Comprehensive Summary of Safety Data on Nirsevimab in Infants and Children from All Pivotal Randomized Clinical Trials.

BACKGROUND: Nirsevimab is approved in the US for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in neonates and infants during their first RSV season and in children aged ≤24 months who remain vulnerable to severe RSV disease through their second RSV season. We summarize a pre-specified analysis of nirsevimab safety data from three randomized controlled trials: Phase 2b (NCT02878330; healthy infants born ≥29 to <35 weeks' gestational age [wGA]); Phase 3 MELODY (NCT03979313; healthy infants born ≥35 wGA); and Phase 2/3 MEDLEY (NCT03959488; infants with congenital heart disease [CHD] and/or chronic lung disease of prematurity [CLD] or born ≤35 wGA). METHODS: Participants (randomized 2:1) received a single intramuscular dose of nirsevimab or comparator (placebo, Phase 2b/MELODY; 5× once-monthly palivizumab, MEDLEY) before their first RSV season (recipients < 5 kg, nirsevimab 50 mg; ≥5 kg, nirsevimab 100 mg). In MEDLEY, children with CHD/CLD continued to a second RSV season: first-season nirsevimab recipients received nirsevimab 200 mg; first-season palivizumab recipients were re-randomized 1:1 to receive nirsevimab 200 mg or 5× once-monthly palivizumab. RESULTS: The incidence, severity, and nature of AEs were similar across treatments (nirsevimab, n = 3184; placebo, n = 1284; palivizumab, n = 304). Most AEs were mild to moderate in severity, with ≥98% unrelated to treatment. AEs of special interest occurred infrequently (<1%): no anaphylaxis or thrombocytopenia were treatment-related, and no immune complex disease was reported. Deaths (incidence < 1.0%) were all unrelated to treatment. CONCLUSIONS: A single dose per season of nirsevimab for the prevention of RSV disease had a favorable safety profile, irrespective of wGA or comorbidities.

Infants Receiving a Single Dose of Nirsevimab to Prevent RSV Do Not Have Evidence of Enhanced Disease in Their Second RSV Season.

To characterize nirsevimab in the prevention of RSV, children from the Phase 3 MELODY trial were followed through their second RSV season. No increase in medically attended RSV lower respiratory tract infections or evidence of antibody-dependent enhancement of infection or disease severity was found for nirsevimab vs placebo recipients. Clinical Trial Registration: Clinicaltrials.gov, NCT03979313, https://clinicaltrials.gov/ct2/show/NCT03979313.

The Need to Rethink Harm Reduction for People Using Drugs Alone to Reduce Overdose Fatalities.

Background: During the ongoing opioid epidemic, Cuyahoga County (second largest in Ohio) reported overdose mortality rates (54/per 100,000) higher than the national average. Prior research demonstrates that people who use drugs often use alone but there is minimal research on people who died of overdose while using alone. The objective of this study is to examine sociodemographic, toxicologic, and injury characteristics, and emergency medical response to overdose decedents who died using drugs alone. Method: Data from the Cuyahoga County Medical Examiner's Office (2016-2020, N = 2944) on unintentional overdose deaths in adults was tabulated including socio-demographic, toxicologic, and injury-related information. Decedents using drugs alone were identified and compared to those not using alone via Chi-square and Fisher's exact tests. We further fit a multivariate logistic regression model to evaluate socio-demographic, toxicologic, and injury-related factors associated with increased odds of using alone. All results are reported with 95% confidence intervals. Result: Among decedents, 75% (n = 2205) were using drugs alone. Decedents using alone were more likely to be using drugs at home (p = 0.001) or be found dead at the scene (p < 0.001) and less likely to receive naloxone (p < 0.001) have other person/bystander, not using, present (p = 0.002). Using drugs at home (aOR = 1.61[1.19-2.20]) was associated with higher odds of using alone; and being married (aOR = 0.57[0.38-0.86]), having history of illicit drug use (aOR = 0.25[0.08-0.81]) and other person present, who was not using (aOR = 0.58[0.42-0.79]) were associated with lower odds of using alone. Conclusion: New harm reduction approaches targeting people using drugs alone are needed to reduce overdose deaths.

Comparative effect of composite management of type II diabetes mellitus with induced emesis and Varadi Ghanavati: A pilot clinical study.

INTRODUCTION: Ayurveda offers a rational view in the management of Prameha. Shodhana (∼bio-purification) is advocated as the first line of treatment to eliminate Kapha, which is followed by palliative treatment to further control disease pathology. Evaluation of such composite treatment has rarely been published. The present study was conducted to assess the comparative efficacy and safety of three interventions in the management of Prameha (Diabetes mellitus type II (T2DM)) - (a) Vamana (induced emesis) and Varadi Ghanavati (oral Ayurvedic medication), (b) Varadi Ghanavati, and (c) glibenclamide. METHODS: It was open labelled, comparative, randomised, prospective, three arm pilot study. A total 49 patients, newly diagnosed or known cases of Prameha (T2DM) were randomised in three groups. The first group (Vamana) received Vamana followed by Varadi Ghanavati (500 mg (mg) thrice daily before food for 12 weeks). The second (Varadi) group received Varadi Ghanavati without prior Vamana, while, the control group received glibenclamide 5 mg twice daily before food for 12 weeks. Patients were evaluated at intervals of each four weeks. Assessment was done on changes seen in blood sugar (BSL) fasting (F), postprandial (PP), glycosylated haemoglobin, lipid profile, body mass index (BMI) and clinical symptoms. RESULTS: Patients in all groups showed better glycaemic control as compared to baseline. Mean BSLF before and after treatment were 166.20 ± 78.39 mg/dL and 125.00 ± 58.77 mg/dL in Vamana group (p < 0.01), 163.60 ± 59.34 mg/dL and 127.73 ± 37.94 mg/dL in Varadi group (p < 0.05), while 163.00 ± 59.03 mg/dL and 129.40 ± 41.91 mg/dL in control (p < 0.05). Similarly, BSL PP values before and after treatment were 254.47 ± 99.59 mg/dL and 178.47 ± 68.45 mg/dL in Vamana group (p < 0.01), 233.93 ± 68.95 mg/dL and 185.20 ± 56.73 mg/dL in Varadi group (p < 0.05), 239.80 ± 77.10 mg/dL and 182.53 ± 42.14 mg/dL in control (p < 0.05). Glycosylated haemoglobin, mean values before and after treatment were 8.23 ± 1.71% and 7.18 ± 1.96% in Vamana group (p < 0.05), 7.83 ± 1.21% and 6.75 ± 1.13% in Varadi group (p < 0.05), 7.17 ± 1.12% and 6.60 ± 0.65% in glibenclamide group (p < 0.05). Comparative evaluation in the three groups showed that there was a statistically significant reduction (p < 0.001) in total cholesterol, low-density lipoproteins (LDL) and BMI in Vamana group as compared the other groups. No adverse event was observed. CONCLUSION: Along with better glycaemic control, composite treatment can reduce deranged lipids and BMI, which can help in better management of Prameha (T2DM). Vamana and Varadi Ghanavati can be administered safely. CLINICAL TRIAL REGISTRATION NO: CTRI/2017/10/010127.

Molecular and phenotypic characteristics of RSV infections in infants during two nirsevimab randomized clinical trials.

Nirsevimab is a monoclonal antibody that binds to the respiratory syncytial virus (RSV) fusion protein. During the Phase 2b (NCT02878330) and MELODY (NCT03979313) clinical trials, infants received one dose of nirsevimab or placebo before their first RSV season. In this pre-specified analysis, isolates from RSV infections were subtyped, sequenced and analyzed for nirsevimab binding site substitutions; subsequently, recombinant RSVs were engineered for microneutralization susceptibility testing. Here we show that the frequency of infections caused by subtypes A and B is similar across and within the two trials. In addition, RSV A had one and RSV B had 10 fusion protein substitutions occurring at >5% frequency. Notably, RSV B binding site substitutions were rare, except for the highly prevalent I206M:Q209R, which increases nirsevimab susceptibility; RSV B isolates from two participants had binding site substitutions that reduce nirsevimab susceptibility. Overall, >99% of isolates from the Phase 2b and MELODY trials retained susceptibility to nirsevimab.

Safety of Re-dosing Nirsevimab Prior to RSV Season 2 in Children With Heart or Lung Disease.

In children with congenital heart disease and/or chronic lung disease entering their second respiratory syncytial virus (RSV) season, 200 mg nirsevimab had a similar safety profile to that of palivizumab and resulted in nirsevimab serum exposures associated with efficacy in healthy infants, supporting efficacy in this population at risk of severe RSV disease.

Circulation of unusual and diverse enteric virus strains in adults with acute gastroenteritis: a study from Pune (Maharashtra), Western India.

In India, studies on the epidemiological and genetic characteristics of enteric viruses in adults with acute gastroenteritis (AGE) are lacking. In this study, fecal samples (n = 110) from adults with acute gastroenteritis in Pune, Western India, were tested for six enteric viruses, and the prevalence of these viruses was as follows: rotavirus A (RVA), 38.5%; enterovirus (EV), 23.1%; astrovirus (AstV), 23.1%; adenovirus (AdV), 7.7%; human bocavirus (HBoV), 7.7%; norovirus (NoV), 0%. Circulation of the RVA G1P[8], G3P[8], G9P[4], CVA-10, echovirus E13, EVC-116, AstV-5, AstV-2, HBoV-1, and AdVC-2 types was observed. When compared to the RotaTeq, Rotarix, and RotaVac vaccine strains, antigenic changes were found in the A, B, C, and F regions of the RVA strains. The circulation of genetically diverse, unusual enteric virus strains, reported here for the first time in adults with acute gastroenteritis, warrants multi-center hospital-based surveillance studies across the country.

Trends in genital ulcer disease: An observational study at a tertiary care teaching hospital.

Introduction: Genital ulcer disease (GUD) often creates diagnostic difficulty in developing countries like India, with limited resources available in the health-care system. The changing etiology in GUDs over the years makes it imperative that a correct diagnosis is made to establish appropriate treatment and formulate awareness programs. Aims: This study was done to determine the recent trends in the demographic parameters, clinical presentations, etiology of GUDs, and their association with human immunodeficiency virus (HIV). Materials and Methods: An observational cross-sectional study was conducted from October 2021 to August 2022 at the Dermatology Outpatient Department in our hospital. All the patients who presented with GUDs were included after written informed consent. The diagnosis of GUD was confirmed by thorough clinical examination and appropriate laboratory test. Data were entered and analyzed using IBM SPSS software. Results: Out of 135 cases of GUDs, the majority were males (79%). The most common age group was 21-30 years, with a mean age of 35.23 ± 14.98 years. Most of the patients were heterosexual (90%). Multiple sexual partners were found in 40% of cases. Herpes genitalis was the most common GUD (59%), followed by syphilis (15%). HIV infection was found in 6.6% of cases. Conclusion: This study represents the increasing burden of viral GUDs compared to the last three decades. The ulcerative sexually transmitted infection facilitates the transmission of HIV. In this HIV era, there is a need for increased efforts toward acknowledgment, safe sexual practices, periodic screening, and sexual health awareness programs in the high-risk population.

The anticonvulsant phytocannabinoids CBGVA and CBDVA inhibit recombinant T-type channels.

Introduction: Cannabidiol (CBD) has been clinically approved for intractable epilepsies, offering hope that novel anticonvulsants in the phytocannabinoid class might be developed. Looking beyond CBD, we have recently reported that a series of biosynthetic precursor molecules found in cannabis display anticonvulsant properties. However, information on the pharmacological activities of these compounds on CNS drug targets is limited. The current study aimed to fill this knowledge gap by investigating whether anticonvulsant phytocannabinoids affect T-type calcium channels, which are known to modulate neuronal excitability, and may be relevant to the anti-seizure effects of this class of compounds. Materials and methods: A fluorescence-based assay was used to screen the ability of the phytocannabinoids to inhibit human T-type calcium channels overexpressed in HEK-293 cells. A subset of compounds was further examined using patch-clamp electrophysiology. Alphascreen technology was used to characterise selected compounds against G-protein coupled-receptor 55 (GPR55) overexpressed in HEK-293 cells, as GPR55 is another target of the phytocannabinoids. Results: A single 10 µM concentration screen in the fluorescence-based assay showed that phytocannabinoids inhibited T-type channels with substantial effects on Cav3.1 and Cav3.2 channels compared to the Cav3.3 channel. The anticonvulsant phytocannabinoids cannabigerovarinic acid (CBGVA) and cannabidivarinic acid (CBDVA) had the greatest magnitudes of effect (≥80% inhibition against Cav3.1 and Cav3.2), so were fully characterized in concentration-response studies. CBGVA and CBDVA had IC50 values of 6 µM and 2 µM on Cav3.1 channels; 2 µM and 11 µM on Cav3.2 channels, respectively. Biophysical studies at Cav3.1 showed that CBGVA caused a hyperpolarisation shift of steady-state inhibition. Both CBGVA and CBDVA had a use-dependent effect and preferentially inhibited Cav3.1 current in a slow inactivated state. CBGVA and CBDVA were also shown to antagonise GPR55. Conclusion and implications: These findings show that CBGVA and CBDVA inhibit T-type calcium channels and GPR55. These compounds should be further investigated to develop novel therapeutics for treating diseases associated with dysfunctional T-type channel activity.

The Spectrum of Cutaneous Adverse Drug Reactions Following the Application of Topical Medications: An Observational Study at a Tertiary Care Center.

Introduction Topical medications are one of the most commonly used therapeutic agents in treating a wide spectrum of dermatological diseases. The misuse of topical medicines for inappropriate indications and an extended period may result in cutaneous adverse drug reactions (ADR). Aims We conducted this study to observe demographic parameters, commonly misused topical medicines, various clinical patterns of cutaneous ADR, and source of drug prescription among study participants. Materials and methods This cross-sectional observational study was conducted from October 2021 to May 2022 at the dermatology outpatient department (OPD) of a tertiary care center. All patients who presented with worsening pre-existing skin diseases or the development of skin disease after the topical application of some cream or ointment were included in the study with written informed consent. A detailed history was taken, and a clinical examination was done. Results We detected 200 cases (1.62%) of cutaneous ADR out of 12,346 OPD patients in the eight-month study period. The most common age group was 21-30 years (30%). Most of the patients had used topical medicines for fungal infections (76%). The most commonly used topical medication was a fixed drug combination (FDC) of steroid, antifungal, and antibacterial agents (40%). Tinea incognito (36%) was the most common cutaneous ADR noted. Conclusion This study shows that misuse of topical medications is rampant in our community because of their free and easy availability. There is an urgent requirement for strict regulations over the manufacturing, sales, and marketing of over-the-counter (OTC) topical medications to reduce the incidence of cutaneous ADR.

Conservative management of acute prolapsed inter-vertebral disc with ayurveda: A case report.

Acute prolapsed inter-vertebral disc (IVDP) is a painful condition that requires immediate treatment by conservative or surgical management. Though majority of patients show remission in symptoms with conservative treatment, regression of herniated disc with non-surgical management has been rarely reported. A 46 years old female patient with acute and severe low back pain, disability and radiating pain towards right lower extremity came to our hospital. Oswestry Disability Index (ODI) score of the patient was 94% indicating bed-ridden condition. MRI of lumbar spine showed diffuse posterior disc bulge between fourth and fifth lumbar vertebra indenting right traversing nerve root and inferior displacement of extruded disc along the body of fifth lumbar vertebra. She was treated according to treatment explained in Ayurveda. She received oral medications, application of medicated oils, fomentation and medicated enema (Basti). After treatment of seven and half months, the patient showed good remission in pain, stiffness and radiculopathy. ODI score reduced to 9% that indicates minimal disability. Follow up MRI showed non significant compression of the nerve root and gross reduction in the inferior displacement of extruded disc. Acute IVDP can be successfully conserved using Ayurveda treatment. The Panchakarma procedures and medicines used in the treatment need further evaluation.

Spindle-cell sarcoma of the heart: A case report of a rare cause of cardiac mass.

Spindle cell sarcoma of heart are the least reported primary cardiac tumours. We present a case of a 60-year-old man reported to us following successful resuscitation after cardiac arrest. This patient presented with symptoms of dyspnoea on exertion. The echocardiography showed features of cardiac tamponade. CT scan chest+ Abdomen + Pelvis confirmed echocardiography findings, and showed significant pericardial effusion with early cardiac tamponade. Patient continued to suffer dyspnoea even after pericardiocentesis and was unstable in the intensive care unit, hence he was shifted to operating room for re-exploration. The mass was excised in a piecemeal without instituting cardiopulmonary bypass. The total weight of the mass was approximately 500gms. The macroscopic examination of the specimen revealed a cystic mass with solid grey brown tissue. Following surgical debulking, chest X -ray in Intensive Care Unit showed improvement. The patient visited the outpatient clinic after 15 days of surgery. 2-D echocardiography revealed minimal pericardial effusion and patient was comfortable.

Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection and hospitalization in infants. Nirsevimab is a monoclonal antibody to the RSV fusion protein that has an extended half-life. The efficacy and safety of nirsevimab in healthy late-preterm and term infants are uncertain. METHODS: We randomly assigned, in a 2:1 ratio, infants who had been born at a gestational age of at least 35 weeks to receive a single intramuscular injection of nirsevimab or placebo before the start of an RSV season. The primary efficacy end point was medically attended RSV-associated lower respiratory tract infection through 150 days after the injection. The secondary efficacy end point was hospitalization for RSV-associated lower respiratory tract infection through 150 days after the injection. RESULTS: A total of 1490 infants underwent randomization: 994 were assigned to the nirsevimab group and 496 to the placebo group. Medically attended RSV-associated lower respiratory tract infection occurred in 12 infants (1.2%) in the nirsevimab group and in 25 infants (5.0%) in the placebo group; these findings correspond to an efficacy of 74.5% (95% confidence interval [CI], 49.6 to 87.1; P<0.001) for nirsevimab. Hospitalization for RSV-associated lower respiratory tract infection occurred in 6 infants (0.6%) in the nirsevimab group and in 8 infants (1.6%) in the placebo group (efficacy, 62.1%; 95% CI, -8.6 to 86.8; P = 0.07). Among infants with data available to day 361, antidrug antibodies after baseline were detected in 58 of 951 (6.1%) in the nirsevimab group and in 5 of 473 (1.1%) in the placebo group. Serious adverse events were reported in 67 of 987 infants (6.8%) who received nirsevimab and in 36 of 491 infants (7.3%) who received placebo. CONCLUSIONS: A single injection of nirsevimab administered before the RSV season protected healthy late-preterm and term infants from medically attended RSV-associated lower respiratory tract infection. (Funded by MedImmune/AstraZeneca and Sanofi; MELODY ClinicalTrials.gov number, NCT03979313.).

Esthetics using monolithic zirconia and hand-layered zirconia fixed partial denture.

Edentulism and dental disease have a major effect on the standard of lifetime of patients. Fixed partial dentures have become the treatment of choice for many people for the replacement of edentulous space in the oral cavity. Therefore, it is of interest to correlate and compare the esthetics between monolithic zirconia and hand layered zirconia among fixed partial dentures in Saveetha Dental College. 100 patients who monolithic zirconia and hand layered zirconia had fixed partial dentures were included within the study. Pink and white esthetic scores were evaluated. Data collected were entered in SPSS and analyzed through Chi square test. It was observed that hand layered zirconia have better white esthetic score (p<0.000) and pink esthetic score (p<0.003) when compared to monolithic zirconia fixed partial dentures, which were statistically significant. It was concluded that hand layered zirconia fixed partial dentures have better esthetics than monolithic zirconia fixed partial dentures.

The association of fingerprint patterns with oral potentially malignant disorders and oral cancer: A dermatoglyphic study.

Background: Dermatoglyphics play an important role in the identification of a person as well as identifying a person with a genetic abnormality. Hence, the present study was conducted with an aim to explore the association between the fingerprint patterns and oral potentially malignant disorders, oral squamous cell carcinoma (OSCC), individuals with habit and without lesion and the control group. Materials and Methods: A cross-sectional study comprising of 100 individuals divided into 5 groups with 20 individuals in each group based on their habit and the presence of oral lesions. Group 1 included individuals with oral leukoplakia (OL), Group 2 included individuals with oral submucous fibrosis (OSMF), Group 3 included individuals who had OSCC, Group 4 individuals had tobacco habits but without lesion and Group 5 comprised of control individuals. The fingerprints of all the study subjects were recorded using a standard ink method. They were analyzed qualitatively and quantitively. Results: The present study showed a predominance of that loop patterns in all the groups. The frequency of the whorled pattern was higher in subjects with OSMF as compared to OL and OSCC. The arch pattern was comparatively lesser in subjects with OL than OSMF subjects. The right-left comparison of the fingerprint patterns in all the five groups, except Group 4, showed a significant association and correlation. The Group 4 individuals were showing the least correlation between sides. Conclusion: The study concluded that dermatoglyphics can be used as a potential marker to identify the subjects with risk for potentially malignant oral disorders and oral cancers.

Computerized Cognitive Training (CCT) versus Yoga Impact on 12 Month Post Intervention Cognitive Outcome in Individuals with Mild Cognitive Impairment.

There is currently limited and mixed evidence for the cognitive benefits of Computerized Cognitive Training (CCT) and yoga in persons with Mild Cognitive Impairment (pwMCI). The objective of this study was to investigate the benefit of computerized cognitive training (CCT) vs. physical (yoga) intervention on cognitive abilities. Participants in this study were part of the larger Mayo Clinic's Healthy Action to Benefit Independence and Thinking (HABIT) program comparative effectiveness trial. The HABIT program is designed for pwMCI and their care partner and consists of five behavioral interventions: CCT, Memory Support System-Calendar (MSS-Calendar), wellness education, support groups, and yoga. The subtractive study design randomly withheld one of the interventions for a total of five study arms. Longitudinal mixed-effects regression models were used to investigate the hypothesis that CCT and yoga has a greater positive impact on psychomotor and basic attention abilities at 12 months post-intervention as compared to the other HABIT interventions. Findings showed CCT had a positive impact compared to yoga on the Cogstate psychomotor/attention composite at 12 months post-intervention (ES = 0.54; unadjusted p value = 0.007, adjusted p value = 0.021). The impact of yoga or combining CCT with yoga did not show statistically significant improvement. Continued CCT practice at home showed further benefit on psychomotor/attention at 12 months post-intervention. There was no significant benefit of CCT or yoga on Cogstate learning/working memory composite.

Comparative Effects of Physical Exercise and Other Behavioral Interventions on Functional Status Outcomes in Mild Cognitive Impairment.

OBJECTIVES: Lifestyle modifications for those with mild cognitive impairment (MCI) may promote functional stability, lesson disease severity, and improve well-being outcomes such as quality of life. The current analysis of our larger comparative effectiveness study evaluated which specific combinations of lifestyle modifications offered as part of the Mayo Clinic Healthy Action to Benefit Independence in Thinking (HABIT) program contributed to the least functional decline in people with MCI (pwMCI) over 18 months. METHODS: We undertook to compare evidence-based interventions with one another rather than to a no-treatment control group. The interventions were five behavioral treatments: computerized cognitive training (CCT), yoga, Memory Support System (MSS) training, peer support group (SG), and wellness education (WE), each delivered to both pwMCI and care partners, in a group-based program. To compare interventions, we randomly withheld one of the five HABIT® interventions in each of the group sessions. We conducted 24 group sessions with between 8 and 20 pwMCI-partner dyads in a session. RESULTS: Withholding yoga led to the greatest declines in functional ability as measured by the Functional Activities Questionnaire and Clinical Dementia Rating. In addition, memory compensation (calendar) training and cognitive exercise appeared to have associations (moderate effect sizes) with better functional outcomes. Withholding SG or WE appeared to have little effect on functioning at 18 months. CONCLUSIONS: Overall, these results add to the growing literature that physical exercise can play a significant and lasting role in modifying outcomes in a host of medical conditions, including neurodegenerative diseases.