Development of Indian Council of Medical Research (ICMR) Standard Treatment Workflows for Skin Diseases: A Step Toward Universal Health Coverage.

Background: Skin conditions form a major bulk of diseases in the community. With a disproportionately low number of dermatologists in the country, and a greatly unequal distribution between urban versus rural areas, ineffective treatment and mismanagement of skin conditions are, however, commonplace. Objective: To develop standard treatment workflows (STWs) for certain skin diseases for use by clinicians at primary, secondary, and tertiary care centers. Methodology: Seven members, from various academic institutes across the country, were selected for formulation of the STWs. They were provided logistic and technical support by the ICMR, Department of Health Research (DHR), and WHO India office. Multiple rounds of online and physical discussions were performed to identify topics that would be most useful in the management of skin diseases for the health care personnel (HCP) and subsequently to frame the STW content. Results: The selected diseases included acne and rosacea, alopecia, bacterial skin infections, cutaneous adverse drug reactions, dermatophytosis, eczema/dermatitis, immunobullous dermatoses, psoriasis, scabies, varicella and herpes, vitiligo, and urticaria. There was one separate module on rational use of topical corticosteroids. The STWs for these conditions have been finalised and are available as physical posters in health centers and can also be accessed online and through mobile applications. Conclusion: Thirteen STW modules have been prepared with a view to optimize management of skin diseases at various levels of health care system of the country.

Context-specific anti-inflammatory roles of type III interferon signaling in the lung in nonviral injuries.

Type III interferons (λ1, λ2, and λ3) are potent antiviral cytokines in the lung. However, their roles in nonviral lung injuries are less well understood. This study investigates the activation of type III interferon signaling in three distinct models of lung injuries caused by diverse stimuli: the bacterial pathogen Pseudomonas aeruginosa, bacterial endotoxin LPS, and the chemotherapeutic agent bleomycin. Our data show that, despite inducing a potent inflammatory response, Pseudomonas and LPS did not increase IFNλ secretion. In contrast, bleomycin instillation increased secretion of IFNλ in the airways at both early and late time points. Consistent with limited secretion, type III interferon signaling had a minimal role in the host response to both Pseudomonas and LPS, as measured by pathogen burden, inflammatory response, and lung injury. Conversely, a deficiency in type III interferon signaling led to increased inflammatory signaling and elevated acute lung injury in the bleomycin model on day 3. This elevated early injury resulted in impaired recovery in IFNLR1 knockout mice, as evidenced by their recovery from bleomycin-induced weight loss. Taken together, these data suggest a context-specific activation of type III interferon signaling, where it plays an anti-inflammatory role in the lung.

Macrolipasemia variant of macroenzymes: An endocrine laboma.

Macroenzymes, formed by polymerization of physiological enzymes with immunoglobulins, have slower renal clearance rates due to their higher molecular mass. They are usually incidentally detected, have no pathophysiological importance, and can potentially lead to over-treatment and iatrogenic morbidity. We present, possibly for the first time, a macro-lipasemia variant of macroenzyme, detected in a 14-year-old girl with type-1 diabetes admitted with severe hyperglycaemia and pain abdomen. Raised lipase levels (414 U/L), initially raised the suspicion of underlying pancreatitis, which was ruled out by the clinical symptoms and normal ultrasound and CT imaging of the pancreas. Upper gastrointestinal endoscopy revealed pangastritis, which could explain the mild upper abdominal pain in the child. She improved with proton pump inhibitor therapy and was discharged after 5 days of hospital admission after good glycaemic control using multiple subcutaneous injections of insulin. Post-polyethylene glycol (PEG) precipitation, the recovery of lipase activity in PEG treated serum sample was 30.6% (127 U/L), which confirmed the presence of macrolipase. An increased clinical suspicion and performing a cheap reliable test (PEG precipitation), whenever there is clinical biochemical discordance can help us in diagnosing more patients with macroenzymes and macrolipasemia.

Clinical features and multiomics profiles indicate coagulation and platelet dysfunction in COVID-19 viral sepsis.

Increased cases of sepsis during COVID-19 in the absence of known bacterial pathogens highlighted role of viruses as causative agents of sepsis. In this study, we investigated clinical, laboratory, proteomic, and metabolomic characteristics of viral sepsis patients (n = 45) and compared them to non-sepsis patients with COVID-19 (n = 186) to identify molecular mechanisms underlying the pathology of viral sepsis in COVID-19. We identified unique metabolomic and proteomic signatures that suggest a substantial perturbation in the coagulation, complement, and platelet activation pathways in viral sepsis. Our proteomic data indicated elevated coagulation pathway protein (fibrinogen), whereas a decrease in many of the complement proteins was observed. These alterations were associated with the functional consequences such as susceptibility to secondary bacterial infections and potentially contributing to both local and systemic disease phenotypes. Our data provide novel aspect of COVID-19 pathology that is centered around presence of sepsis phenotype in COVID-19.

Parent reported outcomes for idiopathic clubfoot children treated with the Ponseti technique: An analysis of 140 feet followed minimum 5 years.

Objective: The treated clubfoot children are often evaluated clinically during follow-up. However, patient reported outcomes (PROM) are seldom analysed for these children. We investigated 87 idiopathic clubfoot children (140 feet) treated by the Ponseti method and followed minimum 5 years to study their clinical outcomes and PROM. Material and methods: This was a cross-sectional study, based on evaluating treated clubfoot children clinically (Pirani score) and PROM (Oxford Ankle and Foot Questionnaire - Parent Version) and comparing them with the age-matched healthy controls (n = 60). The questionnaire has four main domains related to the child's physical, school and play, emotional and footwear profile. The children having persistent deformity (residual/relapse) were specifically studied for their PROM scores. Results: The mean child age at initial treatment was 2.3 months and the mean follow-up duration was 6.9 years. The PROM score of clubfoot children was statistically lower than the healthy controls (p < 0.001). Of the individual domains, the physical domain was the most affected. On calculating the Pirani scores, 10 out of 140 feet (7 %) had some form of persistent deformity. The children with persistent deformity had lower Oxford scores than healthy children or those with corrected feet. The physical domain followed by the emotional domain scored low when persistent deformity was present. Conclusions: Most children (98 %) had a plantigrade foot following Ponseti treatment at follow-up. However, PROM score of the clubfoot children did not correspond to the clinical outcome. Persistent deformity, even minor, was a cause of parental concern and resulted in a low PROM score.

Leveraging Resource Centers for Strengthening Immunization Supply Chain.

The efficacy of immunization programs is critically dependent on robust supply chain management, a complex challenge exacerbated by expanding program scopes and evolving vaccine technologies. This comprehensive review underscores the pivotal role of Resource Centers in fortifying the immunization supply chain, presenting a paradigm shift toward enhanced national and global health outcomes. Through a detailed examination of their key activities, the article elucidates how these centers catalyze improvements across various facets of supply chain management - from the integration of suitable technology technologies and specialized training programs to the development of sustainable models and advocacy for policy prioritization. This further explores the multifaceted challenges these centers confront, including funding constraints, capacity building, and infrastructural gaps, alongside the burgeoning opportunities presented by new vaccine introductions, donor interest in health system strengthening, and the potential for broadened scope beyond immunization. By weaving together examples of existing centers worldwide, the review highlights their contributions towards optimizing vaccine logistics, enhancing data management, and ultimately achieving Sustainable Development Goal 3. The insights provided offer valuable guidance for planning and sustaining resource centers, positioning them as indispensable allies in the global pursuit of universal immunization coverage.

Intranasal neomycin evokes broad-spectrum antiviral immunity in the upper respiratory tract.

Respiratory virus infections in humans cause a broad-spectrum of diseases that result in substantial morbidity and mortality annually worldwide. To reduce the global burden of respiratory viral diseases, preventative and therapeutic interventions that are accessible and effective are urgently needed, especially in countries that are disproportionately affected. Repurposing generic medicine has the potential to bring new treatments for infectious diseases to patients efficiently and equitably. In this study, we found that intranasal delivery of neomycin, a generic aminoglycoside antibiotic, induces the expression of interferon-stimulated genes (ISGs) in the nasal mucosa that is independent of the commensal microbiota. Prophylactic or therapeutic administration of neomycin provided significant protection against upper respiratory infection and lethal disease in a mouse model of COVID-19. Furthermore, neomycin treatment protected Mx1 congenic mice from upper and lower respiratory infections with a highly virulent strain of influenza A virus. In Syrian hamsters, neomycin treatment potently mitigated contact transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In healthy humans, intranasal application of neomycin-containing Neosporin ointment was well tolerated and effective at inducing ISG expression in the nose in a subset of participants. These findings suggest that neomycin has the potential to be harnessed as a host-directed antiviral strategy for the prevention and treatment of respiratory viral infections.

Damage sensing through TLR9 Regulates Inflammatory and Antiviral Responses During Influenza Infection.

Host response aimed at eliminating the infecting pathogen, as well as the pathogen itself, can cause tissue injury. Tissue injury leads to the release of a myriad of cellular components including mitochondrial DNA, which the host senses through pattern recognition receptors. How the sensing of tissue injury by the host shapes the anti-pathogen response remains poorly understood. In this study, we utilized mice that are deficient in toll-like receptor-9 (TLR9), which binds to unmethylated CpG DNA sequences such as those present in bacterial and mitochondrial DNA. To avoid direct pathogen sensing by TLR9, we utilized the influenza virus, which lacks ligands for TLR9, to determine how damage sensing by TLR9 contributes to anti-influenza immunity. Our data show that TLR9-mediated sensing of tissue damage promotes an inflammatory response during early infection, driven by the epithelial and myeloid cells. Along with the diminished inflammatory response, the absence of TLR9 led to impaired viral clearance manifested as a higher and prolonged influenza components in myeloid cells including monocytes and macrophages rendering them highly inflammatory. The persistent inflammation driven by infected myeloid cells led to persistent lung injury and impaired recovery in influenza-infected TLR9-/- mice. Further, we show elevated TLR9 activation in the plasma samples of patients with influenza and its association with the disease severity in hospitalized patients, demonstrating its clinical relevance. Overall, we demonstrate an essential role of damage sensing through TLR9 in promoting anti-influenza immunity and inflammatory response.

Advancing Solar Energy for Primary Healthcare in Developing Nations: Addressing Current Challenges and Enabling Progress Through UNICEF and Collaborative Partnerships.

This comprehensive document explores the intersection of Sustainable Development Goals (SDGs) and the global transition to renewable energy, with a particular focus on solar energy. The text emphasizes the critical role of reliable and sustainable energy, especially solar power, in achieving health-related SDGs, particularly in low- and middle-income countries (LMICs). It discusses the challenges faced by healthcare facilities in these regions, emphasizing the importance of uninterrupted electricity for critical medical equipment and services. The document highlights the increasing significance of solar energy globally and its potential to address challenges in the healthcare sector. The International Energy Agency's (IEA) estimation that solar photovoltaic (PV) energy has become the cheapest source of electricity is discussed, along with the World Bank's active role in supporting solar energy projects in developing countries. The document presents the current status of solarization, emphasizing the exponential growth of solar capacity and generation. It also discusses global initiatives such as Mission Innovation and the contribution of various international aid organizations, including Sustainable Energy for All (SEforALL), Power Africa, Lighting Global, SolarAid, UNDP - Solar for Health (S4H), and the World Bank. A significant portion of the document focuses on the role of solar energy in healthcare, detailing successful solarization projects in India, sub-Saharan Africa, and other regions. It addresses the challenges of implementing solar PV projects in healthcare facilities, emphasizing the importance of maintenance and proper management. The document also provides insights into the contributions of United Nations Children's Fund (UNICEF) in advancing solar-powered health systems, emphasizing its support to over 80 countries in solarization and off-grid energy solutions for healthcare. In conclusion, this article emphasizes the need for collaboration among international aid organizations, governments, and development partners to ensure universal access to reliable and sustainable electricity, particularly in healthcare facilities. It underscores the importance of long-term planning, sustainability, innovative business models, and awareness campaigns to achieve scalable and impactful results in the intersection of solar energy and healthcare delivery.

Developmental changes in lung function of mice are independent of sex as a biological variable.

Pulmonary function testing (PFT) in mice includes biomechanical assessment of lung function relevant to physiology in health and its alteration in disease, hence, it is frequently used in preclinical modeling of human lung pathologies. Despite numerous reports of PFT in mice of various ages, there is a lack of reference data for developing mice collected using consistent methods. Therefore, we profiled PFTs in male and female C57BL/6J mice from 2 to 23 wk of age, providing reference values for age- and sex-dependent changes in mouse lung biomechanics during development and young adulthood. Although males and females have similar weights at birth, females weigh significantly less than males after 5 wk of age (P < 0.001) with largest weight gain observed between 3 and 8 wk in females and 3 and 13 wk in males, after which weight continued to increase more slowly up to 23 wk of age. Lung function parameters including static compliance and inspiratory capacity also increased rapidly between 3 and 8 wk in female and male mice, with male mice having significantly greater static compliance and inspiratory capacity than female mice (P < 0.001). Although these parameters appear higher in males at a given age, allometric scaling showed that static compliance and inspiratory compliance were comparable between the two sexes. This suggests that differences in measurements of lung function are likely body weight-based rather than sex-based. We expect these data to facilitate future lung disease research by filling a critical knowledge gap in our field.NEW & NOTEWORTHY This study provides reference values for changes in mouse lung biomechanics from 2 to 23 wk of age. There are rapid developmental changes in lung structure and function of male and female mice between the ages of 3 and 8 wk. Male mice become noticeably heavier than female mice at or about 5 wk of age. We identified that differences in normal lung function measurements are likely weight-based, not sex-based.

Anti-inflammatory roles of type I interferon signaling in the lung.

Excessive or persistent inflammation may have detrimental effects on lung structure and function. Currently, our understanding of conserved host mechanisms that control the inflammatory response remains incompletely understood. In this study, we investigated the role of type I interferon signaling in the inflammatory response against diverse clinically relevant stimuli. Using mice deficient in type I interferon signaling (IFNAR1-/-), we demonstrate that the absence of interferon signaling resulted in a robust and persistent inflammatory response against Pseudomonas aeruginosa, lipopolysaccharide, and chemotherapeutic agent bleomycin. The elevated inflammatory response in IFNAR1-/- mice was manifested as elevated myeloid cells, such as macrophages and neutrophils, in the bronchoalveolar lavage. The inflammatory cell response in the IFNAR1-/- mice persisted to 14 days and there is impaired recovery and fibrotic remodeling of the lung in IFNAR1-/- mice after bleomycin injury. In the Pseudomonas infection model, the elevated inflammatory cell response led to improved bacterial clearance in IFNAR1-/- mice, although there was similar lung injury and survival. We performed RNA sequencing of lung tissue in wild-type and IFNAR1-/- mice after LPS and bleomycin injury. Our unbiased analysis identified differentially expressed genes between IFNAR1-/- and wild-type mice, including previously unknown regulation of nucleotide-binding oligomerization domain (NOD)-like receptor signaling, retinoic acid-inducible gene-I (RIG-I) signaling, and necroptosis pathway by type I interferon signaling in both models. These data provide novel insights into the conserved anti-inflammatory mechanisms of the type I interferon signaling.NEW & NOTEWORTHY Type I interferons are known for their antiviral activities. In this study, we demonstrate a conserved anti-inflammatory role of type I interferon signaling against diverse stimuli in the lung. We show that exacerbated inflammatory response in the absence of type I interferon signaling has both acute and chronic consequences in the lung including structural changes.

Beneficial and Detrimental Effects of Cytokines during Influenza and COVID-19.

Cytokines are signaling molecules that play a role in myriad processes, including those occurring during diseases and homeostasis. Their homeostatic function begins during embryogenesis and persists throughout life, including appropriate signaling for the cell and organism death. During viral infections, antiviral cytokines such as interferons and inflammatory cytokines are upregulated. Despite the well-known benefits of these cytokines, their levels often correlate with disease severity, linking them to unfavorable outcomes. In this review, we discuss both the beneficial and pathological functions of cytokines and the potential challenges in separating these two roles. Further, we discuss challenges in targeting these cytokines during disease and propose a new method for quantifying the cytokine effect to limit the pathological consequences while preserving their beneficial effects.

Factors influencing correction rate following hemiepiphysiodesis using tension band plates for deformities around the knee: a multivariate analysis study.

PURPOSE: The aim of this study was to appraise various factors influencing the correction rate in temporary hemiepiphysiodesis (THE) around the knee joint. Specifically, the study analysed the relationship of correction rate with age, gender, aetiology, type and location of deformity. METHODS: The retrospective study included children who underwent THE for a coronal plane deformity (genu valgus or varum) around the knee joint (distal femur or proximal tibia) over a ten year period (2010-2020). The primary outcome of interest was the correction rate of the deformity. RESULTS: Thirty-three children (27 females and 6 males) with a mean age of 8.1 years involving 86 plates were included in the study. The mean correction achieved was 12.2° over a treatment period of 13.3 months. Subgroup analysis showed significant differences between the type (varus (0.8° per month), valgus (1.1° per month)) and the location of deformity femur (1.2° per month) and tibia (0.7° per month)]. On multivariate analysis, the location and the duration of treatment showed significant associations with the correction rate. CONCLUSION: The correction of coronal deformities following temporary hemiepiphysiodesis is influenced by several factors. Valgus, femoral and deformities in younger children correct at a faster rate. Location of deformity and duration of treatment emerged as potential factors affecting the correction rate.

Compartmentalized ocular lymphatic system mediates eye-brain immunity.

The eye, an anatomical extension of the central nervous system (CNS), exhibits many molecular and cellular parallels to the brain. Emerging research demonstrates that changes in the brain are often reflected in the eye, particularly in the retina1. Still, the possibility of an immunological nexus between the posterior eye and the rest of the CNS tissues remains unexplored. Here, studying immune responses to herpes simplex virus in the brain, we observed that intravitreal immunization protects mice against intracranial viral challenge. This protection extended to bacteria and even tumours, allowing therapeutic immune responses against glioblastoma through intravitreal immunization. We further show that the anterior and posterior compartments of the eye have distinct lymphatic drainage systems, with the latter draining to the deep cervical lymph nodes through lymphatic vasculature in the optic nerve sheath. This posterior lymphatic drainage, like that of meningeal lymphatics, could be modulated by the lymphatic stimulator VEGFC. Conversely, we show that inhibition of lymphatic signalling on the optic nerve could overcome a major limitation in gene therapy by diminishing the immune response to adeno-associated virus and ensuring continued efficacy after multiple doses. These results reveal a shared lymphatic circuit able to mount a unified immune response between the posterior eye and the brain, highlighting an understudied immunological feature of the eye and opening up the potential for new therapeutic strategies in ocular and CNS diseases.

Exploring the Connection Between Domestic Violence and Masticatory Outcomes in the Pediatric Population: A Systematic Review.

The potential interplay between domestic violence and masticatory outcomes in children and adolescents has garnered increasing attention. Understanding the association between domestic abuse and specific oral health parameters, such as biting habits, temporomandibular disorders (TMDs), and bruxism, holds implications for holistic healthcare interventions. This systematic review aims to synthesize the available evidence to elucidate the potential relationships between domestic abuse and targeted oral health outcomes in the pediatric population. A comprehensive search strategy was conducted across eight databases, namely, PubMed, Embase, Scopus, PsycINFO, Web of Science, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Cochrane Library, and Google Scholar. Boolean operators and Medical Subject Headings (MeSH) keywords were strategically employed to optimize search precision. Clinical studies investigating the relationships between domestic abuse and TMDs, or bruxism, in children and adolescents were included. Two reviewers extracted the data independently. The methodological quality and risk of bias of the selected studies were critically appraised using the Newcastle-Ottawa scale. The systematic search identified three papers investigating the associations between domestic abuse and the targeted oral health parameters. Children in the age group of 6-19 years were assessed. The synthesized evidence revealed a consistent association between domestic abuse and masticatory outcomes. Individuals subjected to domestic abuse exhibited a greater percentage of masticatory anomalies. The methodological assessment of the included studies showed good quality. This systematic review provides a notable synthesis of evidence regarding the associations between domestic abuse and masticatory outcomes in children and adolescents. The complex nature of these relationships necessitates further research to unravel the underlying mechanisms and establish causality. The insights from this review highlight the significance of integrating abuse assessment within oral health evaluations and underscore the need for interdisciplinary collaborations to address the potential impact of abusive experiences on the oral health and well-being of the pediatric population.

The multifaceted nature of plant acid phosphatases: purification, biochemical features, and applications.

Acid phosphatases (EC 3.1.3.2) are the enzymes that catalyse transphosphorylation reactions and promotes the hydrolysis of numerous orthophosphate esters in acidic media, as a crucial element for the metabolism of phosphate in tissues. Inorganic phosphate (Pi) utilisation and scavenging, as well as the turnover of Pi-rich sources found in plant vacuoles, are major processes in which intracellular and secretory acid phosphatases function. Therefore, a thorough understanding of these enzymes' structural characteristics, specificity, and physiochemical properties is required to comprehend the function of acid phosphatases in plant energy metabolism. Furthermore, acid phosphatases are gaining increasing importance in industrial biotechnology due to their involvement in transphosphorylation processes and their ability to reduce phosphate levels in food products. Hence, this review aims to provide a comprehensive overview of the purification methods employed for isolating acid phosphatases from diverse plant sources, as well as their structural and functional properties. Additionally, the review explores the potential applications of these enzymes in various fields.

Post COVID sequelae among COVID-19 survivors: insights from the Indian National Clinical Registry for COVID-19.

INTRODUCTION: The effects of COVID-19 infection persist beyond the active phase. Comprehensive description and analysis of the post COVID sequelae in various population groups are critical to minimise the long-term morbidity and mortality associated with COVID-19. This analysis was conducted with an objective to estimate the frequency of post COVID sequelae and subsequently, design a framework for holistic management of post COVID morbidities. METHODS: Follow-up data collected as part of a registry-based observational study in 31 hospitals across India since September 2020-October 2022 were used for analysis. All consenting hospitalised patients with COVID-19 are telephonically followed up for up to 1 year post-discharge, using a prestructured form focused on symptom reporting. RESULTS: Dyspnoea, fatigue and mental health issues were reported among 18.6%, 10.5% and 9.3% of the 8042 participants at first follow-up of 30-60 days post-discharge, respectively, which reduced to 11.9%, 6.6% and 9%, respectively, at 1-year follow-up in 2192 participants. Patients who died within 90 days post-discharge were significantly older (adjusted OR (aOR): 1.02, 95% CI: 1.01, 1.03), with at least one comorbidity (aOR: 1.76, 95% CI: 1.31, 2.35), and a higher proportion had required intensive care unit admission during the initial hospitalisation due to COVID-19 (aOR: 1.49, 95% CI: 1.08, 2.06) and were discharged at WHO ordinal scale 6-7 (aOR: 49.13 95% CI: 25.43, 94.92). Anti-SARS-CoV-2 vaccination (at least one dose) was protective against such post-discharge mortality (aOR: 0.19, 95% CI: 0.01, 0.03). CONCLUSION: Hospitalised patients with COVID-19 experience a variety of long-term sequelae after discharge from hospitals which persists although in reduced proportions until 12 months post-discharge. Developing a holistic management framework with engagement of care outreach workers as well as teleconsultation is a way forward in effective management of post COVID morbidities as well as reducing mortality.

Association of Sex Hormones and Androgens with Disease Activity in Premenopausal Females with Rheumatoid Arthritis.

Background: Gonadal sex hormone dysfunction is frequently reported in patients with Rheumatoid arthritis (RA). The relationship of these hormones with disease activity is still not clear and whether the hormone imbalance leads to increased severity of RA is not well studied in this part of the world. The present study aimed to elucidate this fact. Methods: It was a cross-sectional observational study performed in 80 premenopausal females with definite RA at a tertiary care hospital in New Delhi, India over one year. Patients were subjected to investigations as per the protocol and a fasting venous blood sample for hormone levels was collected in the follicular phase of their menstrual cycle. Results: A statistically significant correlation by linear logistic regression analysis was found between disease activity (as measured by DAS28) and serum progesterone, FSH, and prolactin, while serum testosterone and DHEAS showed an inverse relationship with disease activity. Low s. prolactin, and s. FSH as well as high s. testosterone and s. DHEAS were found to be associated with target clinical goals in RA (ie, remission and low disease activity). On multivariate logistic regression analysis, serum prolactin showed a direct association. (p=0.016, OR= 1.009. C.I.= 1.0021.017) and serum testosterone were found to have an inverse relationship (p=0.002, OR= 0.017, C.I.=0.001-0.237) with disease activity in this group of individuals. Conclusion: Serum levels of sex hormones may be helpful in predicting disease activity among patients with RA, and in future, may be used to guide treatment of severe refractory disease, unresponsive to conventional treatment with DMARDs, especially in resource-poor settings.