Immunomodulatory Actions of Progesterone in Pregnancy

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, KeepTogether
)
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.platypus import PageBreak

OUTPUT = "/home/daytona/workspace/progesterone-study-guide/Progesterone_Immunology_Study_Guide.pdf"

# ── Colour palette ──────────────────────────────────────────────────────────
PURPLE       = colors.HexColor("#4A235A")   # headers
LIGHT_PURPLE = colors.HexColor("#7D3C98")   # sub-headers
ACCENT       = colors.HexColor("#D7BDE2")   # table header fills
PALE         = colors.HexColor("#F5EEF8")   # alternating row / callout bg
WHITE        = colors.white
RED_WARN     = colors.HexColor("#C0392B")
TEAL         = colors.HexColor("#117A65")
ORANGE       = colors.HexColor("#E67E22")
LIGHT_BLUE   = colors.HexColor("#EAF2FF")
DARK_GREY    = colors.HexColor("#2C3E50")

# ── Document ─────────────────────────────────────────────────────────────────
doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    rightMargin=1.8*cm, leftMargin=1.8*cm,
    topMargin=2*cm, bottomMargin=2*cm,
    title="Progesterone Immunology Study Guide",
    author="Orris Medical Education"
)

styles = getSampleStyleSheet()

# ── Custom styles ─────────────────────────────────────────────────────────────
def S(name, **kw):
    return ParagraphStyle(name, **kw)

title_style = S("MainTitle",
    fontName="Helvetica-Bold", fontSize=22, textColor=WHITE,
    alignment=TA_CENTER, spaceAfter=4)

subtitle_style = S("SubTitle",
    fontName="Helvetica", fontSize=11, textColor=ACCENT,
    alignment=TA_CENTER, spaceAfter=2)

h1 = S("H1",
    fontName="Helvetica-Bold", fontSize=14, textColor=WHITE,
    spaceBefore=14, spaceAfter=6, backColor=PURPLE,
    borderPadding=(5, 8, 5, 8), leftIndent=0)

h2 = S("H2",
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h3 = S("H3",
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body = S("Body",
    fontName="Helvetica", fontSize=9.5, leading=14,
    textColor=DARK_GREY, spaceAfter=4, alignment=TA_JUSTIFY)

bullet = S("Bullet",
    fontName="Helvetica", fontSize=9.5, leading=13,
    textColor=DARK_GREY, leftIndent=14, bulletIndent=4,
    spaceAfter=2)

sub_bullet = S("SubBullet",
    fontName="Helvetica", fontSize=9, leading=12,
    textColor=DARK_GREY, leftIndent=28, bulletIndent=18,
    spaceAfter=1)

bold_bullet = S("BoldBullet",
    fontName="Helvetica-Bold", fontSize=9.5, leading=13,
    textColor=DARK_GREY, leftIndent=14, bulletIndent=4,
    spaceAfter=2)

callout = S("Callout",
    fontName="Helvetica-Oblique", fontSize=9.5, leading=13,
    textColor=RED_WARN, backColor=colors.HexColor("#FDEDEC"),
    borderPadding=(6, 8, 6, 8), spaceBefore=4, spaceAfter=6,
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key_box = S("KeyBox",
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    borderPadding=(6, 8, 6, 8), spaceBefore=4, spaceAfter=6)

footnote = S("Footnote",
    fontName="Helvetica-Oblique", fontSize=7.5,
    textColor=colors.grey, spaceAfter=2)

# ── Helper builders ───────────────────────────────────────────────────────────
def title_block(story):
    """Purple title banner"""
    data = [[Paragraph("PROGESTERONE IMMUNOLOGY IN PREGNANCY", title_style)],
            [Paragraph("Quick Revision Study Guide  •  Exam Edition", subtitle_style)]]
    t = Table(data, colWidths=[17*cm])
    t.setStyle(TableStyle([
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        ("RIGHTPADDING",  (0,0), (-1,-1), 10),
        ("ROUNDEDCORNERS", [6]),
    ]))
    story.append(t)
    story.append(Spacer(1, 8))

def section_header(story, text):
    data = [[Paragraph(text, h1)]]
    t = Table(data, colWidths=[17*cm])
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,-1), PURPLE),
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        ("LEFTPADDING",   (0,0), (-1,-1), 10),
        ("RIGHTPADDING",  (0,0), (-1,-1), 10),
    ]))
    story.append(t)
    story.append(Spacer(1, 4))

def hr(story, color=LIGHT_PURPLE, thickness=0.8):
    story.append(HRFlowable(width="100%", thickness=thickness, color=color, spaceAfter=4))

def two_col_table(story, headers, rows, col_widths=None, alt=True):
    if col_widths is None:
        col_widths = [17*cm / len(headers)] * len(headers)
    data = [[Paragraph(f"<b>{h}</b>", S("TH", fontName="Helvetica-Bold",
                fontSize=9.5, textColor=WHITE, alignment=TA_CENTER))
             for h in headers]]
    for i, row in enumerate(rows):
        data.append([Paragraph(str(cell), body) for cell in row])
    t = Table(data, colWidths=col_widths, repeatRows=1)
    style = [
        ("BACKGROUND",    (0,0), (-1,0),  LIGHT_PURPLE),
        ("GRID",          (0,0), (-1,-1), 0.5, colors.HexColor("#BDC3C7")),
        ("TOPPADDING",    (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
        ("LEFTPADDING",   (0,0), (-1,-1), 6),
        ("RIGHTPADDING",  (0,0), (-1,-1), 6),
        ("VALIGN",        (0,0), (-1,-1), "TOP"),
    ]
    if alt:
        for i in range(1, len(rows)+1):
            if i % 2 == 0:
                style.append(("BACKGROUND", (0,i), (-1,i), PALE))
    t.setStyle(TableStyle(style))
    story.append(t)
    story.append(Spacer(1, 6))


# ══════════════════════════════════════════════════════════════════════════════
# BUILD STORY
# ══════════════════════════════════════════════════════════════════════════════
story = []

# ── Cover / Title ─────────────────────────────────────────────────────────────
title_block(story)

story.append(Paragraph(
    "Progesterone (P4) is the master immunological regulator of pregnancy. It prevents "
    "maternal rejection of the semi-allogeneic fetus by shifting immune responses from "
    "pro-inflammatory (Th1) to tolerogenic (Th2), inducing blocking factors, and "
    "remodelling the uterine immune microenvironment. Understanding these mechanisms is "
    "high-yield for OBGYN, Immunology, and Physiology exams.", body))
story.append(Spacer(1, 4))

story.append(Paragraph(
    "⚠  The Fundamental Problem: The fetus carries PATERNAL (foreign) antigens — it is a "
    "semi-allograft. Without active immune suppression, the maternal immune system would "
    "reject it. Progesterone solves this — primarily at the LOCAL level (concentrations "
    "at the maternal-fetal interface are far higher than in peripheral blood).", callout))

story.append(Spacer(1, 6))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 1 — Th1/Th2 Shift
# ══════════════════════════════════════════════════════════════════════════════
section_header(story, "1.  THE Th1 / Th2 CYTOKINE SHIFT  (Most Exam-Important!)")

story.append(Paragraph("Normal pregnancy = Th2-dominant environment", h2))
story.append(Paragraph(
    "Progesterone drives a fundamental shift from Th1 (cell-mediated, inflammatory) to "
    "Th2 (humoral, anti-inflammatory) immune responses at the maternal-fetal interface.", body))

two_col_table(story,
    ["Feature", "Th1 Response (BAD in pregnancy)", "Th2 Response (GOOD in pregnancy)"],
    [
        ["Key cytokines",  "IFN-γ, TNF-α, IL-12, IL-2", "IL-4, IL-5, IL-10, IL-13, TGF-β"],
        ["Immune type",    "Pro-inflammatory, cell-mediated", "Anti-inflammatory, humoral"],
        ["Effect on fetus","Promotes rejection / miscarriage", "Promotes tolerance / implantation"],
        ["Clinical outcome if dominant", "Spontaneous abortion, preeclampsia, preterm labor",
         "Successful pregnancy maintenance"],
    ],
    col_widths=[4*cm, 6.5*cm, 6.5*cm]
)

story.append(Paragraph("<b>How progesterone achieves this shift:</b>", h3))
for pt in [
    "Inhibits mitogen-induced proliferation of CD8+ T cells",
    "Alters transcription factors that drive Th1 cell development",
    "Promotes synthesis of Th2 cytokines (IL-4, IL-10, IL-13, TGF-β) at the decidua",
    "Downregulates pro-inflammatory cytokines: IL-6, TNF-α, IFN-γ",
]:
    story.append(Paragraph(f"• {pt}", bullet))

story.append(Spacer(1, 4))
story.append(Paragraph(
    "EXAM ALERT: Th1 shift (↑TNF-α, IFN-γ) = associated with recurrent pregnancy loss, "
    "preeclampsia, and preterm labour. TNF-α is a measurable marker of inflammation in RPL.", callout))


# ══════════════════════════════════════════════════════════════════════════════
# SECTION 2 — PIBF
# ══════════════════════════════════════════════════════════════════════════════
section_header(story, "2.  PROGESTERONE-INDUCED BLOCKING FACTOR (PIBF)")

story.append(Paragraph(
    "PIBF is progesterone's KEY indirect immunomediator — arguably the single most "
    "important molecule to memorise for exams.", key_box))

story.append(Paragraph("How PIBF is produced:", h3))
for pt in [
    "Progesterone binds to progesterone receptor (PR) on activated T lymphocytes (esp. CD8+ cells) at the maternal-fetal interface",
    "These cells synthesise and secrete PIBF",
    "PIBF receptor is GPI-anchored; forms a heterodimer with the IL-4 receptor α-chain",
    "PIBF colocalises within cytoplasmic granules of decidual NK (dNK) cells",
]:
    story.append(Paragraph(f"• {pt}", bullet))

story.append(Paragraph("Actions of PIBF:", h3))

two_col_table(story,
    ["PIBF Action", "Mechanism / Significance"],
    [
        ["↑ Th2 cytokine synthesis",         "Reinforces the Th1→Th2 shift"],
        ["↓ Cytotoxic T cell activity",       "Prevents direct fetal cell killing by CTLs"],
        ["↓ NK cell degranulation",           "Prevents NK-mediated trophoblast destruction"],
        ["↓ Arachidonic acid synthesis",      "↓ Prostaglandins → reduces preterm labour risk"],
        ["Modulates lymphocyte proliferation","Suppresses anti-fetal immune responses"],
    ],
    col_widths=[6*cm, 11*cm]
)

story.append(Paragraph(
    "Clinical link: Low PIBF levels are found in women with threatened miscarriage and "
    "recurrent pregnancy loss. Progesterone supplementation raises PIBF and improves "
    "outcomes. (Mehta et al., J Obstet Gynaecol Res, 2026)", footnote))


# ══════════════════════════════════════════════════════════════════════════════
# SECTION 3 — NK cells
# ══════════════════════════════════════════════════════════════════════════════
section_header(story, "3.  UTERINE NK CELL SUPPRESSION")

story.append(Paragraph(
    "Uterine NK cells (uNK) are the most abundant immune cells in the decidua — but "
    "unlike peripheral NK cells, they are TOLEROGENIC, not cytolytic, in normal pregnancy.", body))

story.append(Paragraph("How progesterone suppresses uNK cells:", h3))
for pt in [
    "uNK cells express GLUCOCORTICOID RECEPTOR (GR) — NOT the progesterone receptor (PR)",
    "Progesterone acts via GR to suppress NK cell activation and IFN-γ production",
    "Molecular mechanism: altered STAT4 and IκB phosphorylation (key signal transduction steps)",
    "PIBF also directly inhibits NK cell degranulation within decidual granules",
    "Net effect: uNK cells cannot kill trophoblasts — they assist implantation instead",
]:
    story.append(Paragraph(f"• {pt}", bullet))

story.append(Spacer(1, 4))
story.append(Paragraph(
    "Exam pearl: uNK cells express GR not PR — progesterone's suppression of NK cells is "
    "INDIRECT via the glucocorticoid receptor pathway.", callout))


# ══════════════════════════════════════════════════════════════════════════════
# SECTION 4 — HLA-G
# ══════════════════════════════════════════════════════════════════════════════
section_header(story, "4.  HLA-G UPREGULATION ON TROPHOBLASTS")

story.append(Paragraph("What is HLA-G?", h3))
for pt in [
    "Non-classical MHC class I molecule expressed on trophoblasts",
    "Does NOT present antigens for T cell recognition (unlike classical HLA-A, -B, -C)",
    "Acts as a LIGAND for INHIBITORY RECEPTORS on decidual NK cells and T cells",
    "Progesterone upregulates HLA-G expression on trophoblast cells",
]:
    story.append(Paragraph(f"• {pt}", bullet))

story.append(Paragraph("HLA-G Functions:", h3))
two_col_table(story,
    ["Target Cell", "Receptor on Target", "Effect"],
    [
        ["Decidual NK cells", "ILT2, ILT4, KIR2DL4 (inhibitory receptors)", "Prevents NK killing of trophoblasts"],
        ["CD8+ T cells",      "ILT2", "Suppresses cytotoxic T cell attack"],
        ["γδ T cells",        "NKG2A/CD94", "Activates tolerogenic γδ T cells"],
        ["Macrophages/DCs",   "ILT4", "Induces tolerogenic APC phenotype"],
    ],
    col_widths=[4.5*cm, 7*cm, 5.5*cm]
)

story.append(Paragraph(
    "HLA-G is progesterone-dependent. It is the trophoblast's 'do not kill me' signal — "
    "allowing invasion without immune attack.", key_box))


# ══════════════════════════════════════════════════════════════════════════════
# SECTION 5 — Tregs
# ══════════════════════════════════════════════════════════════════════════════
section_header(story, "5.  REGULATORY T CELLS (Tregs) EXPANSION")

story.append(Paragraph(
    "Tregs (CD4+CD25+FOXP3+) are gatekeepers of immune tolerance. Progesterone expands "
    "their numbers and enhances their function.", body))

story.append(Paragraph("How progesterone promotes Tregs:", h3))
for pt in [
    "Pregnancy-level P4 expands CD4+CD25+FOXP3+ Tregs both systemically and in the uterus",
    "Direct hormone receptor signalling on Tregs → enhanced suppressive capacity",
    "Indirect effects on antigen-presenting cells (APCs) → tolerogenic DC phenotype",
    "P4 promotes T cell differentiation INTO Tregs",
    "P4 SUPPRESSES differentiation into pro-inflammatory Th17 cells",
    "Tregs release TGF-β and IL-10 → further suppress Th1 and Th17 responses",
    "Tregs also interact with uNK cells to promote decidual vascular remodelling",
]:
    story.append(Paragraph(f"• {pt}", bullet))

story.append(Paragraph(
    "P4 also promotes differentiation of fetal T cells into Tregs (cord blood studies), "
    "establishing immune tolerance from the fetal side too.", footnote))


# ══════════════════════════════════════════════════════════════════════════════
# SECTION 6 — Direct T cell effects
# ══════════════════════════════════════════════════════════════════════════════
section_header(story, "6.  DIRECT T CELL MEMBRANE EFFECTS")

story.append(Paragraph(
    "Progesterone has direct biophysical effects on T cells, independent of gene "
    "transcription:", body))
for pt in [
    "Alters membrane-resident POTASSIUM CHANNELS → membrane depolarisation",
    "Membrane depolarisation → disrupts intracellular CALCIUM SIGNALLING cascades",
    "Disrupted Ca²⁺ signalling → reduced T cell activation and cytokine gene expression",
    "Net: T cells cannot mount a full effector response against fetal antigens",
]:
    story.append(Paragraph(f"• {pt}", bullet))

story.append(Spacer(1, 4))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 7 — IDO pathway
# ══════════════════════════════════════════════════════════════════════════════
section_header(story, "7.  TRYPTOPHAN / IDO PATHWAY  (Supplementary Mechanism)")

story.append(Paragraph(
    "Indoleamine 2,3-dioxygenase (IDO) is expressed in human uterine decidua and "
    "provides an additional tolerogenic mechanism:", body))
for pt in [
    "T cells REQUIRE tryptophan for activation and proliferation",
    "IDO catabolises local tryptophan → creates tryptophan-depleted microenvironment",
    "Tryptophan depletion → T cell starvation → cannot mount anti-fetal responses",
    "In mice: IDO inhibition → loss of allogeneic (but not syngeneic) fetuses",
    "IDO expression in human decidua increases with gestational age",
]:
    story.append(Paragraph(f"• {pt}", bullet))

story.append(Paragraph(
    "Note: This pathway is not directly driven by progesterone but is part of the "
    "overall tolerogenic milieu that progesterone helps establish.", footnote))

story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 8 — Summary Flowchart (text-based)
# ══════════════════════════════════════════════════════════════════════════════
section_header(story, "8.  SUMMARY FLOWCHART")

flow_data = [
    ["PROGESTERONE (P4) — Rising throughout pregnancy (corpus luteum → placenta)"],
    ["↓"],
    ["Direct T cell effects\n(K⁺ channels → ↓Ca²⁺ → ↓activation)\n+\nTh1 → Th2 shift\n(↑IL-4, IL-10, TGF-β; ↓IFN-γ, TNF-α)"],
    ["+"],
    ["PIBF induction (via PR on T lymphocytes)\n→ ↓CTL activity  →  ↓NK degranulation  →  ↓PG synthesis"],
    ["+"],
    ["HLA-G upregulation on trophoblasts\n→ binds inhibitory receptors on dNK cells\n→ trophoblasts EVADE immune killing"],
    ["+"],
    ["Treg expansion (CD4+CD25+FOXP3+)\n→ ↑IL-10, TGF-β  →  suppresses Th1 and Th17  →  vascular remodelling"],
    ["↓"],
    ["RESULT: Maternal-fetal immune tolerance → Successful pregnancy"]
]

for row in flow_data:
    bg = PALE if row[0] not in ["↓", "+"] else WHITE
    is_arrow = row[0] in ["↓", "+"]
    txt_style = S("Flow",
        fontName="Helvetica-Bold" if not is_arrow else "Helvetica",
        fontSize=9 if not is_arrow else 14,
        textColor=DARK_GREY if not is_arrow else LIGHT_PURPLE,
        alignment=TA_CENTER,
        leading=13)
    last = row[0] == "RESULT: Maternal-fetal immune tolerance → Successful pregnancy"
    result_style = S("Result",
        fontName="Helvetica-Bold", fontSize=10,
        textColor=WHITE, alignment=TA_CENTER, leading=14)
    t = Table([[Paragraph(row[0], result_style if last else txt_style)]],
              colWidths=[17*cm])
    cell_bg = TEAL if last else bg
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,-1), cell_bg),
        ("TOPPADDING",    (0,0), (-1,-1), 5 if not is_arrow else 0),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5 if not is_arrow else 0),
        ("LEFTPADDING",   (0,0), (-1,-1), 8),
        ("RIGHTPADDING",  (0,0), (-1,-1), 8),
        ("BOX",           (0,0), (-1,-1), 0.5, LIGHT_PURPLE) if not is_arrow else ("LINEBELOW",(0,0),(-1,-1),0,WHITE),
    ]))
    story.append(t)
    if not is_arrow:
        story.append(Spacer(1, 2))


story.append(Spacer(1, 10))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 9 — Clinical Correlations
# ══════════════════════════════════════════════════════════════════════════════
section_header(story, "9.  CLINICAL CORRELATIONS  (High-Yield)")

two_col_table(story,
    ["Clinical Scenario", "Progesterone's Immune Role", "Key Molecule"],
    [
        ["Recurrent miscarriage (RPL)", "Low PIBF / excess Th1 cytokines → fetal rejection;\nP4 supplementation restores tolerance", "PIBF, TNF-α"],
        ["Threatened abortion", "P4 maintains PIBF & Th2 environment;\noral/vaginal P4 reduces risk of loss", "PIBF, IL-10"],
        ["Preterm labour", "↓PIBF → ↑arachidonic acid → ↑prostaglandins → uterine contractions", "PIBF, PGE2"],
        ["Preeclampsia", "Associated with Th1 shift and dysregulated tolerance at spiral arteries", "IFN-γ, TNF-α"],
        ["Luteal phase defect", "Inadequate P4 → poor implantation, Treg deficiency", "Tregs, PIBF"],
        ["IVF / ART failure", "Insufficient P4 supplementation → inadequate tolerance induction", "All pathways"],
    ],
    col_widths=[5*cm, 8*cm, 4*cm]
)


# ══════════════════════════════════════════════════════════════════════════════
# SECTION 10 — Quick Recall Box
# ══════════════════════════════════════════════════════════════════════════════
section_header(story, "10.  RAPID RECALL — 10 MUST-KNOW POINTS")

points = [
    ("1", "Fetus = semi-allograft (paternal antigens) → progesterone prevents immune rejection"),
    ("2", "Normal pregnancy = Th2 dominant; Th1 dominance = miscarriage / preeclampsia / preterm birth"),
    ("3", "PIBF (Progesterone-Induced Blocking Factor) = key indirect immune mediator of P4"),
    ("4", "PIBF suppresses: CTLs + NK degranulation + arachidonic acid → prostaglandins"),
    ("5", "uNK cells express GR (not PR); P4 acts via GR → ↓STAT4/IκB → ↓NK activation + ↓IFN-γ"),
    ("6", "HLA-G on trophoblasts = non-classical MHC I; binds ILT2/ILT4/KIR2DL4 → 'do not kill' signal"),
    ("7", "P4 expands CD4+CD25+FOXP3+ Tregs → ↑IL-10, TGF-β → tolerance"),
    ("8", "P4 promotes Treg differentiation + SUPPRESSES Th17 differentiation"),
    ("9", "Direct T cell effect: P4 alters K⁺ channels → ↓Ca²⁺ signalling → ↓T cell activation"),
    ("10", "IDO in decidua depletes tryptophan → T cell starvation → tolerogenic microenvironment"),
]

data = [[Paragraph(f"<b>{n}.</b>", S("Num", fontName="Helvetica-Bold", fontSize=10,
                    textColor=LIGHT_PURPLE, alignment=TA_CENTER)),
         Paragraph(p, body)] for n, p in points]
t = Table(data, colWidths=[1*cm, 16*cm])
t.setStyle(TableStyle([
    ("VALIGN",        (0,0), (-1,-1), "TOP"),
    ("TOPPADDING",    (0,0), (-1,-1), 5),
    ("BOTTOMPADDING", (0,0), (-1,-1), 5),
    ("LEFTPADDING",   (0,0), (-1,-1), 4),
    ("RIGHTPADDING",  (0,0), (-1,-1), 4),
    ("LINEBELOW",     (0,0), (-1,-2), 0.3, colors.HexColor("#D5D8DC")),
    *[("BACKGROUND",  (0,i), (-1,i), PALE) for i in range(0,10,2)],
]))
story.append(t)
story.append(Spacer(1, 8))

# ══════════════════════════════════════════════════════════════════════════════
# SOURCES
# ══════════════════════════════════════════════════════════════════════════════
hr(story)
story.append(Paragraph("<b>Key Sources</b>", h3))
for src in [
    "Berek & Novak's Gynecology — 'Regulation of Decidual Immune Cells', pp. 1811–1813",
    "Tietz Textbook of Laboratory Medicine 7e — 'Allergy and Pregnancy'",
    "Mehta P et al. (2026) Immunomodulatory Role of Natural Progesterone in Pregnancy. J Obstet Gynaecol Res. PMID: 42303279",
    "Szekeres-Bartho J. Progesterone-related immune modulation of pregnancy and labor. Front Endocrinol, 2019.",
    "Frontiers in Immunology (2026) — Regulatory T cells in human pregnancy. PMID: (in press)",
]:
    story.append(Paragraph(f"• {src}", footnote))

story.append(Spacer(1, 6))
story.append(Paragraph(
    "Generated by Orris Medical Education  •  July 2026  •  For revision purposes only — not a substitute for clinical guidance.",
    S("Disc", fontName="Helvetica-Oblique", fontSize=7, textColor=colors.grey, alignment=TA_CENTER)))

# ══════════════════════════════════════════════════════════════════════════════
# BUILD PDF
# ══════════════════════════════════════════════════════════════════════════════
doc.build(story)
print(f"PDF created: {OUTPUT}")