Teplizumab: type 1 diabetes mellitus preventable?

Type 1 diabetes mellitus (T1DM) is an autoimmune condition driven by T lymphocytes that specifically declines the function of beta cells of pancreas. Immunological treatments aim to stop this decline in ß-cell function thus preventing TIDM. Although TIDM occur at any age, it is one of the most common chronic disorders in children. T1DM accounts for 5 to 10% of all cases of diabetes amounting 21-42 million affected persons. Teplizumab is a novel drug recently approved by the US FDA for the treatment of T1DM. This drug reduces abnormal glucose tolerance who are at high risk for developing T1DM and have antibodies suggesting an immunological attack on their pancreas. A 14-day infusion of the drug prevents T cells' attack of the insulin-producing cells of the pancreas. Adverse events due to teplizumab reported so far mild and of limited duration. This review gives an overview of the preclinical and clinical research on teplizumab for their role in new-onset T1DM.

Development and optimization of drug-loaded nanoemulsion system by phase inversion temperature (PIT) method using Box-Behnken design.

OBJECTIVE: The objective of the present investigation was to develop a stable and optimized drug-loaded nanoemulsion system using the phase inversion temperature (PIT) method. SIGNIFICANCE: The PIT method has been widely used for the development of food-grade nanoemulsion systems. For the first time, a simple and cost-effective, PIT method was used for the development of a stable drug-loaded nanoemulsion system. METHODS: Box-Behnken experimental design was used for the development of an optimized drug-loaded nanoemulsion system by the PIT method. The independent variables were optimized for responses by using the desirability function. The hydrophobic drug, benidipine was used as a modal drug. Optimized oil phase (blend of long-chain triglycerides oil, medium-chain triglycerides oil and essential oil) was used for the development of oil in water (O/W) nanoemulsion system. RESULTS: Optimum nanoemulsion formulation was stable, transparent and contained 50% of oil to surfactant percentage with a droplet size of 96.57 ± 1.61 nm. The optimum formulation also showed higher in-vitro drug diffusion from dialysis membrane as compared to the marketed formulation. Nanoemulsion droplets were observed as spherical in the transmission electron microscopy (TEM) images. Box-Behnken statistical analysis revealed that all the independent variables had a significant impact on characteristics of nanoemulsion and the predicated value of independent variables was found to be valid. CONCLUSION: It was concluded that the PIT method produces a stable and efficient drug-loaded nanoemulsion system. Further, the optimized oil phase can be used as an alternative to costly, commercial medium-chain triglycerides (MCT) oils, for the development of a stable nanoemulsion system.

Dohra- a mixture of potent carcinogens.

BACKGROUND & OBJECTIVES: Dohra is a areca nut preparation used with or without tobacco in a few of the areas of Uttar Pradesh (UP), India. There is evidence that it causes potentially malignant disorders and oral cancer. This study was undertaken to provide information on dohra by searching through literature and also through a survey in three areas of Uttar Pradesh (UP), India. METHODS: The information on dohra was collected through literature search, study tour to different areas of UP, where group discussions with dohra vendors and with community members of different age group were done to obtain information. RESULTS: Dohra was prepared by the users for their personal use or prepared by small-scale industry for sale. It was available mostly in betel shops or any other store/kiosks and was also available in special dohra shops. Dohra was available in both dry and wet form. Its common constituents were areca nut, catechu (Acacia catechu), edible lime, peppermint (Mentha piperita), cardamom (Elettaria cardamomum) and some flavoring agents. Dohra was consumed as such or with tobacco. INTERPRETATION & CONCLUSIONS: Different varieties of Dohra were available such as sukha dohra, sukha mulethi dohra and geela dohra. Different processing methods for producing dohra existed. As dohra increases the risk of cancer, it needs to be banned or it should be sold in packets with the details of its constituents and also statutory warning about its adverse health effects.

Evidences and therapeutic advantages of donanemab in the treatment of early Alzheimer's disease.

The humanised monoclonal antibody donanemab is being developed to treat early onset Alzheimer's disease (AD). This drug targets N-truncated pyroglutamate amyloid-peptide at position 3 (N3pG), a modified form of deposited amyloid-peptide. The symptoms of Alzheimer's disease include gradual memory loss and other cognitive impairments. This disease is characterized by amyloid plaques, which are formed as a result of an accumulation of amyloid-(A-ß) peptides. Despite granting donanemab breakthrough therapy designation in June 2021, the FDA rejected donanemab's accelerated approval application in January 2023, due to inadequate safety data. According to the baseline amyloid level, the time to achieve plaque clearance (amyloid plaque level <24.1 centiloids) varied. Patients with higher baseline levels were more likely to achieve amyloid clearance. The safety of the drug was demonstrated by amyloid-related imaging abnormalities (ARIA), which ranged from 26.1 to 30.5 % in the studies. Clinical trial results have shown that donanemab delays cognitive and functional deterioration in patients with mild to moderate AD. However, it is not yet known whether donenameb offers therapeutic benefits that can change and improve the clinical condition of AD patients. To achieve significant clinical benefits in AD patients with cognitive impairment, further studies may be needed to investigate the interaction between A-ß plaque reduction and toxic tau levels.

Assessment of prevalence and need for screening of diabetic retinopathy using non-mydriatic fundus camera in rural and tribal diabetic populations in Maharashtra.

PURPOSE: To assess the prevalence of DR and the need for screening and management of DR with medical management of diabetes in rural and tribal population in Maharashtra. METHODS: The known diabetics of rural area and tribal area were screened at corresponding primary health centers, subcenters, and village level with the help of local healthcare workers using a portable non-mydriatic fundus camera. The prevalence of blindness among known diabetics in rural area was 1.29%, and 0.84% in tribal area. RESULTS: In the rural area, the prevalence of diabetic retinopathy (DR) was 5.67% ( n = 776), out of those 18.18% had sight threatening diabetic retinopathy (STDR). The prevalence of DR was 7.73% ( n = 711) in tribal areas, out of those, 30.90% had STDR. CONCLUSIONS: The significant risk factors were identified to be the duration of diabetes and poor glycemic control. Implementation of targeted interventions for screening and management are required to reduce the risk of blindness among known diabetics in rural and tribal areas.

Correlation between serum isoniazid concentration and therapeutic response in patients of pulmonary tuberculosis in Central India: A prospective observational study.

BACKGROUND: Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis is one of the top ten causes of death worldwide. Isoniazid (INH) is an important component of anti-tuberculosis therapy (ATT). Low isoniazid levels can serve as a risk factor for the development of treatment failure, relapse of disease and acquired secondary resistance. Hence, serum level of isoniazid becomes a critical factor in determining the treatment outcome of patients on ATT. This study aimed to evaluate the correlation between serum isoniazid concentration and therapeutic response in patients of pulmonary tuberculosis in Central India. METHODS: This was a prospective single cohort observational study conducted at a tertiary care hospital. Therapeutic response in newly diagnosed patients of pulmonary TB was determined based the microbiological, clinical and radiological parameters. Serum INH levels were estimated based on a spectrophotometric method using nano-spectrophotometer. RESULTS: In this study, patients had a significant improvement in treatment outcome as evident by a significant decrease in the TB score I at end of IP (p = 0.001) and a significant decline in the Timika score at end of CP (p = 0.001). Although all patients converted to sputum negative at end of CP, 20% remained positive at end of IP. Lower INH levels were seen in 13.3% of the study population. Higher INH levels were observed in sputum converters, patients with low TB score I and low Timika score, although no statistically significant difference was noted (p > 0.05). CONCLUSION: In this study, we could not find any statistically significant association between serum INH levels and therapeutic outcome of the patients. Further studies on a larger population could provide better understanding about the prevalence of low serum isoniazid levels among the Indian population and establish its relationship with therapeutic outcome. Also, the usage of a comparatively less expensive spectrophotometric method of analysis makes this feasible in almost every district hospital without the need of high-performance liquid chromatography which is costlier and needs more expertise.

Bispecific antibodies and its applications: a novel approach for targeting SARS-Cov-2.

The COVID-19 pandemic remains a severe global threat, with the world engulfed in the struggle against the disease's second or third waves, which are approaching frightening proportions in terms of cases and mortality in many nations. Despite the critical need for effective therapy, there is still uncertainty about the optimal practices for treating COVID-19 with various pharmaceutical approaches. This being third year, global immunity and eradication of SARS-CoV-2 is currently seems to be out of reach. Efforts to produce safe and effective vaccinations have shown promise, and progress is being made. Additional therapeutic modalities, as well as vaccine testing in children, are required for prophylaxis and treatment of high-risk individuals. As a result, neutralising antibodies and other comparable therapeutic options offer a lot of promise as immediate and direct antiviral medications. Bispecific antibodies offer a lot of potential in COVID-19 treatment because of their qualities including stability, small size and ease of manufacture. These can be used to control the virus's infection of the lungs because they are available in an inhalational form. To combat the COVID-19 pandemic, innovative approaches with effective nanobodies, high-expression yield and acceptable costs may be required.

Antimicrobials in COVID-19: strategies for treating a COVID-19 pandemic.

The COVID-19 pandemic continues to pose a serious global challenge, with the world engulfed in fighting second, third and fourth waves of the disease, which is reaching scary proportions in terms of cases and mortality in countries like India. Despite the urgent need of proven management protocols, there is still confusion about the best practices for treating COVID-19 with different pharmaceutical interventions. Antimicrobials are empirically used in COVID-19 patients. During the initial phase of this pandemic, hydroxychloroquine, ivermectin, azithromycin and doxycycline were widely suggested for possible prophylaxis or treatment for COVID-19 in outpatient as well as hospitalized settings. Various national and international guidelines recommended its use. However, cumulative evidence from subsequent clinical trials has revealed no significant clinical benefits in any setting, with the risk of adverse effects being high particularly in combination with azithromycin. Yet, there is continued use of antimicrobials particularly in outpatient settings which should be avoided because there is no justifiable rationale for doing so. Antimicrobial resistance (AMR) was one of the top problems for global public health before the coronavirus 2019 (COVID-19) pandemic began. AMR, which is already a difficult problem, must now be handled in the context of a changing healthcare sector.

Health care associated infections, antimicrobial resistance and outcomes in patients admitted to intensive care unit, India: A five-Year retrospective cohort study.

Background: The present study was conducted to study the prevalence of HAIs in a newly established MICU, common microorganisms causing HAIs and their antibiotic-sensitivity profile, and antimicrobial utilization and mortality rate. Methods: The present retrospective cohort study was carried out at AIIMS, Bhopal (2015-2019). The prevalence of HAIs was determined; sites of HAIs and common causative microorganisms were identified, and their antibiotic-sensitivity profiles were studied. The group of patients with HAIs was matched with a control group drawn from the pool of patients without HAIs; this matching was done with respect to age, gender, and clinical diagnosis. Antimicrobial utilization, Period of ICU stay, comorbidities and patient mortality rates in the two groups were analyzed. The clinical criteria by the CDC- National Nosocomial Infections Surveillance to diagnose HAIs. Results: A total of 281 ICU patients' records were analyzed. The mean age was 47.21 ± 19.07 years. Of these 89 were found to have developed ICU-acquired HAIs (Prevalance:32%). Bloodstream infections (33%) and respiratory tract infections (30.68%), catheter-associated urinary tract infections (25.56%), and surgical site infections (6.76%) were the commonest. The most frequently isolated microorganism causing HAIs was K. pneumonia (18%), A. baumannii (14%) and E. coli (12%), 31% isolates of which were multidrug resistant. The average length of ICU stay was high in patients with HAIs (13.85 vs 8.2 days). The most common co-morbidity was type 2 diabetes mellitus (42.86%). Prolonged ICU stays [OR 1.13, (95% CI; 0.04-0.10)] and the presence of HAIs [OR 1.18(95%CI; (0.03-0.15)] were associated with an increased risk of mortality. Conclusions: An increased prevalence of HAIs essentially bloodstream infections and respiratory infections with MDR organisms to antimicrobials in the watch group is highly considerable. Acquisition of HAIs with MDR organisms and increased length of hospital stay are considerable risk factors for increased mortality in ICU-admitted patients. Regular antimicrobial stewardship activities and revising existing hospital infection control policies accordingly may reduce HAIs.

Study of tear function before and after laser-assisted in-situ keratomileusis.

Purpose: This work assesses the change in tear function after LASIK surgery. Methods: This prospective, observational study was conducted in the Refractive Clinic of a tertiary care rural hospital. Tear dysfunction symptoms and the tear function tests were assessed in 269 eyes of 134 patients, OSDI score was used to document the tear dysfunction symptoms. Tear function was assessed by tear meniscus height, tear film break-up time (TBUT), Lissamine green staining, corneal fluorescein staining, Schirmer test 1 without anesthesia before and at 4-6 weeks and 10-12 weeks after LASIK surgery. Results: Preoperatively OSDI score was 8.54 ± 7.71. It increased to 15.11 ± 9.18 postoperatively at 4-6 weeks after LASIK surgery and 13 ± 9.56 at 10-12 weeks after LASIK surgery Mean TBUT preoperatively was 7.82 ± 3.57 sec which decreased to 5.34 ± 2.56 sec at 4-6 weeks and to 4.53 ± 2.63 sec at 10-12 weeks postoperatively. The number of eyes with clear secretion decreased from 40.5% preoperatively to 23.4% at 4-6 weeks and to 22.3% at 10-12 weeks postoperatively, whereas the granular and cloudy secretions increased significantly in eyes after LASIK surgery. The prevalence of eyes with Lissamine green score >3 (dry eye) increased from 17.1% preoperatively to 27.9% at 4-6 weeks and to 30.5% at 10-12 weeks. Similarly, the number of eyes showing positive fluorescein corneal staining increased from 5.6% preoperatively to 19% postoperatively at 4-6 weeks. Mean Schirmer score was 28.83 ± 6.39 mm preoperatively, 22.47 ± 5.38 mm at 4-6 weeks, and 21.27 ± 4.99 mm at 10-12 weeks after LASIK surgery. Conclusion: The prevalence of dry eye increased after LASIK as was assessed by an increase in the tear dysfunction symptoms using OSDI score and the deranged values of various tear function tests after LASIK surgery.

An observational multi-centric COVID-19 sequelae study among health care workers.

Background: India has seen more than 43 million confirmed cases of COVID-19 as of April 2022, with a recovery rate of 98.8%, resulting in a large section of the population including the healthcare workers (HCWs), susceptible to develop post COVID sequelae. This study was carried out to assess the nature and prevalence of medical sequelae following COVID-19 infection, and risk factors, if any. Methods: This was an observational, multicenter cross-sectional study conducted at eight tertiary care centers. The consenting participants were HCWs between 12 and 52 weeks post discharge after COVID-19 infection. Data on demographics, medical history, clinical features of COVID-19 and various symptoms of COVID sequelae was collected through specific questionnaire. Finding: Mean age of the 679 eligible participants was 31.49 ± 9.54 years. The overall prevalence of COVID sequelae was 30.34%, with fatigue (11.5%) being the most common followed by insomnia (8.5%), difficulty in breathing during activity (6%) and pain in joints (5%). The odds of having any sequelae were significantly higher among participants who had moderate to severe COVID-19 (OR 6.51; 95% CI 3.46-12.23) and lower among males (OR 0.55; 95% CI 0.39-0.76). Besides these, other predictors for having sequelae were age (≥45 years), presence of any comorbidity (especially hypertension and asthma), category of HCW (non-doctors vs doctors) and hospitalisation due to COVID-19. Interpretation: Approximately one-third of the participants experienced COVID sequelae. Severity of COVID illness, female gender, advanced age, co-morbidity were significant risk factors for COVID sequelae. Funding: This work is a part of Indian Council for Medical Research (ICMR)- Rational Use of Medicines network. No additional financial support was received from ICMR to carry out the work, for study materials, medical writing, and APC.

Antibody-dependent enhancement of virus infection and disease: implications in COVID-19.

Antibody-dependent enhancement (ADE) can be seen in a variety of viruses. It has a deleterious impact on antibody treatment of viral infection. This effect was first discovered in the dengue virus, and it has since been discovered in the coronavirus. Over 213 million people have been affected by the rapid spread of the newly emerging coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). The new coronavirus offers a significant threat and has sparked widespread concern. ADE in dengue virus and other viruses are discussed with possible effect on COVID-19 treatment and vaccine development will need to consider this phenomenon to ensure it is mitigated and avoided altogether. In these case scenarios, the role of ADE and its clinical consequences remains to be explored for this newly detected virus.

Clinical implications of anti-idiotype antibodies in COVID-19.

Idiotype-based therapeutics have failed to deliver their promise, necessitating rethinking of the concept and its potential to develop a viable immunotherapy method. The idiotype based hypothesis is discussed in this paper in order to produce effective anti-idiotype vaccinations. Polyclonal anti-idiotype reagents have been shown to be more successful in animal models, and a better understanding of the immune response in humans supports the idea that polyclonal anti-idiotype vaccines will be more effective than monoclonal-based anti-idiotype vaccines. This innovative approach can be used to produce therapeutic antibodies in a Biotech-standard manner. The idiotype network has been tweaked in the lab to provide protection against a variety of microbiological diseases. Antibodies to image-idiotype antigens, both internal and non-internal, can elicit unique immune responses to antigens. The current outbreak of severe acute respiratory syndrome 2 (SARS-2) has presented a fantastic chance to use idiotype/anti-idiotype antibodies as a protective regimen, which might be used to treat COVID-19 patients. The development of various effective vaccinations has been crucial in the pandemic's management, but their effectiveness has been limited. In certain healthy people, the development of viral variations and vaccinations can be linked to rare off-target or hazardous effects, such as allergic responses, myocarditis and immune-mediated thrombosis and thrombocytopenia. Many of these occurrences are most likely immune-mediated. The current analysis reveals successful idiotype/anti-idiotype antibody uses in a variety of viral illnesses, emphazising their importance in the COVID-19 pandemic.

An overview of post COVID sequelae.

After healing from COVID-19, patients often experience a slew of symptoms known as post COVID-19 sequelae. Despite the fact that the SARS-CoV-2 pandemic is still ongoing, post-Covid-19 syndrome is already a difficult problem to address: long-term multiorgan sequelae, while frequently described, have yet to be systematized. As a result, post-Covid-19 syndrome can have a major influence on surviving patients' working capacity as well as their personal lives. The clinical spectrum and long-term course of this clinical entity must be better understood. Post-Covid syndrome affects a wide spectrum of individuals (16-87%), with pneumological and cognitive symptoms being the most common. Pulmonary fibrosis was the most common organic consequence seen in post-Covid patients. In conclusion, post-Covid-19 syndrome can have a major impact on the health of survivors. Working-age patients should seek rehabilitation and follow-up in interdisciplinary rehabilitation programmes. Given the pandemic's global extent, it's obvious that COVID-19-related healthcare demands will continue to climb for the foreseeable future. For COVID-19 survivors' long-term mental and physical health, present outpatient infrastructure will be utilised, scalable healthcare models will be built, and cross-disciplinary collaboration will be required.

Stimulated Reporting of Adverse Events Following Immunization with COVID-19 Vaccines.

In India, up until December 2021, Covishield and Covaxin vaccines against COVID-19 were being used for mass vaccination programs. In view of the urgency of fighting the ongoing pandemic, many vaccines have been granted emergency use approval while phase 2/3 clinical trials were still underway. Even for vaccines that have completed phase 3 trials, safety data may not be comprehensive. This retrospective observational study was conducted at a designated Regional Training Centre for Pharmacovigilance cum Adverse Drug Reaction Monitoring Centre (AMC) under the Pharmacovigilance Programme of India. The data sources were stimulated spontaneous reports of Adverse Events Following Immunization (AEFI) due to the COVID-19 vaccines from 10 January to 31 December 2021. A total of 51,010 COVID vaccine doses were administered during the study period. There were 330 AEFI reported (AEFI rate: 0.65%). Six AEFI were serious events among which three were Adverse Events of Special Interest. The majority of the AEFI were systemic, reported after the first dose, and with an onset between 1 and 24 h after vaccination. On comparing Covishield and Covaxin, there were no statistically significant differences in the AEFI reported with either vaccine in terms of gender, seriousness, lag period, duration, recovery, causality, treatment received for AEFI, presence of co-morbidity, or history of COVID-19 infection. Overall, the rates of AEFI was uncommon, and serious AEFI were rare with both Covishield and Covaxin, with a higher rate after the first dose. Whether immunological tolerance or allayed anxiety was responsible for the lower AEFI risk with the second dose remains to be investigated.

Pooling of neglected and delayed trauma patients - Consequences of 'lockdown' and 'Unlock' phases of COVID-19 pandemic- A retrospective cohort analysis from a tertiary centre.

BACKGROUND: The COVID-19 pandemic resulted in nationwide lockdown and quarantine strategies to break the chain of transmission of the SARS-CoV-2 virus in India. Management of patients with trauma has been particularly challenging across the country. AIMS: To evaluate the effect of delay in surgery in patients with traumatic injuries along with the peri-operative outcomes during the 'Lockdown' and 'Unlock' phases of the COVID-19 pandemic at a Level I Trauma centre in the National Capital Region (NCR) of India. METHODS: This retrospective, observational cohort study included 488 patients. Comparative analysis to assess patient characteristics, mechanism of trauma, clinical outcomes in patients managed operatively during 'Lockdown period' (24 March 2020 to 31 May 2020) Group A with Group B, who presented during 'Unlock phases' (01 June 2020 to 31 December 2020). RESULTS: The average delay in surgery, surgical time and hospital stay was significantly increased in group B patients (p-value <0.05). The average blood loss, stay in the Intensive Care Unit (ICU) and blood transfusion requirement were clinically higher in group B but these differences were not statistically significant (p-value >0.05). Only in group B; 9.01% patients (42 out of 466) required bone grafting. CONCLUSION: 'Neglect' and delay in receiving operative management of orthopaedic trauma has led to unprecedented rise in number of complications of fractures, such as mal-union, delayed union or non-union during COVID-19 Pandemic. Patients have had to undergo longer surgical procedures with increased risk of intra-operative blood loss, need of peri-operative blood transfusion and bone grafting supplementation to facilitate union. Diligent attention to achieve the most optimal configuration of fractures should be planned in conservatively managed injuries during the pandemic to minimize future intra-operative difficulties.