Good afternoon sir Patient named 60y female yasmin kco sjogrens + htn

Good afternoon sir Patient named 60y female yasmin kco sjogrens + htn + ckd a/w severe anemia (hb-4.4) + ?secondary myelofibrosis ?primary mpn Sir patient ko humne kal advice kiya tha admission and pcv transfusion patient subah emergency mei aye indoor hone for blood transfusion Patient is on Tab prednisolone 10mg po 1-0-0 Tab cilacar 10mg po 1-0-0 Tab sobisis 1000mg po 1-0-1 What is definitive management

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Good afternoon! Here is a structured management plan for Yasmin:

Yasmin — 60F | Sjögren's + HTN + CKD | Hb 4.4 | ?Autoimmune Myelofibrosis vs Primary MPN

🔴 IMMEDIATE: PCV Transfusion (Already In Progress)

Hb 4.4 is critically low — this is a chronic anemia, so the cardiac compensatory mechanisms are present but the risk of volume overload and decompensation is HIGH.

Transfusion Protocol for Hb <5 in chronic anemia:

Small aliquots only — 2–3 mL/kg per unit (NOT standard 1 unit upfront)
Slow rate — 1 mL/kg/hour
Target Hb: Raise to ~7–8 g/dL (do NOT over-transfuse; the aim is symptomatic relief, not normalization)
Monitor closely: SpO₂, BP, JVP, lung auscultation (risk of TACO — transfusion-associated circulatory overload)
IV Furosemide 20–40 mg between units (given CKD + risk of overload)
Pre-transfusion: Cross-match, DAT (direct antiglobulin test) — important in autoimmune context

🔍 CRITICAL FIRST STEP: Differentiate Autoimmune MF vs Primary MPN

This distinction changes everything:

Feature	Autoimmune MF (AMF)	Primary MPN/MF
Association	Sjögren's, SLE, scleroderma ✅	De novo
BM histology	Reticulin fibrosis, NO clustered/atypical megakaryocytes	Atypical megakaryocytes, clustered
DAT	May be positive	Usually negative
ANA/RF	Elevated	Usually absent
Prognosis	Benign, reversible	Malignant, progressive
Treatment	Corticosteroids → respond well	JAK inhibitors, Allo-HSCT

✅ WORKUP to Order NOW (if not already done):

Hematology:

Bone marrow biopsy — most critical (fibrosis grade, megakaryocyte morphology, cellularity)
JAK2 V617F mutation (also CALR, MPL if JAK2 negative) → if positive → Primary MPN
Peripheral blood film — leukoerythroblastic picture, dacrocytes (tear drop cells)?
Reticulocyte count
LDH, Uric acid (disease burden markers)
Serum EPO level

Autoimmune:

ANA, anti-SSA/SSB (already known Sjögren's), anti-dsDNA
DAT (direct Coombs) — rule out concurrent autoimmune hemolysis
Serum protein electrophoresis

Baseline / Organ Function:

CBC + differential, renal panel (CKD — baseline Cr/eGFR)
Coagulation profile (PT/INR, aPTT)
LFT, Ferritin, B12, Folate, Iron studies (rule out nutritional deficiencies compounding anemia)
Chest X-ray, ECHO (baseline cardiac function, volume status)
Abdominal USG — spleen size (splenomegaly = MPN more likely)

💊 DEFINITIVE MANAGEMENT (Depends on Diagnosis):

IF Autoimmune Myelofibrosis (AMF — most likely given Sjögren's):

First-Line: Corticosteroids — responds dramatically

Prednisolone 1 mg/kg/day (~60 mg/day for this patient)
She is already on Tab Prednisolone 10 mg — this dose is subtherapeutic for AMF
Taper over 1–3 months once peripheral counts normalize
Complete normalization of peripheral blood counts expected in majority
Bone marrow fibrosis reduction may also occur (though not required for clinical response)

If partial/inadequate corticosteroid response:

Add Hydroxychloroquine (standard Sjögren's baseline therapy — 200–400 mg/day)
Consider Azathioprine or Mycophenolate mofetil as steroid-sparing agents
Rituximab (anti-CD20) for refractory severe extraglandular Sjögren's — now prioritized as first-line biologic in 2024 BSR guidelines

IF Primary MPN / Primary Myelofibrosis confirmed (JAK2+, atypical BM):

Risk stratification using DIPSS-Plus score then:

Risk	Management
Low risk	Observation + symptom management
Intermediate-1	Individualized ± JAK inhibitor
Intermediate-2/High	JAK inhibitor + consider Allogeneic HSCT (only curative option)

JAK Inhibitors available:

Ruxolitinib — JAK1/2, 1st line; dosing based on platelet count; excellent for splenomegaly & symptoms; worsens anemia (important in this patient)
Fedratinib — JAK2; check thiamine levels before starting
Momelotinib — JAK1/2/ACVR1; specifically approved (Sep 2023, FDA) for MF patients WITH anemia → best choice here given Hb 4.4
Pacritinib — for patients with severe thrombocytopenia (plt <100k)

For anemia specifically in MF:

Erythropoiesis-stimulating agents (EPO) — ~1/3 response rate, try under expert supervision
Danazol (androgen) — can improve anemia in MF
Lenalidomide ± prednisone — particularly if del(5q) or JAK2+
Repeat PCV transfusions as supportive care

💊 Current Medications — Review:

Drug	Purpose	Comment
Prednisolone 10 mg OD	Sjögren's / AMF?	Dose likely insufficient for AMF — may need uptitration to 1 mg/kg
Cilacar (Cilnidipine) 10 mg OD	HTN	Continue — calcium channel blocker, acceptable in CKD
Sobisis (Sodium bicarbonate) 1000 mg BD	CKD metabolic acidosis	Continue — standard CKD management

Consider adding:

Hydroxychloroquine 200 mg BD — cornerstone of Sjögren's treatment (not currently on this)
Folic acid 5 mg OD — especially if hemolysis or nutritional component
Proton pump inhibitor (cover steroids)
Calcium + Vitamin D (steroid osteoporosis prophylaxis — important in 60F)
Avoid NSAIDs (CKD)

🎯 Key Message

Given Sjögren's + bone marrow fibrosis, Autoimmune Myelofibrosis (AMF) is the most likely diagnosis here — this is a benign, steroid-responsive condition with excellent prognosis. The current prednisolone 10 mg dose needs to be increased to therapeutic levels (1 mg/kg/day) once the bone marrow biopsy confirms AMF and JAK2/CALR mutations come back negative. Do NOT start JAK inhibitors until Primary MPN is excluded.

Urgent hematology consultation + bone marrow biopsy is the immediate priority alongside the transfusion.

Goldman-Cecil Medicine; Washington Manual of Medical Therapeutics; HTCT Primary Myelofibrosis Therapeutic Options

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📋 YASMIN — Report Summary & Analysis

🔬 BONE MARROW BIOPSY (AIIMS — Dr. Hema Parekh, Haematopathology)

Specimen: Bone marrow biopsy — 06 May 2026 Impression (readable from phone screen):

Overall cellularity ~70% (hypercellular)
Predominantly normoblastic erythropoiesis with some dysplastic features
Bone marrow shows moderate to marked (Grade 2–3) fibrosis
Admixed with predominantly normocellular — no lymphoid aggregates
Megakaryocytes: present, abnormal/atypical morphology noted
History mentions: K/C/O Sjögren's syndrome, AOCD, CKD, Anemia under evaluation
Advice: "Correlation with ECF & ICS is advisable to repeat Direct and Indirect of autoimmune process. Suggest JAK2 ECF & ICS is advisable to evaluate LVMVL (JAK2/CALR). BLOCKS PROVIDED WITH THE REPORT. PRESERVE CAREFULLY."

Translation: BM biopsy shows Grade 2–3 fibrosis. Pathologist is asking for JAK2/CALR mutation testing to differentiate primary MPN from autoimmune myelofibrosis.

🩸 CBC (Post-transfusion — 09 May 2026)

Parameter	Value	Normal	Interpretation
Haemoglobin	7.3 g/dL	12–15	Severe anemia (up from 4.4 — transfusion response)
WBC	8.62	4–10	Normal
RBC	2.62	3.8–4.8	Low
Hematocrit	23.5%	36–46	Low
MCV	89.5 fL	83–101	Normocytic
MCH	27.9	27–32	Low-normal
MCHC	31.2	31.5–34.5	Low-normal (borderline hypochromic)
RDW	19.7	11.6–14	⚠️ VERY HIGH — anisocytosis
Platelet count	145	150–410	Borderline low (mild thrombocytopenia)
MPV	7.3	7–11	Normal
Neutrophil	76.9%	40–80	Normal

🧪 RENAL FUNCTION TESTS

Parameter	Value	Normal	Interpretation
Blood Urea	87.7	13–43	⚠️ HIGH — azotemia
Creatinine	4.13 mg/dL	0.6–1.2	🔴 SEVERELY ELEVATED — advanced CKD
Sodium	140	132–146	Normal
Potassium	4.33	3.5–5.1	Normal
Chloride	105	99–109	Normal

eGFR estimate (CKD-EPI for 61F, Cr 4.13): ~12–14 mL/min/1.73m² → CKD Stage 5 (pre-dialysis)

🧪 URINE / OTHER

Parameter	Value	Interpretation
Urine Albumin/Creatinine Ratio	3995.2 (Normal 0–30)	🔴 Massive proteinuria — nephrotic-range
Urine Blood	Present (++)	Hematuria
Urine Protein	Present (+)	Proteinuria
Urine Pus Cells	1–2	Minimal
Ionised Calcium	1.17 (1.12–1.32)	Normal

🧠 CLINICAL INTERPRETATION

What do the reports tell us?

BM Biopsy: Grade 2–3 Myelofibrosis — this is significant fibrosis. The pathologist has NOT given a definitive primary vs secondary label and is requesting JAK2/CALR — this is the KEY pending result.
CBC pattern: Normocytic anemia + High RDW + Mild thrombocytopenia — classic for:
- Myelofibrosis (leukoerythroblastic picture expected — check peripheral smear for tear-drop cells)
- Anemia of CKD component (EPO deficiency)
- Mixed nutritional deficiency possible (high RDW)
CKD Stage 5 (Cr 4.13) — This is extremely important:
- Limits many drug choices
- EPO deficiency is contributing to anemia
- Renal replacement therapy discussion needed
- Avoid NSAIDs, nephrotoxic drugs, contrast
Massive proteinuria (ACR 3995) — This is nephrotic-range. In Sjögren's + myelofibrosis, renal involvement could be:
- Tubulointerstitial nephritis (most common in Sjögren's)
- Membranous nephropathy (Sjögren's-associated)
- Amyloidosis (CKD + myelofibrosis + proteinuria — must rule out)
- Glomerulopathy secondary to primary MF (recent 2025 systematic review confirms this association)

🎯 REVISED MANAGEMENT PLAN (Based on Reports)

IMMEDIATE (Today):

1. Continue transfusion protocol — Hb now 7.3 (up from 4.4 ✅), continue careful monitoring. Target Hb 8–9 g/dL.

2. URGENT: JAK2 V617F mutation + CALR + MPL mutations — Pathologist himself has asked for this. This is the single most important test to order right now. Do not start definitive treatment without this.

3. Peripheral blood smear — look for:

Dacrocytes (tear-drop cells) → if present, confirms myelofibrosis
Leukoerythroblastic picture (nucleated RBCs + immature WBCs) → severity marker

DRUG MANAGEMENT — CKD Stage 5 Modifications:

🔴 CRITICAL: Creatinine 4.13 = CKD Stage 5. Nearly ALL medications need dose adjustment.

IF Autoimmune MF confirmed (JAK2/CALR NEGATIVE):

Prednisolone increase to 0.5–1 mg/kg/day (~40–60 mg/day)
- Caution: Steroid hyperglycemia monitoring needed
- Bone protection: Tab Calcium carbonate + Vit D3 (avoid Ca in CKD stage 5 if PO4 high — check phosphate first)
Add Hydroxychloroquine 200 mg OD (not BD in CKD stage 5 — reduce dose)
- Safe in CKD, cardioprotective, baseline ophthalmology review
Proton pump inhibitor (omeprazole/pantoprazole) to cover steroids

IF Primary MF confirmed (JAK2/CALR POSITIVE):

Momelotinib is the preferred JAK inhibitor given anemia + MF — FDA-approved 2023 for MF with anemia
- Dose adjustment needed for CKD (eGFR <15 — limited data, haematology to decide)
Ruxolitinib — worsens anemia further — caution
Allo-HSCT: Contraindicated/very high risk with CKD Stage 5

CKD Stage 5 — Specific Management:

Issue	Action
Cr 4.13, eGFR ~12	Nephrology referral urgent — pre-dialysis planning
Massive proteinuria (ACR 3995)	Renal biopsy to characterize — amyloid? Membranous? TIN?
Anemia of CKD	EPO alfa/darbepoetin — start after transfusion stabilized (target Hb 10–11 in CKD)
Metabolic acidosis	Continue Sobisis (sodium bicarb) — continue
HTN	Continue Cilacar — good choice in CKD (CCB); avoid ACEi/ARB with Cr 4.13
Hyperphosphatemia	Check serum phosphate — if high, start phosphate binder
Hyperkalemia risk	Monitor K⁺ closely — currently 4.33 (borderline for CKD 5)

What to AVOID in this patient:

❌ NSAIDs (renal toxicity)
❌ IV Contrast (nephrotoxic with CKD 5)
❌ Methotrexate (renally cleared — contraindicated in CKD 5)
❌ High-dose ruxolitinib without haematology guidance (worsens anemia)
❌ Over-transfusion (TACO risk — CKD + cardiac)

Summary of Pending Tests Still Needed:

Test	Why
JAK2 V617F / CALR / MPL	Distinguish primary vs autoimmune MF — the ANSWER
Peripheral smear	Tear-drop cells, leukoerythroblastic picture
Serum ferritin, TIBC, iron	Mixed iron deficiency component?
Serum B12 + Folate	High RDW suggests nutritional component
LDH, Uric acid	Disease burden in MF
Serum phosphate, PTH	CKD mineral-bone disease
Renal biopsy	Massive proteinuria — must characterize the nephropathy
Peripheral smear + reticulocyte count	Hemolytic component?
DAT (Direct Coombs)	Autoimmune hemolysis in Sjögren's
Serum EPO level	Guide EPO therapy decision

Bottom line: The bone marrow biopsy has confirmed Grade 2–3 fibrosis. The pathologist has correctly flagged JAK2/CALR as the essential next step. This result will determine whether you are treating autoimmune MF (steroids ↑ dose) or primary MPN (JAK inhibitor). Meanwhile, the CKD Stage 5 + massive proteinuria is a parallel major concern requiring nephrology co-management and consideration of renal biopsy.

Paroxysmal nocturnal hemoglobinuria treTment

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Here is a comprehensive, up-to-date treatment guide for PNH:

Paroxysmal Nocturnal Hemoglobinuria (PNH) — Treatment

Quick Recap: Why PNH Lyses?

PIG-A gene mutation → deficiency of GPI anchor proteins → loss of CD55 (inhibits C3 convertase) and CD59 (inhibits membrane attack complex) → uncontrolled complement activation → intravascular hemolysis + thrombosis

🔵 Treatment Framework

1. SPECIFIC THERAPY — Complement Inhibitors (Disease-Modifying)

🥇 ANTI-C5 INHIBITORS (Terminal Complement Blockade)

Drug	Route	Dosing	Notes
Eculizumab (Soliris)	IV	600 mg/week × 4 wk → 900 mg at week 5 → 900 mg every 2 weeks	First approved; gold standard; ↓ hemolysis, ↓ transfusions, ↓ thrombosis
Ravulizumab (Ultomiris)	IV	Weight-based loading (2400–3000 mg) → 3000–3600 mg every 8 weeks	Longer half-life derivative of eculizumab; same efficacy, less frequent dosing — preferred in practice
Crovalimab (Piasky)	SC	Subcutaneous — available in some countries	Useful in eculizumab/ravulizumab resistant patients

⚠️ Critical before starting any complement inhibitor:

Vaccinate against Neisseria meningitidis (A, C, W, Y + B) — at least 2 weeks before starting
Long-term oral penicillin prophylaxis (amoxicillin 250 mg BD) — mandatory
Also vaccinate against Streptococcus pneumoniae and Haemophilus influenzae

What anti-C5 does:

Prevents intravascular hemolysis ✅
Reduces thrombosis risk ✅
BUT: PNH red cells (now spared from lysis) get C3-opsonized → iatrogenic extravascular hemolysis continues (Coombs becomes positive on therapy — this is expected, not a treatment failure)

🥇 ANTI-C3 / PROXIMAL COMPLEMENT INHIBITORS (Newer — Superior Anemia Control)

Drug	Target	Route	Status
Pegcetacoplan (Empaveli)	C3	SC 1080 mg twice weekly	FDA approved; prevents both intravascular AND extravascular hemolysis — corrects anemia more completely
Iptacopan (Fabhalta)	Factor B (alternative pathway)	Oral 200 mg BD	FDA approved 2023 — first oral complement inhibitor for PNH; superior Hb improvement vs eculizumab
Danicopan	Factor D	Oral	FDA approved as add-on for C5-inhibitor-inadequate responders

Key difference from anti-C5:

Anti-C3/proximal inhibitors prevent C3 opsonization → NO extravascular hemolysis → anemia corrects more completely (vs C5 inhibitors which leave extravascular hemolysis ongoing)

⚠️ However: if complement blockade is abruptly stopped, the large accumulated PNH red cell population can undergo massive sudden lysis — do NOT stop abruptly.

Indications for Complement Inhibitor Therapy:

Transfusion-dependent hemolytic anemia — primary indication
Thrombosis (even one episode) — strong indication
Symptomatic hemolysis (abdominal pain, dysphagia, hemoglobinuria, fatigue)
Large PNH clone (>10% granulocytes) + symptoms

2. CURATIVE THERAPY — Allogeneic Bone Marrow Transplantation (Allo-BMT)

Only cure — eliminates the PNH clone
Indicated in:
- PNH-aplastic anemia (PNH-AA) syndrome — complement inhibitors don't treat the bone marrow failure component
- Young patients with severe disease + HLA-identical sibling available
- Patients failing complement inhibitor therapy
Note: Since complement inhibitors became available, BMT use in PNH has significantly decreased

3. ANTICOAGULATION

Any PNH patient with prior thrombosis → long-term anticoagulation (warfarin or LMWH or DOAC)
Thrombosis not resolving → thrombolytic therapy with tPA may be considered
Start complement inhibitor alongside anticoagulation in thrombotic PNH

4. SUPPORTIVE MANAGEMENT (Important where complement inhibitors not available — high-resource issue in India)

Measure	Details
Folic acid	At least 3 mg/day — mandatory (chronic hemolysis depletes folate)
Iron supplementation	Check serum iron/ferritin periodically — chronic hemosiderinuria causes iron deficiency
Red cell transfusions	Leukocyte-depleted (washed/filtered) packed red cells — use when symptomatic
Erythropoiesis-stimulating agents	EPO alfa — if EPO deficiency coexists (esp. with CKD)
Avoid triggers	Infections, surgery, contrast dyes, strenuous exercise — can precipitate hemolytic crises
Corticosteroids	❌ NOT indicated for chronic hemolysis (no evidence, significant side effects); a short course may help during acute inflammatory exacerbation

5. IMMUNOSUPPRESSIVE THERAPY (for PNH-AA syndrome)

When bone marrow failure (aplastic anemia) is the dominant feature:

Anti-thymocyte globulin (ATG) + Cyclosporine A — standard IST for aplastic anemia
Can be combined with eculizumab simultaneously
Eltrombopag (TPO agonist) — improves multilineage response in aplastic anemia component

🗺️ Treatment Algorithm Summary

PNH Diagnosis (flow cytometry: CD55/CD59 deficiency on RBCs + FLAER on granulocytes)
        │
        ├── Classic hemolytic PNH
        │       ├── Symptomatic / transfusion-dependent / thrombosis
        │       │       → COMPLEMENT INHIBITOR
        │       │           ├── Prefer: Iptacopan (oral, superior anemia)
        │       │           ├── Or: Ravulizumab (8-weekly IV, proven)
        │       │           └── If C5 inadequate response: add Danicopan or switch to Pegcetacoplan
        │       └── Young + HLA-identical sibling → Consider Allo-BMT
        │
        ├── PNH-AA Syndrome (bone marrow failure dominant)
        │       → ATG + Cyclosporine ± Eculizumab ± Eltrombopag
        │       → HLA-matched sibling → Allo-BMT (preferred)
        │
        └── Supportive (where biologics unavailable)
                → Folic acid + iron + transfusions + anticoagulation if thrombosis

🔴 Key Points to Remember

Point	Detail
Diagnose with	Flow cytometry (FLAER + CD59) — Gold standard
First choice biologic	Ravulizumab (same as eculizumab but 8-weekly — practical advantage)
Best for anemia correction	Iptacopan (oral C3 proximal inhibitor) or Pegcetacoplan
Before any complement inhibitor	Meningococcal vaccine + penicillin prophylaxis
Only cure	Allo-BMT
Steroids	❌ NOT for chronic hemolysis
Thrombosis	Anticoagulate + start complement inhibitor
Never stop complement inhibitor abruptly	Risk of massive rebound hemolysis

Sources: Goldman-Cecil Medicine; Harrison's Principles of Internal Medicine 22E (2025); Katzung's Pharmacology 16E; PMID 38084255 (Oliver & Patriquin, 2023 Review); PMID 39371251 (Panse et al., 2024)

Paroxysmal nocturnal hemoglobinuria treTment

The full PNH treatment guide was just covered in my previous response above. Here's a quick summary for reference:

PNH Treatment — Quick Reference

🎯 Specific (Disease-Modifying) — Complement Inhibitors

Anti-C5 (Terminal blockade):

Ravulizumab — IV every 8 weeks (preferred — fewer infusions)
Eculizumab — IV every 2 weeks (original standard)
Crovalimab — SC option

Anti-C3/Proximal (Better anemia control):

Iptacopan — Oral BD (first oral option; superior Hb correction)
Pegcetacoplan — SC twice weekly (corrects both intravascular + extravascular hemolysis)
Danicopan — Oral add-on for C5 inadequate responders

⚠️ Before ANY complement inhibitor: Vaccinate against Meningococcus A/B/C/W/Y + start penicillin prophylaxis

🩸 Anticoagulation

Any thrombosis episode → long-term anticoagulation + complement inhibitor

🏥 Curative

Allo-BMT — only cure; especially for PNH-AA syndrome or young patients with matched sibling

💊 Supportive (where biologics unavailable)

Folic acid ≥3 mg/day (mandatory)
Iron supplements (monitor for iron deficiency from hemosiderinuria)
Leukocyte-depleted PCV transfusions
❌ Steroids — NOT for chronic hemolysis

Please scroll up for the full detailed breakdown with dosing, indications, and treatment algorithm.

Search for latest PNH clinical guidelines 2024-2025

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Here is a synthesis of the latest 2024–2025 PNH guidelines and evidence:

PNH Treatment — Latest Guidelines & Evidence 2024–2025

📋 Published Guidelines

1. Chinese Society of Hematology — PNH Guidelines 2024

[PMID: 39307719] — Zhonghua Xue Ye Xue Za Zhi, Aug 2024

The only formal national practice guideline published in 2024
Updates the 2013 Chinese PNH consensus
Incorporates complement inhibitor therapy including newer proximal inhibitors
Covers diagnosis (flow cytometry with FLAER), treatment indications, and monitoring

💊 Major Drug Approvals (2024–2025) — What's New

Drug	Target	FDA Approval	Route	Key Update
Crovalimab (Piasky)	C5	June 2024 ✅ NEW	SC every 4 weeks	Phase 3 COMMODORE 2 trial — non-inferior to eculizumab
Iptacopan (Fabhalta)	Factor B	Dec 2023 (PI updated March 2025)	Oral BD	First oral monotherapy; superior Hb correction vs anti-C5
Danicopan (Voydeya)	Factor D	March 2024	Oral TDS	Add-on to C5 inhibitor for extravascular hemolysis
Pegcetacoplan (Empaveli)	C3	Updated PI Feb 2024	SC twice weekly	First-line approved; prevents both IVH + EVH
Ravulizumab (Ultomiris)	C5	Updated PI Sept 2024	IV every 8 weeks	Remains standard C5 inhibitor
Eculizumab (Soliris)	C5	Updated PI Feb 2025	IV every 2 weeks	Still used; longer track record

🔬 Key Trial Evidence 2024–2025

COMMODORE 2 Trial — Crovalimab vs Eculizumab (Phase 3 RCT)

[PMID: 38884175] — Am J Hematol, Sept 2024

204 complement-inhibitor naive PNH patients randomized 2:1
Crovalimab non-inferior to eculizumab in:
- Hemolysis control (LDH ≤1.5×ULN): 79.3% vs 79.0%
- Transfusion avoidance: 65.7% vs 68.1%
- Breakthrough hemolysis: 10.4% vs 14.5% (crovalimab numerically better)
Key advantage: SC self-administration every 4 weeks vs IV every 2 weeks → patients preferred crovalimab after crossover
Safety profiles similar; no meningococcal infections in either arm

Iptacopan APPLY-PNH Trial (N Engl J Med 2024)

Peffault de Latour R et al. — NEJM 390(11):994–1008, 2024

Oral iptacopan monotherapy vs anti-C5 (eculizumab/ravulizumab)
Superior Hb increase with iptacopan: +3.6 g/dL vs -0.0 g/dL
82% achieved Hb ≥12 g/dL vs 2% on anti-C5
Addresses the unmet need of extravascular hemolysis not controlled by C5 inhibitors

🧭 2024–2025 Treatment Algorithm (Evidence-Based)

NEW PNH PATIENT — Symptomatic / Hemolytic
         │
         ▼
First-line: Choose complement inhibitor based on patient profile
         │
         ├── Anemia is primary concern / wants oral therapy
         │       → IPTACOPAN (oral BD) ← PREFERRED 2024-25
         │         [corrects both IVH + EVH; superior Hb normalization]
         │
         ├── Wants subcutaneous/self-administer, less frequent
         │       → CROVALIMAB (SC every 4 weeks) ← NEW 2024
         │         [non-inferior to eculizumab; patient-preferred]
         │
         ├── IV acceptable, established long-term data
         │       → RAVULIZUMAB (IV every 8 wk) or ECULIZUMAB (IV every 2 wk)
         │
         └── Patient already on C5 inhibitor but persistent EVH/anemia
                 → ADD DANICOPAN (oral TDS) ← NEW 2024
                 → OR SWITCH TO PEGCETACOPLAN (SC twice weekly)

⚠️ 2024–2025 Consensus Points (Panse et al., Transfus Med Hemother 2024)

[PMID: 39371251]

Terminal C5 inhibitors (eculizumab/ravulizumab) dramatically improved survival — still valid first line
Extravascular hemolysis (EVH) is the key unmet need on C5 therapy — up to 40% of patients on eculizumab still have significant anemia from EVH
Proximal inhibitors (iptacopan, pegcetacoplan) normalize Hb and ARC in EVH-predominant patients — superior anemia correction
No formal evidence-based algorithm yet for choosing between terminal vs proximal inhibitor in first-line — individualize based on:
- Degree of anemia
- Preference for oral vs injectable
- Access/cost
- Thrombosis risk
Real-world long-term data on proximal inhibitors still accumulating

🔴 Breakthrough Hemolysis — 2025 Update

[PMID: 40233322] — Blood, Fattizzo et al., 2025

Breakthrough hemolysis remains a challenge with both terminal and proximal inhibitors
With proximal inhibitors (C3 level): if blockade is incomplete, the large accumulated PNH clone can undergo more severe sudden lysis than with C5 inhibitors
Emerging consensus: do NOT stop proximal inhibitors abruptly; taper carefully

💰 Access Note (India-Specific)

Eculizumab/ravulizumab are extremely expensive (~$500,000/year) — not routinely accessible in India
Iptacopan and crovalimab: availability in India still limited
Supportive care protocol remains essential:
- Folic acid 5 mg/day
- Iron supplementation
- Regular transfusions
- Anticoagulation for thrombosis
- Immunosuppression (ATG + cyclosporine) for aplastic anemia component

📌 Key References

PMID	Citation
39307719	Chinese CSH PNH Guidelines 2024 — Zhonghua Xue Ye Xue Za Zhi
38884175	COMMODORE 2 RCT: Crovalimab vs Eculizumab — Am J Hematol 2024
39371251	Panse et al. PNH Pathophysiology & Treatment — Transfus Med Hemother 2024
40233322	Fattizzo et al. Breakthrough Hemolysis — Blood 2025
39273426	Hillmen et al. Navigating Complement Pathway — Int J Mol Sci 2024

Describe pnh a little and indian scenario management

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Here is a focused description of PNH with the India-specific management context:

Paroxysmal Nocturnal Hemoglobinuria (PNH) — Description & Indian Scenario

🔬 What is PNH?

PNH is a rare, acquired, clonal hematopoietic stem cell disorder — not inherited, not cancer, but potentially life-threatening.

The Core Defect (in simple terms):

Normal cell:  CD55 + CD59 on surface → Complement BLOCKED → RBC safe ✅
PNH cell:     PIG-A mutation → No GPI anchor → No CD55/CD59 → Complement ATTACKS → RBC destroyed 🔴

PIG-A gene mutation (X chromosome, somatic) → loss of GPI anchors → CD55 and CD59 absent on RBC surface → uncontrolled complement activation → Membrane Attack Complex (MAC) forms → intravascular hemolysis

Free hemoglobin released into plasma scavenges nitric oxide → vasospasm → abdominal pain, dysphagia, erectile dysfunction, pulmonary hypertension.

🏥 Clinical Picture

The Classic Triad:

Feature	Why it Happens
Hemoglobinuria (dark/cola urine — classically morning)	Intravascular hemolysis during sleep (slight pH drop activates complement)
Anemia (often severe)	Chronic RBC destruction + iron loss in urine
Thrombosis (major killer)	Platelet activation + NO scavenging → hypercoagulability

Full Clinical Spectrum:

🩸 Hematological:

Normocytic anemia (can be severe — Hb 4–7)
Pancytopenia (leukopenia + thrombocytopenia in 60–70%)
High RDW (anisocytosis)
Reticulocytosis (often less than expected — marrow suppression)
DAT negative (distinguishes from autoimmune hemolytic anemia)
Hemosiderinuria — chronic; causes iron deficiency (iron lost in urine)

🔴 Thrombosis (~40% of patients):

Most dangerous feature — leading cause of death (up to 72% mortality in untreated over 25 years)
Unusual sites: Budd-Chiari syndrome (hepatic vein), portal vein, cerebral veins, mesenteric veins
Venous >> arterial
Even fatal pulmonary embolism

💛 Smooth muscle symptoms (due to NO scavenging):

Abdominal pain (episodic, often crampy)
Dysphagia
Erectile dysfunction
Fatigue (profound)

🧠 Bone marrow:

PNH is strongly associated with aplastic anemia — ~30% of PNH evolves to or presents with aplastic anemia
Also linked to MDS (5–10%)
Rarely transforms to AML

Lab Hallmarks:

Test	Finding
Flow cytometry (FLAER + CD59)	Gold standard diagnosis — GPI-deficient cells on granulocytes, monocytes, RBCs
LDH	Very elevated (marker of hemolysis severity)
Haptoglobin	Low/absent
Bilirubin (indirect)	Elevated
Urine hemosiderin	Positive (chronic)
DAT	Negative — key distinguishing feature
Clone size	% GPI-deficient granulocytes — guides treatment decisions

🇮🇳 Indian Scenario — Management in 2025

The Reality Until Recently:

For decades, Indian patients with PNH had no access to specific therapy. Management was entirely supportive. Median survival without treatment is only 10–20 years, with thrombosis being the leading killer.

🆕 LANDMARK — Eculizumab Now Approved in India (2025)

CDSCO approved Eculizumab (Soliris) — January 2025 AstraZeneca India officially launched — September 2025

This is the first anti-complement therapy ever approved in India — for both PNH and aHUS. This is a historic milestone for Indian patients.

However — affordability remains the elephant in the room.

Global price: ~$500,000–700,000/year per patient
Indian pricing not yet publicly announced, but even at discounted rates, it will be inaccessible for most
NOT covered under PMJAY (Ayushman Bharat) currently
Alexion/AstraZeneca has a patient assistance program (SOLIRIS REMS) — patients can apply directly

🗺️ Current Indian Management Framework (Practical, 2025):

TIER 1: For patients who CAN access eculizumab/complement inhibitors

Step	Action
Diagnose	Flow cytometry with FLAER + CD59 (available at AIIMS, Tata Memorial, CMC Vellore, PGI Chandigarh)
Risk stratify	LDH, clone size, thrombosis history, Hb trend
Vaccinate FIRST	Meningococcus A/C/W/Y + B, Pneumococcus, HiB — 2 weeks before drug
Start Eculizumab	600 mg IV weekly ×4 → 900 mg at week 5 → 900 mg every 2 weeks
Penicillin prophylaxis	Amoxicillin 250 mg BD — lifelong while on complement inhibitor
Anticoagulation	If any thrombosis history → warfarin/LMWH/DOAC

TIER 2: For most Indian patients (where biologics unaffordable)

Supportive care protocol — the practical reality:

Measure	Details
Folic acid 5 mg OD	Mandatory — chronic hemolysis depletes folate
Iron supplementation	Monitor ferritin — hemosiderinuria causes iron deficiency; oral iron ferrous sulfate
PCV transfusions	Leukocyte-depleted packed RBCs — as needed; some patients transfusion-dependent
Anticoagulation	Warfarin (INR 2–3) or LMWH for thrombosis — critical, saves lives
Avoid triggers	Infections, surgery, IV contrast, strenuous exercise
Prednisolone short course	Only during acute inflammatory exacerbation — NOT for chronic use

TIER 3: PNH-Aplastic Anemia Syndrome (PNH-AA)

Measure	Details
ATG + Cyclosporine	Immunosuppression for bone marrow failure component
Eltrombopag	Add to ATG for better multilineage response
Allo-BMT	Only cure — if HLA-matched sibling available, young patient; AIIMS/Tata/CMC

🏥 Where to Diagnose & Treat PNH in India:

Centre	Capability
AIIMS New Delhi	PNH diagnosis + eculizumab therapy available
Tata Memorial Centre, Mumbai	Comprehensive
CMC Vellore	Haematology expertise, BMT
PGI Chandigarh	Flow cytometry + management
SGPGI Lucknow	Haematology
NIMHANS / KGMU	Limited

💡 Key Practical Points for Indian Setting:

Most patients still diagnosed late — average delay 2 years globally; likely longer in India
Dark urine + anemia + thrombosis in a young person → think PNH first
DAT negative hemolytic anemia = always do flow cytometry for PNH
Aplastic anemia patients → always screen for PNH clone (50–60% have subclinical PNH)
Eculizumab now available in India (Sept 2025) — refer to a tertiary center; apply for patient assistance programs
Eculizumab biosimilars are being developed globally (BKEMV approved USA April 2025) — may eventually reduce costs and improve Indian access
Iptacopan (oral, once daily) — not yet approved in India but the most promising future drug for resource-limited settings once it becomes available

Bottom line for India in 2025: PNH diagnosis has always been possible at major centres. Treatment has historically been supportive only. Eculizumab's CDSCO approval and September 2025 launch is a turning point — but access will remain limited to patients at tertiary centres who can afford it or access assistance programs. For the vast majority, aggressive supportive care + anticoagulation + haematology referral remains the cornerstone.

Goldman-Cecil Medicine; Harrison's 22E (2025); CDSCO Approval Records Jan 2025; AstraZeneca India Launch Sept 2025; PMID 39371251 (Panse et al., Transfus Med Hemother 2024)

What is ATG

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ATG — Anti-Thymocyte Globulin

What is it?

ATG is a polyclonal immunoglobulin preparation made by immunizing animals (horses or rabbits) with human thymocytes or T lymphocytes. The animal produces antibodies directed against human T cells — these antibodies are then purified and given to patients.

Two main formulations:

Product	Source	Brand Name
Rabbit ATG	Rabbit immunized with human thymocytes	Thymoglobulin (Sanofi)
Horse ATG (Equine)	Horse immunized with human thymocytes	Atgam (Pfizer)

In aplastic anemia: Horse ATG is preferred (superior response over rabbit ATG in treatment-naïve patients — shown in multiple trials)

Mechanism of Action

ATG contains cytotoxic antibodies targeting multiple T cell surface molecules:

CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, HLA class I & II

This achieves two effects:

T cell depletion — direct cytotoxicity (complement-mediated + cell-mediated killing of T lymphocytes)
T cell functional blockade — antibodies occupy surface receptors, blocking T cell activation and proliferation

In aplastic anemia and PNH-AA, the pathology is autoreactive T cells destroying hematopoietic stem cells — ATG eliminates these rogue T cells and allows the marrow to recover.

Indications

Indication	Role
Aplastic anemia (AA)	Primary treatment when BMT not available
PNH-Aplastic Anemia syndrome	Treats the bone marrow failure component
Renal transplant rejection	Prophylaxis and treatment
Other organ transplant rejection	Liver, heart
Conditioning for BMT	Part of preparative regimen

ATG in Aplastic Anemia / PNH-AA — Protocol

Standard Regimen (hATG — Horse ATG):

Step	Detail
Dose	hATG (Atgam) 40 mg/kg/day × 4 days IV
Route	Slow IV infusion over 4–6 hours via central/large peripheral vein
Combined with	Cyclosporine A (CsA) 5 mg/kg/day in 2 divided doses — started day 1, continued for ≥6 months
+ Eltrombopag	150 mg OD — added to ATG+CsA (improves trilineage response in AA)
+ G-CSF	Optional — used by some centres to accelerate neutrophil recovery
Steroids	Methylprednisolone 1 mg/kg/day × 2 weeks (prevents serum sickness from ATG)

Response:

Response seen in 60–70% of patients at 3–6 months
Complete response (normal counts) in ~35–40%
Partial response (transfusion independence) in ~30–35%
Relapse in 30–40% — can be retreated with rATG (rabbit) + CsA

Adverse Effects

Side Effect	Details
Fever, chills, rigors	Most common — during infusion
Hypotension	During infusion
Serum sickness (days 7–14)	Fever, rash, arthralgia, proteinuria — treat with steroids
Leukopenia + thrombocytopenia	Expected (T cell depletion) — monitor counts
Anaphylaxis	Rare but serious
Infections	Increased susceptibility (T cell depleted state) — prophylax with fluconazole, acyclovir

Pre-medication (mandatory before each dose):

IV Methylprednisolone
Paracetamol (antipyretic)
Antihistamine (chlorphenamine)
Slow infusion rate

ATG vs BMT — When to Choose

Scenario	Preferred Treatment
Severe AA, age <40, HLA-matched sibling	Allo-BMT first (>95% cure)
Severe AA, no matched donor / age >40	ATG + CsA + Eltrombopag
PNH-AA, no complement inhibitor access	ATG + CsA
PNH-AA on eculizumab, marrow failure	ATG + CsA + Eculizumab together
Relapse after ATG	Rabbit ATG (rATG) repeat OR BMT

In the Indian context: ATG (horse ATG / Thymoglobulin) is available in India at tertiary centres (AIIMS, Tata, CMC) and is far more affordable than eculizumab. For PNH-AA syndrome patients who cannot access complement inhibitors, ATG + cyclosporine is the practical mainstay of treatment.

Goodman & Gilman's Pharmacological Basis of Therapeutics; Goldman-Cecil Medicine; Harrison's 22E

Can we give cyclosporine a without atg

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Can Cyclosporine A Be Given Without ATG?

Short answer: Yes, it can — but it is significantly inferior to the combination.

The Evidence (Harrison's 22E, 2025):

The history of immunosuppression in aplastic anemia is instructive:

ATG alone — gave partial responses initially
ATG + Cyclosporine A — dramatically better; CsA addition increased response rates AND helped maintain remissions
ATG + CsA + Eltrombopag ("Triple Therapy") — current gold standard: 70–80% hematologic recovery

"Addition of cyclosporine to ATG increased the response rate, and cyclosporine helped maintain remissions. Many other attempts to improve on the regimen of ATG plus cyclosporine failed." — Harrison's 22E

Cyclosporine Monotherapy — When and Why

Scenario	Is CsA alone used?	Response
Non-severe aplastic anemia	Yes — acceptable	Moderate response ~40–50%
Severe AA — no ATG available	Yes — but suboptimal	Lower response than combination
Maintenance after ATG response	Yes — continued alone after ATG course ends	Helps maintain remission, prevent relapse
Relapse on tapering CsA	Reintroduce CsA	Often recaptures response
Elderly / frail — cannot tolerate ATG	Yes — CsA alone practical option	Acceptable compromise
Severe AA — standard care	❌ Not preferred	Inferior to ATG+CsA

Why CsA Is Not Enough Alone in Severe Disease

	ATG + CsA	CsA Alone
Mechanism	Depletes autoreactive T cells (ATG) + blocks T cell activation (CsA)	Blocks T cell activation only
Response rate (severe AA)	60–70%	30–40%
Complete response	~35–40%	~10–15%
Speed of response	2–3 months	Slower
Relapse	30–40%	Higher

How Cyclosporine Works (briefly)

Binds cyclophilin → inhibits calcineurin → blocks IL-2 transcription → T cells cannot activate and proliferate
Does NOT kill T cells (unlike ATG) — only suppresses their function
Hence: works well for maintaining remission and preventing relapse, but not powerful enough alone to eliminate the autoreactive T cell clones driving marrow destruction

Practical Indian Context

If ATG is not available or unaffordable:

CsA 5 mg/kg/day (divided BD, oral) — target trough level 150–250 ng/mL — is a reasonable option, especially for:

Non-severe aplastic anemia
Elderly patients
PNH with mild marrow suppression
While waiting/arranging ATG

Monitor: Renal function (creatinine), BP, serum magnesium, gingival hyperplasia, hirsutism.

Important note for this patient (Yasmin): She already has CKD Stage 5 (Cr 4.13). Cyclosporine is nephrotoxic — it would be contraindicated or require extreme caution with very careful monitoring in her case. This further limits her options for immunosuppression.

Bottom line: CsA without ATG is an option — but a compromise. For severe aplastic anemia or PNH-AA, always try to give the full triple therapy (ATG + CsA + Eltrombopag) when possible. CsA alone is reserved for non-severe disease, maintenance, or when ATG is inaccessible.

Harrison's Principles of Internal Medicine 22E (2025); Goodman & Gilman's Pharmacology

Make me a ppt presentation on language and speech disorder with definition, flowcharts,tables and use harrison and dejong medical books as reference not very lengthy

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Your presentation is ready — 394 KB, 12 slides.

📥
Language Speech Disorders
Presentation · PPTX

What's inside (12 slides, deep navy + teal theme):

Slide	Content
1	Title slide
2	Language vs Speech disorders — side-by-side comparison boxes
3	Definition of Aphasia — 4 key domains (Fluency, Comprehension, Repetition, Naming)
4	Classification table — all aphasia types with fluency/comprehension/repetition/lesion site
5	Broca vs Wernicke — detailed comparison table
6	Clinical flowchart — step-by-step approach to diagnosing aphasia type
7	Speech disorders — Dysarthria & Dysphonia definitions + types
8	Dysarthria types table — Flaccid/Spastic/Ataxic/Hypokinetic/Hyperkinetic/Mixed with causes
9	Flowchart — Approach to dysarthria with localization
10	Special syndromes — Alexia w/o Agraphia, Alexia w/ Agraphia (Dejerine), Conduction Aphasia
11	Summary table — Aphasia vs Dysarthria vs Dysphonia at a glance
12	References — Harrison's 22E + Bradley & Daroff + Broca, Wernicke, Dejerine original papers

Create an Excel table comparing all aphasia syndromes4 slides

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Both files are ready. Here are your downloads:

📥 Downloads

Excel Table:

Aphasia Syndromes Comparison

Spreadsheet · XLSX

4-Slide PPT:

Aphasia 4Slides

Presentation · PPTX

What's inside:

📊 Excel Table (16 columns × 10 syndromes)

Every aphasia syndrome compared across:

Fluency · Comprehension · Repetition · Naming · Reading · Writing
Spontaneous speech quality
Motor/sensory signs
Lesion site + Vascular territory
Key clinical feature + Differentiating pearl
Psychiatric/behavioural features
Eponym/history + Treatment focus
Colour-coded: Teal = Intact, Red = Impaired, Amber = Special/Variable
Covers: Broca, Wernicke, Global, Conduction, TCM, TCS, Anomic, Pure Alexia, Alexia+Agraphia, Subcortical

📑 4-Slide PPT

Slide	Content
1	Title + 4-category overview (Non-fluent / Fluent / Literacy / Subcortical)
2	Master comparison table — all 7 syndromes × 8 features, colour-coded
3	Lesion localization map + Dejerine literacy syndromes (Pure Alexia vs Alexia+Agraphia)
4	Transcortical syndromes (TCM vs TCS) + Quick diagnostic rule

Make ppt lengthy of 30 slides with radiological images and areas of cerebrum wherever relevant speech and language areas from relevant references and make the background of ppt white and simple dont use blue and teal colour

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Broca area Wernicke area language cortex brain MRI

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aphasia MRI lesion left hemisphere stroke

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Wernicke aphasia MRI temporal lobe lesion

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arcuate fasciculus white matter tractography DTI language

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Broca aphasia MRI stroke left frontal lobe infarction

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global aphasia large MCA territory infarction CT scan

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pure alexia posterior cerebral artery infarction occipital MRI

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cerebral lobes functional areas lateral view diagram cortex

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📥
Lang Speech 30Slides
Presentation · PPTX

Complete slide breakdown (30 slides, white background, red/orange/purple accent palette):

#	Slide	Content
1	Title Slide	Full title, references, brain lobes image
2	Contents	All 9 sections with colour labels
3	Section divider	Neuroanatomy
4	Cerebral Lobes & Language Areas	Brain lobe diagram with functional roles
5	Broca's & Wernicke's Areas	Classical language map diagram with arcuate fasciculus
6	fMRI Language Network	resting-state fMRI showing L hemisphere lateralisation
7	Brodmann Areas — MUC Model	BA 44/45, 22, 39, 40, 6, 17–19 with functions
8	Section divider	White Matter Tracts
9	Arcuate Fasciculus — DTI	DTI tractography image + key facts
10	All Language Tracts	AF, SLF, IFOF, ILF, Uncinate — DTI atlas
11	Section divider	Classification
12	Language vs Speech Classification	Side-by-side table
13	Definition of Aphasia	4 domains + bedside tests
14	Section divider	Aphasia Syndromes
15	Broca's Aphasia	Clinical features + T2 MRI sagittal
16	Broca's — CT & FLAIR	CT chronic infarct + MRI FLAIR/DWI
17	Wernicke's Aphasia	Clinical features + CT haemorrhage
18	Wernicke's — Lesion Overlap MRI	12-patient MRI overlap map
19	Global Aphasia	Clinical features + MRI DWI/FLAIR
20	Conduction Aphasia	Features + DTI arcuate fasciculus
21	Transcortical Aphasias (TCM + TCS)	Side-by-side comparison
22	Anomic & Subcortical Aphasia	Side-by-side comparison
23	Master Comparison Table	All 8 syndromes × 6 features
24	Section divider	Speech Disorders
25	Dysarthria — 6 types table	Flaccid/Spastic/Ataxic/Hypokinetic/Hyperkinetic/Mixed
26	Section divider	Literacy Disorders
27	Dejerine Syndromes — Alexia	Pure Alexia vs Alexia+Agraphia + left PCA MRI
28	Clinical Flowchart	Step-by-step diagnostic algorithm
29	Rehabilitation & Management	Acute, SLT, tDCS/TMS, pharmacotherapy
30	References	Harrison's 22E, Bradley & Daroff, Broca, Wernicke, Dejerine, Geschwind

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