Hereditary Spherocytosis: Unravelling the Diagnostic Challenges.

Hereditary spherocytosis (HS) is a genetic disorder characterized by the presence of spherocytes, which are abnormally shaped red blood cells, leading to hemolytic anemia. While HS is not uncommon in hematology, it can present significant diagnostic and therapeutic challenges in its late stages, particularly when complicated by severe cholestasis. We report a case of a 48-year-old male presenting with jaundice and abdominal pain, initially diagnosed with cholecystolithiasis and moderate splenomegaly. Subsequent investigations confirmed HS through clinical observation and eosin-5'-maleimide (EMA) binding by flow cytometry. The patient exhibited severe jaundice (total bilirubin: 19.58 mg/dL) but no anemia. The complexity of his condition necessitated a multidisciplinary approach involving hematologists and gastroenterologists along with general medicine. This case underscores the importance of considering HS in the differential diagnosis of cholestasis and highlights the need for comprehensive diagnostic strategies to manage such complications effectively.

Development and deployment of a solid oral amphotericin B dosage form to treat visceral leishmaniasis within a pediatric population.

Visceral leishmaniasis (VL) is a severe and potentially fatal infection, with over 90% of reported cases occurring in East African countries including Chad, Djibouti, Eritrea, Ethiopia, Kenya, Somalia, South Sudan, Sudan, and Uganda, affecting mainly impoverished individuals, and creating a significant economic burden. Currently, the intravenous single-dose liposomal amphotericin B is the first choice for the treatment of VL. Recently, WHO and DNDi have suggested a combination of intravenous liposomal amphotericin B and oral miltefosine as a potential approach to treat VL. However, miltefosine availability is uncertain, and its side effects frequently cause treatment to be discontinued. Furthermore, due to the difficult route of liposomal amphotericin B administration by intravenous infusion, the lack of formulation's tropical stability, accessibility, injection toxicity, and cost have prevented this injectable formulation of amphotericin B from reaching the most infected populations, particularly the pediatric population. To solve this problem, the development of a solid oral amphotericin B formulation that is cost-effective, safe, tropically stable, and easy to swallow, making it more accessible to children, particularly in rural communities having limited access to medical clinics or trained healthcare professionals is imperative. This viewpoint will discuss the opportunities and challenges of developing an oral amphotericin B formulation for a pediatric population.

Conquering Challenges: A Case Series of Yellow Phosphorus Poisoning at a Tertiary Care Hospital in Pune, Western India.

Rodenticides are easily available in the market and suicidal attempts by ingesting such poisonous products are commonly reported in rural India. We aimed to analyze predictive factors, biological markers, and treatment outcomes among patients who ingested rodenticides (yellow phosphorus) with the brand name, Rattol. Here, we present three such cases who were admitted to a tertiary care hospital. We recorded socio-demographic characteristics, probable predictive factors, and serial charting biological markers. Conventional treatment was given to these cases. All cases were young women (age range: 17-30 years) from rural areas, two were married and one was unmarried. The approximate quantity of ingestion was 20, 10, and 5 grams, respectively. The time lag between the ingestion and sought first health care was 6 hours, 18 hours, and 1 hour, respectively. Major symptoms were vomiting, abdominal pain, and headache. Biological markers, including total bilirubin, alanine aminotransferase, aspartate aminotransferase, creatinine, prothrombin time, international normalized ratio, and model for end-stage liver disease (MELD) score were statistically significant. Two women had toxic hepatitis and acute liver failure and one did not have any organ damage. All of them were recovered within 17 days of mean hospital stay. A lethal dosage of rodenticides and delayed presentation to the hospital can prompt acute liver failure and severe ailment. Creating awareness, promoting mental health and suicide prevention, and framing proper guidelines for treatment will reduce morbidity and mortality.

Evolution of Pathological Techniques for the Screening of Cervical Cancer: A Comprehensive Review.

The evolutionary journey of cervical cancer screening has been a major medical success story, considering the substantial role it has played in dwindling the disease burden. Through sustained collaborative efforts within the medical community, significant advances have been made from the humble yet path-breaking conventional Pap smear to the current automated screening systems and human papillomavirus (HPV) molecular testing. With the integration of artificial intelligence into screening techniques, we are currently at the precipice of circumventing the pitfalls of manual cytology readings and improving the efficiency of the screening systems by a significant margin. Despite the technological milestones traversed, the high logistics and operational cost, besides the technical know-how of operating the automated systems, can pose a major practical challenge in the widespread adoption of these advanced techniques in cervical cancer screening programs. This would suggest the need to adopt strategies that are tailored to the demands and needs of the different settings keeping their limitations in mind. This review aims to take the reader through the entire evolutionary journey of cervical cancer screening programs, highlight the individual merits and demerits of each technique, and discuss the recommendations from the major global guidelines.

An appraisal of psychotherapy training during psychiatry residency program in India: A national survey.

Background: The need for psychotherapy training (PT) has been recognized worldwide and is considered an integral component of postgraduate psychiatry training. Our study aims to assess the quality of PT received by psychiatrists during their postgraduate studies and its impact on their current practice. Aim: To evaluate the quality of PT and its effect on the current psychiatry practice. Methodology: An anonymous web-based survey was conducted on registered psychiatrists practicing in India to evaluate the level and quality of PT received during their postgraduate studies. Results: The survey indicates that PT was included in the postgraduate psychiatry curriculum (73.8%). However, more than 50% of responders reported no separate posting, evaluation, logbook, or guidelines related to PT. Most (95.4%) psychiatrists think their PT could have been better. PT was satisfying in medical colleges in terms of inclusion in the curriculum (7.70, P = .021), psychotherapy rotations (16.48, P = <0.001), supervision of sessions (14.80, P = 0.001), lectures on psychotherapy (10.13, P = 0.006), periodic psychotherapy meet/forum (19.35, P = <0.001), maintenance of psychotherapy logbook/records (7.65, P = 0.022), institutional or departmental guideline related to PT (20.55, P = <0.001), and overall quality of PT (22.05, P = .005 and 31.81, P = <.001). Time constraint is the most common (49.9%) barrier in delivering psychotherapy. Conclusion: PT is not well organized, consistent, and uniform in psychiatry training; there is a prevailing sense of inadequacy and dissatisfaction among the country's psychiatrists with a perceived need to improve and learn PT.

Evaluation of HbA1c from CGM traces in an Indian population.

Introduction: The development of continuous glucose monitoring (CGM) over the last decade has provided access to many consecutive glucose concentration measurements from patients. A standard method for estimating glycated hemoglobin (HbA1c), already established in the literature, is based on its relationship with the average blood glucose concentration (aBG). We showed that the estimates obtained using the standard method were not sufficiently reliable for an Indian population and suggested two new methods for estimating HbA1c. Methods: Two datasets providing a total of 128 CGM and their corresponding HbA1c levels were received from two centers: Health Centre, Savitribai Phule Pune University, Pune and Joshi Hospital, Pune, from patients already diagnosed with diabetes, non-diabetes, and pre-diabetes. We filtered 112 data-sufficient CGM traces, of which 80 traces were used to construct two models using linear regression. The first model estimates HbA1c directly from the average interstitial fluid glucose concentration (aISF) of the CGM trace and the second model proceeds in two steps: first, aISF is scaled to aBG, and then aBG is converted to HbA1c via the Nathan model. Our models were tested on the remaining 32 data- sufficient traces. We also provided 95% confidence and prediction intervals for HbA1c estimates. Results: The direct model (first model) for estimating HbA1c was HbA1cmmol/mol = 0.319 × aISFmg/dL + 16.73 and the adapted Nathan model (second model) for estimating HbA1c is HbA1cmmol/dL = 0.38 × (1.17 × ISFmg/dL) - 5.60. Discussion: Our results show that the new equations are likely to provide better estimates of HbA1c levels than the standard model at the population level, which is especially suited for clinical epidemiology in Indian populations.

A Comparative Study of Ischemia-Modified Albumin: A Promising Biomarker for Early Detection of Acute Coronary Syndrome (ACS).

Introduction The second most common cause of emergency department (ED) visits is chest pain and discomfort. Timely identification or threat stratification is crucial for identifying high-risk individuals who benefit from sophisticated diagnostic investigations (including cardiac biomarkers) and early relevant therapies. We aimed to assess the levels of ischemia-modified albumin (IMA) and also to study its sensitivity and specificity in comparison with cardiac troponin T/troponin I and electrocardiogram (ECG) (alone and in combination) in the diagnosis of acute myocardial infarction. Methods Adults (either gender) presented at the ED of a tertiary care centre with classical chest pain suggestive of angina pectoris or angina-like chest pain and ECG changes suggestive of ACS, ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial MI (NSTEMI), and unstable angina, within three hours of onset were enrolled. Demographic and clinical information was recorded. ECG, haematological investigations like complete blood count, blood sugar level, lipid profile, IMA, troponin I, and creatinine kinase-MB (CK-MB), and radiological investigations like 2D-echocardiography (2D-ECHO) and coronary angiography were performed. Results A total of 100 subjects were enrolled in the study out of which 50 were cases and 50 were controls. Cases were older as compared to controls (mean age 60.5 versus 46.0 years). Of the 50 cases, 33 (66%) were males. There were equal numbers of males (33 each) and females (17 each) subjects in both the groups. Typical chest pain, risk factors, and history of coronary artery disease (CAD) were higher in cases. ECG diagnosis revealed the presence of STEMI (52%) and coronary angiography revealed the presence of double vessel CAD (60%) in cases. Among controls, gastroesophageal reflux disorder was the most common cause of chest pain followed by costochondritis and pneumonia. Glucose (fasting and postprandial), all lipid profile parameters (except high-density lipoprotein) and IMA values were significantly higher in cases as compared to controls. A combination of ECG+IMA has the highest sensitivity (90%) with 79% PPV in the diagnosis of ACS within three hours of the onset of chest pain, and ECG+IMA+2D-ECHO had similar results. However, ECG is equally sensitive. IMA alone has 64% sensitivity with 82% diagnostic accuracy which was higher than other biomarkers (CK-MB, cardiac troponin I). Conclusions As found in our study, among the biomarkers used, the diagnostic accuracy of IMA was the highest and better than that of cardiac troponin I and CK-MB. Although ECG is the preferred diagnostic tool for diagnosing ACS (STEMI, NSTEMI, and unstable angina) in patients presenting within three hours of the onset of chest pain, a confirmation can be done with the help of other diagnostic tests and investigations like serum IMA levels and further treatment can be initiated.

Effects of climate change on soil health resulting in an increased global spread of neglected tropical diseases.

Although it is commonly accepted that climate change will increase the range and abundance of neglected tropical diseases (NTDs) through increased rainfall and temperature, the role of soil and influence of soil health on this effect is not well understood. We propose that understanding the influence of climate change on the physical, chemical, and biological characteristics of soils can explain how favourable environmental conditions for NTDs and vectors of NTDs to reproduce form. This, in turn, can assist local public health experts in predicting and managing the spread of NTDs. We also suggest that unlike unpredictable climatic factors, soil health can be directly managed through appropriate land use practices. This viewpoint seeks to start a discussion between soil scientists and healthcare professionals on how to achieve common goals and strategies required to manage the spread of NTDs.

The Clinical and Laboratory Profiles of Immunocompetent Patients With Short-Duration Fever With Neutropenia in a Tertiary Care Hospital in Pune, India.

Background Management of a febrile patient is based on understanding the pathophysiology of an abnormal temperature and temperature regulation, impacts of fever, and its treatment. In the current study, we aimed to characterize and compare the epidemiological, etiologic, microbiological, serological, clinical, and outcome traits of febrile patients with acute neutropenia admitted to a tertiary care center in Western Maharashtra. Methods Adult patients with a history of fever of less than two weeks' duration and without any immunosuppressive state were screened with predefined inclusion and exclusion criteria. General and demographic information (age and gender), and clinical examinations (type and duration of fever) were recorded. Biochemical, hematologic (total and differential cell counts), and immunologic measurements (rapid malaria, dengue, Leptospira, and viral hepatitis antigen antibodies) were performed. Data were analyzed using an appropriate statistical package. Results A total of 403 (214 males) young adults (aged: 29±11 years) with clinical presentation of fever were studied. The majority (n=361, 89.6%) had low-grade continuous fever with an average duration of 3±1 (mean±standard deviation (SD)) days. Headache and myalgia were the common symptoms present, and patients had an average hospital stay of 4±1 days. Dengue (55%) was the most common cause of febrile neutropenia, and all patients recovered well without antibiotics and granulocyte colony-stimulating factor. The mean C-reactive protein (CRP) level was 61.4±4.4 mg/L. CRP and procalcitonin (PCT) were directly correlated with the degree of neutropenia and inversely correlated with total leucocyte count (TLC). Conclusions It was highlighted from this study that antibiotics are not necessary for viral infections that have been diagnosed to stop the development of secondary bacterial infections. A clinician should be aware of "when not to use antibiotics," or the world will soon have to deal with superbugs.

Implementation and impact of the global access principles at the University of British Columbia: current successes and future challenges.

In 2007, the University of British Columbia (UBC) was the first university in Canada to establish and adopt global access (GA) principles. Toward implementing these principles, UBC then identified a set of strategies for providing affordable access to new UBC-developed technologies throughout low- and middle-income countries and among vulnerable populations. In this perspective, we provide an update of UBC's progress over the past 15 years made on several technologies that fall under the GA principles. The technologies reported on are wide-ranging, including an oral medication for the treatment of leishmaniasis; peptides for potential use against malaria, and various bacterial, viral and fungal infections; a portable vaccine cooler; a diagnostic technology to detect severe sepsis; and an SMS Messaging System to monitor and support patients with HIV, TB and COVID-19. We identify challenges faced by the researchers in implementing the GA principles for these technologies and potential solutions for overcoming them through creative licensing and partnerships with public and private sectors, governments, local companies, and communities. As the UBC example illustrates, universities across the globe have an opportunity to make a significant social impact on improving global health of vulnerable populations and on supporting local infrastructures for sustaining these improvements.

Identification of oral therapeutics using an AI platform against the virus responsible for COVID-19, SARS-CoV-2.

Purpose: This study introduces a sophisticated computational pipeline, eVir, designed for the discovery of antiviral drugs based on their interactions within the human protein network. There is a pressing need for cost-effective therapeutics for infectious diseases (e.g., COVID-19), particularly in resource-limited countries. Therefore, our team devised an Artificial Intelligence (AI) system to explore repurposing opportunities for currently used oral therapies. The eVir system operates by identifying pharmaceutical compounds that mirror the effects of antiviral peptides (AVPs)-fragments of human proteins known to interfere with fundamental phases of the viral life cycle: entry, fusion, and replication. eVir extrapolates the probable antiviral efficacy of a given compound by analyzing its established and predicted impacts on the human protein-protein interaction network. This innovative approach provides a promising platform for drug repurposing against SARS-CoV-2 or any virus for which peptide data is available. Methods: The eVir AI software pipeline processes drug-protein and protein-protein interaction networks generated from open-source datasets. eVir uses Node2Vec, a graph embedding technique, to understand the nuanced connections among drugs and proteins. The embeddings are input a Siamese Network (SNet) and MLPs, each tailored for the specific mechanisms of entry, fusion, and replication, to evaluate the similarity between drugs and AVPs. Scores generated from the SNet and MLPs undergo a Platt probability calibration and are combined into a unified score that gauges the potential antiviral efficacy of a drug. This integrated approach seeks to boost drug identification confidence, offering a potential solution for detecting therapeutic candidates with pronounced antiviral potency. Once identified a number of compounds were tested for efficacy and toxicity in lung carcinoma cells (Calu-3) infected with SARS-CoV-2. A lead compound was further identified to determine its efficacy and toxicity in K18-hACE2 mice infected with SARS-CoV-2. Computational Predictions: The SNet confidently differentiated between similar and dissimilar drug pairs with an accuracy of 97.28% and AUC of 99.47%. Key compounds identified through these networks included Zinc, Mebendazole, Levomenol, Gefitinib, Niclosamide, and Imatinib. Notably, Mebendazole and Zinc showcased the highest similarity scores, while Imatinib, Levemenol, and Gefitinib also ranked within the top 20, suggesting their significant pharmacological potentials. Further examination of protein binding analysis using explainable AI focused on reverse engineering the causality of the networks. Protein interaction scores for Mebendazole and Imatinib revealed their effects on notable proteins such as CDPK1, VEGF2, ABL1, and several tyrosine protein kinases. Laboratory Studies: This study determined that Mebendazole, Gefitinib, Topotecan and to some extent Carfilzomib showed conventional drug-response curves, with IC50 values near or below that of Remdesivir with excellent confidence all above R2>0.91, and no cytotoxicity at the IC50 concentration in Calu-3 cells. Cyclosporine A showed antiviral activity, but also unconventional drug-response curves and low R2 which are explained by the non-dose dependent toxicity of the compound. Additionally, Niclosamide demonstrated a conventional drug-response curve with high confidence; however, its inherent cytotoxicity may be a confounding element that misrepresents true antiviral efficacy, by reflecting cellular damage rather than a genuine antiviral action. Remdesivir was used as a control compound and was evaluated in parallel with the submitted test article and had conventional drug-response curves validating the overall results of the assay. Mebendazole was identified from the cell studies to have efficacy at non-toxic concentrations and were further evaluated in mice infected with SARS-CoV-2. Mebendazole administered to K18-hACE2 mice infected with SARS-CoV-2, resulted in a 44.2% reduction in lung viral load compared to non-treated placebo control respectively. There were no significant differences in body weight and all clinical chemistry determinations evaluated (i.e., kidney and liver enzymes) between the different treatment groups. Conclusion: This research underscores the potential of repurposing existing compounds for treating COVID-19. Our preliminary findings underscore the therapeutic promise of several compounds, notably Mebendazole, in both in vitro and in vivo settings against SARS-CoV-2. Several of the drugs explored, especially Mebendazole, are off-label medication; their cost-effectiveness position them as economical therapies against SARS-CoV-2.

Review of Novel Oral Amphotericin B Formulations for the Treatment of Parasitic Infections.

Amphotericin B (AmpB) is a polyene macrolide antibiotic used in the treatment of blood-borne parasitic and fungal infections. However, its use, particularly in the developing world, has been limited by dose-dependent kidney toxicity, other systemic-related toxicity issues following injection, the inconvenience of parenteral administration, and accessibility. Oral formulation approaches have focused on the dual problem of solubility and permeability of AmpB, which is poorly water soluble, amphoteric and has extremely low oral bioavailability. Therefore, to enhance oral absorption, researchers have employed micellar formulations, polymeric nanoparticles, cochleates, pro-drugs, and self-emulsifying drug delivery systems (SEDDS). This paper will highlight current uses of AmpB against parasitic infections such as leishmaniasis, preclinical and clinical formulation strategies, applications in veterinary medicine and the importance of developing a cost-effective and safe oral AmpB formulation.

A novel study on clinical pharmacist and psychiatrist collaborative pharmacotherapy management services among elderly population with psychiatric illness.

Background: Geriatric psychiatry has yet to receive its due recognition in India. There is increasing evidence of a rise in morbidity, mortality, hospitalization, and loss of functional status related to common mental disorders in the elderly patients. Collaborative care approach, including a clinical pharmacist, is one of the possible approaches to cope with geriatric patients with psychiatric patients. Objective: The study aimed to assess the impact of pharmacotherapy management of geriatric patients in collaboration with pharmacist and psychiatrist. Materials and Methods: A prospective interventional study was conducted in the psychiatry outpatient department of a tertiary care hospital in Mysore over 6 months. Geriatric patients who were newly diagnosed with depression, bipolar affective disorder (BPAD) and alcohol dependency syndrome (ADS) were included in this study. The clinical pharmacist scrutinized the patients for their participation in the study. Included patients were followed up on monthly basis for up to 4 months. Pharmacotherapy management was provided to the enrolled patients. Interventions provided were discussed with the psychiatrist. Descriptive analysis was performed for categorical variables. Results: A total of 84 geriatric patients were enrolled in the study. Majority of the enrolled patients were female (n = 46, 54.7%). Nearly half of the patients were illiterate (n = 40, 47.6%) and unemployed (n = 38, 45.2%). Among the enrolled patients, half of the study participants were diagnosed with depression (63.09%) followed by BPAD (27.38%), Schizophrenia (7.14%), and ADS (2.38%). A total of 155 medication information services were provided to 84 patients including patient counseling (n = 84, 100%), pharmacist interventions (n = 48, 30.96%) and medication information (n = 23, 14.83%). Most of the interventions were adverse drug reactions followed by drug-drug interactions, failure to receive drugs, untreated indication, subtherapeutic dose, drug use without indication, and overdose. Majority of the interventions (n = 46, 95.8%) provided were accepted by the psychiatrist. Conclusion: The study findings indicate that pharmacotherapy management services provided by the clinical pharmacist in collaboration with the psychiatrist benefited the geriatric psychiatric patients.

Assessing the In Vivo Effectiveness of Cationic Lipid Nanoparticles with a Triple Adjuvant for Intranasal Vaccination against the Respiratory Pathogen Bordetella pertussis.

Continuous outbreaks of pertussis around the world suggest inadequate immune protection in infants and weakened immune responses induced over time by the acellular pertussis vaccine. Vaccine adjuvants provide a means to improve vaccine immunogenicity and support long-term adaptive immunity against pertussis. An acellular pertussis vaccine was prepared with pertactin, pertussis toxin, and fimbriae 2/3 antigens combined with a triple-adjuvant system consisting of innate defense regulator peptide IDR 1002, a Toll-like receptor-3 agonist poly(I:C), and a polyphosphazene in a fixed combination. The vaccine was delivered intranasally in a cationic lipid nanoparticle formulation fabricated by simple admixture and two schema for addition of antigens (LT-A, antigens associated outside of L-TriAdj, and LAT, antigens associated inside of L-TriAdj) to optimize particle size and cationic surface charge. In the former, antigens were associated with the lipidic formulation of the triple adjuvant by electrostatic attraction. In the latter, the antigens resided in the interior of the lipid nanoparticle. Two dose levels of antigens were used with adjuvant comprised of the triple adjuvant with or without the lipid nanoparticle carrier. Formulation of vaccines with the triple adjuvant stimulated systemic and mucosal immune responses. The lipid nanoparticle vaccines favored a Th1 type of response with higher IgG2a and IgA serum antibody titers particularly for pertussis toxin and pertactin formulated at the 5 µg dose level in the admixed formulation. Additionally, the lipid nanoparticle vaccines resulted in high nasal SIgA antibodies and an early (4 weeks post vaccination) response after a single vaccination dose. The LT-A nanoparticles trended toward higher titers of serum antibodies compared to LAT. The cationic lipid-based vaccine nanoparticles formulated with a triple adjuvant showed encouraging results as a potential formulation for intranasally administered pertussis vaccines.

Artificial intelligence for the discovery of novel antimicrobial agents for emerging infectious diseases.

The search for effective drugs to treat new and existing diseases is a laborious one requiring a large investment of capital, resources, and time. The coronavirus 2019 (COVID-19) pandemic has been a painful reminder of the lack of development of new antimicrobial agents to treat emerging infectious diseases. Artificial intelligence (AI) and other in silico techniques can drive a more efficient, cost-friendly approach to drug discovery by helping move potential candidates with better clinical tolerance forward in the pipeline. Several research teams have developed successful AI platforms for hit identification, lead generation, and lead optimization. In this review, we investigate the technologies at the forefront of spearheading an AI revolution in drug discovery and pharmaceutical sciences.

Inhibition of Scavenger Receptor Class B Type 1 (SR-B1) Expression and Activity as a Potential Novel Target to Disrupt Cholesterol Availability in Castration-Resistant Prostate Cancer.

There have been several studies that have linked elevated scavenger receptor class b type 1 (SR-B1) expression and activity to the development and progression of castration-resistant prostate cancer (CRPC). SR-B1 facilitates the influx of cholesterol to the cell from lipoproteins in systemic circulation. This influx of cholesterol may be important for many cellular functions, including the synthesis of androgens. Castration-resistant prostate cancer tumors can synthesize androgens de novo to supplement the loss of exogenous sources often induced by androgen deprivation therapy. Silencing of SR-B1 may impact the ability of prostate cancer cells, particularly those of the castration-resistant state, to maintain the intracellular supply of androgens by removing a supply of cholesterol. SR-B1 expression is elevated in CRPC models and has been linked to poor survival of patients. The overarching belief has been that cholesterol modulation, through either synthesis or uptake inhibition, will impact essential signaling processes, impeding the proliferation of prostate cancer. The reduction in cellular cholesterol availability can impede prostate cancer proliferation through both decreased steroid synthesis and steroid-independent mechanisms, providing a potential therapeutic target for the treatment of prostate cancer. In this article, we discuss and highlight the work on SR-B1 as a potential novel drug target for CRPC management.