Target product profiles: leprosy diagnostics.

The World Health Organization (WHO) aims to reduce new leprosy cases by 70% by 2030, necessitating advancements in leprosy diagnostics. Here we discuss the development of two WHO's target product profiles for such diagnostics. These profiles define criteria for product use, design, performance, configuration and distribution, with a focus on accessibility and affordability. The first target product profile outlines requirements for tests to confirm diagnosis of leprosy in individuals with clinical signs and symptoms, to guide multidrug treatment initiation. The second target product profile outlines requirements for tests to detect Mycobacterium leprae or M. lepromatosis infection among asymptomatic contacts of leprosy patients, aiding prophylactic interventions and prevention. Statistical modelling was used to assess sensitivity and specificity requirements for these diagnostic tests. The paper highlights challenges in achieving high specificity, given the varying endemicity of M. leprae, and identifying target analytes with robust performance across leprosy phenotypes. We conclude that diagnostics with appropriate product design and performance characteristics are crucial for early detection and preventive intervention, advocating for the transition from leprosy management to prevention.

L'Organisation mondiale de la Santé (OMS) vise à réduire le nombre de nouveaux cas de lèpre de 70% d'ici 2030, ce qui nécessite un meilleur diagnostic de la maladie. Dans le présent document, nous évoquons le développement de deux profils de produit cible établis par l'OMS à cette fin. Ces profils définissent des critères en matière d'utilisation, de conception, de performances, de configuration et de distribution du produit, en accordant une attention particulière à l'accessibilité et à l'abordabilité. Le premier profil de produit cible décrit les exigences pour les tests servant à confirmer le diagnostic de la lèpre chez les individus qui présentent des signes cliniques et des symptômes, afin d'orienter l'instauration d'un traitement à base de plusieurs médicaments. Le second profil de produit cible décrit les exigences pour les tests servant à détecter une infection à Mycobacterium leprae ou M. lepromatosis parmi les contacts asymptomatiques de patients lépreux, ce qui contribue à l'adoption de mesures prophylactiques et à la prévention. Nous avons eu recours à une modélisation statistique pour évaluer les exigences de sensibilité et de spécificité de ces tests diagnostiques. Cet article met en évidence les obstacles à l'atteinte d'un niveau élevé de spécificité en raison de l'endémicité variable de M. leprae, et à l'identification d'analytes cibles offrant de bons résultats chez les phénotypes lépreux. Nous concluons qu'un diagnostic reposant sur des caractéristiques de performance et de conception appropriées est essentiel pour détecter rapidement la maladie et intervenir en amont, et nous plaidons pour une prévention plutôt qu'une gestion de la lèpre.

La Organización Mundial de la Salud (OMS) pretende reducir los nuevos casos de lepra en un 70% para 2030, lo que requiere avances en el diagnóstico de la lepra. Aquí se analiza el desarrollo de dos perfiles de productos objetivo de la OMS para este tipo de diagnósticos. Estos perfiles definen los criterios de uso, diseño, rendimiento, configuración y distribución de los productos, centrándose en su accesibilidad y asequibilidad. El primer perfil de producto objetivo describe los requisitos de las pruebas para confirmar el diagnóstico de la lepra en personas con signos y síntomas clínicos, con el fin de orientar el inicio del tratamiento con múltiples fármacos. El segundo perfil de producto objetivo describe los requisitos de las pruebas para detectar la infección por Mycobacterium leprae o M. lepromatosis entre los contactos asintomáticos de los pacientes con lepra, para facilitar las intervenciones profilácticas y la prevención. Se utilizaron modelos estadísticos para evaluar los requisitos de sensibilidad y especificidad de estas pruebas diagnósticas. El artículo destaca las dificultades para lograr una alta especificidad, dada la diferente endemicidad de M. leprae, y para identificar analitos diana con un rendimiento sólido en todos los fenotipos de lepra. Concluimos que los diagnósticos con un diseño de producto y unas características de rendimiento adecuados son fundamentales para la detección precoz y la intervención preventiva, lo que favorece la transición del manejo de la lepra a la prevención.

Supramolecular Peptoid Structure Strengthens Complexation with Polyacrylic Acid Microgels.

We have studied the complexation between cationic antimicrobials and polyanionic microgels to create self-defensive surfaces that responsively resist bacterial colonization. An essential property is the stable sequestration of the loaded (complexed) antimicrobial within the microgel under a physiological ionic strength. Here, we assess the complexation strength between poly(acrylic acid) [PAA] microgels and a series of cationic peptoids that display supramolecular structures ranging from an oligomeric monomer to a tetramer. We follow changes in loaded microgel diameter with increasing [Na+] as a measure of the counterion doping level. Consistent with prior findings on colistin/PAA complexation, we find that a monomeric peptoid is fully released at ionic strengths well below physiological conditions, despite its +5 charge. In contrast, progressively higher degrees of peptoid supramolecular structure display progressively greater resistance to salting out, which we attribute to the greater entropic stability associated with the complexation of multimeric peptoid bundles.

The Role of ZO-2 in Modulating JAM-A and γ-Actin Junctional Recruitment, Apical Membrane and Tight Junction Tension, and Cell Response to Substrate Stiffness and Topography.

This work analyzes the role of the tight junction (TJ) protein ZO-2 on mechanosensation. We found that the lack of ZO-2 reduced apical membrane rigidity measured with atomic force microscopy, inhibited the association of γ-actin and JAM-A to the cell border, and instead facilitated p114RhoGEF and afadin accumulation at the junction, leading to an enhanced mechanical tension at the TJ measured by FRET, with a ZO-1 tension probe, and increased tricellular TJ tension. Simultaneously, adherens junction tension measured with an E-cadherin probe was unaltered. The stability of JAM-A and ZO-2 binding was assessed by a collaborative in silico study. The absence of ZO-2 also impacted the cell response to the substrate, as monolayers plated in 20 kPa hydrogels developed holes not seen in parental cultures and displayed a retarded elongation and formation of cell aggregates. The absence of ZO-2 was sufficient to induce YAP and Snail nuclear accumulation in cells cultured over glass, but when ZO-2 KD cells were plated in nanostructured ridge arrays, they displayed an increased abundance of nuclear Snail and conspicuous internalization of claudin-4. These results indicate that the absence of ZO-2 also impairs the response of cells to substrate stiffness and exacerbates transformation triggered by substrate topography.

Building communities of practice through case-based e-learning to prevent and manage TB among people living with HIV-India.

BACKGROUND: Co-management of HIV-TB coinfection remains a challenge globally. Addressing TB among people living with HIV (PLHIV) is a key priority for the Government of India (GoI). In 2016, GoI implemented single-window services to prevent and manage TB in PLHIV. To strengthen HIV-TB service delivery, case-based e-learning was introduced to health care providers at Antiretroviral Therapy centres (ARTc). METHODS: We implemented a hub and spoke model to deliver biweekly, virtual, case-based e-learning at select ARTc (n = 115), from four states of India-Delhi, Uttar Pradesh, Andhra Pradesh and Tamil Nadu. We evaluated feasibility and acceptability of case-based e-learning and its impact on professional satisfaction, self-efficacy, knowledge retention using baseline and completion surveys, session feedback, pre-and post-session assessments. We reviewed routine programmatic data and patient outcomes to assess practices among participating ARTc. RESULTS: Between May 2018 and September 2020, 59 sessions were conducted with mean participation of 55 spokes and 152 participants. For 95% and 88% of sessions ≥ 80% of respondents agreed that topics were clear and relevant to practice, and duration of session was appropriate, respectively. Session participants significantly improved in perceived knowledge, skills and competencies (+ 8.6%; p = 0.025), and technical knowledge (+ 18.3%; p = 0.04) from baseline. Participating ARTc increased TB screening (+ 4.2%, p < 0.0001), TB diagnosis (+ 2.7%, p < 0.0001), ART initiation (+ 4.3%, p < 0.0001) and TB preventive treatment completion (+ 5.2%, p < 0.0001). CONCLUSION: Case-based e-learning is an acceptable and effective modus of capacity building and developing communities of practice to strengthen integrated care. E-learning could address demand for accessible and sustainable continuing professional education to manage complex diseases, and thereby enhance health equity. We recommend expansion of this initiative across the country for management of co-morbidities as well as other communicable and non-communicable diseases to augment the existing capacity building interventions by provide continued learning and routine mentorship through communities of practice.

Caveats of Local Fasciocutaneous Flaps for Distal Leg Defects-Anatomical Study and Clinical Application.

The present trend for the management of distal leg defects is to opt for a free flap with local flaps being relegated to the backseat. We studied the perforator anatomy of the distal leg in the Indian population to see if there were any ethnic differences and then correlated it with a clinical study of local flaps used for the coverage of distal leg defects. A prospective observational study was carried out in 2 phases-anatomical study and clinical study from December 2018 to March 2020. In the anatomical study, 8 fresh cadavers, i.e., 16 lower limbs were dissected and the perforator anatomy in the distal leg was identified. In the clinical study, all patients undergoing local, pedicled fasciocutaneous flap cover for defects involving distal third leg were included with ages between 15 and 60 years. In the anatomical study, posterior tibial artery perforators in the distal-most part were found as a group of up to 3 perforators. In the clinical study, a total of 47 patients were included with a mean age of 38.0 ± 10.9 (range 17-55) years and female:male ratio being 1:2.6. The largest defect size was 120 cm2 (mean 28.2 ± 23.8 [range 6-120] cm2) and the most commonly used flap was the reverse sural artery flap in 20 (42.6%) cases. Overall, complications were seen in 7 (14.9%) cases and there was no case of flap failure. Thus, local flaps are an excellent option for coverage of distal leg defects and offer results comparable to free flaps.

The Leprosy Post-Exposure Prophylaxis (LPEP) programme: update and interim analysis.

Innovative approaches are required to further enhance leprosy control, reduce the number of people developing leprosy, and curb transmission. Early case detection, contact screening, and chemoprophylaxis currently is the most promising approach to achieve this goal. The Leprosy Post-Exposure Prophylaxis (LPEP) programme generates evidence on the feasibility of integrating contact tracing and single-dose rifampicin (SDR) administration into routine leprosy control activities in different settings. The LPEP programme is implemented within the leprosy control programmes of Brazil, Cambodia, India, Indonesia, Myanmar, Nepal, Sri Lanka and Tanzania. Focus is on three key interventions: tracing the contacts of newly diagnosed leprosy patients; screening the contacts for leprosy; and administering SDR to eligible contacts. Country-specific protocol adaptations refer to contact definition, minimal age for SDR, and staff involved. Central coordination, detailed documentation and rigorous supervision ensure quality evidence. Around 2 years of field work had been completed in seven countries by July 2017. The 5,941 enrolled index patients (89·4% of the registered) identified a total of 123,311 contacts, of which 99·1% were traced and screened. Among them, 406 new leprosy patients were identified (329/100,000), and 10,883 (8·9%) were excluded from SDR for various reasons. Also, 785 contacts (0·7%) refused the prophylactic treatment with SDR. Overall, SDR was administered to 89·0% of the listed contacts. Post-exposure prophylaxis with SDR is safe; can be integrated into the routines of different leprosy control programmes; and is generally well accepted by index patients, their contacts and the health workforce. The programme has also invigorated local leprosy control.

Intracecal appendix: an extremely rare anatomical variation. A case report and review of literature.

Appendicitis is the most common surgical abdominal emergency in the developed world. Most of the surprises encountered during an appendectomy are usually due to the various positions of the appendix tip. Anatomical variations are an extremely rare phenomenon, with only a few case reports scattered among volumes of literature on the vermiform appendix. A new variation is described in which the appendix was intracecal and cause for surprise during surgery. A review of literature of rare anatomical variations of the appendix is also presented.

Learning Curve for Pilonidal Sinus Surgery: The Best Option for Budding Surgeons.

BACKGROUND: Surgery for pilonidal sinus has no gold standard, and results depend purely on surgeon preference of procedure and experience. Till date, there has been no study comparing the surgical outcomes when performed by residents. Therefore, we designed our study to compare the short-term outcomes of Karydakis' and Limberg's flap procedures in the treatment of pilonidal disease when performed by surgical residents. METHOD: A prospective, double-blinded, observational study was carried out at Command Hospital, Pune, India. Twenty-five consecutive patients undergoing each of the Karydakis' and Limberg's flap procedures (n = 50) were enrolled in the study. All patients had a primary sinus opening. Patients with a frank pilonidal abscess were excluded, but patients with history of intermittent purulent discharge even during time of surgery were included. RESULTS: There was a significantly higher rate of infection in the Karydakis' group (9/25) as compared to the Limberg's flap group (3/25) and also a higher rate of complete wound dehiscence (2/25 vs 1/25). CONCLUSION: Limberg's flap procedure appears to be superior to Karydakis' procedure, and the results are reproducible even by budding surgeons with little experience in the procedure.

Base of Skull Blocks for Open Reduction and Internal Fixation of Faciomaxillary Fractures.

INTRODUCTION: Faciomaxillary fractures (FMF) occur in a significant proportion of trauma patients. Nearly all polytrauma patients and even those with isolated FMF are managed under general anesthesia for definitive management. We propose the use of regional nerve blocks as a safe and effective means for open reduction and fixation of isolated FMF. AIM AND OBJECTIVES: The aim is to evaluate the feasibility, effectiveness and safety of base of skull maxillomandibular and distal trigeminal nerve blocks in the management of FMF. MATERIALS AND METHODS: Ten young adults with fractures of the zygoma, mandible and Le Fort I/II injuries were included in the study. Patients with associated craniocervical and abdominothoracic injuries were excluded. RESULTS: The patients' ages ranged from 21 to 40 years, with a mean time of onset of anesthesia being 5 to 12 minutes and total duration of 105 to 220 minutes. Supplementary block for patchy anesthesia was needed in three. All underwent unhindered surgery without complication. CONCLUSION: Base of skull maxillary-mandibular and distal trigeminal blocks are an effective and efficient alternative to general anesthesia for the open reduction and internal fixation of FMF.

Laurin-Sandrow Syndrome: A Case Report and Review of Literature.

Laurin-Sandrow syndrome (LSS) is an extremely rare syndrome of mirror hand and leg with less than 20 cases reported in literature. The syndrome has been attributed to a mutation in the MIPOL-1 (mirror-image polydactyly) gene located on locus 14q13.3-q21 coding for CCDC193 (coiled-coli domain containing 193) protein. It is characterised by limb, facial and central nervous system anomalies with the most constant being fibular dimelia with fibular ray duplication, polydactyly with secondary deformities of fixed equinus, knee joint instability and flexion deformity. It is associated less frequently with ulnar dimelia, thumb aplasia/hypoplasia, ulnar ray duplication, symbrachypolydactyly, 'rosette' hands, facial dysmorphism like hypertelorism, broad columella and flat nose, CNS anomalies like aplasia/hypoplasia of corpus callosum, hydrocephalus and muscular dystonia. We report a 2-year-old male child with LSS and perform a literature review to expound on this rare syndrome. Level of Evidence: Level V (Therapeutic).

Appreciative inquiry and the co-creation of an evaluation framework for Extension for Community Healthcare Outcomes (ECHO) implementation: a two-country experience.

Persistent gaps exist in healthcare workers' capacity to address HIV and tuberculosis in Asia and Africa due to constraints in resources and knowledge. Project ECHO (Extension for Community Healthcare Outcomes) leverages video-enabled technology to build workforce capacity and promote collaboration through mentorship and case-based learning. To understand current perceptions of ECHO participants and develop a comprehensive evaluation framework for ECHO implementation, we utilized modified appreciative inquiry guided focus group discussions (FGD) in India and Tanzania and called it SCORE (Strengths, Challenges, Opportunities, Results, and Evaluation). Content and thematic analysis of transcripts from FGDs and key-informant interviews triangulated perceptions of diverse stakeholders about ECHO implementation and identified key elements for development of the framework. The perceived strengths (S) were capacity building and establishing communities of practice. The perceived challenges (C) included securing resources, engaging leadership, and building systems for monitoring impact. Improved internet connectivity, addressing logistical challenges, encouraging session interactivity, and having strategic scale-up plans were perceived opportunities (O). Additionally, gathering measurable results (R) led to development of a comprehensive evaluation (E) framework. Contextualizing and facilitating SCORE with qualitative analysis of findings 6-12 months post-ECHO implementation may serve as a best practice to assess mid-course corrections to improve ECHO implementation quality.

Bivalirudin utilization in cardiac surgery: shifting anticoagulation from indirect to direct thrombin inhibition.

PURPOSE: Bivalirudin use for anticoagulating patients undergoing cardiac surgery, particularly those with or at risk for heparin-induced thrombocytopenia, has expanded over the past several years. The purpose of this review is to provide a summary of the following: the differences between indirect and direct thrombin inhibition, unfractionated heparin's limitations (i.e., heparin-induced thrombocytopenia), bivalirudin's pharmacology, recent cardiac surgery trials comparing bivalirudin and unfractionated heparin as anticoagulants, the growing role of bivalirudin-mediated anticoagulation for various surgical procedures, and the potential of bivalirudin-mediated vascular graft patency. SOURCE: A systematic search of the English literature was performed using PubMed from the United States National Library of Medicine. Pertinent articles from 1992-2010 were obtained from this search, and their reference lists were used to retrieve additional relevant articles. PRINCIPAL FINDINGS: In small studies in the cardiac surgery arena, bivalirudin has demonstrated a similar safety and efficacy profile compared with unfractionated heparin. Bivalirudin's role as an anticoagulant in various cardiac surgical procedures (i.e., heart transplant) and vascular surgical procedures is growing and reviewed. Additionally, the molecular basis for the potential for bivalirudin-mediated improvement in vascular graft patency after coronary artery bypass graft procedures is discussed. CONCLUSION: Although bivalirudin is not approved for cardiac surgery in the United States, it can be used in this setting in Canada as an anticoagulant in patients with heparin-induced thrombocytopenia provided the cardiac anesthesiologist is knowledgeable about potential complications from its use and knows how to manage or mitigate their incidence appropriately. During cardiopulmonary bypass, bivalirudin anticoagulation protocols must be thoroughly followed to attain optimal clinical outcomes. Additionally, further studies with bivalirudin are needed to determine the best monitoring modality and dosing regimen.

Comparison of platelet function and morphology in patients undergoing percutaneous coronary intervention receiving bivalirudin versus unfractionated heparin versus clopidogrel pretreatment and bivalirudin.

We hypothesized that direct thrombin inhibition could attenuate platelet activation and release of soluble CD40 ligand (sCD40L), a marker of inflammation, during percutaneous coronary intervention (PCI). To assess platelet function under flow conditions with bivalirudin versus unfractionated heparin (UFH), we employed the cone and plate(let) analyzer (CPA) assay in drug-spiked blood samples from volunteers (n = 3) in vitro, and then in PCI patients who received bivalirudin alone (n = 20), UFH alone (n = 15), and clopidogrel pretreatment plus bivalirudin (n = 15). Scanning electron microscopy was employed to image bivalirudin or UFH-treated platelets to determine whether platelet function observations had a morphologic explanation. Enzyme immunoassay was used to measure sCD40L levels in PCI patients. In vitro, bivalirudin decreased platelet surface coverage; UFH increased platelet surface coverage. In PCI patients, bivalirudin alone decreased platelet surface coverage, UFH alone increased platelet surface coverage, and clopidogrel pretreatment plus bivalirudin additively reduced platelet surface coverage. Unlike UFH, bivalirudin did not activate platelets in SEM studies. Bivalirudin alone or coupled with clopidogrel significantly reduced plasma sCD40L in PCI patients. In conclusion, our findings suggest that under flow conditions, bivalirudin alone or coupled with clopidogrel may have an antiplatelet effect versus UFH alone during PCI. These data suggest that bivalirudin and UFH may confer an anti-inflammatory effect by reducing sCD40L during PCI.

Tropical Pyomyositis: Revisited.

Since the initial description of tropical pyomyositis 130 years ago, this disease continues to retain some mystery for physicians and surgeons. The infrequency, variable epidemiologic and demographic profile, diagnostic dilemmas and limited literature continue to make it an enigma with limited understanding. In the span of nearly 130 years, worldwide English literature search has revealed an average of only two to three reported cases every year globally. We recently managed a case of tropical pyomyositis which posed a clinical and radiologic diagnostic dilemma. The rarity of disease and published literature prompted us to garner demographic and disease characteristics data from historical review of two Pan-Indian journals, with the aim of aiding management. Data has been screened since 1950 from the Medical Journal Armed Forces India (MJAFI) and the Indian Journal of Surgery (IJS), which report cases from different geographical conditions and ethnicity all over the nation. We found only six case reports in the MJAFI, while there was surprisingly no publication regarding pyomyositis in the IJS. We present a case report of a 39-year-old male who developed pyomyositis of the left calf muscle and review published data from these journals over the last 65 years.

Neglected Tropical Diseases, Cross-Cutting Issues Workshop, 4-6 February 2015, Utrecht, the Netherlands: meeting report.

In the last decade, work on neglected tropical diseases (NTDs) has gained momentum. This was accelerated by the London Declaration on NTDs in January 2012. Work on NTDs has expanded worldwide and many countries have set up NTD control and elimination programs. However, the work has focussed disproportionately on preventive treatment. There is an urgent need for more attention and resources to work with people with NTD-related morbidity and disability. A lot can be gained in the fight against NTDs by combining knowledge and experience from cross-cutting fields. For this reason a workshop was organized bringing together scientists, experts and practitioners from different NTD backgrounds to explore options for cross-cutting strategies, interventions and research in the field of NTDs, particularly focusing on issues related to morbidity management and disability, in the broadest sense. The workshop produced an inventory of cross-cutting issues, an overview of knowledge gaps and research questions, proposals for pilot (research) projects and a list of recommendations. One of the main recommendations is based on the need for baseline data: to review existing indicators used for monitoring and surveillance of NTD-related morbidity and disability in order to identify common indicators that can be shared across NTDs.

The activated clotting time can be used to monitor the low molecular weight heparin dalteparin after intravenous administration.

OBJECTIVES: This study was designed to compare the dose response of dalteparin versus unfractionated heparin (UFH) on the activated clotting time (ACT), and to determine whether the ACT can be used to monitor intravenous (IV) dalteparin during percutaneous coronary intervention (PCI). BACKGROUND: The use of low molecular weight heparin (LMWH) during PCI has been limited by the presumed inability to monitor its anticoagulant effect using bedside assays. METHODS: This study was performed in three phases. In vitro, ACTs were measured on volunteer (n = 10) blood samples spiked with increasing concentrations of dalteparin or UFH. To extend these observations in vivo, ACTs were then measured in patients (n = 15) who were sequentially treated with IV dalteparin and then UFH. Finally, a larger monitoring study was undertaken involving patients (n = 110) who received dalteparin 60 or 80 international U (IU)/kg alone or followed by abciximab. We measured ACT (Hemochron), activated partial thromboplastin time (aPTT), plasma anti-Xa and anti-IIa levels, tissue factor pathway inhibitor (TFPI) concentration, and plasma dalteparin concentration. RESULTS: Dalteparin induced a significant rise in the ACT with a smaller degree of variance as compared to UFH. Five min after administration of IV dalteparin 80 IU/kg the ACT increased from 125 s (122 s, 129 s) to 184 s (176 s, 191 s) (p < 0.001). The aPTT, anti-Xa and anti-IIa activities, and TFPI concentration also demonstrated significant increases following IV dalteparin. CONCLUSIONS: The ACT and aPTT are sensitive to IV dalteparin at clinically relevant doses. These data suggest that the ACT may be useful in monitoring the anticoagulant effect of intravenously administered dalteparin during PCI.