=6)))
story.append(spacer(20))
story.append(Paragraph("Sources: Harrison's Principles of Internal Medicine 22E (2025) · Goldman-Cecil Medicine ·<br/>Tietz Textbook of Laboratory Medicine 7th Ed. · Henry's Clinical Diagnosis &amp; Management",
    ParagraphStyle('src', parent=styles['Normal'], fontSize=8.5, alignment=TA_CENTER,
    textColor=colors.HexColor('#666666'), fontName='Helvetica-Oblique')))
story.append(PageBreak())

# ═══════════════════════════════════════════════════════════════════════════
# SECTION 1 – CHOLERA
# ═══════════════════════════════════════════════════════════════════════════
story.append(h1("1.  CHOLERA"))
story.append(spacer(4))

story.append(h2("Etiology"))
story.append(p("Cholera is caused by <b>Vibrio cholerae</b>, a comma-shaped, Gram-negative, motile facultative anaerobe. It is classified into >200 serogroups based on LPS O-antigens; only <b>serogroups O1 and O139</b> have epidemic potential."))
story.append(b("<b>Serogroup O1</b> – two serotypes: <b>Inaba</b> and <b>Ogawa</b>; two biotypes: <b>Classic</b> (thought extinct) and <b>El Tor</b> (current 7th-pandemic strain)"))
story.append(b("<b>Serogroup O139</b> – emerged 1992 in southeastern India; derivative of El Tor O1 with a distinct capsule; clinically indistinguishable from O1 but cross-immunity does NOT occur"))
story.append(b("Natural habitat: coastal salt water and brackish estuaries (in association with plankton); can also survive in freshwater with adequate nutrients"))
story.append(b("No known animal reservoir"))
story.append(spacer())

story.append(h2("Epidemiology"))
story.append(b("Native to the <b>Ganges delta</b> of the Indian subcontinent; seven global pandemics since 1817"))
story.append(b("Current (7th) pandemic: began in Indonesia in <b>1961</b> (El Tor biotype); >95% of reported cases from <b>Africa and Asia</b>"))
story.append(b("True burden: estimated <b>1–4 million cases/year</b> (only ~400,000 reported to WHO); <b>20,000–140,000 deaths/year</b>"))
story.append(b("<b>Transmission</b>: primarily fecally contaminated water; contaminated food and person-to-person spread also contribute"))
story.append(b("Infectious dose is relatively high; markedly reduced in <b>hypochlorhydric persons</b>, antacid users, and when gastric acid is buffered by a meal"))
story.append(b("In <b>endemic areas</b>: predominantly a pediatric disease; seasonal peaks with warm temperatures, heavy rainfall, flooding"))
story.append(b("In <b>newly affected populations</b>: all ages equally affected; outbreaks precipitated by war, displacement, breakdown of public health (Haiti 2010, Yemen 2016)"))
story.append(spacer())

story.append(h2("Features of Pathogenesis"))
story.append(p("Cholera is fundamentally a <b>toxin-mediated disease</b>. Death results from hypovolemic shock due to massive fluid loss."))
story.append(spacer(4))

story.append(h3("Step 1 – Colonization"))
story.append(b("Ingested V. cholerae survives gastric acid and colonizes the <b>small intestine</b>"))
story.append(b("The <b>toxin-coregulated pilus (TCP)</b> is essential for colonization; its synthesis is co-regulated with cholera toxin by the master regulator <b>ToxR</b> (a cascade responding to environmental signals and quorum sensing)"))
story.append(spacer(4))

story.append(h3("Step 2 – Cholera Toxin (CT) Action"))
story.append(b("<b>B subunit (pentamer)</b>: binds to <b>GM1 ganglioside</b> on the surface of intestinal epithelial cells → delivers A subunit intracellularly"))
story.append(b("<b>A1 subunit</b>: irreversibly <b>ADP-ribosylates the Gs-alpha protein</b> of adenylate cyclase → locks it in active (GTP-bound) state"))
story.append(b("Constitutively active adenylate cyclase → massive ↑ intracellular <b>cAMP</b> → PKA activation → phosphorylation of CFTR (Cl⁻ secretion) + inhibition of Na⁺/H⁺ exchangers"))
story.append(b("Net secretion of Na⁺, Cl⁻, K⁺, HCO₃⁻, and water into intestinal lumen → profuse watery diarrhea"))
story.append(spacer(4))

story.append(h3("Key Point: Basis for ORS"))
story.append(p("The <b>hexose-Na⁺ co-transport (SGLT1)</b> mechanism remains fully intact despite CT activity. This allows glucose-coupled Na⁺ (and water) absorption to continue, forming the physiological basis for oral rehydration solution (ORS)."))
story.append(spacer())

story.append(h2("Clinical Presentation"))
story.append(b("<b>Incubation period</b>: hours to 5 days (usually 1–2 days)"))
story.append(b("~75% of infections: <b>asymptomatic</b> (important reservoir for spread)"))
story.append(b("~20%: mild-moderate diarrhea; ~5%: <b>cholera gravis</b> (severe, life-threatening)"))
story.append(spacer(4))

story.append(h3("Progression in Severe (Gravis) Disease"))
story.append(b("Sudden-onset painless, profuse watery diarrhea – characteristic <b>\"rice-water\" stool</b> (colorless, odorless, containing mucus flecks); up to 1 L/hr in severe cases"))
story.append(b("<b>Vomiting</b>: effortless, without preceding nausea"))
story.append(b("<b>Rapid dehydration</b>: intense thirst, dry mouth/tongue, sunken eyes (sunken fontanelles in infants), decreased skin turgor, oliguria, muscle cramps (hypokalemia)"))
story.append(b("<b>Hypovolemic shock</b>: hypotension, tachycardia, weak/absent pulse, cyanosis, altered consciousness"))
story.append(b("<b>Metabolic derangements</b>: metabolic acidosis (HCO₃⁻ loss), hypokalemia, hyponatremia"))
story.append(spacer(4))

story.append(h3("Degrees of Dehydration"))
story.append(make_table(
    ["Degree", "Clinical Findings"],
    [
        ["None / Mild", "Thirst in some cases; <5% loss of total body weight"],
        ["Moderate", "Thirst, postural hypotension, weakness, tachycardia, decreased skin turgor, dry mouth/tongue, no tears; 5–10% body weight loss"],
        ["Severe", "Unconsciousness, lethargy, or 'floppiness'; weak or absent pulse; inability to drink; sunken eyes (and fontanelles in infants); >10% body weight loss"],
    ],
    col_widths=[4*cm, 12*cm]
))
story.append(Paragraph("Table adapted from Harrison's Principles of Internal Medicine 22E, Table 173-1", source_style))
story.append(spacer())

story.append(h2("Emergency Therapy for Dehydration / Hypovolemic Shock"))
story.append(h3("Severe Dehydration – Immediate IV Resuscitation"))
story.append(b("<b>Ringer's lactate</b> (preferred) or normal saline if unavailable"))
story.append(b("<b>100 mL/kg</b> in the first <b>3 hours</b> (6 hours for infants <12 months); start rapidly, then slow"))
story.append(b("Total <b>200 mL/kg</b> in the first 24 hours"))
story.append(b("Continue until strong pulse, normal BP, and normal mental status restored"))
story.append(b("Then transition to oral rehydration solution (ORS)"))
story.append(spacer(4))

story.append(h3("Moderate Dehydration – ORS Volumes"))
story.append(make_table(
    ["Age / Weight", "ORS Volume"],
    [
        ["<4 months (<5 kg)", "200–400 mL"],
        ["4–11 months (5–<8 kg)", "400–600 mL"],
        ["12–23 months (8–<11 kg)", "600–800 mL"],
        ["2–4 years (11–<16 kg)", "800–1200 mL"],
        ["5–14 years (16–<30 kg)", "1200–2200 mL"],
        ["≥15 years (≥30 kg)", "2200–4000 mL"],
    ],
    col_widths=[7*cm, 9*cm]
))
story.append(Paragraph("Table adapted from Harrison's Principles of Internal Medicine 22E, Table 173-2", source_style))
story.append(spacer(4))
story.append(p("<b>WHO ORS formula:</b> Na⁺ 75 mmol/L · Cl⁻ 65 mmol/L · K⁺ 20 mmol/L · citrate 10 mmol/L · glucose 75 mmol/L · osmolarity 245 mOsm/L"))
story.append(spacer())

story.append(h2("Diagnosis"))
story.append(b("<b>Clinical</b>: acute profuse rice-water diarrhea with rapid dehydration in epidemic context – sufficient for immediate treatment"))
story.append(b("<b>Dark-field microscopy</b>: rapid darting \"shooting-star\" motility of vibrios; immobilized by O1 or O139 antiserum"))
story.append(b("<b>Culture</b>: TCBS agar (O1 = yellow colonies); alkaline peptone water pH 8.5 for enrichment; serotyping with O1/O139 antisera"))
story.append(b("<b>PCR</b>: rapid confirmation and epidemiologic typing"))
story.append(b("<b>Rapid antigen tests</b>: available in field settings"))
story.append(b("<b>Other labs</b>: serum electrolytes (hyponatremia, hypokalemia, metabolic acidosis), BUN/creatinine (prerenal azotemia)"))
story.append(spacer(4))

story.append(h3("Differential Diagnosis"))
story.append(make_table(
    ["Condition", "Key Differentiating Features"],
    [
        ["ETEC", "Similar profuse watery diarrhea; heat-labile toxin also elevates cAMP; distinguished by culture"],
        ["Rotavirus / Norovirus", "Vomiting often precedes diarrhea; less voluminous; mainly children (Rota)"],
        ["Cryptosporidium", "Immunocompromised patients; persistent course"],
        ["V. parahaemolyticus", "Seafood-associated; self-limited; no O1/O139 agglutination"],
        ["Non-cholera secretory diarrhea", "VIPoma, carcinoid – no epidemic context; hormonal markers elevated"],
    ],
    col_widths=[4.5*cm, 11.5*cm]
))
story.append(spacer())

story.append(h2("Principles of Treatment"))
story.append(b("<b>1. Fluid and electrolyte replacement</b> (primary treatment) – reduces mortality from ~50% to <1%"))
story.append(sb("Severity-based: ORS for mild-moderate; IV Ringer's lactate for severe"))
story.append(sb("Monitor and continuously replace ongoing losses"))
story.append(b("<b>2. Antibiotics</b> (adjunct – reduce duration and volume of diarrhea by ~50%)"))
story.append(sb("<b>Doxycycline</b>: 300 mg single dose (adults) – first choice where susceptible"))
story.append(sb("<b>Azithromycin</b>: 1 g single dose (adults); 20 mg/kg (children) – preferred in pregnancy and resistant strains"))
story.append(sb("<b>Ciprofloxacin</b>: 1 g single dose (adults) – fluoroquinolone resistance emerging"))
story.append(sb("<b>Tetracycline</b>: 500 mg QID × 3 days"))
story.append(b("<b>3. Nutritional support</b>: early refeeding after rehydration (especially children)"))
story.append(b("<b>4. Zinc supplementation</b> (children): 20 mg/day × 10–14 days – reduces severity and recurrence"))
story.append(b("<b>5. Public health</b>: safe water supply, sanitation, oral cholera vaccines (Shanchol, OCV)"))

story.append(PageBreak())

# ═══════════════════════════════════════════════════════════════════════════
# SECTION 2 – MALARIA
# ═══════════════════════════════════════════════════════════════════════════
story.append(h1("2.  MALARIA"))
story.append(spacer(4))

story.append(h2("Etiology"))
story.append(p("Malaria is a hematogenous, mosquito-transmitted infection caused by apicomplexan parasites of the genus <b><i>Plasmodium</i></b>. Five species cause human disease:"))
story.append(make_table(
    ["Species", "Key Features"],
    [
        ["P. falciparum", "Most dangerous; infects RBCs of all ages → high parasitemia; sequestration in microvasculature; 36–48 h erythrocytic cycle; banana-shaped gametocytes"],
        ["P. vivax", "Infects young RBCs (reticulocytes); dormant hypnozoites → true relapses; 44–48 h cycle; Schüffner's dots; extends to temperate regions"],
        ["P. ovale", "Infects young RBCs; dormant hypnozoites; 48 h cycle; oval/fimbriated RBCs; mainly West Africa"],
        ["P. malariae", "Infects old RBCs; low parasitemia; 72 h quartan cycle; band-form trophozoites; can persist decades"],
        ["P. knowlesi", "Zoonotic (macaques); Southeast Asia; 24 h cycle; can cause severe disease"],
    ],
    col_widths=[3.5*cm, 12.5*cm]
))
story.append(spacer())

story.append(h2("Epidemiology"))
story.append(b("~<b>3.2 billion people</b> at risk worldwide; ~228 million cases/year; ~405,000 deaths/year"))
story.append(b("<b>94% of deaths</b> in WHO African Region; <b>67% of all deaths</b> in children <5 years"))
story.append(b("Endemic in tropical and subtropical regions; <i>P. vivax</i> also found in some temperate zones"))
story.append(b("<b>Vector</b>: female <i>Anopheles</i> mosquito (>30 implicated species)"))
story.append(b("In non-endemic countries: mainly imported in <b>immigrants and travelers</b> (especially VFRs – visiting friends and relatives)"))
story.append(spacer(4))

story.append(h3("Risk Groups"))
story.append(b("Children <5 years in endemic areas (lack acquired immunity)"))
story.append(b("Non-immune adults (travelers, first-time exposures)"))
story.append(b("Pregnant women (impaired immunity; risk of placental malaria with P. falciparum)"))
story.append(b("HIV-positive individuals"))
story.append(b("Asplenic individuals (functional or anatomic)"))
story.append(b("Travelers from non-endemic countries visiting endemic areas"))
story.append(spacer(4))

story.append(h3("Protective Genetic Traits (Evolutionary Adaptations)"))
story.append(p("Sickle cell trait (HbS), HbC, HbE, alpha/beta-thalassemia, G6PD deficiency, hereditary spherocytosis – all confer partial protection against severe malaria."))
story.append(spacer())

story.append(h2("Life Cycle of the Malaria Parasite"))

story.append(h3("A. Human Asexual Phase"))
story.append(b("<b>Exo-erythrocytic schizogony (liver stage):</b>"))
story.append(sb("Infected female Anopheles injects <b>sporozoites</b> during blood meal → sporozoites travel to liver, invade hepatocytes"))
story.append(sb("Over 5–15 days: asexual replication → <b>hepatic schizonts</b> → rupture, releasing thousands of <b>merozoites</b> into bloodstream"))
story.append(sb("<i>P. vivax</i> and <i>P. ovale</i> ONLY: some sporozoites become dormant <b>hypnozoites</b> → basis for true relapses"))
story.append(b("<b>Erythrocytic schizogony (blood stage – produces all symptoms):</b>"))
story.append(sb("Merozoites invade RBCs via specific receptors (Duffy antigen for P. vivax; glycophorins for P. falciparum)"))
story.append(sb("Ring trophozoite → mature trophozoite → schizont → <b>rupture</b> → merozoites re-infect new RBCs"))
story.append(sb("Some trophozoites differentiate into <b>gametocytes</b> (male microgametocytes, female macrogametocytes)"))
story.append(spacer(4))

story.append(h3("B. Mosquito Sexual Phase"))
story.append(b("Mosquito ingests gametocytes → microgametes undergo <b>exflagellation</b> → fertilize macrogametes → <b>ookinete</b>"))
story.append(b("Ookinete penetrates mosquito midgut → <b>oocyst</b> → ruptures over 8–15 days releasing thousands of <b>sporozoites</b>"))
story.append(b("Sporozoites migrate to salivary glands → ready to infect new human host"))
story.append(spacer(4))

story.append(h3("Features of Asexual Phase by Species"))
story.append(make_table(
    ["Feature", "P. falciparum", "P. malariae", "P. vivax", "P. ovale"],
    [
        ["RBC preference", "All ages", "Old RBCs", "Young (reticulocytes)", "Young RBCs"],
        ["Merozoites/schizont", "8–24", "6–12", "12–24", "4–16"],
        ["Fever cycle", "36–48 h (tertian)", "72 h (quartan)", "44–48 h (tertian)", "48 h (tertian)"],
        ["Hypnozoites", "No", "No", "YES", "YES"],
        ["Schüffner's dots", "No", "No", "Yes", "Yes"],
        ["RBC enlargement", "No", "No", "Yes", "Yes (oval/fimbriated)"],
        ["Maurer's clefts", "Yes", "No", "No", "No"],
        ["Sequestration", "Yes", "No", "No", "No"],
    ],
    col_widths=[3.8*cm, 3.2*cm, 3*cm, 3*cm, 3*cm]
))
story.append(spacer(4))

story.append(h3("Origin of the Febrile Paroxysm"))
story.append(p("The febrile paroxysm is triggered by <b>synchronous rupture of schizonts</b> at the end of erythrocytic schizogony. Rupture releases merozoites, <b>hemozoin</b> (malaria pigment – a byproduct of Hb degradation), and parasite metabolic products/GPI anchors. These stimulate macrophages/monocytes to release <b>TNF-α, IL-1, IL-6, IL-8</b> → systemic inflammatory response → <b>classic triad: chills (rigors, 15–60 min) → high fever (39–41°C, 2–6 h) → profuse sweating with defervescence.</b>"))
story.append(p("Periodicity reflects the synchrony of the intraerythrocytic cycle: <b>48 h (tertian)</b> for P. vivax, P. ovale, P. falciparum; <b>72 h (quartan)</b> for P. malariae. Early in infection, paroxysms may be irregular until synchrony is established."))
story.append(spacer())

story.append(h2("Prevention"))
story.append(h3("Personal Protective Measures"))
story.append(b("Insecticide-treated bed nets (ITNs / LLINs)"))
story.append(b("Indoor residual spraying (IRS)"))
story.append(b("Insect repellents (DEET, picaridin) on exposed skin; protective clothing"))
story.append(spacer(4))

story.append(h3("Chemoprophylaxis (for Travelers)"))
story.append(make_table(
    ["Drug", "Dose / Schedule", "Notes"],
    [
        ["Chloroquine", "Weekly", "Only for chloroquine-sensitive areas (C. America west of Panama Canal, Haiti, parts of Middle East)"],
        ["Atovaquone-proguanil (Malarone)", "Daily; start 1–2 days before travel; continue 7 days after", "Preferred; few side effects"],
        ["Doxycycline", "Daily; start 1–2 days before; continue 4 weeks after", "Cheap; also protects against Rickettsiae"],
        ["Mefloquine", "Weekly; start ≥2 weeks before; continue 4 weeks after", "Neuropsychiatric side effects"],
        ["Primaquine", "Daily; requires G6PD screening", "Terminal prophylaxis for P. vivax/ovale"],
    ],
    col_widths=[4*cm, 5.5*cm, 6.5*cm]
))
story.append(spacer(4))

story.append(h3("Vaccines"))
story.append(b("<b>RTS,S/AS01 (Mosquirix)</b>: first approved malaria vaccine; targets P. falciparum circumsporozoite protein; ~30–40% efficacy; WHO-recommended for children in endemic Africa"))
story.append(b("<b>R21/Matrix-M</b>: newer; ~75% efficacy in trials; WHO prequalified 2023"))
story.append(spacer())

story.append(h2("Pathogenesis of Relapses in Malaria"))
story.append(b("<b>Recrudescence</b> (all species): re-emergence from persisting blood-stage parasites due to inadequate treatment or drug resistance"))
story.append(b("<b>True relapse</b> (P. vivax and P. ovale ONLY): re-emergence from dormant <b>hypnozoites</b> in hepatocytes"))
story.append(sb("Hypnozoite = quiescent, metabolically inactive liver-stage parasite"))
story.append(sb("P. vivax: relapses 3 weeks to 8+ months after primary infection; temperate strains may have longer latency"))
story.append(sb("P. ovale: typically 1–4 months after primary infection"))
story.append(sb("Reactivation stimuli unclear (possibly stress, febrile illness, immune changes)"))
story.append(b("<b>Radical cure (prevention of relapse)</b>: requires <b>primaquine</b> 0.5 mg base/kg/day × 14 days, or <b>tafenoquine</b> 300 mg single dose"))
story.append(b("Both drugs require <b>G6PD screening</b> before use – risk of hemolytic anemia in G6PD-deficient patients"))
story.append(spacer())

story.append(h2("Complications of Malaria"))
story.append(p("Primarily with <i>P. falciparum</i>; some complications may occur with other species:"))
story.append(make_table(
    ["Complication", "Mechanism / Features"],
    [
        ["Cerebral malaria", "Sequestration of infected RBCs in cerebral microvasculature → ring hemorrhages, local hypoxia, cytokine storm; unarousable coma, seizures; mortality ~15–25%"],
        ["Severe anemia", "RBC destruction, dyserythropoiesis, hypersplenism; Hgb <7 g/dL"],
        ["Hypoglycemia", "Parasite glucose consumption + quinine-stimulated insulin secretion; frequent in children and pregnant women"],
        ["ARDS / Pulmonary edema", "Inflammatory/cytokine-mediated alveolar damage"],
        ["Acute kidney injury", "Hemoglobinuria, renal tubular damage, hypovolemia"],
        ["Blackwater fever", "Massive intravascular hemolysis → hemoglobinuria ('cola-colored' urine); associated with G6PD deficiency + quinine use"],
        ["Algid malaria", "Circulatory collapse / septic shock from concurrent Gram-negative bacteremia"],
        ["Hyperparasitemia", ">5–10% parasitized RBCs; indicator of severity"],
        ["Placental malaria", "P. falciparum cytoadherence to syncytiotrophoblasts → IUGR, low birth weight, maternal anemia"],
        ["Splenic rupture", "Especially P. vivax; massive splenomegaly → spontaneous rupture"],
    ],
    col_widths=[4.5*cm, 11.5*cm]
))
story.append(spacer())

story.append(h2("Diagnosis of Malaria"))
story.append(h3("Microscopy (Gold Standard)"))
story.append(b("<b>Thick blood film</b>: concentrated; more sensitive for detecting low-parasitemia infections; allows species identification with Giemsa or Field's stain"))
story.append(b("<b>Thin blood film</b>: monolayer; accurate species morphology identification; determines % parasitemia"))
story.append(b("Must be performed <b>urgently</b>, 7 days/week, 24 hours/day – malaria is life-threatening"))
story.append(spacer(4))

story.append(h3("Species Differentiation on Blood Smear"))
story.append(make_table(
    ["Species", "Smear Characteristics"],
    [
        ["P. falciparum", "Small delicate rings; double chromatin dots; appliqué (accolé) forms at RBC margin; Maurer's clefts; banana-shaped gametocytes; no RBC enlargement"],
        ["P. vivax", "Enlarged RBCs; ameboid trophozoites; Schüffner's dots (James' stippling)"],
        ["P. ovale", "Oval/fimbriated RBCs; Schüffner's dots; compact trophozoites"],
        ["P. malariae", "Normal-sized RBCs; band-form trophozoites; rosette schizonts"],
    ],
    col_widths=[3.5*cm, 12.5*cm]
))
story.append(spacer(4))

story.append(h3("Rapid Diagnostic Tests (RDTs)"))
story.append(b("Detect parasite antigens: <b>HRP-2</b> for P. falciparum; <b>pLDH/aldolase</b> for all species"))
story.append(b("Point-of-care; no microscopy needed; cannot quantify parasitemia; false negatives with pfhrp2/3 gene deletions"))
story.append(spacer(4))

story.append(h3("PCR"))
story.append(b("Most sensitive and specific; differentiates species; detects mixed infections; used when microscopy/RDT is inconclusive"))
story.append(spacer())

story.append(h2("Treatment of Malaria"))
story.append(h3("P. falciparum (and Unknown Species)"))
story.append(b("<b>Uncomplicated, chloroquine-sensitive areas</b> (rare): Chloroquine 25 mg base/kg over 3 days"))
story.append(b("<b>Uncomplicated, chloroquine-resistant areas (= most of the world)</b>: Artemisinin-based Combination Therapies (ACTs)"))
story.append(sb("<b>Artemether-lumefantrine (Coartem)</b>: 3-day course; most widely available ACT"))
story.append(sb("Artesunate-amodiaquine; Artesunate-mefloquine (SE Asia); Dihydroartemisinin-piperaquine"))
story.append(sb("Alternative: Atovaquone-proguanil, Quinine + doxycycline, Quinine + clindamycin (in pregnancy)"))
story.append(b("<b>Severe malaria</b>: IV/IM <b>artesunate</b> (drug of choice; superior to quinine); IV quinine + doxycycline if artesunate unavailable; exchange transfusion for parasitemia >10% (ASFA guidelines)"))
story.append(spacer(4))

story.append(h3("P. vivax / P. ovale"))
story.append(b("Chloroquine (if sensitive) + <b>Primaquine</b> 0.5 mg base/kg/day × 14 days OR <b>Tafenoquine</b> 300 mg single dose – to eradicate hypnozoites"))
story.append(b("Chloroquine-resistant P. vivax (Indonesia, Oceania): ACT or mefloquine + primaquine"))
story.append(b("Always screen for <b>G6PD deficiency</b> before primaquine/tafenoquine"))
story.append(spacer(4))

story.append(h3("P. malariae"))
story.append(b("Chloroquine alone (no hypnozoites; no radical cure needed)"))
story.append(spacer(4))

story.append(h3("Drug Groups Summary"))
story.append(make_table(
    ["Drug Group", "Main Representatives", "Mechanism"],
    [
        ["4-Aminoquinolines", "Chloroquine, amodiaquine", "Inhibit heme polymerization in parasite food vacuole"],
        ["Artemisinins", "Artesunate, artemether, dihydroartemisinin", "Rapid-acting; free radical damage to parasite proteins"],
        ["8-Aminoquinolines", "Primaquine, tafenoquine", "Eradicate hypnozoites and gametocytes; oxidative stress mechanism; G6PD-sensitive"],
        ["Antifolates", "Pyrimethamine, proguanil, sulfadoxine-pyrimethamine", "Inhibit DHFR/DHPS in parasite folate synthesis"],
        ["Aryl aminoalcohols", "Quinine, mefloquine, lumefantrine", "Inhibit heme polymerization"],
        ["Naphthoquinones", "Atovaquone", "Inhibits mitochondrial electron transport chain (complex III)"],
    ],
    col_widths=[4*cm, 5.5*cm, 6.5*cm]
))

story.append(PageBreak())

# ═══════════════════════════════════════════════════════════════════════════
# SECTION 3 – VIRAL HEPATITIS A & E
# ═══════════════════════════════════════════════════════════════════════════
story.append(h1("3.  VIRAL HEPATITIS A AND E"))
story.append(spacer(4))

story.append(h2("Etiology"))
story.append(h3("Hepatitis A Virus (HAV)"))
story.append(b("Family <b>Picornaviridae</b>, genus <i>Hepatovirus</i>"))
story.append(b("<b>27-nm nonenveloped icosahedral nucleocapsid</b>"))
story.append(b("Positive-sense single-stranded RNA genome, ~7.5 kb; single open reading frame"))
story.append(b("Three genotypes in humans (I, II, III); <b>genotype I predominates worldwide</b> (subtypes A and B)"))
story.append(b("Highly stable in environment; resistant to acid and detergents; destroyed by boiling (1 min) or autoclaving"))
story.append(spacer(4))

story.append(h3("Hepatitis E Virus (HEV)"))
story.append(b("Family <b>Hepeviridae</b>, genus <i>Orthohepevirus</i>"))
story.append(b("Non-enveloped, positive-sense ssRNA, ~7.2 kb"))
story.append(b("<b>5 genotypes</b>:"))
story.append(sb("<b>Genotypes 1 and 2</b>: exclusively human; cause large waterborne epidemics in developing countries; affect younger populations"))
story.append(sb("<b>Genotypes 3 and 4</b>: zoonotic (humans and swine/boar/deer); responsible for sporadic cases in developed countries; affect older/immunocompromised"))
story.append(sb("<b>Genotype 5</b>: avian HEV (chickens)"))
story.append(spacer())

story.append(h2("Epidemiology"))
story.append(h3("Hepatitis A"))
story.append(b("<b>Worldwide distribution</b>; seroprevalence reflects sanitation standards"))
story.append(b("Developing countries: near-universal childhood exposure; seroprevalence approaches 100% in adults"))
story.append(b("Developed countries: US incidence declined from 12/100,000 in 1995 to 0.5/100,000 by 2012; subsequently rose to 3.8/100,000 in 2018 (outbreaks in drug users and homeless persons)"))
story.append(b("<b>Route</b>: primarily <b>fecal-oral</b> (person-to-person, contaminated water/food); rarely blood transfusion or perinatal"))
story.append(b("<b>High-risk groups</b>: travelers to developing countries · children in day-care centers and their parents · MSM · injection drug users · homeless persons · hemophilia patients receiving plasma products · persons in institutions"))
story.append(spacer(4))

story.append(h3("Hepatitis E"))
story.append(b("Common in <b>parts of Asia (India, Central Asia), Africa, and Mexico</b>"))
story.append(b("Rare in US except in returned travelers and, increasingly, via zoonotic routes (genotypes 3/4)"))
story.append(b("<b>Route</b>: primarily <b>fecal-oral via contaminated water</b>; waterborne epidemic pattern; person-to-person transmission is uncommon"))
story.append(b("<b>Zoonotic route</b>: uncooked boar, deer, or pork (genotypes 3/4)"))
story.append(b("<b>Special risk – Pregnant women</b>: fatality rate ~20% with genotype 1 infection (especially 3rd trimester); general fatality rate 0.5–4%"))
story.append(spacer())

story.append(h2("Clinical Classification"))
story.append(make_table(
    ["Clinical Form", "Description"],
    [
        ["Inapparent (subclinical)", "No symptoms; detected only by serology; common in young children with HAV"],
        ["Anicteric", "Symptoms (fatigue, nausea, myalgia) without jaundice"],
        ["Icteric (typical acute)", "Full clinical picture: prodrome + jaundice; see below"],
        ["Cholestatic", "Prolonged jaundice (weeks–months); mainly HAV; usually self-resolves"],
        ["Relapsing", "HAV: 10% of patients; secondary rise in enzymes and symptoms; self-limited; HAV is the most common cause of relapsing cholestatic hepatitis"],
        ["Fulminant hepatic failure", "<0.1% for HAV; 0.5–4% for HEV; up to 20% for HEV in pregnant women"],
        ["Chronic", "Does NOT occur with HAV or HEV in immunocompetent patients. Chronic HEV CAN occur in immunocompromised (transplant, HIV) with genotype 3/4"],
    ],
    col_widths=[4.5*cm, 11.5*cm]
))
story.append(spacer())

story.append(h2("Clinical Presentation"))
story.append(h3("Incubation Period"))
story.append(b("<b>HAV</b>: 15–45 days (mean ~28–30 days); depends on inoculum size"))
story.append(b("<b>HEV</b>: 15–60 days (mean ~40 days)"))
story.append(spacer(4))

story.append(h3("Phase 1 – Prodrome (Pre-icteric Phase, 1–2 Weeks)"))
story.append(b("Fatigue, malaise, anorexia"))
story.append(b("Nausea, vomiting (more prominent in HAV)"))
story.append(b("Low-grade fever, myalgia, arthralgia, headache"))
story.append(b("Right upper quadrant discomfort/pain (tender hepatomegaly)"))
story.append(spacer(4))

story.append(h3("Phase 2 – Icteric Phase (1–4 Weeks)"))
story.append(b("<b>Jaundice</b> (scleral icterus precedes skin jaundice)"))
story.append(b("<b>Dark urine</b> (bilirubinuria – conjugated bilirubin; appears before clinical jaundice)"))
story.append(b("<b>Pale/clay-colored stools</b> (acholic – reduced bile in intestine)"))
story.append(b("<b>Pruritus</b> (especially in cholestatic forms)"))
story.append(b("Hepatomegaly (tender), sometimes splenomegaly"))
story.append(b("Constitutional symptoms often <b>improve</b> with onset of jaundice"))
story.append(b("<b>ALT/AST markedly elevated</b>: often >1000 IU/L; ALT > AST typically"))
story.append(spacer(4))

story.append(h3("Phase 3 – Convalescence"))
story.append(b("Gradual resolution of jaundice over 2–8 weeks; full recovery the rule in immunocompetent patients"))
story.append(b("Residual fatigue may persist months"))
story.append(b("HAV prolonged course (6–9 months) reported in 10% of adult patients; hospitalization required in up to 13% of adults"))
story.append(spacer())

story.append(h2("Diagnosis"))
story.append(h3("Hepatitis A – Serology"))
story.append(make_table(
    ["Marker", "Interpretation"],
    [
        ["IgM anti-HAV", "DIAGNOSTIC of acute infection; appears 2–3 weeks after infection; persists 3–6 months. Only test symptomatic individuals (false positives exist)"],
        ["IgG anti-HAV", "Past infection or vaccination; appears 1–2 weeks after IgM; lifelong protective immunity"],
        ["Total anti-HAV", "Detects IgM + IgG; used for seroprevalence studies"],
        ["HAV RNA (PCR)", "Present in stool and plasma during incubation and early acute phase; useful in outbreak investigation"],
    ],
    col_widths=[4.5*cm, 11.5*cm]
))
story.append(spacer(4))

story.append(h3("Hepatitis E – Serology and Molecular"))
story.append(make_table(
    ["Marker", "Interpretation"],
    [
        ["IgM anti-HEV", "Recent or current infection"],
        ["IgG anti-HEV", "Current or past infection"],
        ["HEV RNA (PCR)", "Definitive indicator of acute infection; gold standard; detection window 2–7 weeks after infection; tested in serum, plasma, bile, or feces"],
        ["HEV antigen (ELISA)", "Newer test; detects viral antigen with higher sensitivity than IgM or HEV RNA; antigen detectable ~3 weeks longer than previously thought"],
    ],
    col_widths=[4.5*cm, 11.5*cm]
))
story.append(p("<i>Note: HEV serology has frequent false positives depending on assay antigens; confirmatory PCR testing is required.</i>"))
story.append(spacer(4))

story.append(h3("Liver Function Tests (Both HAV and HEV)"))
story.append(b("<b>ALT and AST</b>: markedly elevated (often 1000–5000 IU/L); peaks before or at onset of jaundice"))
story.append(b("<b>Serum bilirubin</b>: elevated (both direct and indirect)"))
story.append(b("<b>ALP/GGT</b>: elevated, especially in cholestatic variants"))
story.append(b("<b>PT/INR</b>: elevated in severe/fulminant cases – marker of synthetic liver function"))
story.append(spacer(4))

story.append(h3("Differential Diagnosis – Other Causes to Exclude"))
story.append(b("Hepatitis B (HBsAg, anti-HBc IgM), Hepatitis C (anti-HCV, HCV RNA)"))
story.append(b("CMV hepatitis, EBV (infectious mononucleosis)"))
story.append(b("Drug-induced liver injury (DILI) – detailed drug history essential"))
story.append(b("Autoimmune hepatitis, Wilson's disease (in younger patients with fulminant presentation)"))
story.append(spacer())

story.append(h2("Treatment"))
story.append(p("<b>No specific antiviral therapy</b> is available for acute hepatitis A or uncomplicated acute hepatitis E. Treatment is <b>supportive</b>:"))
story.append(b("<b>Rest</b>: activity restriction proportional to symptoms"))
story.append(b("<b>Diet</b>: low-fat, high-carbohydrate diet (reduces nausea); adequate caloric intake; no fasting"))
story.append(b("<b>Avoid hepatotoxins</b>: strict alcohol abstinence; avoid paracetamol in large doses and NSAIDs"))
story.append(b("<b>Antiemetics</b>: metoclopramide or ondansetron for severe nausea/vomiting"))
story.append(b("<b>Antipruritics</b>: antihistamines or cholestyramine for cholestatic pruritus"))
story.append(b("<b>IV glucose</b>: for severe anorexia/vomiting with hypoglycemia risk"))
story.append(spacer(4))

story.append(h3("Indications for Hospitalization"))
story.append(b("Inability to maintain oral intake"))
story.append(b("INR >1.5, encephalopathy, or hypoglycemia"))
story.append(b("Signs of fulminant hepatic failure"))
story.append(spacer(4))

story.append(h3("Fulminant Hepatic Failure"))
story.append(b("Transfer to <b>liver transplant center</b>"))
story.append(b("Lactulose/rifaximin for encephalopathy; FFP for coagulopathy; N-acetylcysteine (NAC); liver transplant evaluation"))
story.append(b("<b>HEV in immunocompromised patients</b> (chronic genotype 3/4): <b>ribavirin</b> has been used with some benefit (off-label); dose reduction of immunosuppression"))
story.append(spacer(4))

story.append(h3("Prevention"))
story.append(make_table(
    ["Measure", "HAV", "HEV"],
    [
        ["Vaccine", "Inactivated vaccine (2-dose schedule); >95% effective; recommended for all children ≥1 year, travelers, MSM, IDU, homeless, CLD", "HEV 239 (Hecolin) – approved in China; not yet globally available"],
        ["Post-exposure prophylaxis", "HAV vaccine (preferred) or immunoglobulin within 2 weeks of exposure", "No proven PEP available"],
        ["Public health", "Safe water, proper sewage disposal, handwashing, food hygiene", "Safe water supply especially during floods; avoid raw boar/pork meat (genotypes 3/4)"],
    ],
    col_widths=[3.5*cm, 6.5*cm, 6*cm]
))

story.append(spacer(12))
story.append(hr())
story.append(Paragraph(
    "<i>Sources: Harrison's Principles of Internal Medicine 22E (2025) · Goldman-Cecil Medicine (Int'l Ed.) · "
    "Tietz Textbook of Laboratory Medicine 7th Ed. · Henry's Clinical Diagnosis &amp; Management by Laboratory Methods</i>",
    source_style
))

doc.build(story)
print("PDF generated:", OUTPUT)