Respiratory disease according to Harrison with pathophysiology

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Excellent. I now have comprehensive, authoritative content from Robbins Pathology, Katzung Pharmacology, Goodman & Gilman, and Brenner & Rector's Kidney. Here is the full synthesis:

Vascular Endothelial Growth Factor (VEGF)

1. The VEGF Family

VEGF is a family of homodimeric glycoproteins with five major members:

Member	Primary Role
VEGF-A	The dominant angiogenic factor; simply called "VEGF"
VEGF-B	Embryonic vessel development
VEGF-C	Angiogenesis + lymphangiogenesis
VEGF-D	Angiogenesis + lymphangiogenesis
PlGF (Placental Growth Factor)	Embryonic vessel development, preeclampsia

— Robbins, Cotran & Kumar Pathologic Basis of Disease

2. Receptors

VEGFs bind to a family of transmembrane receptor tyrosine kinases:

Receptor	Alias	Key Function
VEGFR-1	FLT1	Modulates VEGF bioavailability; role in embryogenesis
VEGFR-2	KDR	Main signaling receptor — mediates virtually all angiogenic effects
VEGFR-3	FLT4	Lymphangiogenesis

Binding of VEGF to VEGFR activates intracellular tyrosine kinase activity, initiating:

Mitogenic signaling → endothelial cell proliferation
Antiapoptotic signaling → endothelial cell survival
PI3K → AKT pathway → cell growth and proliferation

— Goodman & Gilman's Pharmacological Basis of Therapeutics

3. Physiological Functions

Angiogenesis — endothelial cell migration, proliferation, capillary sprouting, and vascular lumen formation
Vascular permeability — VEGF was originally named vascular permeability factor (VPF) for its potent ability to increase vessel leakiness
Normal endothelial maintenance — highest expression in epithelial cells adjacent to fenestrated endothelium:
- Kidney podocytes
- Retinal pigment epithelium
- Choroid plexus
Lymphangiogenesis (via VEGF-C and VEGF-D)
Embryonic vasculogenesis (VEGF-B, PlGF)

4. Regulation: The HIF-1 / Hypoxia Axis

The single most important inducer of VEGF is hypoxia, acting via:

Low O₂ → stabilization of HIF-1α → HIF-1 transcription factor → VEGF gene transcription → angiogenesis

The VHL (von Hippel-Lindau) tumor suppressor normally targets HIF-1α for proteasomal degradation. Loss of VHL (e.g., in clear cell renal carcinoma) → constitutive HIF-1 activation → massive VEGF overproduction → hypervascular tumors.

Other inducers at sites of injury and inflammation:

PDGF
TGF-α
Oncogenes (RAS, MYC)

— Robbins Pathologic Basis of Disease; Brenner & Rector's The Kidney

5. VEGF in Pathology

Tumour Angiogenesis

All solid tumours >1–2 mm require new vasculature to sustain growth. Tumour cells secrete VEGF to recruit vessels from the surrounding stroma — the angiogenic switch. Anti-VEGF therapy was developed directly from this insight.

Preeclampsia

Elevated soluble sFLT-1 (soluble VEGFR-1) in pregnant women acts as a decoy receptor, sequestering circulating VEGF and PlGF → reduced VEGF bioavailability → endothelial dysfunction → hypertension and proteinuria, mirroring the pathophysiology of VEGF inhibitor toxicity.

Diabetic Macular Edema & Wet AMD

Retinal ischaemia → upregulation of VEGF → pathological choroidal/retinal neovascularisation and vascular leakage → vision loss.

Psoriasis

Prominent angiogenesis within plaques; increased VEGF expression contributes to the characteristic dermal vascularity. Anti-VEGF therapy reduces inflammation in mouse psoriasis models.

6. VEGF-Targeted Therapies

6a. Antibodies Against VEGF Ligand

Drug	Type	Key Approvals
Bevacizumab	Humanized IgG1 mAb vs. VEGF-A	mCRC, NSCLC (non-squamous), glioblastoma, RCC, cervical Ca, ovarian Ca
Ziv-aflibercept	Recombinant decoy receptor (VEGFR1+2 domains fused to IgG1 Fc); binds VEGF-A, VEGF-B, PlGF with higher affinity than bevacizumab	mCRC after oxaliplatin failure
Ranibizumab / Brolucizumab / Faricimab	Engineered humanized Ab fragments vs. VEGF-A	Wet AMD, diabetic macular edema (intravitreal)
Pegaptanib	Pegylated oligonucleotide binding extracellular VEGF	Wet AMD (intravitreal)

6b. Antibodies Against VEGFR

Drug	Target	Key Approvals
Ramucirumab	VEGFR-2 antagonist (blocks VEGF-A/C/D binding)	Gastric/GEJ adenocarcinoma, NSCLC, mCRC, hepatocellular Ca

6c. Small Molecule VEGFR Tyrosine Kinase Inhibitors (TKIs)

Target the intracellular kinase domain of VEGFR (and often PDGFR, RAF, KIT):

Axitinib, Pazopanib, Sorafenib, Sunitinib, Tivozanib, Cabozantinib, Lenvatinib

These are used predominantly in RCC, hepatocellular carcinoma, thyroid cancer, and other solid tumours.

— Katzung Basic & Clinical Pharmacology, 16th ed.; Goodman & Gilman's

7. Adverse Effects of VEGF Inhibition

Because VEGF is essential for normal endothelial maintenance — especially in the kidney glomerulus — inhibiting it produces predictable toxicities:

Toxicity	Mechanism	Frequency
Hypertension	Loss of endothelial VEGF → reduced NO production, vasoconstriction	11–43%
Proteinuria	Disruption of glomerular slit diaphragm integrity (podocyte VEGF loss)	41–63%
Thrombotic microangiopathy	Primary glomerular pathology seen on biopsy	Variable
Arterial thromboembolic events	Endothelial injury	Significant
Wound healing impairment	Angiogenesis required for tissue repair	Must withhold peri-surgically
GI perforation	Microvascular compromise	~1–2% with bevacizumab
Haemorrhage	Endothelial fragility	Variable

Management: ACEIs/ARBs for hypertension and proteinuria; dose reduction or temporary cessation for severe AKI or TMA.

— Brenner & Rector's The Kidney

8. Pathway Diagram

Tumor growth, angiogenesis, immune pathways, and targeted therapy including VEGF/VEGFR, mTOR/HIF-1, and immune checkpoint pathways

Tumour angiogenesis and targeted therapy. VEGF binds VEGFRs on endothelial cells; bevacizumab blocks the ligand while TKIs block the receptor. Upstream, VHL loss → HIF-1 activation → VEGF transcription. mTOR inhibitors (everolimus, temsirolimus) suppress HIF-1 indirectly. — Brenner & Rector's The Kidney

Summary

Aspect	Key Points
Family	VEGF-A/B/C/D, PlGF
Main receptor	VEGFR-2 (KDR) → tyrosine kinase → pro-angiogenic signalling
Primary inducer	Hypoxia via HIF-1 transcription factor
Physiological roles	Angiogenesis, vascular permeability, endothelial maintenance, lymphangiogenesis
Pathological roles	Tumour angiogenesis, wet AMD, diabetic macular edema, preeclampsia, psoriasis
Therapeutic targets	Anti-VEGF mAbs (bevacizumab), VEGFR mAbs (ramucirumab), TKIs (sunitinib, sorafenib…), intravitreal fragments (ranibizumab)
Key toxicities	Hypertension, proteinuria, TMA, thromboembolism, wound healing impairment

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I now have rich, detailed content from Harrison's on PH pathobiology, classification, diagnosis, and treatment. Here is the full case presentation:

Case Presentation: Pulmonary Hypertension

Patient Profile

Name: S.M. Age: 34-year-old woman Occupation: Schoolteacher Referral: Cardiology → Pulmonary Hypertension Specialty Centre

Chief Complaint

"I have been getting more and more breathless over the past 18 months, even when walking short distances."

History of Present Illness

S.M. is a 34-year-old woman with no prior cardiac or pulmonary history who presents with an 18-month progressive history of exertional dyspnoea, now present on climbing a single flight of stairs (WHO Functional Class III). She initially attributed her symptoms to deconditioning. Over the past 6 months she has developed:

Exertional pre-syncope on two occasions (dizziness on rapid standing, relieved by sitting)
Non-exertional chest tightness, dull and central
Bilateral ankle oedema, worse in the evenings
Fatigue disproportionate to activity level
No orthopnoea, PND, or cough
No haemoptysis

A delay of approximately 22 months elapsed between symptom onset and specialist referral — consistent with the well-documented mean diagnostic delay of up to 2 years in PAH. — Harrison's Principles of Internal Medicine 22E

Past Medical History

Raynaud's phenomenon (diagnosed age 28) — intermittent bilateral finger colour change in the cold
No prior DVT, PE, or cardiac disease
No connective tissue disease formally diagnosed

Medications

Combined oral contraceptive pill (started age 22)
Nifedipine 10 mg PRN for Raynaud's

Family History

Paternal aunt: died of "heart failure of unknown cause" at age 41

Social History

Non-smoker
Occasional alcohol
No illicit drug use (specifically no appetite suppressants, methamphetamine, or cocaine)

Review of Systems

Arthralgia in small joints of hands — mild, non-deforming
Dry eyes and dry mouth (intermittent)
No skin rash or photosensitivity

Physical Examination

Vital Signs:

Parameter	Value
BP	108/72 mmHg
HR	96 bpm, regular
RR	18/min
SpO₂	94% on room air
Temperature	37.0°C

General: Thin, anxious-appearing woman, not in acute distress at rest

Cardiovascular:

Elevated JVP (4 cm above sternal angle) with prominent a-wave
Left parasternal heave (right ventricular hypertrophy/dilatation)
Loud P₂ (palpable pulmonary component of S₂)
Right ventricular S₄ gallop at left lower sternal border
Pansystolic murmur at left lower sternal border, increasing with inspiration — consistent with tricuspid regurgitation
No peripheral clubbing

Respiratory:

Lungs clear to auscultation bilaterally
No wheeze, crackles, or pleural rub

Abdomen:

Hepatomegaly (liver edge 3 cm below costal margin)
No ascites

Extremities:

Bilateral pitting oedema to mid-shin
Cool peripheries; Raynaud's changes bilaterally

Skin/Joints:

No sclerodactyly, telangiectasiae, or skin thickening
No synovitis

Investigations

Bloods

Test	Result	Reference
FBC	Normal	—
U&E	Normal	—
LFTs	Mildly elevated ALP/bilirubin	—
BNP	820 pg/mL	<100 pg/mL
Anti-nuclear antibody (ANA)	Positive 1:160, speckled	Negative
Anti-centromere antibody	Positive	Negative
dsDNA, Ro/La	Negative	—
HIV serology	Negative	—
LFTs/hepatitis serology	Normal; Hep B/C negative	—
Thyroid function	Normal	—
Thrombophilia screen	Negative	—

The presence of Raynaud's phenomenon + anti-centromere antibody + arthralgia raises strong suspicion for limited systemic sclerosis (lcSSc/CREST syndrome), a major risk factor for PAH (Group 1 PAH — connective tissue disease-associated).

ECG

Sinus tachycardia
Right axis deviation
Right ventricular hypertrophy (R > S in V1; S1Q3T3 pattern)
P pulmonale (tall, peaked P waves in II)

Chest X-Ray

Enlarged main pulmonary artery and bilateral hilar prominence
Oligaemic peripheral lung fields ("pruning" of peripheral vessels)
Mild cardiomegaly — right heart predominant
No parenchymal infiltrates; no pleural effusion

Pulmonary Function Tests

Parameter	Result	% Predicted
FEV₁	2.4 L	88%
FVC	3.0 L	90%
FEV₁/FVC	0.80	Normal
TLC	4.8 L	86%
DLCO	52%	Reduced

Normal spirometry + normal lung volumes + reduced DLCO in isolation — this pattern should always prompt evaluation for pulmonary vascular disease. — Harrison's Principles of Internal Medicine 22E

Transthoracic Echocardiogram (TTE)

Right ventricular dilatation and hypertrophy with reduced systolic function (TAPSE 14 mm)
Interventricular septal flattening ("D-sign") — consistent with right ventricular pressure overload
Estimated RVSP: 72 mmHg (via tricuspid regurgitation jet velocity)
Left ventricular size and function: normal (EF 62%)
No intracardiac shunt on bubble study
Small pericardial effusion

CT Pulmonary Angiography (CTPA)

Enlarged main pulmonary artery (diameter 34 mm; >29 mm is abnormal)
No filling defects — chronic thromboembolic disease excluded
No significant parenchymal lung disease; no honeycombing
No evidence of interstitial fibrosis

Right Heart Catheterisation (RHC) — Gold Standard

Haemodynamic Parameter	Value	Threshold
Mean pulmonary artery pressure (mPAP)	46 mmHg	>20 mmHg = PH
Pulmonary capillary wedge pressure (PCWP)	9 mmHg	≤15 mmHg = precapillary
Pulmonary vascular resistance (PVR)	7.2 Wood units	>2 WU = precapillary PH
Cardiac output (thermodilution)	3.8 L/min	Low-normal
Cardiac index	2.2 L/min/m²	Borderline low

RHC confirms precapillary pulmonary hypertension: mPAP >20 mmHg + PCWP ≤15 mmHg + PVR >2 WU — consistent with Group 1 PAH (connective tissue disease-associated). Updated 2022 diagnostic thresholds now define PH as mPAP >20 mmHg (previously ≥25 mmHg) to enable earlier detection. — Harrison's 22E

Vasoreactivity Testing (inhaled NO):

mPAP fell by only 4 mmHg → Non-responder (negative test; response requires ≥10 mmHg fall to <40 mmHg with maintained/increased CO)

Diagnosis

Pulmonary Arterial Hypertension (PAH) — Group 1 Associated with limited systemic sclerosis (lcSSc) WHO Functional Class III

Pathophysiology Summary

In this patient, PAH arises from the interplay of immune-mediated endothelial injury (SSc) and intrinsic vascular biology:

Endothelial dysfunction — autoimmune-driven injury to pulmonary arteriolar endothelium disrupts the balance between vasoconstrictors (endothelin-1, thromboxane A₂) and vasodilators (prostacyclin, nitric oxide)
Obliterative arteriopathy — apoptosis resistance + smooth muscle cell and fibroblast proliferation → hypertrophic and plexogenic remodelling of distal pulmonary arterioles → reduced vascular compliance
In situ thrombosis — platelet activation and reduced prostacyclin promote microthrombus formation within remodelled arterioles
Extracellular matrix expansion — integrins, nonfibrillar collagens, and fibronectin further stiffen affected vessels
Genetic predisposition — mutations in BMPR2 (BMP receptor 2, within the TGF-β superfamily) are the most common hereditary driver; the family history of early cardiac death is relevant here. Sporadic BMPR2 mutations account for a significant proportion of apparently idiopathic cases
Right ventricular failure — sustained pressure overload → RV hypertrophy → dilation → reduced cardiac output → systemic venous congestion (elevated JVP, hepatomegaly, peripheral oedema)

"Apoptosis resistance, cell proliferation, dysregulated metabolism, and increased oxidant stress involving pulmonary vascular cells, pericytes, and adventitial fibroblasts underlie the pathogenesis of PAH." — Harrison's 22E

Management

General Measures

Supplemental oxygen to maintain SpO₂ ≥90–92% (hypoxia is a potent pulmonary vasoconstrictor)
Diuretics (furosemide) for RV volume overload — oedema and hepatic congestion
Anticoagulation: warfarin (INR 1.5–2.5) — evidence-based for idiopathic/heritable PAH; more variable in CTD-PAH
Exercise rehabilitation — supervised; avoid strenuous exertion
Vaccination: influenza, pneumococcal, COVID-19, RSV
Avoid pregnancy — carries very high mortality in PAH
Cease oestrogen-containing OCP — oestrogens are a risk factor for PAH

Pharmacologic Treatment

This patient is a vasoreactivity non-responder — calcium channel blockers are not indicated. All 14 FDA-approved PAH therapies target three pathways:

1. Endothelin Receptor Antagonists (ERAs) — Endothelin Pathway

Drug	Route
Ambrisentan	Oral
Bosentan	Oral
Macitentan	Oral

Endothelin-1 is a potent vasoconstrictor and mitogen overproduced in PAH. ERAs block ET_A and/or ET_B receptors.

2. PDE-5 Inhibitors / sGC Stimulators — Nitric Oxide Pathway

Drug	Route
Sildenafil	Oral
Tadalafil	Oral
Riociguat (sGC stimulator)	Oral

Enhance cGMP-mediated vasodilation in pulmonary vasculature.

3. Prostanoids — Prostacyclin Pathway

Drug	Route
Epoprostenol	IV (continuous) — gold standard for severe disease
Treprostinil	IV/SC/inhaled/oral
Iloprost	Inhaled
Selexipag (IP receptor agonist)	Oral

Replaces deficient prostacyclin; produces vasodilation, antiproliferation, and platelet inhibition.

4. Novel: Activin Signal Inhibitor

Sotatercept — rebalances TGF-β/BMPR2 signalling; approved 2024 as add-on therapy

Recommended initial strategy for this patient (WHO FC III, non-vasoreactive):

Dual oral combination therapy: ERA (e.g., macitentan) + PDE-5 inhibitor (e.g., tadalafil) initiated at a PH specialty centre, with planned escalation to triple therapy (adding a prostanoid) if insufficient response at 3–4 months.

Monitoring

6-minute walk distance (6MWD) — functional status marker
BNP/NT-proBNP — right ventricular stress marker; target normalisation
Echocardiography — RV function, RVSP trend
Repeat RHC at 3–6 months to assess haemodynamic response
WHO functional class reassessment at every visit

Prognosis

Among optimally treated PAH patients:

Timepoint	Survival
1 year	~82%
3 years	~67%
5 years	~58%

Adverse prognostic indicators in this patient: WHO FC III, reduced cardiac index, elevated BNP, pericardial effusion, RV dysfunction.

Escalation / Refractory Disease

Lung transplantation (bilateral) — referral should be considered early given young age and CTD-associated PAH
Atrial septostomy — palliative in refractory RV failure

Clinical Pearls

Key Point	Detail
Diagnostic delay	Mean delay of ~2 years is common; maintain suspicion in young women with unexplained dyspnoea
New mPAP threshold	PH now defined as mPAP >20 mmHg (was ≥25 mmHg) — enables earlier diagnosis
PVR threshold	Precapillary PH: PVR >2 Wood units (was ≥3 WU)
Isolated reduced DLCO	Normal spirometry + normal lung volumes + low DLCO → always investigate pulmonary vasculature
BMPR2	Most common hereditary PAH gene; family history of early cardiac death should raise suspicion
Vasoreactivity	Only ~10–15% of PAH patients are responders; non-responders should NOT receive CCBs
Oestrogens	OCP is a modifiable risk factor — must be stopped

Sources: Harrison's Principles of Internal Medicine 22E (2025), Chapters 294–295

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/home/user/pulmonary_hypertension_case.py

from pptx import Presentation
from pptx.util import Inches, Pt, Emu
from pptx.dml.color import RGBColor
from pptx.enum.text import PP_ALIGN
from pptx.util import Inches, Pt
import copy

# ── Colour palette ────────────────────────────────────────────────────────────
DARK_BLUE   = RGBColor(0x0D, 0x2D, 0x5E)   # slide background / title bg
MID_BLUE    = RGBColor(0x1B, 0x5E, 0xA7)   # accent bar / heading
LIGHT_BLUE  = RGBColor(0xD6, 0xE8, 0xF7)   # table header fill
WHITE       = RGBColor(0xFF, 0xFF, 0xFF)
ORANGE      = RGBColor(0xE8, 0x7C, 0x1E)   # highlight / key value
DARK_TEXT   = RGBColor(0x1A, 0x1A, 0x2E)
LIGHT_GREY  = RGBColor(0xF4, 0xF6, 0xF9)   # table row alt

prs = Presentation()
prs.slide_width  = Inches(13.33)
prs.slide_height = Inches(7.5)

BLANK_LAYOUT = prs.slide_layouts[6]   # completely blank


# ══════════════════════════════════════════════════════════════════════════════
# HELPER FUNCTIONS
# ══════════════════════════════════════════════════════════════════════════════

def add_rect(slide, l, t, w, h, fill_rgb=None, line_rgb=None, line_width_pt=0):
    shape = slide.shapes.add_shape(1, Inches(l), Inches(t), Inches(w), Inches(h))
    shape.line.fill.background()
    if fill_rgb:
        shape.fill.solid()
        shape.fill.fore_color.rgb = fill_rgb
    else:
        shape.fill.background()
    if line_rgb and line_width_pt:
        shape.line.color.rgb = line_rgb
        shape.line.width = Pt(line_width_pt)
    else:
        shape.line.fill.background()
    return shape


def add_textbox(slide, l, t, w, h, text, font_size=18, bold=False,
                color=WHITE, align=PP_ALIGN.LEFT, italic=False, wrap=True):
    txBox = slide.shapes.add_textbox(Inches(l), Inches(t), Inches(w), Inches(h))
    txBox.word_wrap = wrap
    tf = txBox.text_frame
    tf.word_wrap = wrap
    p = tf.paragraphs[0]
    p.alignment = align
    run = p.add_run()
    run.text = text
    run.font.size = Pt(font_size)
    run.font.bold = bold
    run.font.italic = italic
    run.font.color.rgb = color
    return txBox


def add_para(tf, text, font_size=16, bold=False, color=DARK_TEXT,
             align=PP_ALIGN.LEFT, italic=False, space_before=0, level=0,
             bullet=False):
    p = tf.add_paragraph()
    p.level = level
    p.alignment = align
    if space_before:
        p.space_before = Pt(space_before)
    run = p.add_run()
    run.text = text
    run.font.size = Pt(font_size)
    run.font.bold = bold
    run.font.italic = italic
    run.font.color.rgb = color
    return p


def make_slide_bg(slide, header_height=1.1):
    """White slide with dark-blue top bar."""
    # Full white bg
    add_rect(slide, 0, 0, 13.33, 7.5, fill_rgb=WHITE)
    # Top bar
    add_rect(slide, 0, 0, 13.33, header_height, fill_rgb=DARK_BLUE)
    # Thin orange accent line below bar
    add_rect(slide, 0, header_height, 13.33, 0.06, fill_rgb=ORANGE)


def slide_title(slide, title, subtitle=None):
    """Write title into the top bar."""
    add_textbox(slide, 0.3, 0.1, 12.5, 0.85, title,
                font_size=28, bold=True, color=WHITE, align=PP_ALIGN.LEFT)
    if subtitle:
        add_textbox(slide, 0.3, 0.82, 12.5, 0.35, subtitle,
                    font_size=14, bold=False, color=LIGHT_BLUE, align=PP_ALIGN.LEFT)


def content_box(slide, l, t, w, h):
    """Return a text-frame inside a white box with subtle border."""
    shape = slide.shapes.add_textbox(Inches(l), Inches(t), Inches(w), Inches(h))
    shape.word_wrap = True
    shape.text_frame.word_wrap = True
    return shape.text_frame


def bullet_section(tf, heading, items, h_size=17, b_size=15,
                   h_color=MID_BLUE, b_color=DARK_TEXT, space=6):
    """Add a bold heading then indented bullets to a text frame."""
    add_para(tf, heading, font_size=h_size, bold=True, color=h_color,
             space_before=space)
    for item in items:
        add_para(tf, f"  \u2022  {item}", font_size=b_size, color=b_color)


def simple_table(slide, headers, rows, l, t, w, h,
                 col_widths=None, h_font=13, r_font=12):
    """Draw a lightweight table."""
    n_cols = len(headers)
    n_rows = len(rows)
    total_rows = n_rows + 1
    row_h = h / total_rows
    if col_widths is None:
        col_widths = [w / n_cols] * n_cols

    # Header row
    x = l
    for i, hdr in enumerate(headers):
        add_rect(slide, x, t, col_widths[i], row_h, fill_rgb=MID_BLUE)
        add_textbox(slide, x + 0.05, t + 0.03, col_widths[i] - 0.1, row_h - 0.05,
                    hdr, font_size=h_font, bold=True, color=WHITE)
        x += col_widths[i]

    # Data rows
    for r_idx, row in enumerate(rows):
        y = t + row_h * (r_idx + 1)
        fill = LIGHT_GREY if r_idx % 2 == 0 else WHITE
        x = l
        for c_idx, cell in enumerate(row):
            add_rect(slide, x, y, col_widths[c_idx], row_h, fill_rgb=fill,
                     line_rgb=RGBColor(0xCC, 0xCC, 0xCC), line_width_pt=0.5)
            add_textbox(slide, x + 0.05, y + 0.02, col_widths[c_idx] - 0.1,
                        row_h - 0.04, str(cell), font_size=r_font, color=DARK_TEXT)
            x += col_widths[c_idx]


def footer(slide, text="Case Presentation: Pulmonary Hypertension  |  Source: Harrison's Principles of Internal Medicine 22E"):
    add_rect(slide, 0, 7.2, 13.33, 0.3, fill_rgb=DARK_BLUE)
    add_textbox(slide, 0.2, 7.21, 12.9, 0.28, text,
                font_size=9, color=LIGHT_BLUE, align=PP_ALIGN.LEFT)


# ══════════════════════════════════════════════════════════════════════════════
# SLIDE 1 — TITLE SLIDE
# ══════════════════════════════════════════════════════════════════════════════
slide = prs.slides.add_slide(BLANK_LAYOUT)
add_rect(slide, 0, 0, 13.33, 7.5, fill_rgb=DARK_BLUE)
add_rect(slide, 0, 2.9, 13.33, 0.08, fill_rgb=ORANGE)
add_rect(slide, 0, 3.0, 13.33, 0.08, fill_rgb=ORANGE)

add_textbox(slide, 1.0, 1.2, 11.0, 1.2,
            "PULMONARY HYPERTENSION",
            font_size=44, bold=True, color=WHITE, align=PP_ALIGN.CENTER)
add_textbox(slide, 1.0, 2.4, 11.0, 0.55,
            "A Clinical Case Presentation",
            font_size=24, bold=False, color=LIGHT_BLUE, align=PP_ALIGN.CENTER)
add_textbox(slide, 1.0, 3.2, 11.0, 0.5,
            "Patient: S.M.  |  34-year-old Female  |  WHO FC III",
            font_size=18, bold=False, color=ORANGE, align=PP_ALIGN.CENTER)
add_textbox(slide, 1.0, 3.85, 11.0, 0.45,
            "Based on Harrison's Principles of Internal Medicine, 22nd Edition (2025)",
            font_size=14, italic=True, color=LIGHT_BLUE, align=PP_ALIGN.CENTER)
add_textbox(slide, 1.0, 6.9, 11.0, 0.4,
            "Pulmonary Hypertension Specialty Centre",
            font_size=13, color=RGBColor(0xAA, 0xCC, 0xEE), align=PP_ALIGN.CENTER)


# ══════════════════════════════════════════════════════════════════════════════
# SLIDE 2 — PATIENT PROFILE & CHIEF COMPLAINT
# ══════════════════════════════════════════════════════════════════════════════
slide = prs.slides.add_slide(BLANK_LAYOUT)
make_slide_bg(slide)
slide_title(slide, "Patient Profile & Chief Complaint")
footer(slide)

# Left column — profile
tf = content_box(slide, 0.3, 1.25, 5.8, 5.8)
bullet_section(tf, "Patient Details", [
    "Name: S.M.",
    "Age: 34 years",
    "Sex: Female",
    "Occupation: Schoolteacher",
    "Referral: Cardiology → PH Specialty Centre",
])
bullet_section(tf, "Chief Complaint", [
    '"I have been getting more and more breathless',
    ' over the past 18 months, even walking short distances."',
])

# Right column — key timeline box
add_rect(slide, 6.5, 1.25, 6.5, 2.5, fill_rgb=LIGHT_BLUE,
         line_rgb=MID_BLUE, line_width_pt=1.5)
add_textbox(slide, 6.7, 1.3, 6.1, 0.45, "Symptom Timeline",
            font_size=15, bold=True, color=MID_BLUE)

timeline = [
    ("18 months ago", "Progressive exertional dyspnoea begins"),
    ("12 months ago", "Symptoms worsen — single flight of stairs"),
    ("6 months ago",  "Pre-syncope (×2), chest tightness, ankle oedema"),
    ("Now",           "WHO FC III — referred to specialist"),
]
y = 1.78
for t_label, t_text in timeline:
    add_rect(slide, 6.6, y, 1.3, 0.38, fill_rgb=MID_BLUE)
    add_textbox(slide, 6.62, y + 0.02, 1.26, 0.34, t_label,
                font_size=10, bold=True, color=WHITE, align=PP_ALIGN.CENTER)
    add_textbox(slide, 8.0, y + 0.04, 4.8, 0.34, t_text,
                font_size=12, color=DARK_TEXT)
    y += 0.46

# Diagnostic delay highlight box
add_rect(slide, 6.5, 3.95, 6.5, 0.9, fill_rgb=ORANGE)
add_textbox(slide, 6.6, 3.98, 6.2, 0.85,
            "⚠  Mean diagnostic delay in PAH: up to 2 years\n"
            "    Early recognition is critical for outcomes",
            font_size=13, bold=True, color=WHITE)


# ══════════════════════════════════════════════════════════════════════════════
# SLIDE 3 — HISTORY
# ══════════════════════════════════════════════════════════════════════════════
slide = prs.slides.add_slide(BLANK_LAYOUT)
make_slide_bg(slide)
slide_title(slide, "History")
footer(slide)

tf_l = content_box(slide, 0.3, 1.25, 6.2, 5.8)
bullet_section(tf_l, "History of Present Illness", [
    "Progressive exertional dyspnoea × 18 months (now WHO FC III)",
    "Exertional pre-syncope × 2 episodes",
    "Non-exertional central chest tightness",
    "Bilateral ankle oedema (worse evenings)",
    "Disproportionate fatigue",
    "No orthopnoea, PND, haemoptysis, or cough",
])
bullet_section(tf_l, "Past Medical History", [
    "Raynaud's phenomenon (diagnosed age 28)",
    "No prior DVT, PE, or cardiac disease",
    "No formally diagnosed connective tissue disease",
])
bullet_section(tf_l, "Medications", [
    "Combined oral contraceptive pill (since age 22)",
    "Nifedipine 10 mg PRN for Raynaud's",
])

tf_r = content_box(slide, 6.8, 1.25, 6.2, 5.8)
bullet_section(tf_r, "Family History", [
    "Paternal aunt: died of 'unknown heart failure' aged 41",
    "Raises suspicion for heritable PAH / BMPR2 variant",
])
bullet_section(tf_r, "Social History", [
    "Non-smoker",
    "Occasional alcohol",
    "No illicit drugs; no appetite suppressants",
])
bullet_section(tf_r, "Review of Systems", [
    "Mild arthralgia — small joints of hands (non-deforming)",
    "Intermittent dry eyes and dry mouth",
    "No skin rash, photosensitivity, or dysphagia",
])


# ══════════════════════════════════════════════════════════════════════════════
# SLIDE 4 — PHYSICAL EXAMINATION
# ══════════════════════════════════════════════════════════════════════════════
slide = prs.slides.add_slide(BLANK_LAYOUT)
make_slide_bg(slide)
slide_title(slide, "Physical Examination")
footer(slide)

# Vitals table
simple_table(slide,
    ["Parameter", "Value", "Significance"],
    [
        ["BP",          "108/72 mmHg",       "Low-normal — reduced cardiac output"],
        ["HR",          "96 bpm (regular)",  "Compensatory tachycardia"],
        ["RR",          "18/min",            "—"],
        ["SpO₂",        "94% (room air)",    "Mild hypoxaemia"],
        ["Temperature", "37.0°C",            "—"],
    ],
    l=0.3, t=1.25, w=8.5, h=2.15,
    col_widths=[2.2, 2.5, 3.8], h_font=13, r_font=12)

# Key exam findings
tf = content_box(slide, 0.3, 3.55, 12.7, 3.6)
bullet_section(tf, "Cardiovascular (Key Findings)", [
    "Elevated JVP with prominent a-wave — raised RA pressure",
    "Left parasternal heave — RV hypertrophy / dilatation",
    "Loud P₂ (palpable) — pulmonary hypertension",
    "RV S₄ gallop at left lower sternal border",
    "Pansystolic murmur ↑ with inspiration — tricuspid regurgitation",
    "Hepatomegaly (3 cm) + bilateral pitting oedema — RV failure",
], h_size=16, b_size=14)

add_rect(slide, 9.0, 1.25, 4.1, 2.15, fill_rgb=LIGHT_BLUE,
         line_rgb=MID_BLUE, line_width_pt=1)
add_textbox(slide, 9.1, 1.3, 3.9, 0.4, "Respiratory", font_size=14,
            bold=True, color=MID_BLUE)
add_textbox(slide, 9.1, 1.7, 3.9, 0.5,
            "Lungs clear bilaterally\nNo wheeze, crackles, or rub",
            font_size=13, color=DARK_TEXT)
add_textbox(slide, 9.1, 2.25, 3.9, 0.4, "Skin / Joints", font_size=14,
            bold=True, color=MID_BLUE)
add_textbox(slide, 9.1, 2.65, 3.9, 0.6,
            "No sclerodactyly or telangiectasiae\nCool peripheries; Raynaud's changes",
            font_size=13, color=DARK_TEXT)


# ══════════════════════════════════════════════════════════════════════════════
# SLIDE 5 — INVESTIGATIONS: BLOODS & ECG
# ══════════════════════════════════════════════════════════════════════════════
slide = prs.slides.add_slide(BLANK_LAYOUT)
make_slide_bg(slide)
slide_title(slide, "Investigations — Bloods & ECG")
footer(slide)

simple_table(slide,
    ["Investigation", "Result", "Interpretation"],
    [
        ["BNP",                       "820 pg/mL  ↑↑",        "RV wall stress / impending failure"],
        ["ANA",                       "Positive 1:160 (speckled)", "Autoimmune screen positive"],
        ["Anti-centromere Ab",        "POSITIVE",              "Strongly suggests limited SSc (CREST)"],
        ["dsDNA / Ro / La",           "Negative",              "SLE / Sjögren's less likely"],
        ["HIV serology",              "Negative",              "Group 1 cause excluded"],
        ["Hepatitis B/C",             "Negative",              "Porto-pulmonary PH less likely"],
        ["Thrombophilia screen",      "Negative",              "CTEPH less likely"],
        ["TFTs / FBC / U&E / LFTs",  "Normal (mild ↑ ALP)",   "Background organ function"],
    ],
    l=0.3, t=1.25, w=9.5, h=3.4,
    col_widths=[3.2, 2.9, 3.4], h_font=13, r_font=11)

add_rect(slide, 10.0, 1.25, 3.1, 3.4, fill_rgb=LIGHT_BLUE,
         line_rgb=MID_BLUE, line_width_pt=1)
add_textbox(slide, 10.1, 1.3, 2.9, 0.4, "ECG Findings",
            font_size=15, bold=True, color=MID_BLUE)
ecg_items = [
    "Sinus tachycardia",
    "Right axis deviation",
    "RV hypertrophy",
    "  (R > S in V1)",
    "P pulmonale",
    "  (tall peaked P in II)",
    "S1Q3T3 pattern",
]
y = 1.78
for item in ecg_items:
    bold = not item.startswith("  ")
    add_textbox(slide, 10.15, y, 2.85, 0.33, item,
                font_size=12, bold=bold, color=DARK_TEXT if bold else MID_BLUE)
    y += 0.33

# Key box
add_rect(slide, 0.3, 4.75, 12.7, 0.75, fill_rgb=ORANGE)
add_textbox(slide, 0.5, 4.78, 12.3, 0.7,
            "Anti-centromere Ab + Raynaud's + arthralgia = Limited Systemic Sclerosis (lcSSc/CREST)  "
            "→  CTD-associated PAH (Group 1)",
            font_size=14, bold=True, color=WHITE)


# ══════════════════════════════════════════════════════════════════════════════
# SLIDE 6 — INVESTIGATIONS: IMAGING & PFTs
# ══════════════════════════════════════════════════════════════════════════════
slide = prs.slides.add_slide(BLANK_LAYOUT)
make_slide_bg(slide)
slide_title(slide, "Investigations — Imaging & Pulmonary Function Tests")
footer(slide)

tf_l = content_box(slide, 0.3, 1.25, 6.0, 5.8)
bullet_section(tf_l, "Chest X-Ray", [
    "Enlarged main pulmonary artery",
    "Bilateral hilar prominence",
    "Peripheral oligaemia — 'pruning' of vessels",
    "Right-heart predominant cardiomegaly",
    "No parenchymal infiltrates",
    "No pleural effusion",
], h_size=16, b_size=14)
bullet_section(tf_l, "CTPA", [
    "Main PA diameter 34 mm (normal <29 mm)  ↑",
    "No filling defects — CTEPH excluded",
    "No interstitial fibrosis / honeycombing",
    "No significant parenchymal lung disease",
], h_size=16, b_size=14)

# PFT table right
simple_table(slide,
    ["PFT Parameter", "Result", "% Predicted"],
    [
        ["FEV₁",       "2.4 L",   "88%  (Normal)"],
        ["FVC",        "3.0 L",   "90%  (Normal)"],
        ["FEV₁/FVC",   "0.80",    "Normal"],
        ["TLC",        "4.8 L",   "86%  (Normal)"],
        ["DLCO",       "52%",     "REDUCED ↓↓"],
    ],
    l=6.6, t=1.25, w=6.4, h=2.6,
    col_widths=[2.6, 1.8, 2.0], h_font=13, r_font=12)

add_rect(slide, 6.6, 4.0, 6.4, 1.0, fill_rgb=LIGHT_BLUE,
         line_rgb=MID_BLUE, line_width_pt=1.5)
add_textbox(slide, 6.75, 4.05, 6.1, 0.9,
            "Clinical Pearl:  Normal spirometry + normal lung volumes\n"
            "+ isolated ↓DLCO  →  Always investigate pulmonary vasculature",
            font_size=13, bold=False, color=MID_BLUE)


# ══════════════════════════════════════════════════════════════════════════════
# SLIDE 7 — RIGHT HEART CATHETERISATION
# ══════════════════════════════════════════════════════════════════════════════
slide = prs.slides.add_slide(BLANK_LAYOUT)
make_slide_bg(slide)
slide_title(slide, "Right Heart Catheterisation — Gold Standard Diagnosis")
footer(slide)

simple_table(slide,
    ["Haemodynamic Parameter", "Value", "Threshold", "Interpretation"],
    [
        ["Mean PAP (mPAP)",           "46 mmHg",       ">20 mmHg",    "ELEVATED — PH confirmed"],
        ["Pulmonary Wedge (PCWP)",    "9 mmHg",        "≤15 mmHg",    "Precapillary pattern"],
        ["Pulmonary Vasc. Resistance","7.2 Wood units", ">2 WU",       "Significantly elevated"],
        ["Cardiac Output",            "3.8 L/min",     "Normal 4–8",   "Low-normal"],
        ["Cardiac Index",             "2.2 L/min/m²",  "Normal >2.5",  "Borderline low"],
    ],
    l=0.3, t=1.25, w=12.7, h=2.6,
    col_widths=[3.5, 2.2, 2.0, 5.0], h_font=13, r_font=12)

# Vasoreactivity
add_rect(slide, 0.3, 4.0, 6.1, 1.2, fill_rgb=LIGHT_BLUE,
         line_rgb=MID_BLUE, line_width_pt=1)
add_textbox(slide, 0.45, 4.05, 5.8, 1.1,
            "Vasoreactivity Test (inhaled NO)\n"
            "mPAP fell by only 4 mmHg  →  NEGATIVE\n"
            "Calcium channel blockers NOT indicated",
            font_size=13, color=MID_BLUE, bold=False)

# Updated thresholds
add_rect(slide, 6.6, 4.0, 6.4, 1.2, fill_rgb=ORANGE)
add_textbox(slide, 6.75, 4.05, 6.1, 1.1,
            "2022 Updated Diagnostic Thresholds:\n"
            "PH: mPAP >20 mmHg  (was ≥25 mmHg)\n"
            "Precapillary PH: PVR >2 WU  (was ≥3 WU)",
            font_size=13, bold=True, color=WHITE)

# Echocardiogram summary
tf = content_box(slide, 0.3, 5.35, 12.7, 1.8)
bullet_section(tf, "Echocardiogram Summary", [
    "RV dilatation & hypertrophy; TAPSE 14 mm (reduced RV function)",
    "Septal D-sign — RV pressure overload",
    "Estimated RVSP: 72 mmHg  |  Normal LV function (EF 62%)",
    "No intracardiac shunt  |  Small pericardial effusion",
], h_size=15, b_size=13)


# ══════════════════════════════════════════════════════════════════════════════
# SLIDE 8 — DIAGNOSIS
# ══════════════════════════════════════════════════════════════════════════════
slide = prs.slides.add_slide(BLANK_LAYOUT)
make_slide_bg(slide)
slide_title(slide, "Diagnosis")
footer(slide)

# Large diagnosis box
add_rect(slide, 1.0, 1.3, 11.0, 1.4, fill_rgb=MID_BLUE)
add_textbox(slide, 1.1, 1.35, 10.8, 1.3,
            "Pulmonary Arterial Hypertension (PAH) — Group 1\n"
            "Associated with Limited Systemic Sclerosis (lcSSc)  |  WHO Functional Class III",
            font_size=22, bold=True, color=WHITE, align=PP_ALIGN.CENTER)

# Classification table
simple_table(slide,
    ["WHO Group", "Cause", "This Patient?"],
    [
        ["Group 1 — PAH",     "Idiopathic, heritable, CTD, drugs/toxins, HIV, porto-PH", "YES — lcSSc-PAH"],
        ["Group 2 — LHD",     "Left heart disease (systolic/diastolic dysfunction)",     "No (PCWP = 9)"],
        ["Group 3 — Lung Dz", "COPD, ILD, sleep-disordered breathing",                  "No (PFTs normal)"],
        ["Group 4 — CTEPH",   "Chronic thromboembolic PH",                              "No (CTPA clear)"],
        ["Group 5 — Misc",    "Sarcoid, myeloproliferative, metabolic",                 "No"],
    ],
    l=0.3, t=2.85, w=12.7, h=3.0,
    col_widths=[2.8, 6.8, 3.1], h_font=13, r_font=12)

add_rect(slide, 0.3, 6.0, 12.7, 0.6, fill_rgb=LIGHT_BLUE,
         line_rgb=MID_BLUE, line_width_pt=1)
add_textbox(slide, 0.5, 6.03, 12.3, 0.55,
            "Confirmed precapillary PH:  mPAP 46 mmHg  |  PCWP 9 mmHg  |  PVR 7.2 WU  |  No secondary cause identified",
            font_size=13, bold=True, color=MID_BLUE)


# ══════════════════════════════════════════════════════════════════════════════
# SLIDE 9 — PATHOPHYSIOLOGY
# ══════════════════════════════════════════════════════════════════════════════
slide = prs.slides.add_slide(BLANK_LAYOUT)
make_slide_bg(slide)
slide_title(slide, "Pathophysiology of PAH")
footer(slide)

steps = [
    ("1", "Endothelial Injury",       "Autoimmune (SSc) → endothelial dysfunction\n↓ Prostacyclin / NO   |   ↑ Endothelin-1 / TXA₂"),
    ("2", "Obliterative Arteriopathy","Apoptosis resistance + SMC & fibroblast proliferation\n→ Hypertrophic, fibrotic, plexogenic remodelling"),
    ("3", "ECM Expansion",            "Integrins, nonfibrillar collagens, fibronectin\n→ Vessel stiffening & reduced compliance"),
    ("4", "In situ Thrombosis",       "Platelet activation + ↓ prostacyclin\n→ Microthrombus formation in arterioles"),
    ("5", "RV Pressure Overload",     "↑ PVR → RV hypertrophy → RV dilatation\n→ Reduced CO → systemic venous congestion"),
]

x_positions = [0.25, 2.8, 5.35, 7.9, 10.45]
for i, (num, heading, body) in enumerate(steps):
    x = x_positions[i]
    add_rect(slide, x, 1.25, 2.3, 0.55, fill_rgb=MID_BLUE)
    add_textbox(slide, x + 0.05, 1.27, 2.2, 0.5, f"{num}.  {heading}",
                font_size=13, bold=True, color=WHITE)
    add_rect(slide, x, 1.8, 2.3, 2.2, fill_rgb=LIGHT_BLUE,
             line_rgb=MID_BLUE, line_width_pt=1)
    add_textbox(slide, x + 0.08, 1.85, 2.15, 2.1, body,
                font_size=11, color=DARK_TEXT)
    if i < 4:
        add_textbox(slide, x + 2.32, 2.4, 0.4, 0.5, "→",
                    font_size=22, bold=True, color=ORANGE)

# Genetic drivers box
add_rect(slide, 0.3, 4.2, 12.7, 1.1, fill_rgb=WHITE,
         line_rgb=MID_BLUE, line_width_pt=1.5)
add_textbox(slide, 0.5, 4.25, 12.3, 1.0,
            "Genetic Drivers:  BMPR2 (most common — TGF-β superfamily) • TBX4 • SOX17\n"
            "BMPR2 variant: hereditary PAH — penetrance as low as 20%  |  "
            "Imbalance of TGF-β receptor signalling → therapeutic target (sotatercept)",
            font_size=13, color=DARK_TEXT)

# RV failure note
add_rect(slide, 0.3, 5.45, 12.7, 0.95, fill_rgb=ORANGE)
add_textbox(slide, 0.5, 5.5, 12.3, 0.85,
            "RV Dysfunction: Occurs due to ↑ afterload AND depressed sarcomere function "
            "from chronic inflammation / autoimmune mechanisms\n"
            "→ If untreated, PH carries high mortality from decompensated right heart failure",
            font_size=13, bold=False, color=WHITE)


# ══════════════════════════════════════════════════════════════════════════════
# SLIDE 10 — MANAGEMENT: GENERAL MEASURES
# ══════════════════════════════════════════════════════════════════════════════
slide = prs.slides.add_slide(BLANK_LAYOUT)
make_slide_bg(slide)
slide_title(slide, "Management — General & Supportive Measures")
footer(slide)

tf_l = content_box(slide, 0.3, 1.25, 6.2, 5.8)
bullet_section(tf_l, "Supportive Measures", [
    "Supplemental O₂ → maintain SpO₂ ≥90–92%",
    "  (Hypoxia = potent pulmonary vasoconstrictor)",
    "Diuretics (furosemide) — RV volume overload",
    "Anticoagulation — warfarin (INR 1.5–2.5)",
    "  (Evidence-based for idiopathic/heritable PAH)",
    "Supervised exercise rehabilitation",
    "Avoid strenuous exertion",
], h_size=16, b_size=14)
bullet_section(tf_l, "Vaccinations", [
    "Influenza (yearly)",
    "Pneumococcal (regardless of age)",
    "COVID-19 + RSV vaccines",
], h_size=16, b_size=14)

tf_r = content_box(slide, 6.8, 1.25, 6.2, 5.8)
bullet_section(tf_r, "Patient-Specific Actions", [
    "STOP combined oral contraceptive pill",
    "  (Oestrogens are a PAH risk factor)",
    "Avoid pregnancy — carries very high mortality",
    "Genetic counselling — BMPR2 testing",
    "  (Family history of early cardiac death)",
    "Screen first-degree relatives",
], h_size=16, b_size=14, h_color=ORANGE)
bullet_section(tf_r, "Monitoring Targets", [
    "6-minute walk distance (6MWD)",
    "BNP/NT-proBNP — target normalisation",
    "Echocardiography — RV function trend",
    "Repeat RHC at 3–6 months",
    "WHO FC reassessment every visit",
], h_size=16, b_size=14)


# ══════════════════════════════════════════════════════════════════════════════
# SLIDE 11 — PHARMACOLOGIC TREATMENT
# ══════════════════════════════════════════════════════════════════════════════
slide = prs.slides.add_slide(BLANK_LAYOUT)
make_slide_bg(slide)
slide_title(slide, "Pharmacologic Treatment of PAH — Three Pathways")
footer(slide)

# Three pathway boxes
pathways = [
    ("Endothelin\nPathway", "ERAs", ["Ambrisentan", "Bosentan", "Macitentan"],
     "ET-1 = potent vasoconstrictor + mitogen\nERAs block ETA / ETB receptors",
     MID_BLUE),
    ("Nitric Oxide\nPathway", "PDE-5i / sGC Stimulators",
     ["Sildenafil", "Tadalafil", "Riociguat (sGC)"],
     "Enhance cGMP-mediated\npulmonary vasodilation",
     RGBColor(0x17, 0x7D, 0x7D)),
    ("Prostacyclin\nPathway", "Prostanoids / IP Agonists",
     ["Epoprostenol (IV)", "Treprostinil (IV/SC/inhaled/oral)",
      "Iloprost (inhaled)", "Selexipag (oral)"],
     "Replaces deficient PGI₂\nVasodilation + antiproliferation\n+ platelet inhibition",
     RGBColor(0x5B, 0x2D, 0x8E)),
]

for i, (pw, drug_class, drugs, mech, col) in enumerate(pathways):
    x = 0.3 + i * 4.3
    add_rect(slide, x, 1.25, 4.1, 0.6, fill_rgb=col)
    add_textbox(slide, x + 0.05, 1.27, 4.0, 0.56, pw,
                font_size=14, bold=True, color=WHITE, align=PP_ALIGN.CENTER)
    add_rect(slide, x, 1.85, 4.1, 0.4, fill_rgb=LIGHT_BLUE,
             line_rgb=col, line_width_pt=1)
    add_textbox(slide, x + 0.08, 1.88, 3.95, 0.36, drug_class,
                font_size=13, bold=True, color=col)
    y = 2.35
    for d in drugs:
        add_textbox(slide, x + 0.15, y, 3.9, 0.35, f"• {d}",
                    font_size=12, color=DARK_TEXT)
        y += 0.35
    add_rect(slide, x, y + 0.05, 4.1, 1.1, fill_rgb=LIGHT_GREY,
             line_rgb=col, line_width_pt=0.5)
    add_textbox(slide, x + 0.1, y + 0.08, 3.9, 1.0, mech,
                font_size=11, italic=True, color=col)

# Recommended strategy
add_rect(slide, 0.3, 5.85, 12.7, 0.9, fill_rgb=ORANGE)
add_textbox(slide, 0.5, 5.88, 12.3, 0.85,
            "Recommended for S.M. (WHO FC III, vasoreactivity NEGATIVE):  "
            "Dual oral therapy  →  ERA (Macitentan) + PDE-5i (Tadalafil)\n"
            "Escalate to triple therapy (+ prostanoid) if insufficient response at 3–4 months",
            font_size=13, bold=True, color=WHITE)


# ══════════════════════════════════════════════════════════════════════════════
# SLIDE 12 — NOVEL THERAPY & ESCALATION
# ══════════════════════════════════════════════════════════════════════════════
slide = prs.slides.add_slide(BLANK_LAYOUT)
make_slide_bg(slide)
slide_title(slide, "Novel Therapy, Escalation & Prognosis")
footer(slide)

tf_l = content_box(slide, 0.3, 1.25, 6.2, 5.6)
bullet_section(tf_l, "Novel Agent: Sotatercept (2024)", [
    "Activin signal inhibitor",
    "Rebalances TGF-β / BMPR2 signalling",
    "Approved as add-on therapy for PAH",
    "Directly targets the genetic driver (BMPR2 axis)",
], h_size=16, b_size=14, h_color=ORANGE)
bullet_section(tf_l, "Refractory / Advanced Disease", [
    "Bilateral lung transplantation",
    "  (Refer early given young age + CTD-PAH)",
    "Atrial septostomy",
    "  (Palliative for refractory RV failure)",
], h_size=16, b_size=14)

# Prognosis table
simple_table(slide,
    ["Survival Timepoint", "Estimated Survival"],
    [
        ["1 year",  "~82%"],
        ["3 years", "~67%"],
        ["5 years", "~58%"],
    ],
    l=6.8, t=1.25, w=6.1, h=1.8,
    col_widths=[3.5, 2.6], h_font=14, r_font=13)

add_textbox(slide, 6.8, 3.15, 6.1, 0.35,
            "Adverse Prognostic Indicators in S.M.:",
            font_size=14, bold=True, color=MID_BLUE)
poor_prog = [
    "WHO Functional Class III",
    "Reduced cardiac index (2.2 L/min/m²)",
    "Markedly elevated BNP (820 pg/mL)",
    "Pericardial effusion",
    "RV systolic dysfunction (TAPSE 14 mm)",
]
y = 3.55
for item in poor_prog:
    add_textbox(slide, 7.0, y, 5.8, 0.35, f"  ✕  {item}",
                font_size=13, color=DARK_TEXT)
    y += 0.36


# ══════════════════════════════════════════════════════════════════════════════
# SLIDE 13 — CLINICAL PEARLS
# ══════════════════════════════════════════════════════════════════════════════
slide = prs.slides.add_slide(BLANK_LAYOUT)
make_slide_bg(slide)
slide_title(slide, "Clinical Pearls")
footer(slide)

pearls = [
    ("Diagnostic Delay",
     "Mean delay up to 2 years in PAH — maintain suspicion in young women with unexplained dyspnoea"),
    ("New mPAP Threshold",
     "PH now defined as mPAP >20 mmHg (was ≥25 mmHg) — enables earlier diagnosis"),
    ("New PVR Threshold",
     "Precapillary PH: PVR >2 Wood units (was ≥3 WU)"),
    ("Isolated ↓ DLCO",
     "Normal spirometry + normal lung volumes + low DLCO → always evaluate pulmonary vasculature"),
    ("BMPR2",
     "Most common hereditary PAH gene; family history of early unexplained cardiac death is a clue"),
    ("Vasoreactivity",
     "Only ~10–15% of PAH patients respond; non-responders must NOT receive calcium channel blockers"),
    ("OCP",
     "Combined oral contraceptive pill is a modifiable PAH risk factor — must be stopped"),
    ("Pregnancy",
     "Contraindicated in PAH — associated with very high maternal mortality"),
]

x_positions_p = [0.3, 6.65]
y_start = 1.3
for i, (title_p, body_p) in enumerate(pearls):
    col = i % 2
    row = i // 2
    x = x_positions_p[col]
    y = y_start + row * 1.35
    add_rect(slide, x, y, 6.1, 0.42, fill_rgb=MID_BLUE)
    add_textbox(slide, x + 0.1, y + 0.03, 5.9, 0.38, title_p,
                font_size=13, bold=True, color=WHITE)
    add_rect(slide, x, y + 0.42, 6.1, 0.82, fill_rgb=LIGHT_GREY,
             line_rgb=MID_BLUE, line_width_pt=0.5)
    add_textbox(slide, x + 0.12, y + 0.46, 5.86, 0.78, body_p,
                font_size=12, color=DARK_TEXT)


# ══════════════════════════════════════════════════════════════════════════════
# SLIDE 14 — SUMMARY
# ══════════════════════════════════════════════════════════════════════════════
slide = prs.slides.add_slide(BLANK_LAYOUT)
make_slide_bg(slide)
slide_title(slide, "Case Summary")
footer(slide)

simple_table(slide,
    ["Domain", "Finding"],
    [
        ["Patient",        "34F, lcSSc, Raynaud's, family history of early cardiac death"],
        ["Presentation",   "18 months progressive dyspnoea, pre-syncope, oedema — WHO FC III"],
        ["Key Tests",      "Anti-centromere Ab+, BNP 820, ECG RVH, Echo RVSP 72 mmHg, ↓DLCO"],
        ["RHC",            "mPAP 46 | PCWP 9 | PVR 7.2 WU — Precapillary PH confirmed"],
        ["Diagnosis",      "PAH Group 1 — Limited Systemic Sclerosis-associated"],
        ["Pathophysiology","Endothelial injury → obliterative arteriopathy → RV failure"],
        ["Genetic Driver", "BMPR2 pathway (TGF-β superfamily) disruption"],
        ["Treatment",      "Dual oral therapy: ERA + PDE-5i; add prostanoid if FC III persists"],
        ["Novel Rx",       "Sotatercept — activin signal inhibitor targeting BMPR2 axis"],
        ["Prognosis",      "5-year survival ~58%; early specialist referral & dual therapy critical"],
    ],
    l=0.3, t=1.25, w=12.7, h=5.3,
    col_widths=[2.8, 9.9], h_font=14, r_font=12)


# ══════════════════════════════════════════════════════════════════════════════
# SAVE
# ══════════════════════════════════════════════════════════════════════════════
output_path = "/home/user/Pulmonary_Hypertension_Case_Presentation.pptx"
prs.save(output_path)
print(f"Saved: {output_path}")

general-purpose

Run the Python script at `/home/user/pulmonary_hypertension_case.py` to generate a PowerPoint file. Steps: 1. Read the file at `/home/user/pulmonary_hypertension_case.py` to confirm its contents 2. Execute it using a shell command: `cd /home/user && python3 pulmonary_hypertension_case.py` 3. Confirm that the output file `/home/user/Pulmonary_Hypertension_Case_Presentation.pptx` was created successfully 4. If there are any errors, fix them in the script file and re-run until the file is successfully created 5. Report back: whether the file was created successfully, the file path, and any errors encountered along the way (and how you fixed them) Important: The script uses the `python-pptx` library. If it's not installed, install it with `pip3 install python-pptx` first.

I'm unable to execute the script directly in this environment, but the full Python script has been saved and is ready to use. Here's what to do:

Your PowerPoint is Ready to Generate

The complete script has been saved at:

/home/user/pulmonary_hypertension_case.py

To generate the `.pptx` file, run:

pip3 install python-pptx
python3 /home/user/pulmonary_hypertension_case.py

This will create: /home/user/Pulmonary_Hypertension_Case_Presentation.pptx

What's in the Presentation (14 Slides)

#	Slide Title
1	Title Slide — dark blue, branded
2	Patient Profile & Chief Complaint — timeline with diagnostic delay highlight
3	History — HPI, PMH, medications, family/social history
4	Physical Examination — vitals table + key cardiovascular findings
5	Investigations: Bloods & ECG — autoimmune panel, BNP, ECG findings
6	Investigations: Imaging & PFTs — CXR, CTPA, PFT table with DLCO pearl
7	Right Heart Catheterisation — haemodynamics table + updated thresholds
8	Diagnosis — WHO Group classification table
9	Pathophysiology — 5-step cascade diagram + BMPR2 genetics
10	General Management — O₂, diuretics, anticoagulation, lifestyle
11	Pharmacologic Treatment — 3 pathways (ERA / PDE-5i / Prostanoids)
12	Novel Therapy & Prognosis — Sotatercept, lung transplant, survival table
13	Clinical Pearls — 8 key take-home points in card format
14	Case Summary — full domain-by-domain recap table

Design features:

Dark navy + white + orange accent colour scheme
Structured tables, bullet boxes, and pathway diagrams
Footer on every slide citing Harrison's 22E

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Vascular Endothelial Growth Factor (VEGF)

1. The VEGF Family

2. Receptors

3. Physiological Functions

4. Regulation: The HIF-1 / Hypoxia Axis

5. VEGF in Pathology

Tumour Angiogenesis

Preeclampsia

Diabetic Macular Edema & Wet AMD

Psoriasis

6. VEGF-Targeted Therapies

6a. Antibodies Against VEGF Ligand

6b. Antibodies Against VEGFR

6c. Small Molecule VEGFR Tyrosine Kinase Inhibitors (TKIs)

7. Adverse Effects of VEGF Inhibition

8. Pathway Diagram

Summary

Case Presentation: Pulmonary Hypertension

Patient Profile

Chief Complaint

History of Present Illness

Past Medical History

Medications

Family History

Social History

Review of Systems

Physical Examination

Investigations

Bloods

ECG

Chest X-Ray

Pulmonary Function Tests

Transthoracic Echocardiogram (TTE)

CT Pulmonary Angiography (CTPA)

Right Heart Catheterisation (RHC) — Gold Standard

Diagnosis

Pathophysiology Summary

Management

General Measures

Pharmacologic Treatment

1. Endothelin Receptor Antagonists (ERAs) — Endothelin Pathway

2. PDE-5 Inhibitors / sGC Stimulators — Nitric Oxide Pathway

3. Prostanoids — Prostacyclin Pathway

4. Novel: Activin Signal Inhibitor

Monitoring

Prognosis

Escalation / Refractory Disease

Clinical Pearls

Your PowerPoint is Ready to Generate

To generate the .pptx file, run:

What's in the Presentation (14 Slides)

Design features:

To generate the `.pptx` file, run: