Preventing fraud in biomedical research.

Scientific fraud represents, to varying degrees, an increasingly important part of medical literature and is estimated to make up nearly 20% of this literature. The increase in the number of articles accessible in preprint without peer review during the COVID-19 pandemic has led to an increase in the accessibility of fraudulent articles. In recent years, the viral increase in the number of predatory journals has contributed to polluting the scientific literature with articles whose content is unverifiable. Given the international nature of biomedical research, there is an urgent need to define unequivocally what is considered scientific fraud. In order to counter scientific misconduct, national and supranational procedures should be implemented to inform researchers at the beginning of their medical and biomedical training. Ethics commissions should implement local procedures for monitoring ongoing research. Finally, the fight against predatory journals requires information for researchers and the availability of tools to identify these journals.

Case Report: Comorbid Hyper-IgD Syndrome and Hidradenitis Suppurativa - A New Syndromic Form of HS? A Report of Two Cases.

Hidradenitis Suppurativa (HS) is a chronic suppurative disease of the pilosebaceous unit. The current model of HS pathophysiology describes the condition as the product of hyperkeratinisation and inflammation at the hair follicular unit. Environmental factors (such as smoking and obesity), gender, genetic predisposition, and skin dysbiosis are considered the main pathogenic drivers of the disease. Autoinflammatory syndromes associated with HS are rare but may help to highlight the potential roles of autoinflammation and dysregulated innate immune system in HS. Therefore, it is of major relevance to increase the awareness about these diseases in order to improve the understanding of the disease and to optimize the management of the patients. Herein, we report for the first time, to our knowledge, two clinical cases of Hyper-IgD syndrome-associated HS. Hyper-IgD is an autoinflammatory syndrome caused by a mevalonate kinase deficiency (MKD), a key kinase in the sterol and isoprenoid production pathway. We describe the potentially shared pathophysiological mechanisms underpinning comorbid MKD-HS and propose therapeutic options for the management of these patients.

Rapid Progression of Angioimmunoblastic T Cell Lymphoma Following BNT162b2 mRNA Vaccine Booster Shot: A Case Report.

Since nucleoside-modified mRNA vaccines strongly activate T follicular helper cells, it is important to explore the possible impact of approved SARS-CoV-2 mRNA vaccines on neoplasms affecting this cell type. Herein, we report and discuss unexpected rapid progression of lymphomatous lesions after administration of a BNT162b2 mRNA vaccine booster in a man recently diagnosed with AITL.

CD3-CD4+ Lymphocytic Variant Hypereosinophilic Syndrome: Diagnostic Tools Revisited.

BACKGROUND: Identification of patients with lymphocytic variant hypereosinophilic syndrome (L-HES) is challenging, and has important prognostic and therapeutic implications. OBJECTIVE: This study was undertaken to assess diagnostic tools for L-HES and to develop evidence-based diagnostic recommendations. METHODS: Biomarkers of T-cell-driven disease were compared between patients with L-HES versus idiopathic HES (I-HES) variants. Those performed routinely (serum immunoglobulin levels, T-cell phenotyping, T-cell receptor [TCR] gene rearrangement patterns) were collected from medical files, whereas others were prospectively assessed on stored blood samples (serum CCL17/thymus and activation regulated chemokine [TARC] levels, in vitro cytokine production). RESULTS: This study included 48 patients with I-HES and 20 with L-HES associated with a CD3-CD4+ T-cell subset, including 7 with less than 5% aberrant cells. Neither increased serum immunoglobulin levels nor clonal TCR gene rearrangements were sufficiently sensitive or specific for L-HES. In contrast, systematically enhanced expression of the T-cell surface antigens CD2, CD5, CD45RO, and CD95 by these cells allowed for accurate detection by flow cytometry. Serum CCL17/TARC levels were significantly higher in patients with L-HES compared with those with I-HES, and a threshold of 3000 pg/mL allowed for detection of all subjects with L-HES with 75% specificity. Quantification of intracytoplasmic cytokine production by flow cytometry is the most reliable method for detection of enhanced type 2 cytokine expression, most notably for IL-4 and IL-13. CONCLUSION: Adapting the standard of procedure for T-cell phenotyping in patients with unexplained hypereosinophilia is currently the most reliable means of identifying those with CD3-CD4+ L-HES.

Laser Doppler imaging evaluation of nitroglycerin patch application in systemic sclerosis patients.

Recent studies suggest the use of topical nitroglycerin (NTG) application in systemic sclerosis (SSc)-associated Raynaud phenomenon (RP). With the current study, we aimed to characterize for the first time the microvascular response to a NTG patch (Trinipatch® 5 mg/24 h) applied to the hand dorsum in patients with SSc using Laser Doppler imaging (LDI) at baseline and following a cold challenge. The study included 21 patients with SSc and 13 controls. Blood flow was evaluated by LDI at the level of the fingertips and metacarpus. Microvascular morphology was evaluated by nailfold capillaroscopy (NC). LDI revealed decreased fingertip baseline perfusion and a stronger vasoconstrictor response to a cold challenge in patients with SSc versus control. Metacarpal application of a NTG patch led to an increase in blood flow and hand temperature in patients with SSc. Furthermore, NTG administration led to a faster reperfusion after cold challenge. Correlation analyses revealed that the magnitude of the vasodilatory response was inversely related to baseline fingertip perfusion and hand temperature, but unrelated to the number of capillaries/mm assessed using NC. In conclusion, we provide evidence of a vasodilatory reaction following NTG patch application in patients with SSc using LDI and a protective effect against cold challenge. The magnitude of the response to NTG was related to functional, but not structural features. Our results support a further evaluation of the NTG patch as a possible therapeutic agent in SSc-associated RP.

Multisystem Inflammatory Syndrome With Complete Kawasaki Disease Features Associated With SARS-CoV-2 Infection in a Young Adult. A Case Report.

A severe multisystem inflammatory syndrome associated with Kawasaki disease manifestations (MIS-C) has been recently reported in children with signs of recent infection with SARS-CoV-2. We here reported the case of a young adult woman who presented the complete manifestations of Kawasaki disease associated with a severe myocarditis, acute respiratory distress syndrome and hemodynamic instability a few weeks after a transient anosmia. The detection of specific antibodies to SARS-CoV-2 in the absence of detection of the virus suggested that the syndrome was the result of a delayed immune response to a recent COVID-19 infection. A combined treatment with colchicine, tocilizumab, high dose immunoglobulins, and methylprednisolone allowed to control the inflammatory process and to limit the development of coronary aneurysm. The patient recovered without sequelae. This case emphasized the importance of SARS-CoV-2 serology for the diagnosis of delayed immune complications of COVID-19. Clinicians caring for adult patients must be aware that not only children but also young adults can be affected by a multisystem inflammatory syndrome with KD features associated with COVID-19.

Eosinophilia Associated With CD3-CD4+ T Cells: Characterization and Outcome of a Single-Center Cohort of 26 Patients.

Background: Lymphocytic variant hypereosinophilic syndrome is characterized by marked over-production of eosinophilopoietic factor(s) by dysregulated T cells leading to eosinophil expansion. In most cases, these T cells are clonal and express a CD3-CD4+ phenotype. As this is a rare disorder, presenting manifestations, disease course, treatment responses, and outcome are not well-characterized. Materials and Methods: In this retrospective single-center observational study, we reviewed medical files of all patients with persistent hypereosinophilia seen between 1994 and 2019 in whom CD3-CD4+ T cells were detected. Data collection included clinical and biological findings at presentation, treatment responses, disease course, and serial CD3-CD4+ T cell counts. Results: Our cohort comprises 26 patients, including 2 with hypereosinophilia of undetermined significance. All 24 symptomatic patients had cutaneous lesions and/or angioedema, and fasciitis was present in several cases. The aberrant T cell subset represented 2% or less total lymphocytes in 11 subjects. TCR gene rearrangement patterns on whole blood were polyclonal in these cases, while they all had serum CCL17/TARC levels above 1,500 pg/ml. Disease manifestations were mild and did not require maintenance therapy in roughly one third of the cohort, while two thirds required long-term oral corticosteroids and/or second-line agents. Among these, interferon-alpha was the most effective treatment option with a response observed in 8/8 patients, one of whom was cured of disease. Treatment had to be interrupted in most cases however due to poor tolerance and/or development of secondary resistance. Anti-interleukin-5 antibodies reduced blood eosinophilia in 5/5 patients, but clinical responses were disappointing. A sub-group of 5 patients had severe treatment-refractory disease, and experienced significant disease- and treatment-related morbidity and mortality, including progression to T cell lymphoma in three. Conclusions: This retrospective longitudinal analysis of the largest monocentric cohort of CD3-CD4+ T cell associated lymphocytic variant hypereosinophilic syndrome published so far provides clinicians confronted with this rare disorder with relevant new data on patient presentation and outcome that should help tailor therapy and follow-up to different levels of disease severity. It highlights the need for novel therapeutic options, especially for the subset of patients with severe treatment-refractory disease. Future research efforts should be made toward understanding CD3-CD4+ T cell biology in order to develop new treatments that target primary pathogenic mechanisms.

[How to formalise the supervision of learning of clinical reasoning]. / Formalisation de la supervision de l'apprentissage du raisonnement clinique.

Since clinical reasoning is central to most decisions made in the clinic, it is essential to teach it with the greatest relevance. Knowing that around 10% of learners encounter major difficulties in clinical reasoning during their course, training supervisors in effective pedagogical interventions is crucial. Here we summarize the methods allowing supervisors to identify errors of clinical reasoning in medical students and interns and we explain remediation techniques adapted to the types of error identified. Access to short illustrative videos of a MOOC (Massive Open On line Course) devoted to the supervision of clinical reasoning constitutes practical help for supervisors who are not expert in the complexity of medical pedagogy at bedside.

Outcome of permanent vascular access for haemodialysis in patients with end-stage renal disease in Cameroon: results from the pilot experience of the Douala general hospital.

Background Chronic Kidney disease is a major health problem in the world. Native arteriovenous Fistula (AVF) is well established as the best vascular access for haemodialysis. Little is known about the outcome of AVF in sub-Saharan Africa. We aim to analyze the outcome of patients undergoing AVF creation during the pilot program established at the Douala general hospital (DGH). Method This was hospital-based, longitudinal study with a retrospective phase (April 2010-January 2014) and a prospective phase (January 2014-April 2014). All consecutive patients operated for AVF creation were included in this study. Socio-demographics data, functionality, and complications were analyzed. Results Eighty-one patients including 52 men were enrolled in this study (49 prospectively and 32 retrospectively). The mean age was 52, 3 years (range 18-81 years). Hypertension (66, 7%), diabetes (17, 3%), and HIV (8, 6%) were the most observed co-morbidities. About 96.3% of AVF were native and 3.7% were prosthetic graft. Radiocephalic AVF was performed at a rate of 77.8%. The primary function rate was 97.7% and the mean follow-up period 43.4 weeks. The overall rate of complications was 44.4% of whom 30.5% were early, 30.5% secondary, and 39% lasted. The treatment of these complications was conservative in 48.7% of cases. Conclusions The results of the pilot program of AVF creation at the DGH are encouraging. However, the sustainability of this project requires human capacity building.

Methylprednisolone-Induced Lymphocytosis in Patients with Immune-Mediated Inflammatory Disorders.

BACKGROUND: Transient acute reversible lymphopenia occurring within hours after glucocorticoid administration is a well-known phenomenon. The objective of this study was to establish the impact of chronic methylprednisolone (mPDN) administration on lymphocyte counts in patients with immune-mediated inflammatory disorders. METHODS: The charts of 44 women and 17 men (median age, 59 years) with several immune-mediated inflammatory disorders receiving oral mPDN for at least 4 months were reviewed. Morning lymphocyte counts measured during treatment (LP) were compared with pretreatment values (LA). In addition, the acute effect of mPDN on lymphocyte counts was evaluated in 43 of these patients by quantifying lymphocyte subpopulations before and 8 hours after mPDN administration. Values are expressed as median with 25%-75% interquartile range. RESULTS: The initial daily oral mPDN dose was 28 mg (12-32 mg). An increase in morning lymphocyte counts was detected 13 days (8.5-16 days) after initiation of mPDN treatment (LP: 2130/µL vs LA: 1650/µL; P = .0121) and persisted over time. Morning lymphocytosis (LP ≥4000/µL) was observed in 15 patients, including 7 with hyperlymphocytosis (LP ≥5000/µL). The increase in morning lymphocyte counts during treatment was most marked for CD4 T cells. In the subset of patients who agreed to a second blood test after mPDN absorption, a 49% decrease in the lymphocyte count (P <.0001) was transiently observed at the 8-hour time point. CONCLUSIONS: A significant increase of the morning lymphocyte count is frequently observed in patients with immune-mediated inflammatory disorders chronically treated with oral mPDN. Heightened awareness that the timing of blood sampling in corticosteroid-treated patients affects lymphocyte counts, with possible hyperlymphocytosis before absorption, should help avoid unnecessary investigations and worry.

Positron emission tomography scanning in anti-neutrophil cytoplasmic antibodies-associated vasculitis.

Tools for evaluation of disease activity in patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) include scoring clinical manifestations, determination of biochemical parameters of inflammation, and obtaining tissue biopsies. These tools, however, are sometimes inconclusive. 2-deoxy-2-[F]-fluoro-D-glucose (FDG) positron emission tomography (PET) scans are commonly used to detect inflammatory or malignant lesions. Our objective is to explore the ability of PET scanning to assess the extent of disease activity in patients with AAV.Consecutive PET scans made between December 2006 and March 2014 in Maastricht (MUMC) and between July 2008 and June 2013 in Brussels (EUH) to assess disease activity in patients with AAV were retrospectively included. Scans were re-examined and quantitatively scored using maximum standard uptake values (SUVmax). PET findings were compared with C-reactive protein (CRP) and ANCA positivity at the time of scanning.Forty-four scans were performed in 33 patients during a period of suspected active disease. All but 2 scans showed PET-positive sites, most commonly the nasopharynx (n = 22) and the lung (n = 22). Forty-one clinically occult lesions were found, including the thyroid gland (n = 4 patients), aorta (n = 8), and bone marrow (n = 7). The amount of hotspots, but not the highest observed SUVmax value, was higher if CRP levels were elevated. Seventeen follow-up scans were made in 13 patients and showed decreased SUVmax values.FDG PET scans in AAV patients with active disease show positive findings in multiple sites of the body even when biochemical parameters are inconclusive, including sites clinically unsuspected and difficult to assess otherwise.

The Belgian Systemic Sclerosis Cohort: correlations between disease severity scores, cutaneous subsets, and autoantibody profile.

OBJECTIVE: To report baseline and followup data on the first 438 patients with systemic sclerosis (SSc) included in the Belgian Systemic Sclerosis Cohort. METHODS: According to LeRoy and Medsger's classification, 73 patients with limited SSc (lSSc), 279 with limited cutaneous SSc (lcSSc), and 86 with diffuse cutaneous SSc (dcSSc) were included. History was collected and clinical examination, blood tests, and paraclinical investigations were repeated. The Disease Activity Score (DAS) and Disease Severity Score (DSS) of several organ systems were computed. An organ system was considered to demonstrate SSc if the corresponding DSS was ≥ 1. RESULTS: At baseline, patients with dcSSc had more general, joint/tendon, muscle, gastrointestinal, and kidney involvement. Mean DLCO was below normal in patients with lSSc, indicating unsuspected lung involvement. Patients with anti-Scl-70 had more vascular, skin, joint/tendon, and lung involvement. Patients with anti-RNA polymerase III had more skin and joint/tendon involvement compared to patients with anticentromere. Time to death was statistically shorter for patients with dcSSc. New-onset lung disease was the most common complication over time. No changes in DAS were observed. By contrast, the general and the skin DSS worsened in patients with lcSSc and lSSc, respectively. Fifteen percent of patients with lSSc shifted to lcSSc at Month 30, but neither serology nor capillaroscopy findings at baseline were helpful in identifying those at risk. CONCLUSION: Our data indicate that the DSS can be used to define organ involvement in SSc. Differences can be seen between subsets classified not only according to cutaneous subtypes but also to autoantibody profile.

Clinical management of the hypereosinophilic syndromes.

Hypereosinophilic syndromes (HESs) are rare disorders characterized by marked hypereosinophilia that is directly responsible for organ damage or dysfunction. Different pathogenic mechanisms have been discovered in patient subgroups leading to the characterization of myeloproliferative and lymphocytic disease variants. In the updated terminology, idiopathic HES is now restricted to patients with HES of undetermined etiology. The practical clinical approach of patients with the different HES variants is reviewed herein, focusing on specific diagnostic tools and therapeutic options. Corticosteroids, hydroxyurea and IFN-α remain the classical agents for treatment of most patients with HESs. The specific role of therapeutic compounds that have become available more recently, namely, tyrosine kinase inhibitors and IL-5 antagonists, is discussed.

Clinical significance of Cryofibrinogenemia: possible pathophysiological link with Raynaud's phenomenon.

OBJECTIVE: To describe the clinical findings and prevalence of patients with cryofibrinogenemia (CF) and to determine whether CF is associated with primary Raynaud's phenomenon. METHODS: Between June 2006 and December 2009, 227 patients were tested for CF in a single university hospital. Forty-five patients with primary Raynaud's phenomenon were tested for CF. RESULTS: A total of 117 patients with CF without cryoglobulinemia were included. The main clinical manifestations included skin manifestations (50%) and arthralgia (35%). There were 67 patients with primary CF and 50 patients with secondary CF. There was no significant difference in the mean concentration of the cryoprecipitate in primary CF as compared to the secondary form (172 ± 18.6 vs 192 ± 20.9 mg/dl, respectively; p = 0.41). Highest concentrations of cryoprecipitate were observed in those containing fibrinogen only as compared to cryoprecipitates containing fibrinogen and fibronectin (301 ± 43.5 vs 125 ± 10.6 mg/dl; p < 0.001). Patients having skin necrosis (n = 3) had significantly higher values of cryofibrinogen compared to those without necrosis (638 ± 105 vs 160 ± 10.2 mg/dl; p = 0.0046). Among the 45 patients with primary Raynaud's phenomenon, 36 had associated CF. There was no significant difference in the mean concentration of the cryoprecipitate in these patients compared to those with primary CF. CONCLUSION: There seems to be a significant correlation between cryofibrinogen concentration and the severity of the clinical signs, particularly when cryoprecipitate is composed of fibrinogen alone. CF might have a possible pathophysiological role in primary Raynaud's phenomenon.

Mepolizumab as a corticosteroid-sparing agent in lymphocytic variant hypereosinophilic syndrome.

BACKGROUND: Mepolizumab, a monoclonal anti-IL-5 antibody, is an effective corticosteroid-sparing agent for patients with Fip1-like 1/platelet-derived growth factor receptor α fusion (F/P)-negative hypereosinophilic syndrome (HES). Lymphocytic variant hypereosinophilic syndrome (L-HES) is characterized by marked overproduction of IL-5 by dysregulated T cells. OBJECTIVE: To determine whether patients with L-HES respond to mepolizumab in terms of corticosteroid tapering and eosinophil depletion to the same extent as corticosteroid-responsive F/P-negative patients with HES and a normal T-cell profile. METHODS: Patients enrolled in the mepolizumab trial were evaluated for L-HES on the basis of T-cell phenotyping and T-cell receptor gene rearrangement patterns, and their serum thymus-and-activation-regulated chemokine (TARC) levels were measured. Response to treatment was compared in patient subgroups based on results of these analyses. RESULTS: Lymphocytic variant HES was diagnosed in 13 of 63 patients with HES with complete T-cell assessments. The ability to taper corticosteroids on mepolizumab was similar in patients with L-HES and those with a normal T-cell profile, although a lower proportion of patients with L-HES maintained eosinophil levels below 600/µL. Increased serum TARC levels (>1000 pg/mL) had no significant impact on the ability to reduce corticosteroid doses, but a lower proportion of patients with elevated TARC achieved eosinophil control on mepolizumab. CONCLUSION: Mepolizumab is an effective corticosteroid-sparing agent for patients with L-HES. In some cases however, eosinophil levels remain above 600/µL, suggesting incomplete neutralization of overproduced IL-5 or involvement of other eosinophilopoietic factors.

Safety of furosemide administration in an elderly woman recovered from thiazide-induced hyponatremia.

BACKGROUND: Elderly women are at risk to develop severe hyponatremia after thiazide but not loop diuretic administration. In patients with previous thiazide-induced hyponatremia, the risk for recurrent hyponatremia after furosemide has not been established. METHODS: In order to determine how both diuretics affect water metabolism, we here compare the effects of a rechallenge with either amiloride-hydrochlorothiazide fixed association (AmHTZ; amiloride chlorhydrate 5 mg+hydrochlorothiazide 50 mg; Moduretic) or furosemide (F; 40 mg; Lasix) on water excretion in a 79 year old woman who was previously admitted for severe symptomatic hyponatremia secondary to a 5 days course of AmHTZ for systolic hypertension. After correction of initial hydromineral disturbances, a standard oral water load (WL; 20 mL per kg body weight) was administered before, during and after AmHTZ or F challenges. RESULTS: Hyponatremia developed after AmHTZ but not after F challenge. A negative free water clearance (CH(2)O) was only observed during AmHTZ (-0.39 mL/min), while maximal CH(2)O during F was 3.17 mL/min. Based on the results obtained during WL, the calculated maximal daily electrolyte free water clearance ability was only 888 mL after AmHTZ but 10,166 mL after F therapy. Taking into account a measured mean daily water intake of 1830 mL, severe hyponatremia could be predicted to occur after a few days treatment with AmHTZ. In comparison, F appears to be safer, without risk of hyponatremia, during an equivalent period of time. CONCLUSIONS: We here showed that F may be administered to a patient with previous AmHTZ induced hyponatremia without risk for recurrent hyponatremia.

Optic neuropathy, renal failure and pulmonary sarcoidosis in a 50-year-old man: where is the link?

Eye disorders are frequently associated with renal diseases, mostly linked to underlying causes such as hypertension, diabetes or autoimmune diseases. Conversely, advanced uraemic states may also lead to progressive vision impairment. The present report concerns a 50-year-old patient who presented with a bilateral, painless, progressive vision loss, a moderate systemic inflammation and chronic renal failure due to hypertension nephrosclerosis. Steroids were given and haemodialysis was initiated, resulting in vision improvement. At 4 months later when the steroids were stopped, the patient developed dyspnoea, cough, fever and fatigue of unclear origin. A lung biopsy showed non-caseating granuloma consistent with pulmonary sarcoidosis. Re-challenge with steroids rapidly improved the respiratory disease. Ophthalmological examinations performed early and later in the course excluded anterior ischaemic optic neuropathy and ocular manifestations of sarcoidosis, leading to a diagnosis of uraemic optic neuropathy. This rare ophthalmological disorder should be promptly recognised since haemodialysis and steroid therapy are highly effective.

Lymphocytic variant hypereosinophilic syndromes.

A large body of evidence establishing the existence of an underlying T-cell disorder in a subset of patients fulfilling hypereosinophilic syndrome (HES) diagnostic criteria has accumulated over the past decade, resulting in the definition of a novel HES variant termed "lymphocytic" HES. Although end-organ complications of hypereosinophilia are generally benign, with predominant cutaneous manifestations, long-term prognosis is overshadowed by an increased risk of developing T-cell lymphoma, as a result of malignant transformation of aberrant T cells years after HES diagnosis. Therapeutic strategies should target pathogenic T cells in addition to eosinophils, but the practical implications remain largely unexplored.