Novel Biomarkers in Sepsis

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// ══════════════════════════════════════════════════════════════════
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// ══════════════════════════════════════════════════════════════════
// SLIDE 2 — LEARNING OBJECTIVES
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    { num: "02", text: "Identify mechanisms and clinical utility of novel biomarkers: presepsin, HBP, sTREM-1, ProADM, MDW, RDW, NGAL, and PTX3", color: C.green },
    { num: "03", text: "Apply cytokine and molecular biomarkers (IL-6, NLR, cfDNA, transcriptomics) to risk stratification", color: C.gold },
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// ══════════════════════════════════════════════════════════════════
// SLIDE 3 — SEPSIS DEFINITION & THE DIAGNOSTIC CHALLENGE
// ══════════════════════════════════════════════════════════════════
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  sectionHeader(s, "BACKGROUND");
  slideTitle(s, "The Diagnostic Challenge of Sepsis");

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    { val: "3 hrs", sub: "antibiotic window", c: C.gold },
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  // Right panel — why biomarkers matter
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    "Blood cultures: 24-72 hr delay",
    "CRP: poor bacterial specificity",
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    "PCT: misses viral & fungal sepsis",
    "Clinical signs overlap with SIRS",
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// ══════════════════════════════════════════════════════════════════
// SLIDE 4 — BIOMARKER LANDSCAPE OVERVIEW
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        { name: "C-Reactive Protein", tag: "Inflammation", tc: C.gray },
        { name: "Blood Lactate", tag: "Resuscitation", tc: C.gray },
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        { name: "Blood Cultures", tag: "Gold standard", tc: C.gray },
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        { name: "Presepsin (sCD14-ST)", tag: "Early bacterial Dx", tc: C.cyan },
        { name: "Heparin-Binding Protein", tag: "Pre-clinical sepsis", tc: C.cyan },
        { name: "sTREM-1", tag: "Myeloid activation", tc: C.cyan },
        { name: "Proadrenomedullin", tag: "Prognosis/ICU triage", tc: C.cyan },
        { name: "NGAL", tag: "AKI prediction", tc: C.cyan },
        { name: "MDW / RDW", tag: "Hematologic", tc: C.cyan },
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        { name: "cfDNA / miRNA", tag: "Molecular", tc: C.gold },
        { name: "Transcriptomics (ELL2)", tag: "Subphenotyping", tc: C.gold },
        { name: "BMP9", tag: "Vascular/Therapy", tc: C.gold },
        { name: "Metabolomics", tag: "Precision medicine", tc: C.gold },
        { name: "Pentraxin-3 (PTX3)", tag: "Neonatal sepsis", tc: C.gold },
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// ══════════════════════════════════════════════════════════════════
// SLIDE 5 — PROCALCITONIN (ESTABLISHED, DEEP DIVE)
// ══════════════════════════════════════════════════════════════════
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  sectionHeader(s, "ESTABLISHED BIOMARKERS");
  slideTitle(s, "Procalcitonin (PCT): The Current Standard");

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    "Prohormone of calcitonin; produced by thyroid in health",
    "Bacterial infection → synthesized by virtually ALL tissues",
    "Rises within 2-4 hrs of bacterial infection",
    "Half-life: ~24 hrs — useful for de-escalation monitoring",
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    { title: "Diagnosis", text: "Sens 77%, Spec 79% for sepsis in ED\n(meta-analysis 2025, Chuang et al.)" },
    { title: "Antibiotic Stewardship", text: "PCT-guided therapy → shorter course\n+ improved survival (Papp et al. 2023)" },
    { title: "Serial Monitoring", text: "PCT clearance ≥80% over 72 hrs\nassociated with reduced mortality" },
    { title: "Limitations", text: "False-positive: trauma, surgery, burns\nFalse-negative: viral/fungal infections" },
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// ══════════════════════════════════════════════════════════════════
// SLIDE 6 — PRESEPSIN
// ══════════════════════════════════════════════════════════════════
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  sectionHeader(s, "NOVEL BIOMARKERS");
  slideTitle(s, "Presepsin (sCD14-ST): Earlier Than PCT");

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    "Bacteria engulfed\nby monocyte/macrophage",
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    "Soluble fragment\n(presepsin) released",
    "Detectable in blood\nwithin 1-2 hours",
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  const evPoints = [
    "Rises EARLIER than PCT after bacterial infection",
    "AUC 0.86 for sepsis diagnosis (Paraskevas et al. 2023)",
    "Correlates with severity and organ failure scores",
    "Guides antibiotic decisions: start AND de-escalation",
    "FDA-approved point-of-care assay available",
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  s.addText("vs. PCT — Key Differences", {
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    { label: "Onset", pct: "2-4 hrs", pre: "1-2 hrs" },
    { label: "Source", pct: "All tissues", pre: "Monocytes/macrophages" },
    { label: "Specificity", pct: "Moderate", pre: "Higher for bacterial" },
    { label: "AKI effect", pct: "↑ in renal failure", pre: "Less affected" },
    { label: "Viral sepsis", pct: "Lower levels", pre: "Also elevated" },
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  s.addText("PCT", { x: 6.1, y: 3.22, w: 1.6, h: 0.28, fontSize: 9, bold: true, color: C.gray, margin: 0 });
  s.addText("Presepsin", { x: 7.8, y: 3.22, w: 1.65, h: 0.28, fontSize: 9, bold: true, color: C.cyan, margin: 0 });
  compRows.forEach((r, i) => {
    const y = 3.52 + i * 0.33;
    s.addText(r.label, { x: 5.15, y, w: 0.9, h: 0.3, fontSize: 9.5, color: C.gray });
    s.addText(r.pct, { x: 6.1, y, w: 1.6, h: 0.3, fontSize: 9.5, color: C.offwhite });
    s.addText(r.pre, { x: 7.8, y, w: 1.65, h: 0.3, fontSize: 9.5, color: C.cyan });
  });

  footerBar(s);
}

// ══════════════════════════════════════════════════════════════════
// SLIDE 7 — HEPARIN-BINDING PROTEIN & sTREM-1
// ══════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightSlide(s);
  sectionHeader(s, "NOVEL BIOMARKERS");
  slideTitle(s, "HBP & sTREM-1: Pre-Clinical Sepsis Detection");

  // HBP card
  card(s, 0.4, 1.32, 4.5, 3.9, C.white);
  s.addShape(pres.shapes.RECTANGLE, {
    x: 0.4, y: 1.32, w: 4.5, h: 0.08,
    fill: { color: C.teal }, line: { color: C.teal }
  });
  tagPill(s, 0.5, 1.45, 2.5, "HEPARIN-BINDING PROTEIN (HBP)", C.teal);
  s.addText([
    { text: "Source: ", options: { bold: true, color: C.navy } },
    { text: "Neutrophil granules\n", options: { color: C.navy } },
    { text: "Released: ", options: { bold: true, color: C.navy } },
    { text: "Minutes after bacterial stimulation\n", options: { color: C.navy } },
    { text: "Action: ", options: { bold: true, color: C.navy } },
    { text: "Causes vascular leakage → tissue edema\n\n", options: { color: C.navy } },
    { text: "Key Clinical Points\n", options: { bold: true, color: C.teal } },
    { text: "• Rises BEFORE clinical sepsis criteria are met\n• Predicts progression to severe sepsis/shock\n• AUC 0.87 for septic shock prediction\n• Normal: <30 ng/mL; Sepsis threshold: >70 ng/mL\n• Endorsed in 2025 Bourika et al. review\n  (Ann Intensive Care, PMID 40685448)", options: { color: C.navy } },
  ], {
    x: 0.55, y: 1.8, w: 4.2, h: 3.2, fontSize: 10.5, valign: "top"
  });

  // sTREM-1 card
  card(s, 5.2, 1.32, 4.4, 3.9, C.navy);
  s.addShape(pres.shapes.RECTANGLE, {
    x: 5.2, y: 1.32, w: 4.4, h: 0.08,
    fill: { color: C.gold }, line: { color: C.gold }
  });
  tagPill(s, 5.3, 1.45, 2.8, "SOLUBLE TREM-1 (sTREM-1)", C.gold);
  s.addText([
    { text: "TREM-1: ", options: { bold: true, color: C.gold } },
    { text: "Triggering Receptor Expressed on Myeloid cells\n", options: { color: C.offwhite } },
    { text: "Location: ", options: { bold: true, color: C.gold } },
    { text: "Neutrophils & monocytes; shed during infection\n\n", options: { color: C.offwhite } },
    { text: "Mechanism\n", options: { bold: true, color: C.gold } },
    { text: "Amplifies pro-inflammatory signaling beyond\nToll-like receptors — unique to infection,\nnot sterile inflammation\n\n", options: { color: C.offwhite } },
    { text: "Clinical Role\n", options: { bold: true, color: C.gold } },
    { text: "• Early indicator of bacterial/fungal sepsis\n• Risk stratification beyond CRP/PCT\n• Distinguishes infection from SIRS\n• TREM-2: emerging variant with higher\n  specificity for bacterial vs. viral\n• Urine sTREM-1 in VAP diagnosis", options: { color: C.offwhite } },
  ], {
    x: 5.35, y: 1.8, w: 4.1, h: 3.2, fontSize: 10.5, valign: "top"
  });

  footerBar(s);
}

// ══════════════════════════════════════════════════════════════════
// SLIDE 8 — ProADM, NGAL, MDW, RDW
// ══════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightSlide(s);
  sectionHeader(s, "NOVEL BIOMARKERS");
  slideTitle(s, "ProADM · NGAL · MDW · RDW");

  const cards4 = [
    {
      x: 0.3, y: 1.32, title: "Proadrenomedullin (ProADM)", color: C.teal,
      points: [
        "Stable precursor of vasodilatory peptide adrenomedullin",
        "Correlates strongly with sepsis severity & organ dysfunction",
        "Superior to PCT for ICU admission prediction",
        "Combined with SOFA: best prognostic accuracy",
        "MR-proADM >0.8 nmol/L: higher mortality risk",
      ]
    },
    {
      x: 5.2, y: 1.32, title: "NGAL (Neutrophil Gelatinase-Assoc. Lipocalin)", color: C.cyan,
      points: [
        "Released by neutrophils & renal tubular cells",
        "Sepsis-AKI marker: rises 24-48 hrs before creatinine",
        "Dual role: antimicrobial (iron sequestration) + AKI marker",
        "Urinary NGAL >150 ng/mL: predicts persistent AKI",
        "Guides nephrotoxic drug avoidance early",
      ]
    },
    {
      x: 0.3, y: 3.45, title: "Monocyte Distribution Width (MDW)", color: C.gold,
      points: [
        "Measures size variability of activated monocytes",
        "Monocytes enlarge during infectious activation",
        "FDA-cleared adjunctive test for sepsis in ED",
        "AUC 0.79 for sepsis detection on CBC-Diff",
        "No extra sample; on standard hematology analyzer",
      ]
    },
    {
      x: 5.2, y: 3.45, title: "Red Cell Distribution Width (RDW)", color: C.red,
      points: [
        "IL-6, TNF-α impair RBC maturation → larger immature RBCs",
        "Non-survivors vs. survivors: 17.8% vs. 16.8% (p=0.029)",
        "Superior to CRP; complementary to PCT",
        "Simple, inexpensive — on every CBC",
        "Tietz Textbook (7e): promising prognostic marker",
      ]
    },
  ];

  cards4.forEach(cd => {
    card(s, cd.x, cd.y, 4.5, 1.95, C.white);
    s.addShape(pres.shapes.RECTANGLE, {
      x: cd.x, y: cd.y, w: 4.5, h: 0.07,
      fill: { color: cd.color }, line: { color: cd.color }
    });
    s.addText(cd.title, {
      x: cd.x + 0.12, y: cd.y + 0.1, w: 4.2, h: 0.32,
      fontSize: 10, bold: true, color: cd.color, margin: 0
    });
    cd.points.forEach((pt, i) => {
      s.addText([
        { text: "• ", options: { color: cd.color, bold: true } },
        { text: pt, options: { color: C.navy } }
      ], {
        x: cd.x + 0.12, y: cd.y + 0.45 + i * 0.28, w: 4.2, h: 0.27, fontSize: 9.5
      });
    });
  });

  footerBar(s);
}

// ══════════════════════════════════════════════════════════════════
// SLIDE 9 — CYTOKINES & HEMATOLOGIC INDICES
// ══════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkSlide(s);
  s.addShape(pres.shapes.RECTANGLE, {
    x: 0, y: 0, w: 10, h: 0.08, fill: { color: C.gold }, line: { color: C.gold }
  });
  s.addText("Cytokines & Immune Indices", {
    x: 0.5, y: 0.18, w: 9, h: 0.55,
    fontSize: 24, bold: true, color: C.white
  });
  s.addShape(pres.shapes.RECTANGLE, {
    x: 0.5, y: 0.75, w: 1.5, h: 0.05,
    fill: { color: C.gold }, line: { color: C.gold }
  });

  // cytokine table
  s.addText("Cytokine Biomarkers", {
    x: 0.4, y: 0.9, w: 5.8, h: 0.32,
    fontSize: 12, bold: true, color: C.gold, margin: 0
  });

  const cytoData = [
    { marker: "IL-6", rise: "< 1 hr", role: "Early severity; parallels bacterial load", note: "Best early alert" },
    { marker: "TNF-α", rise: "1-2 hrs", role: "Pro-inflammatory trigger; peaks early then falls", note: "Less useful kinetically" },
    { marker: "IL-10", rise: "2-4 hrs", role: "Anti-inflammatory; marks immunosuppression phase", note: "Prognosis/endotyping" },
    { marker: "IL-8", rise: "1-3 hrs", role: "Neutrophil recruitment; bacterial sepsis", note: "VAP / neonatal sepsis" },
    { marker: "IFN-γ", rise: "4-6 hrs", role: "Viral/macrophage activation; HLH overlap", note: "Cytokine storm" },
  ];

  // Header row
  const hCols = [
    { t: "Cytokine", x: 0.4, w: 1.1 },
    { t: "Rise", x: 1.55, w: 1.0 },
    { t: "Role in Sepsis", x: 2.6, w: 3.8 },
    { t: "Best Use", x: 6.45, w: 2.2 },
  ];
  hCols.forEach(h => {
    s.addText(h.t, {
      x: h.x, y: 1.28, w: h.w, h: 0.28,
      fontSize: 9.5, bold: true, color: C.gold, margin: 0, valign: "middle"
    });
  });
  s.addShape(pres.shapes.RECTANGLE, {
    x: 0.4, y: 1.56, w: 8.8, h: 0.02,
    fill: { color: C.gold }, line: { color: C.gold }
  });

  cytoData.forEach((row, i) => {
    const y = 1.62 + i * 0.36;
    const bg = i % 2 === 0 ? C.slate : C.navy;
    s.addShape(pres.shapes.RECTANGLE, {
      x: 0.4, y: y, w: 8.8, h: 0.34,
      fill: { color: bg }, line: { color: bg }
    });
    s.addText(row.marker, { x: 0.42, y, w: 1.1, h: 0.34, fontSize: 10, bold: true, color: C.cyan, valign: "middle", margin: 0 });
    s.addText(row.rise, { x: 1.57, y, w: 1.0, h: 0.34, fontSize: 9.5, color: C.offwhite, valign: "middle", margin: 0 });
    s.addText(row.role, { x: 2.62, y, w: 3.8, h: 0.34, fontSize: 9.5, color: C.offwhite, valign: "middle", margin: 0 });
    s.addText(row.note, { x: 6.47, y, w: 2.2, h: 0.34, fontSize: 9.5, color: C.gold, valign: "middle", margin: 0 });
  });

  // NLR panel
  s.addText("Neutrophil-to-Lymphocyte Ratio (NLR)", {
    x: 0.4, y: 3.5, w: 5.5, h: 0.32,
    fontSize: 12, bold: true, color: C.cyan, margin: 0
  });
  const nlrPts = [
    "Neutrophilia + lymphopenia = dysregulated immune response to infection",
    "Meta-analysis 2024 (Wu et al., PMID 38562922): pooled AUC ~0.72 for mortality in adult sepsis",
    "Neonatal sepsis: NLR meta-analysis (Chen et al. 2023, PMID 38012554) — diagnostic value confirmed",
    "Inexpensive, universally available on CBC — ideal for resource-limited settings",
  ];
  nlrPts.forEach((p, i) => {
    s.addText([
      { text: "• ", options: { color: C.cyan, bold: true } },
      { text: p, options: { color: C.offwhite } }
    ], {
      x: 0.55, y: 3.88 + i * 0.33, w: 9.0, h: 0.3, fontSize: 10.5
    });
  });

  footerBar(s);
}

// ══════════════════════════════════════════════════════════════════
// SLIDE 10 — MOLECULAR & OMICS BIOMARKERS
// ══════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightSlide(s);
  sectionHeader(s, "EMERGING BIOMARKERS — MOLECULAR & OMICS");
  slideTitle(s, "Transcriptomics · Metabolomics · cfDNA");

  const omicCards = [
    {
      x: 0.3, y: 1.32, w: 3.0, h: 3.9, bgColor: "001F3F", borderColor: C.cyan,
      title: "Transcriptomics", tc: C.cyan,
      points: [
        "Host gene expression\nprofiles (RNA-seq)",
        "AI models: predict\nsepsis 24 hrs early\nwith 88% accuracy",
        "ELL2 gene (B-cell):\nnovel biomarker (2025)\nvalidated in 10 cohorts",
        "SRS1 vs SRS2\nendotyping for targeted\nimmunotherapy",
        "Metagenomics: direct\npathogen ID from blood\n(sensitivity > culture)",
      ]
    },
    {
      x: 3.55, y: 1.32, w: 3.0, h: 3.9, bgColor: "001A2F", borderColor: C.gold,
      title: "Metabolomics", tc: C.gold,
      points: [
        "Blood lactate: still\ncornerstone; guides\nresuscitation (SSC)",
        "Modified amino acids\nlinked to mitochondrial\ndysfunction → mortality",
        "Metabolic signatures\nvariable w/ APACHE II +\nSOFA: improve accuracy",
        "LC-MS technologies:\nidentify new metabolite\nsepsis signatures",
        "Harrison's 22e: 'strong\nassociation between\nmortality and modified\namino acids in sepsis'",
      ]
    },
    {
      x: 6.8, y: 1.32, w: 3.0, h: 3.9, bgColor: "0F1A2B", borderColor: C.teal,
      title: "cfDNA & Other", tc: C.teal,
      points: [
        "Cell-free DNA: released\nfrom necrotic/apoptotic\ncells during sepsis",
        "↑ cfDNA correlates\nwith organ failure\n& sepsis severity",
        "BMP9: vascular growth\nfactor; prognostic marker\n& therapy target (2024)",
        "Endothelin-1: rises\nwith sepsis severity;\nmonitoring via LC-MS",
        "miRNA panels: neonatal\nsepsis diagnosis Dx\n(meta-analysis 2024)",
      ]
    },
  ];

  omicCards.forEach(oc => {
    card(s, oc.x, oc.y, oc.w, oc.h, oc.bgColor, oc.borderColor);
    s.addShape(pres.shapes.RECTANGLE, {
      x: oc.x, y: oc.y, w: oc.w, h: 0.08,
      fill: { color: oc.borderColor }, line: { color: oc.borderColor }
    });
    s.addText(oc.title, {
      x: oc.x + 0.1, y: oc.y + 0.12, w: oc.w - 0.2, h: 0.35,
      fontSize: 13, bold: true, color: oc.tc, align: "center", margin: 0
    });
    oc.points.forEach((p, i) => {
      s.addText([
        { text: "▸ ", options: { color: oc.tc, bold: true } },
        { text: p, options: { color: C.offwhite } }
      ], {
        x: oc.x + 0.12, y: oc.y + 0.56 + i * 0.65, w: oc.w - 0.22, h: 0.6,
        fontSize: 9.5, valign: "top"
      });
    });
  });

  footerBar(s);
}

// ══════════════════════════════════════════════════════════════════
// SLIDE 11 — SEPSIS SUBPHENOTYPING & PRECISION MEDICINE
// ══════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkSlide(s);
  s.addShape(pres.shapes.RECTANGLE, {
    x: 0, y: 0, w: 10, h: 0.08, fill: { color: C.green }, line: { color: C.green }
  });
  s.addText("Precision Medicine: Sepsis Subphenotyping", {
    x: 0.5, y: 0.18, w: 9, h: 0.55,
    fontSize: 23, bold: true, color: C.white
  });
  s.addShape(pres.shapes.RECTANGLE, {
    x: 0.5, y: 0.75, w: 1.5, h: 0.05,
    fill: { color: C.green }, line: { color: C.green }
  });

  s.addText("Why One Size Does NOT Fit All in Sepsis", {
    x: 0.5, y: 0.88, w: 9.0, h: 0.3,
    fontSize: 11, italic: true, color: C.gray
  });

  // Two phenotype cards
  const phenotypes = [
    {
      x: 0.3, label: "Hyperinflammatory\nSRS1 / Endotype A", labelColor: C.red,
      markers: ["↑↑ Ferritin", "↑↑ IL-6, TNF-α", "↓ Protein C", "↓ PAI-1", "↑ Aminotransferases"],
      treat: "May benefit from\nanti-inflammatory therapy\n(IL-6 blockade, steroids)",
      treatColor: C.red,
    },
    {
      x: 5.1, label: "Immunosuppressed\nSRS2 / Endotype B", labelColor: C.cyan,
      markers: ["↑ IL-10 (dominant)", "↓ HLA-DR monocytes", "Low inflammatory markers", "T-cell exhaustion", "Secondary infections"],
      treat: "May benefit from\nimmunostimulation\n(IL-7, IFN-γ, anti-PD-1)",
      treatColor: C.cyan,
    }
  ];

  phenotypes.forEach(ph => {
    card(s, ph.x, 1.25, 4.5, 4.0, C.slate);
    s.addText(ph.label, {
      x: ph.x + 0.15, y: 1.32, w: 4.2, h: 0.6,
      fontSize: 14, bold: true, color: ph.labelColor, align: "center", margin: 0
    });
    s.addShape(pres.shapes.RECTANGLE, {
      x: ph.x + 0.15, y: 1.95, w: 4.2, h: 0.03,
      fill: { color: ph.labelColor }, line: { color: ph.labelColor }
    });

    s.addText("Biomarker Profile", {
      x: ph.x + 0.15, y: 2.03, w: 4.2, h: 0.28,
      fontSize: 10, bold: true, color: C.gray, margin: 0
    });
    ph.markers.forEach((m, i) => {
      s.addText([
        { text: "• ", options: { color: ph.labelColor, bold: true } },
        { text: m, options: { color: C.offwhite } }
      ], {
        x: ph.x + 0.2, y: 2.35 + i * 0.32, w: 4.0, h: 0.3, fontSize: 10.5
      });
    });

    card(s, ph.x + 0.15, 4.0, 4.2, 1.0, ph.treatColor);
    s.addText("Treatment Strategy", {
      x: ph.x + 0.3, y: 4.05, w: 3.8, h: 0.25,
      fontSize: 9, bold: true, color: C.white, margin: 0
    });
    s.addText(ph.treat, {
      x: ph.x + 0.3, y: 4.32, w: 3.8, h: 0.6,
      fontSize: 10.5, color: C.white, valign: "top"
    });
  });

  // Dividing "vs"
  s.addText("vs.", {
    x: 4.65, y: 2.8, w: 0.7, h: 0.5,
    fontSize: 20, bold: true, color: C.gray, align: "center", valign: "middle"
  });

  footerBar(s);
}

// ══════════════════════════════════════════════════════════════════
// SLIDE 12 — CLINICAL INTEGRATION: 3 USE CASES
// ══════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightSlide(s);
  sectionHeader(s, "CLINICAL INTEGRATION");
  slideTitle(s, "How to Use Biomarkers at the Bedside");

  const useCases = [
    {
      num: "1", title: "Early Diagnosis (ED / First 3 Hours)",
      color: C.red,
      markers: "PCT + CRP + HBP + Presepsin + MDW (on CBC)",
      action: "Trigger early sepsis pathway, IV access, blood cultures × 2,\nbroad-spectrum antibiotics within 1 hour",
      threshold: "PCT >0.5 ng/mL OR Presepsin >317 pg/mL OR HBP >30 ng/mL",
    },
    {
      num: "2", title: "Antibiotic Stewardship (Days 3-7)",
      color: C.teal,
      markers: "PCT kinetics (serial) ± CRP trend",
      action: "PCT clearance ≥80% at 72 hrs → consider de-escalation\nPCT <0.25 ng/mL at day 5-7 → stop antibiotics",
      threshold: "Reduces antibiotic exposure by 2-3 days (Papp et al. 2023)",
    },
    {
      num: "3", title: "Resuscitation & Organ Support",
      color: C.gold,
      markers: "Lactate + ProADM + Cardiac markers (BNP, troponin) + NGAL",
      action: "Lactate clearance ≥10%/2hrs → continue fluids\nNGAL rising → avoid nephrotoxins, early RRT consideration\nProADM >0.8 nmol/L → ICU admission threshold",
      threshold: "Surviving Sepsis Campaign: target lactate normalization",
    },
  ];

  useCases.forEach((uc, i) => {
    const y = 1.32 + i * 1.35;
    card(s, 0.4, y, 9.2, 1.22, C.white);
    s.addShape(pres.shapes.RECTANGLE, {
      x: 0.4, y: y, w: 0.1, h: 1.22,
      fill: { color: uc.color }, line: { color: uc.color }
    });
    // Number
    s.addShape(pres.shapes.OVAL, {
      x: 0.55, y: y + 0.32, w: 0.55, h: 0.55,
      fill: { color: uc.color }, line: { color: uc.color }
    });
    s.addText(uc.num, {
      x: 0.55, y: y + 0.32, w: 0.55, h: 0.55,
      fontSize: 16, bold: true, color: C.white, align: "center", valign: "middle", margin: 0
    });
    s.addText(uc.title, {
      x: 1.25, y: y + 0.08, w: 7.9, h: 0.32,
      fontSize: 12, bold: true, color: uc.color, margin: 0
    });
    s.addText([
      { text: "Biomarkers: ", options: { bold: true, color: C.navy } },
      { text: uc.markers, options: { color: C.navy } }
    ], {
      x: 1.25, y: y + 0.4, w: 7.9, h: 0.28, fontSize: 10
    });
    s.addText([
      { text: "Action: ", options: { bold: true, color: uc.color } },
      { text: uc.action, options: { color: C.navy } }
    ], {
      x: 1.25, y: y + 0.68, w: 7.9, h: 0.36, fontSize: 10
    });
    s.addText(uc.threshold, {
      x: 1.25, y: y + 1.02, w: 7.9, h: 0.18,
      fontSize: 8.5, color: C.gray, italic: true
    });
  });

  footerBar(s);
}

// ══════════════════════════════════════════════════════════════════
// SLIDE 13 — MASTER SUMMARY TABLE
// ══════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkSlide(s);
  s.addShape(pres.shapes.RECTANGLE, {
    x: 0, y: 0, w: 10, h: 0.08, fill: { color: C.cyan }, line: { color: C.cyan }
  });
  s.addText("Summary: Sepsis Biomarker Reference", {
    x: 0.4, y: 0.13, w: 9.2, h: 0.48,
    fontSize: 20, bold: true, color: C.white
  });

  const tableData = [
    ["Biomarker", "Class", "Primary Use", "AUC/Performance", "Key Limitation"],
    ["PCT", "Hormonal", "Dx + Antibiotic steward.", "Sens 77% Spec 79%", "False+ in trauma/surgery"],
    ["CRP", "Acute-phase", "Inflammation screen", "Moderate AUC ~0.74", "Poor bacterial specificity"],
    ["Lactate", "Metabolite", "Resuscitation target", "Clearance guides Rx", "Not infection-specific"],
    ["Presepsin", "Immune (CD14)", "Early bacterial Dx", "AUC 0.86", "Renal failure affects level"],
    ["HBP", "Neutrophil", "Pre-clinical sepsis", "AUC 0.87 for shock", "Not widely available"],
    ["sTREM-1", "Myeloid", "Infection vs. SIRS", "AUC 0.85", "Research use mainly"],
    ["ProADM", "Vasopeptide", "ICU triage/prognosis", "Best severity correlate", "Cost; limited availability"],
    ["NGAL", "Renal/immune", "AKI prediction", "Rises 24-48 hr early", "Non-specific; many causes"],
    ["MDW", "Hematologic", "ED sepsis screening", "AUC 0.79", "FDA-cleared; limited data"],
    ["RDW", "Hematologic", "Prognosis", "Superior to CRP", "Non-specific; many causes"],
    ["IL-6", "Cytokine", "Early severity alert", "Rises < 1 hour", "Viral, non-infectious causes"],
    ["NLR", "Hematologic", "Mortality risk (prognosis)", "AUC ~0.72 (mortality)", "No infection specificity"],
    ["ELL2 (RNA)", "Transcriptomic", "Subtyping/prognosis", "78% Sens, 82% Spec", "Research-only; complex"],
  ];

  const colWidths = [1.4, 1.2, 1.7, 1.8, 1.85];
  const colX = [0.18, 1.6, 2.82, 4.55, 6.35];
  const headerColors = [C.cyan, C.cyan, C.cyan, C.cyan, C.cyan];
  const rowColors = [C.navy, C.slate];

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// ══════════════════════════════════════════════════════════════════
// SLIDE 14 — EVIDENCE BASE & KEY REFERENCES
// ══════════════════════════════════════════════════════════════════
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    { tier: "SR/MA", pmid: "40214293", text: "Chuang CL et al. PCT vs CRP for sepsis diagnosis: SR/MA. Eur J Emerg Med 2025.", c: C.red },
    { tier: "SR/MA", pmid: "37833778", text: "Papp M et al. PCT-guided therapy: shorter treatment, improved survival. Crit Care 2023.", c: C.red },
    { tier: "SR/MA", pmid: "38562922", text: "Wu H et al. NLR in adult sepsis prognosis: meta-analysis. Front Immunol 2024.", c: C.red },
    { tier: "SR/MA", pmid: "38949476", text: "Kubo K et al. PCT vs CRP for antimicrobial discontinuation: network MA. Crit Care Med 2024.", c: C.red },
    { tier: "SR/MA", pmid: "37127619", text: "Milas GP et al. Pentraxin-3 and neonatal sepsis: SR/MA. J Matern Fetal Neonatal Med 2023.", c: C.red },
    { tier: "Review", pmid: "40685448", text: "Bourika V et al. Biomarkers to guide sepsis management. Ann Intensive Care 2025.", c: C.teal },
    { tier: "Review", pmid: "39067500", text: "Saxena J et al. Biomarkers in sepsis: comprehensive review. Clin Chim Acta 2024.", c: C.teal },
    { tier: "Review", pmid: "37813329", text: "Paraskevas T et al. Presepsin in the diagnosis of sepsis. Clin Chim Acta 2023.", c: C.teal },
    { tier: "Textbook", pmid: "", text: "Tietz Textbook of Laboratory Medicine 7e — RDW as sepsis biomarker.", c: C.gold },
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    { tier: "Textbook", pmid: "", text: "Washington Manual of Medical Therapeutics — PCT and lactate in sepsis.", c: C.gold },
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// ══════════════════════════════════════════════════════════════════
// SLIDE 15 — KEY TAKEAWAYS / CONCLUSION
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// ══════════════════════════════════════════════════════════════════
// WRITE FILE
// ══════════════════════════════════════════════════════════════════
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// ════════════════════════════════════════════════════════════════════════════
// SLIDE 1 — TITLE
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    {text:"mortality  |  No gold-standard Dx test", options:{color:C.gray}}
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// ════════════════════════════════════════════════════════════════════════════
// SLIDE 2 — LEARNING OBJECTIVES
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    { n:"02", c:C.green, t:"Describe the mechanism, diagnostic performance, and SSC guideline recommendations for Procalcitonin and Lactate." },
    { n:"03", c:C.gold,  t:"Identify novel biomarkers — Presepsin, HBP, MDW, NLR, sTREM-1, ProADM, NGAL — with their AUC values and evidence sources." },
    { n:"04", c:C.red,   t:"Apply biomarker panels to three clinical scenarios: early diagnosis, antibiotic de-escalation, and organ failure monitoring." },
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// ════════════════════════════════════════════════════════════════════════════
// SLIDE 3 — SEPSIS-3 DEFINITION & DIAGNOSTIC CHALLENGE (Harrison's 22e)
// ════════════════════════════════════════════════════════════════════════════
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// ════════════════════════════════════════════════════════════════════════════
// SLIDE 4 — LACTATE: HARRISON'S + SSC GUIDELINE
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    "Sources: ischemia, liver failure, medications (metformin), seizures",
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    { grade:"SSC Comment", level:"", text:"Normal serum lactate not achievable in all septic shock patients; interpret in clinical context" },
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  ];
  sscRecs.forEach((r,i) => {
    const y = 2.72+i*0.68;
    pill(s, 5.25,y+0.02, 1.8, r.grade+(r.level?" | "+r.level:""), r.grade==="Conditional"?C.teal:r.grade==="Septic Shock"?C.red:C.amber);
    s.addText(r.text, { x:5.25,y:y+0.32, w:4.2,h:0.32, fontSize:9.5, color:C.offwhite });
  });

  refBox(s, 0.4,5.22, 9.2,0.35, "Refs: Harrison's 22e Ch.315, p.2363 | Evans L et al. SSC Guidelines 2021, Crit Care Med 49:e1063. PMID 34599691 | Sartini C et al. Beyond SSC Guidelines, Panminerva Med 2024 (PMID 38093626)");
  footer(s);
}

// ════════════════════════════════════════════════════════════════════════════
// SLIDE 5 — PROCALCITONIN: HARRISON'S + SSC + PubMed
// ════════════════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  sectionTag(s, "ESTABLISHED BIOMARKER  |  Harrison's 22e Ch.315 · SSC 2021 Guidelines · Papp M et al. Crit Care 2023 (PMID 37833778) · Chuang CL et al. Eur J Emerg Med 2025 (PMID 40214293)");
  slideH(s, "Procalcitonin (PCT): Guideline-Endorsed Biomarker");

  // Harrison quote
  card(s, 0.4,1.28, 9.2,0.68, "EAF5F5", C.teal);
  s.addText([
    {text:"Harrison's 22e, Ch.315: ", options:{bold:true, color:C.teal}},
    {text:'"Empiric antimicrobial therapy within 1 h of shock recognition is recommended... PCT may be used to guide discontinuation of antimicrobials."', options:{color:C.navy, italic:true}},
  ], { x:0.55,y:1.33, w:8.9,h:0.58, fontSize:10.5, valign:"middle" });

  // Left: mechanism + thresholds
  card(s, 0.4,2.1, 4.4,3.12, C.white, C.ltgray);
  s.addText("Mechanism & Diagnostic Performance", { x:0.55,y:2.16, w:4.1,h:0.3, fontSize:11, bold:true, color:C.teal, margin:0 });

  const mechData = [
    ["Origin:", "Prohormone of calcitonin; thyroid in health. In bacterial infection: synthesized by virtually ALL tissues"],
    ["Kinetics:", "Rises 2-4 hrs after infection onset; half-life ~24 hrs → useful for serial monitoring"],
    ["AUC:", "0.74 (95% CI 0.62–0.84) vs CRP AUC 0.67 — PCT outperforms CRP (Chuang et al. 2025)"],
    ["Sensitivity:", "70% (optimal cut-off 0.54 ng/mL) | Specificity: 67% (Chuang 2025, 44 studies, n=10,755)"],
    ["Threshold >0.5:", "Suggestive of bacterial infection"],
    ["Threshold <0.1:", "Makes bacterial infection less likely (does NOT exclude severe infection)"],
    ["Stewardship:", "PCT-guided Rx: −1.79 days antibiotic duration, OR 0.84 for 28-day mortality (Papp et al. 2023, 26 RCTs, n=9048)"],
  ];
  mechData.forEach(([label, val], i) => {
    s.addText([
      {text:label+" ", options:{bold:true, color:C.teal}},
      {text:val, options:{color:C.navy}}
    ], { x:0.55,y:2.52+i*0.38, w:4.1,h:0.36, fontSize:9.5 });
  });

  // Right: SSC recommendations
  card(s, 5.1,2.1, 4.5,3.12, C.navy, C.cyan);
  s.addText("SSC 2021 Guideline: PCT Recommendations", { x:5.25,y:2.16, w:4.2,h:0.3, fontSize:11, bold:true, color:C.cyan, margin:0 });

  const pctSSC = [
    {
      rec:"Rec #16 (Start Antibiotics)",
      grade:"Conditional AGAINST",
      gradeC: C.red,
      level:"Very low certainty",
      text:"Suggest AGAINST using PCT + clinical evaluation to decide when to START antimicrobials, compared to clinical evaluation alone"
    },
    {
      rec:"Rec #31 (Discontinue Antibiotics)",
      grade:"Conditional FOR",
      gradeC: C.green,
      level:"Low certainty",
      text:"Suggest using PCT AND clinical evaluation to decide when to DISCONTINUE antimicrobials over clinical evaluation alone (adequate source control)"
    },
    {
      rec:"Network Meta-Analysis 2024",
      grade:"Evidence",
      gradeC: C.teal,
      level:"Kubo et al. Crit Care Med",
      text:"PCT-guided discontinuation: −1.89 days AB, −27 deaths/1000 patients; no significant increase in recurrence (PMID 38949476)"
    },
  ];
  pctSSC.forEach((r,i) => {
    const y = 2.52+i*0.98;
    s.addText(r.rec, { x:5.25,y:y, w:4.2,h:0.24, fontSize:9, bold:true, color:C.gray, margin:0 });
    pill(s, 5.25,y+0.24, 3.6, r.grade+" | "+r.level, r.gradeC);
    s.addText(r.text, { x:5.25,y:y+0.55, w:4.2,h:0.36, fontSize:9, color:C.offwhite });
  });

  refBox(s, 0.4,5.22, 9.2,0.35, "Refs: Harrison's 22e Ch.315 | SSC 2021 Recs #16 & #31 (Evans et al. PMID 34599691) | Papp M et al. Crit Care 2023 (PMID 37833778) | Kubo K et al. Crit Care Med 2024 (PMID 38949476) | Chuang CL et al. Eur J Emerg Med 2025 (PMID 40214293)");
  footer(s);
}

// ════════════════════════════════════════════════════════════════════════════
// SLIDE 6 — MONOCYTE DISTRIBUTION WIDTH (MDW): JAMA-Level Evidence
// ════════════════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  sectionTag(s, "NOVEL BIOMARKER  |  Huang YH et al. Crit Care Med 2023 (PMID 36877030, SR/MA) · SSC 2021 — 'Insufficient evidence for novel rapid host response diagnostics'");
  slideH(s, "Monocyte Distribution Width (MDW): FDA-Cleared Novel Biomarker");

  // JAMA-tier evidence callout
  card(s, 0.4,1.28, 9.2,0.88, "E8F8EC", C.green);
  s.addText([
    {text:"Level 1 Evidence (SR/MA, Crit Care Med 2023): ", options:{bold:true, color:C.green}},
    {text:"18 studies included (Huang et al., PMID 36877030). Pooled sensitivity 84% (95%CI 79-88%), specificity 68% (95%CI 60-75%), AUC 0.85 (95%CI 0.81-0.89). MDW AUC (0.88) comparable to PCT (0.82) and CRP (0.86). MDW is a \"reliable diagnostic biomarker for sepsis as procalcitonin and CRP.\"', options:{color:C.navy}},
  ], { x:0.55,y:1.33, w:8.9,h:0.78, fontSize:10.5, valign:"top" });

  // Mechanism
  card(s, 0.4,2.28, 4.4,2.94, C.white, C.ltgray);
  s.addText("Mechanism", { x:0.55,y:2.34, w:4.1,h:0.3, fontSize:12, bold:true, color:C.teal, margin:0 });
  const mdwMech = [
    "Measures the SIZE VARIABILITY of circulating monocytes on standard CBC analyzer",
    "During infection: monocytes are activated → increase in volume and morphologic heterogeneity",
    "Reflected as wider distribution width on automated hematology analyzer (no extra sample required)",
    "FDA-cleared in 2019 as sepsis adjunctive biomarker (Abbott Cell-DxH platform)",
    "Available from standard CBC with differential — zero additional cost per test",
    "Normal MDW: <20 U; Sepsis flag threshold: ≥20 U",
  ];
  mdwMech.forEach((p,i) => {
    s.addText([{text:"▸ ", options:{color:C.teal, bold:true}},{text:p, options:{color:C.navy}}],
      { x:0.55,y:2.7+i*0.42, w:4.1,h:0.4, fontSize:9.5 });
  });

  // Performance table
  card(s, 5.1,2.28, 4.5,2.94, C.navy, C.teal);
  s.addText("Diagnostic Performance vs. Comparators", { x:5.25,y:2.34, w:4.2,h:0.3, fontSize:11, bold:true, color:C.cyan, margin:0 });

  const perfData = [
    ["Biomarker", "Sens", "Spec", "AUC"],
    ["MDW", "84%", "68%", "0.85"],
    ["MDW (vs PCT)", "—", "—", "0.88"],
    ["PCT (vs MDW)", "—", "—", "0.82"],
    ["CRP (vs MDW)", "—", "—", "0.86"],
    ["MDW+PCT combo", "↑↑", "↑↑", "Recommended"],
  ];
  const cx = [5.15,6.55,7.45,8.35];
  perfData.forEach((row,ri) => {
    row.forEach((cell,ci) => {
      s.addText(cell, {
        x:cx[ci]+0.05, y:2.72+ri*0.38, w:0.9, h:0.36,
        fontSize: ri===0?9:10, bold:ri===0||ci===0,
        color: ri===0?C.gold:ci===0?C.cyan:C.offwhite,
        valign:"middle", margin:0
      });
    });
    if(ri===0) s.addShape(pres.shapes.RECTANGLE,{x:5.15,y:3.1,w:4.3,h:0.02,fill:{color:C.teal},line:{color:C.teal}});
  });

  s.addText("Huang et al. Crit Care Med 2023 (PMID 36877030)\nSR/MA: 18 studies | Diagnostic accuracy", {
    x:5.25,y:4.88,w:4.2,h:0.3, fontSize:8, color:C.gray, italic:true
  });

  refBox(s, 0.4,5.22, 9.2,0.35, "Refs: Huang YH et al. Crit Care Med 2023 (PMID 36877030) – SR/MA, 18 studies. SSC 2021 Note: 'Insufficient evidence to recommend novel rapid host response diagnostics' (Evans et al. Crit Care Med 2021, PMID 34599691)");
  footer(s);
}

// ════════════════════════════════════════════════════════════════════════════
// SLIDE 7 — PRESEPSIN: Meta-Analysis Evidence
// ════════════════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  sectionTag(s, "NOVEL BIOMARKER  |  Poggi C et al. JAMA Pediatr 2022 (PMID 35639395) · Paraskevas T et al. Clin Chim Acta 2023 (PMID 37813329) · Bourika V et al. Ann Intensive Care 2025 (PMID 40685448)", C.deepblue);
  slideH(s, "Presepsin (sCD14-ST): Early Bacterial Sepsis Detection");

  // Mechanism flowchart
  card(s, 0.4,1.28, 9.2,1.2, "E8F0F8", C.teal);
  s.addText("MECHANISM OF RELEASE", { x:0.55,y:1.33, w:2.5,h:0.26, fontSize:9, bold:true, color:C.teal, charSpacing:1, margin:0 });
  const steps = [
    ["Bacteria\nPhagocytosed\nby Monocyte","→"],
    ["CD14 receptor\ncleaved from\nmembrane","→"],
    ["Soluble CD14\nfragment\n(sCD14-ST) shed","→"],
    ["Detectable\nin plasma\nwithin 1-2 hrs",""],
  ];
  steps.forEach(([text, arrow], i) => {
    const x = 0.5+i*2.28;
    s.addShape(pres.shapes.ROUNDED_RECTANGLE,{x,y:1.65,w:2.0,h:0.72, fill:{color:C.teal,transparency:72}, line:{color:C.teal}, rectRadius:0.06});
    s.addText(text,{x,y:1.65,w:2.0,h:0.72, fontSize:9.5, color:C.navy, align:"center", valign:"middle"});
    if(arrow) s.addText("→",{x:x+1.97,y:1.9,w:0.3,h:0.3, fontSize:16, bold:true, color:C.teal, align:"center"});
  });

  // Left: evidence
  card(s, 0.4,2.62, 4.4,2.6, C.white, C.ltgray);
  s.addText("Evidence Summary", { x:0.55,y:2.68, w:4.1,h:0.3, fontSize:12, bold:true, color:C.teal, margin:0 });
  const presEvid = [
    { src:"JAMA Pediatr 2022", detail:"Poggi C et al. SR/MA (PMID 35639395): Presepsin for neonatal early-onset sepsis. Pooled Sens 82%, Spec 86%." },
    { src:"Clin Chim Acta 2023", detail:"Paraskevas T et al. (PMID 37813329): Review – AUC 0.86 for sepsis Dx; rises earlier than PCT." },
    { src:"Ann Intensive Care 2025", detail:"Bourika V et al. (PMID 40685448): Presepsin endorsed for early sepsis Dx; guides antibiotic start and de-escalation." },
    { src:"Key comparison", detail:"Presepsin rises EARLIER than PCT (1-2 hrs vs. 2-4 hrs); less affected by renal failure than PCT." },
  ];
  presEvid.forEach((e,i) => {
    s.addText([
      {text:e.src+": ", options:{bold:true, color:C.teal}},
      {text:e.detail, options:{color:C.navy}}
    ], { x:0.55,y:3.06+i*0.52, w:4.1,h:0.48, fontSize:9.5, valign:"top" });
  });

  // Right: PCT vs Presepsin
  card(s, 5.1,2.62, 4.5,2.6, C.navy, C.cyan);
  s.addText("Presepsin vs. PCT — Head-to-Head", { x:5.25,y:2.68, w:4.2,h:0.3, fontSize:12, bold:true, color:C.cyan, margin:0 });

  const compRows=[
    ["Feature","PCT","Presepsin"],
    ["Time to rise","2-4 hrs","1-2 hrs"],
    ["Source","All tissues","Monocytes/macrophages"],
    ["Bacterial specificity","Moderate","Higher"],
    ["Renal failure effect","↑ falsely (accumulates)","Less affected"],
    ["Viral/fungal","Low/absent","Also elevated"],
    ["Guideline status","SSC Rec #31","Endorsed (2025 review)"],
  ];
  compRows.forEach((row,ri)=>{
    const y = 2.72+ri*0.35;
    if(ri===0){
      s.addShape(pres.shapes.RECTANGLE,{x:5.15,y,w:4.3,h:0.33,fill:{color:C.slate},line:{color:C.slate}});
    }
    [5.15,6.45,7.85].forEach((x,ci)=>{
      s.addText(row[ci],{
        x:x+0.06,y,w:ci===0?1.22:1.32,h:0.33,
        fontSize:ci===0&&ri>0?9:ri===0?8.5:9.5,
        bold:ri===0||ci===0,
        color:ri===0?C.gold:ci===0?C.gray:ci===1?C.offwhite:C.cyan,
        valign:"middle",margin:0
      });
    });
  });

  refBox(s, 0.4,5.22, 9.2,0.35, "Refs: Poggi C et al. JAMA Pediatr 2022 (PMID 35639395) SR/MA | Paraskevas T et al. Clin Chim Acta 2023 (PMID 37813329) | Bourika V et al. Ann Intensive Care 2025 (PMID 40685448)");
  footer(s);
}

// ════════════════════════════════════════════════════════════════════════════
// SLIDE 8 — NLR & CALPROTECTIN: Meta-Analysis Evidence
// ════════════════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  sectionTag(s, "NOVEL BIOMARKERS  |  Wu H et al. Front Immunol 2024 (PMID 38562922, n=10,811) · Gao RY et al. Front Cell Infect Microbiol 2022 (PMID 36519133) · Chen J et al. BMC Infect Dis 2023 (PMID 38012554)", C.slate);
  slideH(s, "Neutrophil-to-Lymphocyte Ratio (NLR) & Calprotectin");

  // NLR big evidence card
  card(s, 0.4,1.28, 9.2,1.55, "E8F2F8", C.teal);
  s.addShape(pres.shapes.RECTANGLE,{x:0.4,y:1.28,w:9.2,h:0.06,fill:{color:C.teal},line:{color:C.teal}});
  s.addText([
    {text:"Meta-Analysis Evidence (Wu H et al. Front Immunol 2024, PMID 38562922 — PROSPERO CRD42023433143):\n", options:{bold:true, color:C.teal}},
    {text:"12 studies | n=10,811 adult sepsis patients | Random-effects model | HR 1.63 (95%CI 1.40–1.90) for poor prognosis\n", options:{color:C.navy}},
    {text:"Conclusion: \"NLR is a RELIABLE and VALUABLE biomarker for predicting prognosis and the risk of death in adult sepsis patients.\"", options:{color:C.navy, italic:true}},
  ], { x:0.55,y:1.35, w:8.9,h:1.42, fontSize:10.5, valign:"top" });

  // Left: NLR details
  card(s, 0.4,2.98, 4.4,2.24, C.white, C.ltgray);
  s.addText("NLR: Biology & Clinical Use", { x:0.55,y:3.04, w:4.1,h:0.3, fontSize:12, bold:true, color:C.teal, margin:0 });
  const nlrPoints = [
    "NLR = Absolute Neutrophil Count ÷ Absolute Lymphocyte Count",
    "Neutrophilia: excessive pro-inflammatory activation in early sepsis",
    "Lymphopenia: hallmark of sepsis-induced immunosuppression",
    "High NLR = dysequilibrium of innate/adaptive immunity",
    "Prognostic, not purely diagnostic — best for mortality risk stratification",
    "Neonatal sepsis: NLR SR/MA (Chen et al. BMC Infect Dis 2023, PMID 38012554) — confirmed diagnostic value",
  ];
  nlrPoints.forEach((p,i)=>{
    s.addText([{text:"• ",options:{color:C.teal,bold:true}},{text:p,options:{color:C.navy}}],
      {x:0.55,y:3.4+i*0.33,w:4.1,h:0.3,fontSize:9.5});
  });

  // Right: Calprotectin
  card(s, 5.1,2.98, 4.5,2.24, C.navy, C.gold);
  s.addText("Calprotectin: Emerging Neutrophil Marker", { x:5.25,y:3.04, w:4.2,h:0.3, fontSize:12, bold:true, color:C.gold, margin:0 });
  card(s, 5.25,3.4, 4.1,0.7, C.slate, C.gold);
  s.addText([
    {text:"Meta-Analysis (Gao RY et al. Front Cell Infect Microbiol 2022, PMID 36519133):\n",options:{bold:true,color:C.gold}},
    {text:"Serum calprotectin as diagnostic marker for sepsis — pooled sensitivity 83%, specificity 77%",options:{color:C.offwhite}},
  ],{x:5.32,y:3.44,w:4.0,h:0.62,fontSize:9.5,valign:"top"});
  const calPoints=[
    "Neutrophil-derived protein (S100A8/A9 complex)",
    "Released during neutrophil activation and degranulation",
    "Rises faster than CRP; reflects active neutrophil burden",
    "Correlates with bacteremia; useful in ICU setting",
  ];
  calPoints.forEach((p,i)=>{
    s.addText([{text:"▸ ",options:{color:C.gold,bold:true}},{text:p,options:{color:C.offwhite}}],
      {x:5.25,y:4.15+i*0.22,w:4.2,h:0.2,fontSize:9.5});
  });

  refBox(s, 0.4,5.22, 9.2,0.35, "Refs: Wu H et al. Front Immunol 2024 (PMID 38562922) SR/MA n=10,811 | Chen J et al. BMC Infect Dis 2023 (PMID 38012554) SR/MA | Gao RY et al. Front Cell Infect Microbiol 2022 (PMID 36519133) MA");
  footer(s);
}

// ════════════════════════════════════════════════════════════════════════════
// SLIDE 9 — PENTRAXIN-3, NGAL, ProADM
// ════════════════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  sectionTag(s, "NOVEL BIOMARKERS  |  Milas GP et al. J Matern Fetal Neonatal Med 2023 (PMID 37127619) · Van Leeuwen LM et al. Clin Microbiol Infect 2024 (PMID 38467246) · Bourika V et al. Ann Intensive Care 2025 (PMID 40685448)", C.deepblue);
  slideH(s, "PTX3 · NGAL · Proadrenomedullin (ProADM)");

  const cols3 = [
    {
      x:0.35, color:C.teal,
      title:"Pentraxin-3 (PTX3)",
      evidence:"SR/MA (Milas et al. PMID 37127619, 2023): PTX3 for neonatal sepsis — pooled Sens/Spec superior to CRP in neonates",
      points:[
        "Long pentraxin produced LOCALLY at infection site (vs CRP from liver)",
        "Reflects innate immune activation more accurately",
        "Produced by neutrophils, macrophages, dendritic cells",
        "Rises earlier than CRP in bacterial infection",
        "SR/MA 2024 (Van Leeuwen PMID 38467246): PTX3 among best biomarkers for neonatal early-onset sepsis",
        "Limited adult sepsis data — current use mainly neonatal/research",
      ]
    },
    {
      x:3.55, color:C.cyan,
      title:"NGAL (Neutrophil Gelatinase-Assoc. Lipocalin)",
      evidence:"Bourika et al. Ann Intensive Care 2025 (PMID 40685448): NGAL endorsed for sepsis-AKI detection",
      points:[
        "Stored in neutrophil granules + produced by renal tubular cells",
        "Sepsis-AKI marker: rises 24-48 hrs BEFORE creatinine elevation",
        "Dual role: AKI prediction + antimicrobial (iron sequestration)",
        "Urinary NGAL >150 ng/mL → predicts persistent AKI",
        "Guides timing of nephrotoxic drug avoidance (aminoglycosides, NSAIDs)",
        "Validated in multiple ICU cohort studies; used in conjunction with SOFA",
      ]
    },
    {
      x:6.75, color:C.gold,
      title:"Proadrenomedullin (MR-proADM)",
      evidence:"Bourika et al. Ann Intensive Care 2025 (PMID 40685448): ProADM among endothelial markers for circulatory support guidance",
      points:[
        "Stable mid-regional precursor of vasodilatory peptide adrenomedullin",
        "Produced by endothelium + immune cells during systemic stress",
        "Correlates strongly with sepsis severity + SOFA score",
        "MR-proADM >0.8 nmol/L: superior to PCT for ICU admission prediction",
        "PCT + ProADM combination: AUC 0.86 for septic shock prediction (Bourika 2025)",
        "Used for fluid therapy and vasopressor decision support",
      ]
    }
  ];

  cols3.forEach(col=>{
    card(s, col.x,1.28, 3.0,3.94, C.white, col.color);
    s.addShape(pres.shapes.RECTANGLE,{x:col.x,y:1.28,w:3.0,h:0.07,fill:{color:col.color},line:{color:col.color}});
    s.addText(col.title,{x:col.x+0.1,y:1.38,w:2.8,h:0.32, fontSize:11,bold:true,color:col.color,align:"center",margin:0});

    // Evidence band
    s.addShape(pres.shapes.ROUNDED_RECTANGLE,{x:col.x+0.1,y:1.76,w:2.8,h:0.52, fill:{color:col.color,transparency:85}, line:{color:col.color,width:1}, rectRadius:0.05});
    s.addText(col.evidence,{x:col.x+0.15,y:1.8,w:2.72,h:0.44, fontSize:8,color:"1A3050",italic:true,valign:"top"});

    col.points.forEach((p,i)=>{
      s.addText([{text:"• ",options:{color:col.color,bold:true}},{text:p,options:{color:C.navy}}],
        {x:col.x+0.12,y:2.34+i*0.44,w:2.78,h:0.42,fontSize:9,valign:"top"});
    });
  });

  refBox(s, 0.4,5.22, 9.2,0.35, "Refs: Milas GP et al. J Matern Fetal Neonatal Med 2023 (PMID 37127619) SR/MA | Van Leeuwen LM et al. Clin Microbiol Infect 2024 (PMID 38467246) SR/MA | Bourika V et al. Ann Intensive Care 2025 (PMID 40685448)");
  footer(s);
}

// ════════════════════════════════════════════════════════════════════════════
// SLIDE 10 — CYTOKINES: IL-6, IL-10, TNF-α (Evidence-Based)
// ════════════════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  topBar(s, C.gold);
  s.addText("Cytokine Biomarkers in Sepsis", {x:0.5,y:0.16,w:9,h:0.52, fontSize:23,bold:true,color:C.white});
  s.addShape(pres.shapes.RECTANGLE,{x:0.5,y:0.7,w:1.3,h:0.05,fill:{color:C.gold},line:{color:C.gold}});

  // Harrison's 22e pathophysiology quote
  card(s, 0.4,0.84, 9.2,0.7, C.slate, C.gold);
  s.addText([
    {text:"Harrison's 22e Ch.315 (Pathophysiology of Sepsis): ",options:{bold:true,color:C.gold}},
    {text:'"Cell death or dysfunction can result from direct interactions with PAMPs, DAMPs, activated leukocytes, and their associated mediators including cytokines, chemokines, toxic granules, ROS, and reactive nitrogen species."',options:{color:C.offwhite,italic:true}},
  ],{x:0.55,y:0.9,w:8.9,h:0.58,fontSize:10,valign:"middle"});

  const cytokines = [
    {
      name:"IL-6", rise:"<1 hr",
      color:C.cyan,
      mech:"Released by macrophages, dendritic cells. Master regulator of acute-phase response. Directly correlates with bacterial load and sepsis severity.",
      clin:"Best EARLY alert in sepsis. Sensitivity ~80% at 1 hour. Used in neonatal sepsis scoring. Elevated in COVID-19 cytokine storm.",
      limit:"Also elevated in: trauma, surgery, burns, autoimmune disease, cancer.",
    },
    {
      name:"TNF-α", rise:"1-2 hrs",
      color:C.red,
      mech:"Primary pro-inflammatory cytokine. Triggers cytokine cascade, NF-κB activation, endothelial injury, coagulopathy, and organ dysfunction.",
      clin:"Early peak then rapidly declines — less useful for serial monitoring. Important in gram-negative bacterial sepsis (LPS-driven).",
      limit:"Short half-life; sampling timing critical. Poor specificity. Anti-TNF therapy showed no benefit in sepsis trials.",
    },
    {
      name:"IL-10", rise:"2-4 hrs",
      color:C.green,
      mech:"Anti-inflammatory cytokine. Counter-regulatory response to pro-inflammatory cascade. Marks immune paralysis / immunosuppression phase.",
      clin:"High IL-10 → identifies Endotype B (immunosuppressed). Guides consideration of immunostimulatory therapy. Predicts secondary infections.",
      limit:"Elevated in both severe sepsis (protective) and immunosuppression (harmful) — context-dependent interpretation.",
    },
  ];

  cytokines.forEach((cyt,i)=>{
    const y = 1.67+i*1.2;
    card(s, 0.4,y, 9.2,1.08, C.deepblue, cyt.color);
    s.addShape(pres.shapes.RECTANGLE,{x:0.4,y,w:0.1,h:1.08,fill:{color:cyt.color},line:{color:cyt.color}});

    s.addText(cyt.name,{x:0.6,y:y+0.04,w:0.85,h:0.45,fontSize:18,bold:true,color:cyt.color,align:"center",valign:"middle",margin:0});
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    s.addText([
      {text:"Mechanism: ",options:{bold:true,color:cyt.color}},
      {text:cyt.mech+" ",options:{color:C.offwhite}},
      {text:"  Clinical: ",options:{bold:true,color:cyt.color}},
      {text:cyt.clin,options:{color:C.offwhite}},
    ],{x:1.58,y:y+0.06,w:5.3,h:0.95,fontSize:9.5,valign:"top"});

    s.addText([{text:"Limitation: ",options:{bold:true,color:C.amber}},{text:cyt.limit,options:{color:C.gray}}],
      {x:7.0,y:y+0.08,w:2.5,h:0.9,fontSize:9,valign:"top"});
  });

  refBox(s, 0.4,5.22, 9.2,0.35, "Refs: Harrison's 22e Ch.315 Pathophysiology section (Strich & Chertow) | Bourika V et al. Ann Intensive Care 2025 (PMID 40685448) — IL-10 for sepsis immunophenotyping | SSC 2021: no specific cytokine biomarker recommendations");
  footer(s);
}

// ════════════════════════════════════════════════════════════════════════════
// SLIDE 11 — SSC 2021 BIOMARKER RECOMMENDATIONS SUMMARY
// ════════════════════════════════════════════════════════════════════════════
{
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  darkBg(s);
  topBar(s, C.green);
  s.addText("Surviving Sepsis Campaign 2021 Guidelines: Biomarker Recommendations", {x:0.4,y:0.16,w:9.2,h:0.52,fontSize:20,bold:true,color:C.white});
  s.addShape(pres.shapes.RECTANGLE,{x:0.4,y:0.7,w:1.3,h:0.05,fill:{color:C.green},line:{color:C.green}});
  s.addText("Evans L et al. Crit Care Med 2021; 49(11):e1063–e1143 | PMID 34599691 | International Society of Intensive Care & Emergency Medicine",{
    x:0.4,y:0.78,w:9.2,h:0.24,fontSize:8.5,color:C.gray,italic:true
  });

  const recs = [
    {
      num:"Rec #16", topic:"Blood Cultures (Diagnostics)",
      grade:"Strong RECOMMENDATION", gradeC:C.red,
      evidence:"Low certainty",
      text:"Collect blood cultures as soon as possible and ideally BEFORE administration of antimicrobial therapy in adults with suspected sepsis or septic shock.",
      biomarker:"Blood Culture"
    },
    {
      num:"Conditional", topic:"Blood Lactate (Diagnostics)",
      grade:"Conditional FOR",gradeC:C.green,
      evidence:"Low certainty",
      text:"Suggest measuring blood lactate in adults with possible/probable/definite sepsis or septic shock. Note: 'Insufficient evidence for novel rapid host response diagnostics.'",
      biomarker:"Lactate"
    },
    {
      num:"Rec #16", topic:"PCT to START Antibiotics",
      grade:"Conditional AGAINST",gradeC:C.red,
      evidence:"Very low certainty",
      text:"Suggest AGAINST using procalcitonin + clinical evaluation to decide when to START antimicrobials vs. clinical evaluation alone.",
      biomarker:"Procalcitonin"
    },
    {
      num:"Rec #31", topic:"PCT to STOP Antibiotics",
      grade:"Conditional FOR",gradeC:C.green,
      evidence:"Low certainty",
      text:"Suggest using procalcitonin AND clinical evaluation to decide when to DISCONTINUE antimicrobials over clinical evaluation alone (adequate source control).",
      biomarker:"Procalcitonin"
    },
    {
      num:"GPS", topic:"Novel Rapid Diagnostics",
      grade:"Good Practice Statement",gradeC:C.amber,
      evidence:"Insufficient evidence",
      text:"'Insufficient evidence to make a recommendation regarding use of novel rapid host response diagnostics.' Biomarker panels: research setting.",
      biomarker:"Novel Biomarkers"
    },
  ];

  recs.forEach((r,i)=>{
    const y = 1.06+i*0.84;
    s.addShape(pres.shapes.RECTANGLE,{x:0.35,y,w:9.3,h:0.76,fill:{color:i%2===0?C.slate:C.deepblue},line:{color:i%2===0?C.slate:C.deepblue}});
    // Grade pill
    pill(s, 0.45,y+0.08, 2.2, r.grade+" | "+r.evidence, r.gradeC);
    // Biomarker tag
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    // Topic
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    // Text
    s.addText(r.text,{x:0.45,y:y+0.39,w:8.8,h:0.34,fontSize:9.5,color:C.offwhite});
  });

  refBox(s, 0.35,5.22, 9.3,0.35, "Source: Evans L et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med 2021;49(11):e1063. PMID 34599691 | Also: Harrison's 22e Ch.315 references SSC 2021 directly.");
  footer(s);
}

// ════════════════════════════════════════════════════════════════════════════
// SLIDE 12 — CLINICAL INTEGRATION: 3 SCENARIOS
// ════════════════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  sectionTag(s, "CLINICAL APPLICATION  |  SSC 2021 (PMID 34599691) · Harrison's 22e Ch.315 · Kubo K et al. Crit Care Med 2024 (PMID 38949476) · Papp M et al. Crit Care 2023 (PMID 37833778)");
  slideH(s, "Biomarker-Guided Management: 3 Clinical Scenarios");

  const scenarios = [
    {
      num:"1", color:C.red,
      title:"Early Diagnosis — First 3 Hours (ED / Floor)",
      guideline:"SSC 2021: Collect blood cultures BEFORE antibiotics (Strong Rec, Low certainty) | Measure blood lactate (Conditional, Low certainty)",
      markers:"Blood Culture × 2  |  Serum Lactate  |  PCT  |  MDW (if available on CBC)  |  Presepsin (if available)",
      action:"Harrison's 22e Ch.315: 'Immediate empiric antimicrobial therapy within 1 hr of SHOCK recognition.' If no shock but sepsis suspected: empiric ABx by 3 hrs if no alternative Dx.",
      threshold:"Lactate >2 mmol/L + vasopressor need → septic shock. PCT >0.5 ng/mL suggestive of bacterial infection.",
    },
    {
      num:"2", color:C.teal,
      title:"Antibiotic Stewardship — Days 3-7",
      guideline:"SSC 2021 Rec #31 (Conditional, Low certainty): Use PCT AND clinical evaluation to DISCONTINUE antimicrobials",
      markers:"Serial PCT every 24-48 hrs  |  CRP trend  |  Clinical response (temperature, WBC, clinical trajectory)",
      action:"Papp et al. SR/MA (PMID 37833778): PCT-guided therapy → −1.79 days AB duration, OR 0.84 for 28-day mortality. Kubo et al. (PMID 38949476): −1.89 days AB, −27 deaths/1000. Best protocol: PCT cutoff 0.5 µg/L + 80% reduction.",
      threshold:"PCT clearance ≥80% from peak OR PCT <0.25 ng/mL → consider discontinuation per SSC Rec #31.",
    },
    {
      num:"3", color:C.gold,
      title:"Organ Failure Monitoring & Resuscitation Guidance",
      guideline:"SSC 2021: Guide resuscitation to decrease serum lactate (Conditional, Low certainty) | SOFA score monitoring",
      markers:"Serial Lactate (q2h) | NGAL (AKI early detection) | ProADM (circulatory support) | SOFA score",
      action:"Harrison's 22e Ch.315: 'Lactate clearance associated with improved survival. Resuscitation targeting lactate normalization.' Bourika 2025: Endothelial (ProADM) and cardiac markers guide vasopressor and fluid decisions.",
      threshold:"Lactate clearance ≥10%/2hrs → continue resuscitation. NGAL >150 ng/mL → avoid nephrotoxins. ProADM >0.8 nmol/L → ICU admission threshold.",
    },
  ];

  scenarios.forEach((sc,i)=>{
    const y = 1.26+i*1.3;
    card(s, 0.4,y, 9.2,1.18, C.white, sc.color);
    s.addShape(pres.shapes.RECTANGLE,{x:0.4,y,w:0.1,h:1.18,fill:{color:sc.color},line:{color:sc.color}});
    s.addShape(pres.shapes.OVAL,{x:0.56,y:y+0.28,w:0.5,h:0.5,fill:{color:sc.color},line:{color:sc.color}});
    s.addText(sc.num,{x:0.56,y:y+0.28,w:0.5,h:0.5,fontSize:16,bold:true,color:C.white,align:"center",valign:"middle",margin:0});

    s.addText(sc.title,{x:1.2,y:y+0.06,w:7.9,h:0.3,fontSize:12,bold:true,color:sc.color,margin:0});
    s.addText([{text:"Guideline Basis: ",options:{bold:true,color:C.navy}},{text:sc.guideline,options:{color:C.navy}}],
      {x:1.2,y:y+0.36,w:7.9,h:0.26,fontSize:9});
    s.addText([{text:"Biomarkers: ",options:{bold:true,color:sc.color}},{text:sc.markers,options:{color:C.navy}},{text:"  |  Action: ",options:{bold:true,color:C.navy}},{text:sc.action,options:{color:C.navy}}],
      {x:1.2,y:y+0.62,w:7.9,h:0.32,fontSize:8.8});
    s.addText(sc.threshold,{x:1.2,y:y+0.96,w:7.9,h:0.18,fontSize:8,color:C.gray,italic:true});
  });

  footer(s);
}

// ════════════════════════════════════════════════════════════════════════════
// SLIDE 13 — EVIDENCE GRADING SUMMARY TABLE (all biomarkers)
// ════════════════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  topBar(s, C.cyan);
  s.addText("Sepsis Biomarker Evidence Summary Table", {x:0.4,y:0.14,w:9.2,h:0.46,fontSize:20,bold:true,color:C.white});

  const headers = ["Biomarker","Class","AUC/Performance","Best Use","Evidence Level","Key Reference"];
  const hx = [0.15, 1.45, 2.7, 4.25, 6.2, 7.75];
  const hw = [1.25, 1.2, 1.5, 1.9, 1.5, 2.1];

  // header row
  headers.forEach((h,ci)=>{
    s.addShape(pres.shapes.RECTANGLE,{x:hx[ci],y:0.65,w:hw[ci],h:0.28,fill:{color:C.teal},line:{color:C.teal}});
    s.addText(h,{x:hx[ci]+0.04,y:0.65,w:hw[ci]-0.04,h:0.28,fontSize:8.5,bold:true,color:C.white,valign:"middle",margin:0});
  });

  const rows = [
    ["Lactate","Metabolite",">2 mmol/L: septic shock","Resuscitation target","SSC 2021 Cond. (Low)","Evans et al. PMID 34599691"],
    ["Procalcitonin","Hormonal","AUC 0.74 (Sens 70%, Spec 67%)","AB stewardship (STOP)","SSC 2021 Cond. (Low)","Papp PMID 37833778"],
    ["CRP","Acute-phase","AUC 0.67; lower than PCT","Inflammation screen","SR/MA 2025","Chuang PMID 40214293"],
    ["MDW","Hematologic","AUC 0.85, Sens 84%, Spec 68%","Early Dx; CBC add-on","SR/MA 2023 (18 studies)","Huang PMID 36877030"],
    ["NLR","Hematologic","HR 1.63 for mortality","Prognosis/risk stratif.","SR/MA 2024 (n=10,811)","Wu PMID 38562922"],
    ["Presepsin","Immune (CD14)","AUC 0.86 (Sens 82%, Spec 86%)","Early bacterial Dx","SR/MA 2022 (JAMA Pediatr)","Poggi PMID 35639395"],
    ["PTX3","Long pentraxin","Superior to CRP (neonates)","Neonatal early sepsis","SR/MA 2023","Milas PMID 37127619"],
    ["Calprotectin","Neutrophil","Sens 83%, Spec 77%","Bacteremia/ICU","Meta-analysis 2022","Gao PMID 36519133"],
    ["NGAL","Renal/immune","Rises 24-48h before Cr","Sepsis-AKI detection","Cohort studies/Review","Bourika PMID 40685448"],
    ["ProADM","Vasopeptide","AUC 0.86 (with PCT) for shock","ICU/vasopressor guidance","Review 2025","Bourika PMID 40685448"],
    ["IL-6","Cytokine","Rises <1 hr; early marker","Severity/subphenotyping","Harrison's 22e + Review","Strich/Chertow Ch.315"],
    ["IL-10","Cytokine","Marks immunosuppression","Endotype B (SRS2)","Harrison's 22e + Review","Strich/Chertow Ch.315"],
  ];

  rows.forEach((row,ri)=>{
    const y = 0.96+ri*0.35;
    const bg = ri%2===0?C.slate:C.deepblue;
    s.addShape(pres.shapes.RECTANGLE,{x:0.15,y,w:9.6,h:0.33,fill:{color:bg},line:{color:bg}});
    row.forEach((cell,ci)=>{
      s.addText(cell,{
        x:hx[ci]+0.04, y, w:hw[ci]-0.04, h:0.33,
        fontSize:ci===0?9:8.5, bold:ci===0,
        color:ci===0?C.cyan:ci===4?C.gold:C.offwhite,
        valign:"middle", margin:0
      });
    });
  });

  refBox(s, 0.15,5.22, 9.6,0.35, "Note: 'Sufficient evidence' = formal SR/MA with defined sepsis populations. SSC 2021 states 'insufficient evidence for novel rapid diagnostics' but this is not equivalent to evidence of lack of benefit — ongoing research is active.");
  footer(s);
}

// ════════════════════════════════════════════════════════════════════════════
// SLIDE 14 — COMPLETE REFERENCES
// ════════════════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  sectionTag(s, "REFERENCES  |  All sources: Harrison's 22e · SSC Guidelines 2021 · PubMed Systematic Reviews & Meta-Analyses (2022-2025)");
  slideH(s, "References");

  const refs = [
    { tier:"TEXTBOOK", color:C.gold, text:"Strich JR, Chertow DS. 'Chapter 315: Sepsis and Septic Shock.' Harrison's Principles of Internal Medicine, 22nd Edition. McGraw Hill Medical, 2025." },
    { tier:"GUIDELINE", color:C.green, text:"Evans L et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063–e1143. PMID 34599691" },
    { tier:"SR/MA", color:C.red, text:"Chuang CL et al. Diagnostic performances of procalcitonin and C-reactive protein for sepsis: SR/MA (44 studies, n=10,755). Eur J Emerg Med. 2025. PMID 40214293" },
    { tier:"SR/MA", color:C.red, text:"Papp M et al. Procalcitonin-guided antibiotic therapy may shorten treatment and improve survival (26 RCTs, n=9048). Crit Care. 2023;27(1):394. PMID 37833778" },
    { tier:"SR/MA", color:C.red, text:"Kubo K et al. PCT- or CRP-guided antimicrobial discontinuation in critically ill adults (18 RCTs, n=5023). Crit Care Med. 2024 Oct. PMID 38949476" },
    { tier:"SR/MA", color:C.red, text:"Huang YH et al. Diagnostic accuracies of MDW, PCT, and CRP for sepsis (18 studies). Crit Care Med. 2023;51(5). PMID 36877030" },
    { tier:"SR/MA", color:C.red, text:"Wu H et al. NLR predictive value in adult sepsis prognosis (12 studies, n=10,811). Front Immunol. 2024. PMID 38562922 [PROSPERO CRD42023433143]" },
    { tier:"SR/MA", color:C.red, text:"Poggi C et al. Presepsin for neonatal early-onset sepsis: SR/MA. JAMA Pediatr. 2022;176(8). PMID 35639395" },
    { tier:"SR/MA", color:C.red, text:"Milas GP et al. Pentraxin-3 and neonatal sepsis: SR/MA. J Matern Fetal Neonatal Med. 2023 Dec. PMID 37127619" },
    { tier:"SR/MA", color:C.red, text:"Van Leeuwen LM et al. Diagnostic value of biomarkers for early-onset sepsis: SR/MA. Clin Microbiol Infect. 2024 Jul. PMID 38467246" },
    { tier:"SR/MA", color:C.red, text:"Gao RY et al. Calprotectin as diagnostic marker for sepsis: meta-analysis. Front Cell Infect Microbiol. 2022. PMID 36519133" },
    { tier:"REVIEW", color:C.teal, text:"Bourika V, Rekoumi EA, Giamarellos-Bourboulis EJ. Biomarkers to guide sepsis management. Ann Intensive Care. 2025;15(1). PMID 40685448" },
  ];

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  footer(s);
}

// ════════════════════════════════════════════════════════════════════════════
// SLIDE 15 — KEY TAKEAWAYS
// ════════════════════════════════════════════════════════════════════════════
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      t:"Harrison's 22e defines sepsis as 'no gold standard diagnostic test' — laboratory evaluation including serum lactate is mandatory; blood cultures before antibiotics (SSC 2021 Strong Recommendation)."
    },
    {
      n:"02", c:C.teal,
      t:"PCT has an AUC of only 0.74 for sepsis diagnosis (Chuang 2025, 44 studies). SSC 2021 recommends PCT for STOPPING antibiotics (Rec #31) but is AGAINST using it to START antibiotics (Rec #16)."
    },
    {
      n:"03", c:C.gold,
      t:"MDW (AUC 0.85, SR/MA 18 studies, Huang 2023) is FDA-cleared and available on the standard CBC — requires no extra sample and performs comparably to PCT for early sepsis detection."
    },
    {
      n:"04", c:C.green,
      t:"NLR is a reliable prognostic biomarker: HR 1.63 for mortality (12 studies, n=10,811, Wu 2024). Presepsin outperforms PCT in onset time (1-2 hrs vs 2-4 hrs) with AUC 0.86 (Poggi 2022 JAMA Pediatr)."
    },
    {
      n:"05", c:C.red,
      t:"SSC 2021 explicitly states 'insufficient evidence to recommend novel rapid host response diagnostics' — panels combining biomarkers are still research-stage. Clinical application must be adjunctive to clinical judgment."
    },
  ];
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    s.addShape(pres.shapes.OVAL,{x:0.3,y:y+0.14,w:0.5,h:0.5,fill:{color:tk.c,transparency:20},line:{color:tk.c}});
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  footer(s);
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// ── WRITE ────────────────────────────────────────────────────────────────────
const out = "/home/daytona/workspace/sepsis-biomarkers-pptx/Novel_Biomarkers_Sepsis_EvidenceBased.pptx";
pres.writeFile({fileName:out})
  .then(()=>console.log("SUCCESS: "+out))
  .catch(e=>{console.error("ERROR:",e);process.exit(1);});

Successfully replaced 1 instance(s) of the string in '/home/daytona/workspace/sepsis-biomarkers-pptx/build_v2.js'