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Background: Depression is a psychiatric illness that affects the overall life quality of an individual. In depression along with other symptoms, one of the features affecting the personal life of individuals is loss of libido which is influenced by the hypothalamic-pituitary-testicular axis. This study was aimed to determine the serum levels of Follicular stimulating hormone (FSH) and Luteinizing hormone (LH) in depressed male patients. Methodology: This comparative cross sectional study was done at Islamic International Medical College and Armed Forces Institute of Mental Health, Military Hospital Rawalpindi after being approved by ethical review committee. After informed consent, 96 male individuals having 18 – 60 years of age participated in the current study. Participants were segregated into groups A and B. Gender and age-matched healthy subjects in a quantity of 24 were taken in group A whereas group B consisted of 72 male depressed patients. Serum gonadotropins levels of both groups were compared by using an independent student t-test in SPSS 21. Results: Serum FSH (2.66 ± 0.34 mIU/ml) and LH (2.67 ±0.18 mIU/ml) levels of Group A have shown no significant difference as compared to serum FSH (3.32 ± 0.43 mIU/ml) and LH (3.12 ± 0.19 mIU/ml) levels of Group B. Conclusion: It is concluded from the study that serum FSH and LH levels were not significantly decreased in individuals with depression. Keywords: Depression, Follicle stimulating hormone, Luteinizing hormone

Background: Distal symmetrical polyneuropathy is the most common form of diabetic peripheral neuropathy. Management of peripheral neuropathy through dietary modification and exercise synchronized with circadian rhythm optimizes metabolic parameters, thus restoring nerve functions. Aim: To determine the effect of Synchronized lifestyle modification program (SLP) and Physiotherapy on Michigan neuropathy screening instrument (MNSI), Fasting blood glucose (FBG), HbA1c, Lipid profile and Nerve conduction studies (NCS) in insulin dependent type 2 diabetic neuropathy patients. Study Design: Randomized Controlled Trial Place and Duration: Study was carried out in Physiology department of Islamic International Medical College (Riphah international University) in collaboration with Physiotherapy Department, Railway Hospital, Rawalpindi for a duration of 1 year from October 2020 to October 2021. Methodology: 120 Type 2 diabetic neuropathic patients on insulin were recruited after written informed consent. Baseline evaluation included; assessment of lifestyle pattern, MNSI, FBG, HbA1c, lipid profile and NCS. Patients were divided into Group A (Control) and Group B (Experimental). Group B was subdivided into Group B1 who received SLP, Group B2 received combined SLP and Physiotherapy and Group B3 received Physiotherapy for 12 weeks. Analysis of parameters was done by repeated measure ANOVA. p≤0.05 was considered as significant. Results: MNSI, FBG, HbA1c, serum cholesterol, TGs and LDLs were significantly improved in Group B2. HDL levels and Nerve conduction parameters were not found to be significant. Conclusion: Combined Synchronized Lifestyle Modification Program and Physiotherapy is more effective in type 2 diabetic neuropathy patients on Insulin. Keywords: Synchronized lifestyle modification programme, Diabetic peripheral neuropathy, Distal symmetrical polyneuropathy.

There is an unmet need for COVID-19 prevention in patient populations who have not mounted or are not expected to mount an adequate immune response to complete COVID-19 vaccination. We previously reported that a single subcutaneous 1200 mg dose of the monoclonal antibody combination casirivimab and imdevimab (CAS + IMD) prevented symptomatic SARS-CoV-2 infections by 81·4% in generally healthy household contacts of SARS-CoV-2-infected individuals over a 1-month efficacy assessment period. Here we present additional results, including the 7-month follow-up period (months 2-8), providing additional insights about the potential for efficacy in pre-exposure prophylaxis settings.This was a randomised, double-blind, placebo-controlled trial done in the USA, Romania, and Moldova in 2020-2021, before the emergence of omicron (B.1.1.529) and omicron-lineage variants. Uninfected and unvaccinated household contacts of infected individuals, judged by the investigator to be in good health, were randomly assigned (1:1) to receive 1200 mg CAS + IMD or placebo by subcutaneous injection according to a central randomisation scheme provided by an interactive web response system; randomisation was stratified per site by the test results of a local diagnostic assay for SARS-CoV-2 and age group at baseline. COVID-19 vaccines were prohibited before randomisation, but participants were allowed to receive COVID-19 vaccination during the follow-up period. Participants who developed COVID-19 symptoms during the follow-up period underwent RT-PCR testing. Prespecified endpoints included the proportion of previously uninfected and baseline-seronegative participants (seronegative-modified full analysis set) who had RT-PCR-confirmed COVID-19 in the follow-up period (post-hoc for the timepoints of months 2-5 and 6-8 only) and underwent seroconversion (ie, became seropositive, considered a proxy for any SARS-CoV-2 infections [symptomatic and asymptomatic]; prespecified up to day 57, post-hoc for all timepoints thereafter). We also assessed the incidence of treatment-emergent adverse events. This study is registered with ClinicalTrials.gov, NCT04452318.From July 13, 2020, to Oct 4, 2021, 2317 participants who were RT-PCR-negative for SARS-CoV-2 were randomly assigned, of whom 1683 (841 assigned to CAS + IMD and 842 assigned to placebo) were seronegative at baseline. During the entirety of the 8-month study, CAS + IMD reduced the risk of COVID-19 by 81·2% (nominal plt;0·0001) versus placebo (prespecified analysis). During the 7-month follow-up period, protection was greatest during months 2-5, with a 100% relative risk reduction in COVID-19 (nominal plt;0·0001; post-hoc analysis). Efficacy waned during months 6-8 (post-hoc analysis). Seroconversion occurred in 38 (4·5%) of 841 participants in the CAS + IMD group and in 181 (21·5%) of 842 in the placebo group during the 8-month study (79·0% relative risk reduction vs placebo; nominal plt;0·0001). Six participants in the placebo group were hospitalised due to COVID-19 versus none who received CAS + IMD. Serious treatment-emergent adverse events (including COVID-19) were reported in 24 (1·7%) of 1439 participants receiving CAS + IMD and in 23 (1·6%) of 1428 receiving placebo. Five deaths were reported, none of which were due to COVID-19 or related to the study drugs.CAS + IMD is not authorised in any US region as of Jan 24, 2022, because data show that CAS + IMD is not active against omicron-lineage variants. In this study, done before the emergence of omicron-lineage variants, a single subcutaneous 1200 mg dose of CAS + IMD protected against COVID-19 for up to 5 months of community exposure to susceptible strains of SARS-CoV-2 in the pre-exposure prophylaxis setting, in addition to the post-exposure prophylaxis setting that was previously shown.Regeneron Pharmaceuticals, F Hoffmann-La Roche, US National Institute of Allergy and Infectious Diseases, US National Institutes of Health.

Background: Stress in medical students is a global concern. Stress disturbs the sympathovagal balance and affects heart rate variability, a sign of healthy cardiovascular homeostasis. Various strategies have been used globally to combat stress and its effects. Aim: To determine how blowing balloon exercise modulatesheart rate variability (HRV) in stressed medical students. Methodology: A pretest-posttest quasi-experimental study wasconducted among stressed medical students at Islamic international medical college Rawalpindi Pakistan. Sixty students diagnosed with moderate stress were enrolled based on Depression Anxiety Stress Scale (DASS) Proforma. The study population was selected by simple random sampling via the balloting method among the stressed medical students. Study participants underwent a supervised blowing balloon exercise.Before and after a supervised blowing balloon exercise, the participants' pulmonary function tests, electrocardiograms, and DASS scores were measured. Participants' ECGs and pulmonary function tests were recorded viaPower lab (A.D. Instruments, model yam 4/25T, South Wales, Australia). Results: Blowing balloon exercise resulted in a significant reduction of DASS score (p

Background Individuals who are immunocompromised (IC) are at high risk for severe coronavirus disease 2019 (COVID-19). Methods Post hoc analyses of a double-blind trial conducted prior to Omicron (June 2020–April 2021), in hospitalized patients with COVID-19 assessed viral load, clinical outcomes, and safety of casirivimab plus imdevimab (CAS + IMD) versus placebo in IC versus overall study patients. Results Ninety-nine of 1940 (5.1%) patients were IC. IC versus overall patients were more frequently seronegative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies (68.7% vs 41.2%) and had higher median baseline viral loads (7.21 vs 6.32 log10 copies/mL). On placebo, IC versus overall patients had slower viral load declines. CAS + IMD reduced viral load in IC and overall patients; least-squares mean difference versus placebo in time-weighted average change from baseline viral load at day 7 was −0.69 (95% confidence interval [CI], −1.25 to −.14) log10 copies/mL for IC patients and −0.31 (95% CI, −.42 to −.20) log10 copies/mL for overall patients. For IC patients, the cumulative incidence of death or mechanical ventilation at day 29 was lower with CAS + IMD (11.0%) versus placebo (17.2%), consistent with overall patients (15.7% CAS + IMD vs 18.3% placebo). IC and overall patients receiving CAS + IMD exhibited similar rates of treatment-emergent adverse events (30.4% and 26.6%, respectively), grade ≥2 hypersensitivity or infusion-related reactions (1.4% and 2.5%), and deaths (8.7% and 12.2%). Conclusions IC patients were more likely to exhibit high viral loads and be seronegative at baseline. For susceptible SARS-CoV-2 variants, CAS + IMD reduced viral load and resulted in fewer death or mechanical ventilation events in IC and overall study patients. There were no new safety findings among IC patients. Clinical Trials Registration. NCT04426695.

Epilepsy impacts around 46 million individuals worldwide, with an exacerbated incidence and mortality in lower-income settings Objective: To evaluate the use of EEG in determining the diagnosis of epilepsy, with its particular subtypes. This study also assessed the vital correlation between age and sex with subnormal EEG findings. Methods: It is a cross-sectional study conducted at MMI Pead’s Memon Hospital, Karachi, from January 2020 to December 2020. Age ranges between 1 month and 18 years. Study evaluated the correlation of EEG findings. The EEG patterns was also assessed. EEG patterns were categorized as normal, abnormal with either background slowing or interictal epileptiform discharges (IED) or both, types of seizure and day of admission when the EEG was performed. Using SPSS latest version, association of age, and sex with abnormal EEGs was determined Results: Two-third of the children reported normal EEG, whereas abnormal background findings were observed in the remaining one-third. Inter- ictal epileptic discharge was noted on 18 EEG reports. This finding was most frequent in children within the age bracket of 30 months to more than 67 months. A combination of inter-ictal epileptic discharge and abnormal background findings were noted in children older than 49 months. However, hypsarrhythmia was noted in 2 subjects, both under 30 months of age. With regards to diagnosis, majority of the children categorized as having generalized epilepsy were over 67 months of age. Focal epilepsy was the second most frequent diagnosis, with majority under 30 months of age. On the association of EEG findings with sex, out findings were insignificant. Conclusions: EEG has been determined as the investigation of choice among patients with epilepsy, however it may have certain limitations in providing an accurate diagnosis, and must not be relied on as the sole determinant of epilepsy.

Background: Prevalence of diabetic neuropathy (DPN) is associated with increased Body Mass Index (BMI). Synchronized lifestyle modification program attempts to synchronize the circadian rhythm of the body through diet and exercise. Objective: Determine the role of Synchronized Lifestyle Modification Program (SLP) and Physiotherapy on fasting blood glucose (FBG), HbA1c, lipid profile, and degree of neuropathy in Type 2 DPN patients on Oral Hypoglycemic Agents (OHAs) having increased BMI. Materials and Methods: Randomized-controlled trial. Evaluation of 120 DPN patients on OHAs included, MNSI, BBS, FBG, HbA1c, Lipid profile and NCS. Participants divided into Group A and B, then divided into A1 and B1, that were overweight and A2 and B2, that were obese. B1 was divided into 1, 2 and 3 and B2 was divided into 4, 5 and 6. Groups 1 and 4 received SLP, Groups 2 and 5 received both SLP and Physiotherapy and Groups 3 and 6 received Physiotherapy for 12 weeks. p≤0.05 was considered significant. Results: MNSI, BBS, FBG, HbA1c, Total Cholesterol, TGs, HDL and LDL were significantly improved in Group 2. Conclusion: Combined Synchronized Lifestyle Modification Program and Physiotherapy is effective in DSPN patients that were overweight. Keywords: Diabetic neuropathy, Synchronized lifestyle modification program, Physiotherapy.

Sub endothelial infarcts leads to non-ST-elevation acute coronary syndrome. Proinflammatory cytokines are raised in serum, the severity of which is a poor prognostic sign. Vitamin D deficiency is prevalent among patients of ACS. Vitamin D has immunomodulatory roles having effects on various aspects of inflammation. A total of 40 patients were divided into experimental (n=20) and control (n=20) groups. Experimental group was given single dose of vitamin D 200,000 IU. They were assessed for baseline C-reactive protein, interleukin-6, tumor necrosis factor-α levels by using sandwich ELISA technique. Four months after intervention resampling was done for the same parameters. Findings were expressed as mean±SD. Independent sample t-test was used to compare effect of vitamin D intervention between control group and intervention group. p-value of ≤0.05 was considered to be significant. The serum C-reactive protein showed significant reduction (p=0.028*) after intervention with vitamin D. Serum interleukin-6 (p=0.848), tumor necrosis factor-α (p=0.20) were decreased non-significantly in experimental as compared to the control group. It was concluded that a single large dose of vitamin D was able to reduce the C-reactive protein in non-ST-elevation acute coronary syndrome patients while non-significant reductions in interleukin-6 and tumor necrosis factor-α were observed.

Introduction: Iron deficiency anemia (IDA) is a significant health problem that is seen in about 40% of children worldwide. It affects a child’s physical and mental development, performance of work and maintenance of their health. Anemia increases the risk of lower respiratory tract infection in children, yet there is not enough evidence that shows the effect of iron deficiency anemia on acute bronchiolitis. Aim: To evaluate the effect of anemia on the severity of acute bronchiolitis in infants. Methodology: A total of 160 infants were included in the study, 100 of whom were having acute bronchiolitis while 60 of them were included as a control group. This contrast analysis was conducted on 3 groups of patients having mild, moderate and severe bronchiolitis. A low haemoglobin level (HB) was below 12 grams/dL. This is considered to be an SD of

Introduction: A condition in which bacteria, viruses or fungi causes hemodynamic changes in the neonates and results in morbidity and mortality is called Neonatal sepsis. The symptoms of neonatal sepsis are nonspecific but some of them are respiratory distress convulsions and temperature dysregulation. Aim: To determine the Neonatal Sepsis and its Bacteriological Profile in a tertiary care hospital: Methodology: All neonates who were suspected of having neonatal sepsis were included in the study. Sepsis was diagnosed through clinical examination. Some clinical features were observed such as fever, lethargy, respiratory distress, jaundice and umbilical infections. Under aseptic conditions, sepsis cultures and screens were sent. Analyzation of data was done using STATA version 11. Chi-square test was used to analyze clinical features. Descriptive statistics was helpful in analyzing bacteriological profile. Results: A total of 2325 neonates were admitted to the hospital. Out of these admissions, 312 were eligible for clinical sepsis. The blood culture positivity rate was 12%. Early onset sepsis was present in 52.2% cases. Culture positive rate in late onset sepsis was increased due to low birth weight, prematurity and parenteral nutrition. Positive screen had sensitivity of 80.1% and negative value of 85.6%. Isolation of gram-negative organisms was more common. Klebsiella pneumoniae and Acinetobacter were the commonly isolates. Conclusion: Neonatal sepsis was associated with low birth weight, low APGAR score, preterm and parenteral nutrition. Klebsiella pneumoniae, Acinetobacter and Staphylococci are the main causative organisms. Gram-negative bacteria were resistant to a wide range of medications.

Objective: To find out the frequency of acute bacterial meningitis (ABM) in children presented with fever and fits aged 6-59 months old. Methodology: This cross-sectional study was done at The Department of Pediatric Medicine, Bolan Medical College/Hospital Quetta from September 2017 to February 2019. A total of 168 children, of either gender, aged between 6-59 months who presented with 1st episode of febrile seizure, and who arrived at emergency department within 12 hours of episode were included. Samples of cerebrospinal fluid (CSF) were obtained. Later, results were analyzed. Results: Of total 168 patients, 111 (66.1%) were male. The mean age was 27.19±13.80 months while the mean weight and frontooccipital circumference (FOC) was found 12.01 ± 2.05 kg and 48.68 ± 2.77 cm correspondingly. Twenty-four (14.3%) patients were diagnosed with ABM. The most common organism found among 11 positive CSF cultures was Streptococcus pneumonia in 6 (54.6%). Conclusion: Every clinician needs to thoroughly evaluate infants or young children after a simple febrile seizure. Lumber puncture can be done in every child if there is any suspicion of meningitis. Keywords: Acute bacterial meningitis, febrile seizures, fever, fits.

Aims: To determine the effect of Ethanolic extract of walnut leaves on lipid profile i.e seum total cholesterol, triglycerides, Low density and high-density lipoprotein. Atherogenic index in Hypercholesterolemic rats was calculated using serum TC/HDL and LDL/HDL ratios. Methodology: Total 30 male Sprague Dawley rats were further divided into three groups (C, HC and EE) comprising ten rats per group. Group 1 (Control group, C). Group 2 (Hypercholesterolemic control, HC) and Group 3 (Ethanolic Extract Group EE) were fed high fat diet for 8 weeks before administration of walnut leaf extract. Ethanolic extract (EE) of walnut leaves was given in a dose of (200mg/kg) through gavage needle once daily for four weeks. Blood Sampling was done at the beginning (Baseline, after week 8 and week 12 to perform lipid profile. Results: Serum mid- cholesterol levels (08 weeks) in HC were significantly raised to 164±7.90 mg/dl (p

Background Immunocompromised (IC) individuals are at high risk for severe COVID-19, with high morbidity and mortality. CAS+IMD is a monoclonal antibody combination that neutralizes susceptible SARS-CoV-2 variants. We examined the natural history of COVID-19 and the efficacy and safety of CAS+IMD in IC patients (pts) hospitalized with COVID-19. Methods In a phase 1/2/3 double-blind trial (NCT04426695) conducted Jun 2020 to Apr 2021, prior to the emergence of Omicron-lineage variants, hospitalized COVID-19 pts were randomized 1:1:1 to a single 2.4 g or 8.0 g dose (combined for analyses) of CAS+IMD or placebo (P). Post hoc analyses assessed change in viral load (VL), clinical outcomes (death or mechanical ventilation [MV]), and safety for IC pts with B-cell deficiency or dysfunction (Table 1) vs all pts. Results 99/1940 (5.1%) treated pts were identified as IC (Table 2). At baseline, IC vs all pts were more likely to be seronegative for SARS-CoV-2 antibodies (68.7% vs 41.2%), and to have higher median VLs (7.21 vs 6.32 log10 copies/mL). Compared to all pts receiving P, IC pts receiving P had slower VL declines. Treatment with CAS+IMD led to a reduction in VL from baseline, with a least-squares mean time-weighted average change in VL difference vs P at Day 7 for IC pts of -0.69 (95% CI: -1.25, -0.41) vs -0.31 (CI: -0.42, -0.20) for all pts; treatment benefit persisted through Day 29 (Fig. 1). Although sample size was small for IC pts, trends in clinical outcomes of death or MV at Day 29 for IC pts (7/64 [11.0%] CAS+IMD vs 6/35 [17.2%] P) were consistent with those in all pts (200/1307 [15.3%] CAS+IMD vs 113/633 [17.9%] P). IC vs all pts treated with CAS+IMD exhibited similar rates of treatment emergent adverse events (TEAEs, 30.4% vs 26.6%), AEs of special interest (grade ≥2 hypersensitivity or infusion-related reactions; 1.4% vs 2.5%), and death (8.7% vs 12.2%; Table 3). IC and all pts exhibited fewer TEAEs with CAS+IMD vs P. Conclusion IC vs all pts hospitalized with COVID-19 were more likely to exhibit high VLs at baseline and to be seronegative. In the study, a single dose of CAS+IMD significantly reduced VL in IC pts (for variants circulating at the time, predominantly Alpha) and resulted in fewer events of death or MV. There were no new safety findings in IC pts vs all study pts. Disclosures Selin Somersan-Karakaya, PhD, BARDA: Grant/Research Support|Regeneron Pharmaceuticals, Inc.: Employement|Regeneron Pharmaceuticals, Inc.: Stocks/Bonds Eleftherios Mylonakis, MD, PhD, Chemic Labs/KODA Therapeutics: Grant/Research Support|Cidara: Grant/Research Support|Leidos Biomedical Research Inc./NCI: Grant/Research Support|NIH/NIAID, NIH/NIGMS: Grant/Research Support|Pfizer: Grant/Research Support|Regeneron Pharmaceuticals, Inc.: Grant/Research Support|SciClone Pharmaceuticals: Grant/Research Support Ernesto Oviedo-Orta, MD, PhD, MBA, Regeneron Pharmaceuticals, Inc.: Employement|Regeneron Pharmaceuticals, Inc.: Stocks/Bonds Meagan P. O’Brien, MD, Regeneron Pharmaceuticals, Inc.: Employement|Regeneron Pharmaceuticals, Inc.: Stocks/Bonds Veronica Mas Casullo, MD, Regeneron Pharmaceuticals, Inc.: Employement|Regeneron Pharmaceuticals, Inc.: Stocks/Bonds Jenni Mou, PhD, Regeneron Pharmaceuticals, Inc.: Employement|Regeneron Pharmaceuticals, Inc.: Stocks/Bonds Jing Xiao, PhD, Regeneron Pharmaceuticals, Inc.: Stocks/Bonds Rafia Bhore, PhD, Regeneron Pharmaceuticals, Inc.: Employement|Regeneron Pharmaceuticals, Inc.: Stocks/Bonds Adnan Mahmood, MD, Regeneron Pharmaceuticals, Inc.: Employement|Regeneron Pharmaceuticals, Inc.: Stocks/Bonds Andrea T. Hooper, PhD, Regeneron Pharmaceuticals, Inc.: Employement|Regeneron Pharmaceuticals, Inc.: Stocks/Bonds Mohamed Hussein, PhD, Regeneron Pharmaceuticals, Inc.: Employement|Regeneron Pharmaceuticals, Inc.: Stocks/Bonds Shazia Ali, PharmD, Regeneron Pharmaceuticals, Inc.: Employement|Regeneron Pharmaceuticals, Inc.: Stocks/Bonds Eduardo Forleo-Neto, MD, Regeneron Pharmaceuticals, Inc.: Employement|Regeneron Pharmaceuticals, Inc.: Stocks/Bonds Gary A. Herman, MD, Regeneron Pharmaceuticals, Inc.: Employement|Regeneron Pharmaceuticals, Inc.: Stocks/Bonds Boaz Hirshberg, MD, MBA, Regeneron Pharmaceuticals, Inc.: Employement|Regeneron Pharmaceuticals, Inc.: Stocks/Bonds David M. Weinreich, MD, Regeneron Pharmaceuticals, Inc.: Employement|Regeneron Pharmaceuticals, Inc.: Stocks/Bonds.

Discriminating between temporal features in sensory stimuli is critical to complex behavior and decision making. However, how sensory cortical circuit mechanisms contribute to discrimination between subsecond temporal components in sensory events is unclear. To elucidate the mechanistic underpinnings of timing in primary visual cortex (V1), we recorded from V1 using 2-photon calcium imaging in awake-behaving mice performing a go/no-go discrimination timing task, which was composed of patterns of subsecond audio-visual stimuli. In both conditions, activity during the early stimulus period was temporally coordinated with the preferred stimulus. However, while network activity increased in the preferred condition, network activity was increasingly suppressed in the nonpreferred condition over the stimulus period. Our results demonstrate that discrimination between subsecond intervals that are contained in rhythmic patterns can be accomplished by local networks and suggest the contribution of neural resonance as a mechanism.

Background Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads. Methods In this ongoing, double-blind, phase 1–3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody–positive or serum antibody–negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19–related medically attended visit through day 29. Safety was assessed in all patients. Results Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was −0.56 log10 copies per milliliter (95% confidence interval [CI], −1.02 to −0.11) among patients who were serum antibody–negative at baseline and −0.41 log10 copies per milliliter (95% CI, −0.71 to −0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody–negative at baseline, the corresponding percentages were 15% and 6% (difference, −9 percentage points; 95% CI, −29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group. Conclusions In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.)

Patients with refractory hypercholesterolemia, who have high low-density lipoprotein (LDL) cholesterol levels despite treatment with lipid-lowering therapies at maximum tolerated doses, have an increased risk of atherosclerosis. In such patients, the efficacy and safety of subcutaneous and intravenous evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, are not known.In this double-blind, placebo-controlled, phase 2 trial, we enrolled patients with or without heterozygous familial hypercholesterolemia who had refractory hypercholesterolemia, with a screening LDL cholesterol level of 70 mg per deciliter or higher with atherosclerosis or of 100 mg per deciliter or higher without atherosclerosis. Patients were randomly assigned to receive subcutaneous or intravenous evinacumab or placebo. The primary end point was the percent change from baseline in the LDL cholesterol level at week 16 with evinacumab as compared with placebo.In total, 272 patients were randomly assigned to the following groups: subcutaneous evinacumab at a dose of 450 mg weekly (40 patients), 300 mg weekly (43 patients), or 300 mg every 2 weeks (39 patients) or placebo (41 patients); or intravenous evinacumab at a dose of 15 mg per kilogram of body weight every 4 weeks (39 patients) or 5 mg per kilogram every 4 weeks (36 patients) or placebo (34 patients). At week 16, the differences in the least-squares mean change from baseline in the LDL cholesterol level between the groups assigned to receive subcutaneous evinacumab at a dose of 450 mg weekly, 300 mg weekly, and 300 mg every 2 weeks and the placebo group were -56.0, -52.9, and -38.5 percentage points, respectively (P0.001 for all comparisons). The differences between the groups assigned to receive intravenous evinacumab at a dose of 15 mg per kilogram and 5 mg per kilogram and the placebo group were -50.5 percentage points (P0.001) and -24.2 percentage points, respectively. The incidence of serious adverse events during the treatment period ranged from 3 to 16% across trial groups.In patients with refractory hypercholesterolemia, the use of evinacumab significantly reduced the LDL cholesterol level, by more than 50% at the maximum dose. (Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03175367.).

Evinacumab, an angiopoietin-like protein 3 monoclonal antibody, reduced low-density lipoprotein cholesterol (LDL-C) significantly in a Phase 2 study of patients with homozygous familial hypercholesterolemia. In this double-blind, placebo-controlled Phase 1 study, we compared safety, tolerability, pharmacokinetics, and pharmacodynamics of evinacumab between healthy Japanese and Caucasian adults.Subjects with LDL-C ≥2.6 and4.1 mmol/L were enrolled to one of four dose cohorts: evinacumab subcutaneous (SC) 300 mg single dose, SC 300 mg once weekly for eight doses, intravenous (IV) 5 mg/kg, or IV 15 mg/kg once every 4 weeks for two doses. Each cohort comprised 24 subjects (12 Japanese; 12 Caucasian), randomized (3:1) to receive evinacumab or placebo within each ethnic group with a 24-week follow-up.The safety profile of evinacumab (IV and SC) in both ethnicities was comparable with placebo, with no serious or severe treatment-emergent adverse events. Pharmacokinetic profiles were comparable between Japanese and Caucasian subjects across IV and SC groups. Mean calculated LDL-C decreased from baseline with both IV doses, beginning on day 3 up to week 8. Triglyceride changes observed with evinacumab IV were rapid (seen by day 2) and sustained up to week 8. Evinacumab SC doses also reduced LDL-C and triglyceride levels, although lower doses induced smaller changes. Evinacumab (IV and SC) reduced other lipids, including apolipoprotein B, versus placebo.In both ethnicities, evinacumab (IV and SC) was generally well tolerated, exhibiting comparable pharmacokinetic profiles. Dose-related reductions in LDL-C and triglycerides were observed with evinacumab in both ethnic groups.

Objectives: Self-directed learning is an active learning strategy in which students are accountable for their own learning by taking initiative. It has been supplemented with other instructional strategies like interactive lecturing, in order to enhance student’s learning. The current study was carried out to determine the effect of supplementing self-directed learning with video clipping on students learning outcome. Study Design: Randomized Control study. Setting: Islamic International Medical College. Period: For one day at 16th September 2016. Material & Methods: This study was conducted among seventy six students of Islamic International Medical College. Students participated in a quiz competition whose syllabus of content and suggested reading materials were communicated to the students three week prior to the competition date. The registered students were than randomly divided into two Groups each comprising of 38 students. Self-directed learning of one group was supplemented with a video while the other group did not watch the video. Learning outcome of both groups was assessed by an MCQ exam. Results: The overall score of Self-directed learning group supplemented with a video was 65.17(7.68) while the score of self-directed learning group was 59.54 (8.54). A significant difference were found among the score of both groups (p = .042). Conclusion: Self-directed learning when supplemented with the instructional strategy of video clipping leads to the improvement in the learning outcome of the students.

Introduction Balochistan is the largest of Pakistan's four provinces, yet it is also the poorest and most impoverished, particularly in terms of neonatal healthcare. In order to build and tailor strategies to improve neonatal outcomes, it is necessary to identify barriers and facilitators for interventions. Therefore, we conducted this study to provide an overview of neonatal healthcare quality and assess the structural capacity for the improvement and further development of neonatal healthcare facilities in Balochistan. Methods A descriptive, observational, cross-sectional study was conducted in Balochistan, a province of Pakistan. The survey was designed to assess the level of staffing and facilities in the neonatal health care units. Data were gathered through trained staff either by in-person visits to the facility or via telephone. Results A total of 177 facilities were assessed in 25 districts of Balochistan. A majority (88.7%) of the facilities were from the public sector. Birth and neonatal care services were provided at only 63 (36%) of the assessed facilities and only three had newborn intensive care units (NICUs) with a 1:5 staff: patient ratio. Unfortunately, all NICUs lacked the basic advanced facilities. None of the hospitals had an infection control policy or staff nor any training program for doctors. Conclusion In conclusion, healthcare facilities to manage neonatal patients requiring hospital care are extremely limited in Balochistan and the ones that are available have very limited resources. To improve the healthcare system in Balochistan, all stakeholders should be involved in the planning, decision-making, and implementation of healthcare programs at all levels to ensure sustainability and efficiency.

Breast cancer (BC) is a global public health burden, constituting the highest cancer incidence in women worldwide. Connexins 43 proteins propagate intercellular communication, gap junction intercellular communication (GJIC), remarkably expressed in several tumor types including liver, prostate, and breast. This domain of Cx43 possesses functionally critical sites identical to those involved in gating of channel and phosphorylation sites for various kinases. However, the mechanism by which Cx43 down regulation occurs in breast cancer is far from clear. Several mechanisms like Cx43 promoter hyper-methylation or a cancer-specific reduction of Cx43 expression/trafficking by the modulation of various components of the Cx43 life cycle give the idea to be involved in the down regulation of Connexins in mammary glands, but irreversible mutational alterations have not yet been proved to be among them. Summarily, the efficacy or specificity of these drugs can be increased by a combinatory approach considering an effect on both the Connexins and their regulatory molecules. This chapter will summarize the knowledge about the connexins and gap junction activities in breast cancer highlighting the differential expression and functional dynamics of connexins in the pathogenesis of the disease.

JAK/STAT signaling pathway is one of the important regulatory signaling cascades for the myriad of cellular processes initiated by various types of ligands such as growth factors, hormones, and cytokines. The physiological processes regulated by JAK/STAT signaling are immune regulation, cell proliferation, cell survival, apoptosis and hematopoiesis of myeloid and non-myeloid cells. Dysregulation of JAK/STAT signaling is reported in various immunological disorders, hematological and other solid malignancies through various oncogenic activation mutations in receptors, downstream mediators, and associated transcriptional factors such as STATs. STATs typically have a dual role when explored in the context of cancer. While several members of the STAT family are involved in malignancies, however, a few members which include STAT3 and STAT5 are linked to tumor initiation and progression. Other STAT members such as STAT1 and STAT2 are pivotal for antitumor defense and maintenance of an effective and long-term immune response through evolutionarily conserved programs. The effects of JAK/STAT signaling and the persistent activation of STATs in tumor cell survival; proliferation and invasion have made the JAK/STAT pathway an ideal target for drug development and cancer therapy. Therefore, understanding the intricate JAK/STAT signaling in the pathogenesis of solid malignancies needs extensive research. A better understanding of the functionally redundant roles of JAKs and STATs may provide a rationale for improving existing cancer therapies which have deleterious effects on normal cells and to identifying novel targets for therapeutic intervention in solid malignancies.

Background: Homozygous familial hypercholesterolemia (HoFH) is characterized by markedly elevated levels of low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease. This analysis evaluated LDL-C changes in patients with HoFH who sequentially participated in interventional trials with alirocumab (NCT03156621) and evinacumab (NCT03399786). Methods: A total of 25 patients completed the alirocumab trial and entered the evinacumab trial and were randomized to intravenous evinacumab 15 mg/kg (n=16) or placebo (n=9) every 4 weeks. The primary outcome for the evinacumab trial was percent change in LDL-C from baseline to week 24. Results: Baseline characteristics were generally well balanced. Among patients who participated in the alirocumab trial, a reduction in LDL-C of –44.6% and –1.1% was observed at week 24 in patients treated with evinacumab versus placebo, respectively. Overall, mean total reductions in LDL-C (Figure) and apolipoprotein B of -62.9% and -54.9%, respectively, were observed in patients treated with the combination of alirocumab and evinacumab; and triglycerides were lowered by -54.5%. The absolute LDL-C reduction from their baseline in patients treated with the combination of alirocumab and evinacumab was -216.3 mg/dL. No new safety signals were observed when treated with alirocumab and evinacumab, and were consistent with the respective trial results. Conclusions: Combination therapy with alirocumab and evinacumab reduced LDL-C by more than 60% in patients with HoFH and was well tolerated.

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic lipid disorder characterized by marked elevations in LDL-C and premature atherosclerotic cardiovascular disease (ASCVD). EU guidelines recommend LDL-C treatment goals of Methods: This post-hoc analysis assessed the long-term effect of EVIN on LDL-C goal attainment in pts with HoFH who participated in the subsequent 24-week open-label treatment period (OLTP) of the pivotal Phase 3 study. All pts received intravenous EVIN 15 mg/kg every 4 weeks. Efficacy by background lipid lowering medication (LLM) subgroups and the effect of EVIN on eligibility for apheresis were also assessed. Results: In total, 65 pts entered the OLTP and 64 pts (98.5%) received OL EVIN. Overall, 50.0% achieved LDL-C Conclusions: EVIN enabled 31.7% of all pts to achieve LDL-C

ObjectiveThe study was aimed to evaluate the levels of NT-proBNP in mild, moderate and frequent Premature Ventricular Contractions (PVCs) burden in patients with preserved left ventricular function.Material and methodsA case control study was conducted in Islamic International Medical College (IIMC) in collaboration with Armed Forces Institute of Cardiology (AFIC) after approval from ethical review committee (ERC) of Riphah University (Ref #Riphah/IIMC/ERC/17/0230). The study comprised of 160 participants which included 120 Premature ventricular contractions (PVCs) patients with 40 patients in each group of mild (20%) PVCs burden. 40 healthy subjects with no PVCs were taken as a control group. NT-proBNP levels were measured in all groups and statistical analysis was done by applying ANOVA and Pearson correlation test to evaluate its association with PVCs burdenResultsNT-proBNP levels were found to be raised in all PVCs burden of 20% as compare to control group with p value of 0.039*, 0.02* and 0.009* respectively. p value of ≤0.05 was considered significant. PVCs patients show higher NT-proBNP levels as compared to control group whether they were symptomatic or asymptomatic with p-value of 0.002* and 0.04*.Conclusion It is concluded that NT-proBNP levels are raised in patients of PVCs. This finding can be helpful for diagnostic and screening purposes of PVCs in a population.

BackgroundContinued SARS-CoV-2 infections and COVID-19-related hospitalizations highlight the need for effective anti-viral treatments in the outpatient setting. In a descriptive interim analysis of the phase 1/2 portion of a double-blind phase 1/2/3 trial in COVID-19 outpatients conducted between June 16, 2020 and September 4, 2020, REGEN-COV® (casirivimab plus imdevimab) antibody combination reduced SARS-CoV-2 viral load versus placebo.MethodsThis final phase 1/2 analysis comprises 799 outpatients, including 275 from the previous descriptive analysis (group-1) and 524 from phase 2 (group-2). Patients were randomized (1:1:1) to placebo, REGEN-COV 2400mg, or REGEN-COV 8000mg. Prespecified hierarchical analyses of virologic endpoints were performed in group-2. The proportion of patients with ≥1 COVID-19–related medically attended visit (MAV) through day 29 was assessed in group-1+2. Efficacy was assessed in patients confirmed SARS-CoV-2–positive by baseline nasopharyngeal RT-qPCR. Safety was assessed in all treated patients.ResultsData from 799 outpatients enrolled from June 16, 2020 to September 23, 2020 are reported. Time-weighted average daily reduction in viral load through day 7 was significantly greater in the REGEN-COV combined 2400mg+8000mg group versus placebo in patients with baseline viral load >107 copies/mL (prespecified primary endpoint): -0.68 log10 copies/ml (95% CI, -0.94 to -0.41; PPP=.0003) log10 copies/mL in serum antibody–negative patients and in the overall population, respectively. REGEN-COV reduced the proportion of patients with ≥1 COVID-19–related MAV versus placebo (2.8% [12/434] REGEN-COV combined dose group versus 6.5% [15/231] placebo; P=.024; relative risk reduction [RRR]=57%); in patients with ≥1 risk factor for hospitalization, the treatment effect was more pronounced (RRR=71%). Adverse events were similar across groups.ConclusionsIn COVID-19 outpatients enrolled prior to the widespread circulation of delta and omicron variants, treatment with REGEN-COV significantly reduced viral load and COVID-19–related MAVs.

BackgroundREGEN-COV antibody cocktail (casirivimab with imdevimab) rapidly reduced viral load and decreased medically-attended visits in the phase 1/2 portion of this trial; REGEN-COV, retains activity in vitro against emerging SARS-CoV-2 variants of concern.MethodsThe phase 3 portion of this adaptive, randomized, master protocol, included 4,057 Covid-19 outpatients with one or more risk factors for severe disease. Patients were randomized to a single treatment of intravenous placebo, or various doses of REGEN-COV, and followed for 28 days. The prespecified hierarchical analysis first compared REGEN-COV 2400mg dose vs concurrent placebo, then compared the 1200mg dose vs concurrent placebo, for endpoints assessing risk of hospitalization or death, and time to symptom resolution. Safety was evaluated in all treated patients.ResultsBoth REGEN-COV 2400mg and 1200mg significantly reduced Covid-19-related hospitalization or all-cause death compared to placebo (71.3% reduction [1.3% vs 4.6%; pConclusionsTreatment with REGEN-COV was well-tolerated and significantly reduced Covid-19-related hospitalization or all-cause death, rapidly resolved symptoms, and reduced viral load.(Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.)

The advancement in the processing speeds of computing machines has facilitated the development of complex physiologically based pharmacokinetic (PBPK) models. These PBPK models can incorporate disease-specific data and could be used to predict pharmacokinetics (PK) of administered drugs in different chronic conditions. The present study aimed to develop and evaluate PBPK drug-disease models for captopril after incorporating relevant pathophysiological changes occurring in adult chronic kidney disease (CKD) and chronic heart failure (CHF) populations. The population-based PBPK simulator Simcyp was used as a modeling and simulation platform. The visual predictive checks and mean observed/predicted ratios (ratio(Obs/pred)) of the PK parameters were used for model evaluation. The developed disease models were successful in predicting captopril PK in all three stages of CKD (mild, moderate, and severe) and CHF, as the observed and predicted PK profiles and the ratio(obs/pred) for the PK parameters were in close agreement. The developed captopril PBPK models can assist in tailoring captopril dosages in patients with different disease severity (CKD and CHF).

SummaryMonoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. As rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of minor virus variants in SARS-COV-2 isolates found in COVID-19 patients or identified from preclinical in vitro and in vivo studies. This study demonstrates that a combination of non-competing antibodies, REGEN-COV, not only provides full coverage against current variants of concern/interest but also protects against emergence of new such variants and their potential seeding into the population in a clinical setting.

ObjectiveThe study was aimed to evaluate the levels of NT-proBNP in mild, moderate and frequent ventricular ectopic burden in patients with preserved left ventricular function.Material and methodsA case control study was conducted in Islamic International Medical College (IIMC) in collaboration with Armed Forces Institute of Cardiology (AFIC) after approval from ethical review committee (ERC) of Riphah University (Ref #Riphah/IIMC/ERC/17/0230). It comprised of 120 Premature ventricular contractions (PVCs) patients with 40 patients in each group of mild (20%) PVCs burden. 40 healthy subjects with no PVCs were taken as a control group. NT-proBNP levels were measured in all groups and statistical analysis was done by applying ANOVA and Pearson correlation tests to evaluate its association with PVCs burdenResultsNT-proBNP levels were found to be raised in all PVCs burden of 20% as compare to control group with p value of 0.039, 0.02 and 0.009 respectively. p value of ≤0.05 was considered significant. Symptomatic and asymptomatic patients show higher NT-proBNP levels as compared to control group with p-value of .002 and .04.Conclusion It is concluded that NT-proBNP levels are raised in patients of PVCs. This finding can be helpful for diagnostic purposes of PVCs.

Cancer is the second biggest killer worldwide. It has been estimated that specific lifestyle and dietary measures can prevent 30–40% of all cancers. Consumption of nutrient sparse foods, such as refined flour products and concentrated sugars, consumption of red meat, low fibre intake, and disproportion of omega 3 and omega 6 fatty acids, contributes to cancer risks. Microbiological and chemical food contaminants as well as conventional and industrial food processing methods may further increase the carcinogenicity of diets while protective agents in a cancer prevention diet include folic acid, selenium, vitamin D, vitamin B-12, chlorophyll, and antioxidants such as the carotenoids, kryptoxanthin, lycopene, and lutein. Diet can also influence the gut microbes that may have positive or adverse effects on cancer risk. The authors summarize cancer prevention by functional foods and discuss the role of different dietary factors such as promoter or inhibitor in pathogenesis of different subtypes of cancer worldwide.