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Rimple Jeet Kaur,1 Jaykaran Charan,2 Siddhartha Dutta,2 Paras Sharma,3 Pankaj Bhardwaj,4 Praveen Sharma,5 Halyna Lugova,6 Ambigga Krishnapillai,7 Salequl Islam,8 Mainul Haque,9 Sanjeev Misra10 1Department of Pharmacology, Dr. S.N Medical College, Jodhpur, Rajasthan, India; 2Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India; 3Department of Pharmacognosy, BVM College of Pharmacy, Gwalior, India; 4Department of Community and Family Medicine, All India Institute of Medical Sciences (AIIMS), Jodhpur, Rajasthan, India; 5Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Jodhpur, Rajasthan, India; 6The Unit of Community Medicine, Faculty of Medicine and Defence Health, National Defence University of Malaysia, Kuala Lumpur; 7Family Medicine, Faculty of Medicine and Defence Health, National Defence University of Malaysia; 8Department of Microbiology, Jahangirnagar University, Savar, Dhaka 1342, Bangladesh; 9The Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan, Nasional Malaysia (National Defence University of Malaysia), Kuala Lumpur, Malaysia; 10All India Institute of Medical Sciences (AIIMS), Jodhpur, Rajasthan, IndiaCorrespondence: Mainul HaqueThe Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan, Nasional Malaysia (National Defence University of Malaysia), Kem Perdana Sungai Besi, Kuala Lumpur 57000, MalaysiaTel +60109265543Email runurono@gmail.comBackground: COVID-19 caused by SARS-CoV-2 virus emerged as an unprecedented challenge to discover effective drugs for its prevention and cure. Hyperinflammation-induced lung damage is one of the poor prognostic indicators causing a higher rate of morbidity and mortality of COVID-19 patients. Favipiravir, an antiviral drug, is being used for COVID-19 treatment, and we currently have limited information regarding its efficacy and safety. Thus, the present study was undertaken to evaluate the adverse drug events (ADEs) reported in the WHO pharmacovigilance database.Methods: This study analyzed all suspected ADEs related to favipiravir reported from 2015. The reports were analyzed based on age, gender, and seriousness of ADEs at the System Organ Classification (SOC) level and the individual Preferred Term (PT) level.Results: This study is based on 194 ADEs reported from 93 patients. Most frequent ADEs suspected to be caused by the favipiravir included increased hepatic enzymes, nausea and vomiting, tachycardia, and diarrhea. Severe and fatal ADEs occurred more frequently in men and those over the age of 64 years. Blood and lymphatic disorders, cardiac disorders, hepatobiliary disorders, injury poisoning, and procedural complications were more common manifestations of severe ADEs.Conclusion: This study revealed that favipiravir appears to be a relatively safe drug. An undiscovered anti-inflammatory activity of favipiravir may explain the improvement in critically ill patients and reduce inflammatory markers. Currently, the data is based on very few patients. A more detailed assessment of the uncommon ADEs needs to be analyzed when more information will be available.Keywords: favipiravir, usage, SARS-Cov-2, scrutiny, assumed, adverse drug events, described, World Health Organization, record

Siddhartha Dutta,1 Rimple Jeet Kaur,2 Pankaj Bhardwaj,3 Jaykaran Charan,1 Sunil Kumar Singh Bist,4 Mohan Dan Detha,5 Tanuj Kanchan,6 Praveen Sharma,7 Sanjeev Misra8 1Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India; 2Department of Pharmacology, S. N. Medical College, Jodhpur, Rajasthan, India; 3Department of Community and Family Medicine, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India; 4Medical and Health, Jodhpur Zone and COVID 19 Nodal Officer, Jodhpur District, Rajasthan, India; 5Block CMHO, Luni, Jodhpur and Medical Officer in Charge, COVID Care Centre, Boranada, Jodhpur, Rajasthan, India; 6Department of Forensic Medicine, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India; 7Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India; 8All India Institute of Medical Sciences, Jodhpur, Rajasthan, IndiaCorrespondence: Jaykaran CharanDepartment of Pharmacology, AIIMS, Jodhpur, Rajasthan, IndiaTel +919825219196Email dr.jaykaran78@gmail.comIntroduction: The COVID-19 pandemic has brought the entire world to a standstill. The disease is rapidly transmitting in the community. Imposed lockdowns due to the COVID-19 pandemic have effectively delayed the transmission in the community but the transmissibility in households needs to be explored. The aim of this study was to estimate the household transmission of COVID-19 and assess the factors affecting transmission.Patients and Methods: A cross-sectional study where the data were collected from a single isolation center, was conducted. Patients were contacted by phone. Information regarding number of COVID-19-positive cases in the family, their demographic details, along with number of rooms in their household was collected.Results: A total of 369 families of COVID-19-positive patients were contacted. Nineteen families with a single member were excluded. Out of 350 families with a total 2126 members, 480 (22.5%) were COVID-19 positive. Mean age was 30.12 years (± 14.39) and majority of them were males (68.9%). Majority of the cases (67.3%) were in the age group (19– 49 years). Mean rooms per person were 0.51± 0.20 (0.14 to 1.50). Mild negative correlation was seen between number of positive COVID-19 cases and rooms per person (r= − 0.138, p=0.008) while moderate negative correlation with number of family members and proportion of family members being COVID-19 positive (r= − 0.542, p≤ 0.0001).Conclusion: One in four family members got infected with COVID-19, they were majority males and in the working age group. Negative correlation of positive cases with number of family members and mild negative correlation between rooms per person and proportion of family member affected indicates some other factors may be responsible for household transmission than these factors.Keywords: COVID-19, household transmission, SARS-CoV-2, coronavirus, isolation

Context: Guidelines suggest performing urine steroid profiling in patients with indeterminate adrenal tumors to make a noninvasive diagnosis of adrenocortical carcinoma (ACC). However, urine steroid profiling is not widely available., Objective: To determine the accuracy of clinically available serum 11-deoxycortisol, 17OH-progesterone, and 17OH-pregnenolone in diagnosing ACC., Methods: We conducted a prospective single-center cohort study of patients with adrenal masses evaluated between 2015-2023. Serum was analyzed by liquid chromatography-mass spectrometry for 17OH-pregnenolone, 17OH-progesterone, 11-deoxycortisol. Reference standard for adrenal mass included histopathology, imaging characteristics, imaging follow up of 2 years, or clinical follow up of 5 years. Localized Generalized Matrix Learning Vector Quantization (LGMLVQ) analysis was used to develop serum steroid score and assessed with area under receiver operating curve (AUROC)., Results: Of 263 patients with adrenal masses, 44 (16.7%) were diagnosed with ACC, 161 (61%) with adrenocortical adenomas (ACAs), 27 (10%) with other adrenal malignancies, and 31 (12%) with other. Hounsfield unit (HU) ≥ 20 was demonstrated in all ACCs, in all but one other adrenal malignancy, and in 58 (31%) ACAs. All 3 steroids were higher in patients with ACCs vs non-ACCs, including when comparing ACCs with functioning ACAs, and with ACAs with HU ≥ 20 (P<0.0001 for all). LGMLVQ analysis yielded a serum steroid score that discriminated between ACC and non-ACC groups with a mean threshold fixed AUROC of 0.823., Conclusions: We showed that measurements of 11-deoxycortisol, 17OH-progesterone, and 17OH-pregnenolone could be valuable in diagnosing ACC. After appropriate validation, serum steroid score could be integrated in clinical practice., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: Customized and standard automated insulin delivery (AID) systems for use in pregnancies of women with preexisting type 1 diabetes (T1D) are being developed and tested to achieve pregnancy appropriate continuous glucose monitoring (CGM) targets. Guidance on the use of CGM for treatment decisions during pregnancy in the United States is limited., Methods: Ten pregnant women with preexisting T1D participated in a trial evaluating at-home use of a pregnancy-specific AID system. Seven-point self-monitoring of blood glucose (SMBG) was compared to the closest sensor glucose (Dexcom G6 CGM) value biweekly to assess safety and reliability based on the 20%/20 mg/dL criteria., Results: All participants completed the study with 7 participants satisfying the safety and reliability criteria with a mean absolute relative difference of 10.3%. Three participants did not fulfill the criteria, mainly because the frequency of SMBG did not meet the requirements., Conclusion: Dexcom G6 CGM is safe and accurate in the real-world setting for use in pregnant women with preexisting T1D with reduced SMBG testing as part of a pregnancy-specific AID system., (Published by Oxford University Press on behalf of the Endocrine Society 2024.)

Pancreas transplantation alone (PTA) is a β cell replacement option for selected patients with type 1 diabetes mellitus; concerns have been raised regarding deterioration in kidney function (KF) after PTA. This retrospective multicenter study assessed actual impact of transplantation and immunosuppression on KF in PTA recipients at three Transplant Centers. The primary composite endpoint 10 years after PTA was >50% eGFR decline, eGFR < 30 mL/min/1.73 m 2 , and/or receiving a kidney transplant (KT). Overall, 822 PTA recipients met eligibility. Median baseline and 10-year eGFR (mL/min/1.73 m 2 ) were 76.3 (58.1-100.8) and 51.3 (35.3-65.9), respectively. Primary composite endpoint occurred in 98 patients (53.5%) with 45 experiencing a >50% decrease in eGFR by 10 years post-transplant, 38 eGFR < 30 mL/min/1.73 m 2 and 49 requiring KT. KF declined most significantly within 6 months post-PTA, more often in females and patients with better preserved GFR up to 5 years with 11.6% kidney failure at 10 years. Patient survival and death-censored graft survival were both 68% at 10 years with overall graft thrombosis rate 8%. KF declined initially after PTA but stabilized with further slow progression. In conclusion, prospective intervention studies are needed to test renal sparing interventions while gathering more granular data., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Adrenal adenomas are commonly encountered in clinical practice. To date, population-based data on their impact on cognition, mental health, and sleep are lacking. We aimed to study possible associations between adrenal adenomas and dementia, psychiatric or sleep disorders., Design: Population-based cohort study, Olmsted County, MN, 1995-2017., Methods: Patients with adrenal adenoma and absent overt hormone excess were age- and sex-matched 1:1 to a referent person without adrenal adenoma. Outcomes were baseline and incident diagnoses of dementia, psychiatric or sleep disorders, assessed using ICD codes., Results: Of 1004 patients with adrenal adenomas, 582 (58%) were women, and median age at diagnosis was 63 years. At baseline, and after adjusting for age, sex, education, BMI, and tobacco use, patients with adenoma had higher odds of depression (adjusted odds ratio, aOR: 1.3, 95% CI, 1.1-1.6), anxiety (aOR: 1.4, 95% CI, 1.1-1.8), and substance abuse (aOR: 2.4, 95% CI, 1.7-3.4) compared to referents. During a median follow-up of 6.8 years, and after adjusting for age, sex, socioeconomic status, BMI, tobacco, and substance abuse, patients demonstrated a higher risk of psychiatric and sleep disorders [adjusted hazard ratio (95% CI)]: depression [1.7 (1.3-2.2)], anxiety [1.4, CI (1.1-1.7)], insomnia [1.4 (1.0-1.9)], sleep-related breathing disorders [1.5 (1.1-1.9)], hypersomnias [2.1 (1.0-4.2)], parasomnias [2.1 (1.0-4.2)], and sleep-related movement disorders [1.5 (1.0-2.1)], but not dementia., Conclusions: Patients with adenomas demonstrate a higher incidence of psychiatric and sleep disorders, possibly due to the underlying subtle increase in cortisol secretion., Competing Interests: Conflict of interest: Co-author I.B. is on the editorial board of EJE. She was not involved in the review or editorial process for this paper, on which she is listed as author. D.L. is currently an employee of BridgeBio, which is unrelated to the submitted work. M.M.M. has consulted or served on advisory boards for Biogen, LabCorp, Lilly, Merck, Nova Nordisk, Roche, Sunbird Bio, and Siemens Healthineers unrelated to the current manuscript. A.E. received speaker fee from Pfizer unrelated to the current manuscript. I.B. reports advisory board participation/consulting (fees to institution) with HRA Pharma, Corcept, Recordati, Sparrow Pharmaceutics, Neurocrine, Spruce, and Diurnal outside the submitted work, and data monitoring and safety board participation for Adrenas. The remainder of the authors have nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The increasing pressure to publish research has led to a rise in plagiarism incidents, creating a need for effective plagiarism detection software. The importance of this study lies in the high cost variation amongst the available options for plagiarism detection. By uncovering the advantages of these low-cost or free alternatives, researchers could access the appropriate tools for plagiarism detection. This is the first study to compare four plagiarism detection tools and assess factors impacting their effectiveness in identifying plagiarism in AI-generated articles., Methodology: A prospective cross-over study was conducted with the primary objective to compare Overall Similarity Index(OSI) of four plagiarism detection software(iThenticate, Grammarly, Small SEO Tools, and DupliChecker) on AI-generated articles. ChatGPT was used to generate 100 articles, ten from each of ten general domains affecting various aspects of life. These were run through four software, recording the OSI. Flesch Reading Ease Score(FRES), Gunning Fog Index(GFI), and Flesch-Kincaid Grade Level(FKGL) were used to assess how factors, such as article length and language complexity, impact plagiarism detection., Results: The study found significant variation in OSI(p < 0.001) among the four software, with Grammarly having the highest mean rank(3.56) and Small SEO Tools having the lowest(1.67). Pairwise analyses revealed significant differences(p < 0.001) between all pairs except for Small SEO Tools-DupliChecker. Number of words showed a significant correlation with OSI for iThenticate(p < 0.05) but not for the other three. FRES had a positive correlation, and GFI had a negative correlation with OSI by DupliChecker. FKGL negatively correlated with OSI by Small SEO Tools and DupliChecker., Conclusion: Grammarly is unexpectedly most effective in detecting plagiarism in AI-generated articles compared to the other tools. This could be due to different softwares using diverse data sources. This highlights the potential for lower-cost plagiarism detection tools to be utilized by researchers., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Objective: There are no commercially available hybrid closed-loop insulin delivery systems customized to achieve pregnancy-specific glucose targets in the U.S. This study aimed to evaluate the feasibility and performance of at-home use of a zone model predictive controller-based closed-loop insulin delivery system customized for pregnancies complicated by type 1 diabetes (CLC-P)., Research Design and Methods: Pregnant women with type 1 diabetes using insulin pumps were enrolled in the second or early third trimester. After study sensor wear collecting run-in data on personal pump therapy and 2 days of supervised training, participants used CLC-P targeting 80-110 mg/dL during the day and 80-100 mg/dL overnight running on an unlocked smartphone at home. Meals and activities were unrestricted throughout the trial. The primary outcome was the continuous glucose monitoring percentage of time in the target range 63-140 mg/dL versus run-in., Results: Ten participants (HbA1c 5.8 ± 0.6%) used the system from mean gestational age of 23.7 ± 3.5 weeks. Mean percentage time in range increased 14.1 percentage points, equivalent to 3.4 h per day, compared with run-in (run-in 64.5 ± 16.3% versus CLC-P 78.6 ± 9.2%; P = 0.002). During CLC-P use, there was significant decrease in both time over 140 mg/dL (P = 0.033) and the hypoglycemic ranges of less than 63 mg/dL and 54 mg/dL (P = 0.037 for both). Nine participants exceeded consensus goals of above 70% time in range during CLC-P use., Conclusions: The results show that the extended use of CLC-P at home until delivery is feasible. Larger, randomized studies are needed to further evaluate system efficacy and pregnancy outcomes., (© 2023 by the American Diabetes Association.)

Background: Automated insulin delivery (AID) systems have proven effective in increasing time-in-range during both clinical trials and real-world use. Further improvements in outcomes for single-hormone (insulin only) AID may be limited by suboptimal insulin delivery settings. Methods: Adults (≥18 years of age) with type 1 diabetes were randomized to either sensor-augmented pump (SAP) (inclusive of predictive low-glucose suspend) or adaptive zone model predictive control AID for 13 weeks, then crossed over to the other arm. Each week, the AID insulin delivery settings were sequentially and automatically updated by an adaptation system running on the study phone. Primary outcome was sensor glucose time-in-range 70-180 mg/dL, with noninferiority in percent time below 54 mg/dL as a hierarchical outcome. Results: Thirty-five participants completed the trial (mean age 39 ± 16 years, HbA1c at enrollment 6.9% ± 1.0%). Mean time-in-range 70-180 mg/dL was 66% with SAP versus 69% with AID (mean adjusted difference +2% [95% confidence interval: -1% to +6%], P  = 0.22). Median time <70 mg/dL improved from 3.0% with SAP to 1.6% with AID (-1.5% [-2.4% to -0.5%], P  = 0.002). The adaptation system decreased initial basal rates by a median of 4% (-8%, 16%) and increased initial carbohydrate ratios by a median of 45% (32%, 59%) after 13 weeks. Conclusions: Automated adaptation of insulin delivery settings with AID use did not significantly improve time-in-range in this very well-controlled population. Additional study and further refinement of the adaptation system are needed, especially in populations with differing degrees of baseline glycemic control, who may show larger benefits from adaptation.

Background: Pregnancies in type 1 diabetes are high risk, and data in the United States are limited regarding continuous glucose monitoring (CGM)-based hypoglycemia throughout pregnancy while on sensor-augmented insulin pump therapy. Materials and Methods: Pregnant women with type 1 diabetes in the LOIS-P Study (Longitudinal Observation of Insulin use and glucose Sensor metrics in Pregnant women with type 1 diabetes using continuous glucose monitors and insulin pumps) were enrolled before 17 weeks gestation at three U.S. centers and we used their personal insulin pump and a study Dexcom G6 CGM. We analyzed data of 25 pregnant women for CGM hypoglycemia based on international consensus guidelines for percentage time <63 and 54 mg/dL, hypoglycemic events and prolonged hypoglycemia events for 24-h, daytime, and overnight periods, and severe hypoglycemia (SH) episodes. Results: For a 24-h period, biweekly median percentage of time <63 mg/dL ranged from 0.8% at biweek 4-5 to 3.7% at biweek 14-15 with high variability throughout pregnancy. Median percentage of time <63 and 54 mg/dL was higher overnight than daytime ( P  < 0.01). Hypoglycemic events occurred throughout the pregnancy, ranged 1-4 events per 2 weeks, significantly decreased after the 20th week, and occurred predominantly during daytime ( P  < 0.01). For overnight period, hypoglycemia and events were more concentrated from 12 to 3 am. Seven prolonged hypoglycemia events without any associated SH occurred in four participants (16%), primarily overnight. Three participants experienced a single episode of SH. Conclusions: Our results suggest a higher overall risk of hypoglycemia throughout pregnancy during the overnight period with continued daytime risk of hypoglycemic events in pregnancies complicated by type 1 diabetes.

Background: Evidence from the basic research and epidemiological studies indicates a beneficial effect of vitamin D in the treatment of tuberculosis (TB). However, the evidence from randomized controlled trials (RCTs) is inconsistent., Objectives: This systematic review and meta-analysis was performed to synthesize evidence regarding role of vitamin D versus placebo for the management of TB., Materials and Methods: We searched PubMed and Cochrane Clinical Trial Registry for RCTs comparing vitamin D versus placebo for the treatment of TB. RCTs enrolling adult patients with TB receiving vitamin D in addition to standard treatment were included. Data were pooled using random effects model. The study was conducted according to PRISMA guidelines and protocol was registered with PROSPERO (CRD42016052841)., Results: Of 605 identified references, 12 RCTs were included. The overall risk of bias in included studies was low or unclear. There was no significant difference between vitamin D and placebo group for any outcomes of efficacy (time to culture conversion, time to smear conversion, rate of culture conversion, and rate of smear conversion) or safety (mortality, serious adverse events, and nonserious adverse events)., Conclusion: Vitamin D administered with standard treatment has no beneficial effect in the TB patients as compared to the placebo.

Objective: Evaluating the feasibility of closed-loop insulin delivery with a zone model predictive control (zone-MPC) algorithm designed for pregnancy complicated by type 1 diabetes (T1D). Research Design and Methods: Pregnant women with T1D from 14 to 32 weeks gestation already using continuous glucose monitor (CGM) augmented pump therapy were enrolled in a 2-day multicenter supervised outpatient study evaluating pregnancy-specific zone-MPC based closed-loop control (CLC) with the interoperable artificial pancreas system (iAPS) running on an unlocked smartphone. Meals and activities were unrestricted. The primary outcome was the CGM percentage of time between 63 and 140 mg/dL compared with participants' 1-week run-in period. Early (2-h) postprandial glucose control was also evaluated. Results: Eleven participants completed the study (age: 30.6 ± 4.1 years; gestational age: 20.7 ± 3.5 weeks; weight: 76.5 ± 15.3 kg; hemoglobin A1c: 5.6% ± 0.5% at enrollment). No serious adverse events occurred. Compared with the 1-week run-in, there was an increased percentage of time in 63-140 mg/dL during supervised CLC (CLC: 81.5%, run-in: 64%, P  = 0.007) with less time >140 mg/dL (CLC: 16.5%, run-in: 30.8%, P  = 0.029) and time <63 mg/dL (CLC: 2.0%, run-in:5.2%, P  = 0.039). There was also less time <54 mg/dL (CLC: 0.7%, run-in:1.6%, P  = 0.030) and >180 mg/dL (CLC: 4.9%, run-in: 13.1%, P  = 0.032). Overnight glucose control was comparable, except for less time >250 mg/dL (CLC: 0%, run-in:3.9%, P  = 0.030) and lower glucose standard deviation (CLC: 23.8 mg/dL, run-in:42.8 mg/dL, P  = 0.007) during CLC. Conclusion: In this pilot study, use of the pregnancy-specific zone-MPC was feasible in pregnant women with T1D. Although the duration of our study was short and the number of participants was small, our findings add to the limited data available on the use of CLC systems during pregnancy (NCT04492566).

Background: Automated insulin delivery (AID) systems have not been evaluated in the context of psychological and pharmacological stress in type 1 diabetes. Our objective was to determine glycemic control and insulin use with Zone Model Predictive Control (zone-MPC) AID system enhanced for states of persistent hyperglycemia versus sensor-augmented pump (SAP) during outpatient use, including in-clinic induced stress. Materials and Methods: Randomized, crossover, 2-week trial of zone-MPC AID versus SAP in 14 adults with type 1 diabetes. In each arm, each participant was studied in-clinic with psychological stress induction (Trier Social Stress Test [TSST] and Socially Evaluated Cold Pressor Test [SECPT]), followed by pharmacological stress induction with oral hydrocortisone (total four sessions per participant). The main outcomes were 2-week continuous glucose monitor percent time in range (TIR) 70-180 mg/dL, and glucose and insulin outcomes during and overnight following stress induction. Results: During psychological stress, AID decreased glycemic variability percentage by 13.4% ( P  = 0.009). During pharmacological stress, including the following overnight, there were no differences in glucose outcomes and total insulin between AID and physician-assisted SAP. However, with AID total user-requested insulin was lower by 6.9 U ( P  = 0.01) for pharmacological stress. Stress induction was validated by changes in heart rate and salivary cortisol levels. During the 2-week AID use, TIR was 74.4% (vs. SAP 63.1%, P  = 0.001) and overnight TIR was 78.3% (vs. SAP 63.1%, P  = 0.004). There were no adverse events. Conclusions: Zone-MPC AID can reduce glycemic variability and the need for user-requested insulin during pharmacological stress and can improve overall glycemic outcomes. Clinical Trial Identifier NCT04142229.

During present decade, targeted drug therapy has been the epitome for treatment of cancer. Drugs like Imatinib, a tyrosine kinase receptor inhibitor and Trastuzumab, an human epidermal growth factor receptor-2/neu inhibitor, has been developed and accepted widely for management of chronic myeloid leukaemia and breast cancer respectively. Recent development among the various immunotherapies is adoptive cell transfer (ACT). Research on development of various types of ACT immunotherapy is going on, but so far, Chimeric antigen receptors T cell therapy (CAR-T) has achieved the maximum advancement in terms of clinical development. CARs are the modified receptors that integrates specificity and responsiveness onto immune cells to enhance the recognition of cancer cells. For the CAR-T, the T cells are sequestered from a blood of a participant via apheresis. DNA of particular antigen is injected into harvested T cells to generate CARs on cell surface. Following surface manifestation of receptors, multiplication is carried out in enriched media followed by infusion into patient. After infusion, CAR-T cells targeted and exterminate the cancer cells. Initially, only two drugs targeting CD19 as genetically modified autologous immunotherapy has been approved in CAR-T therapy i.e., Tisagenlecleucel and Axicabtagene Ciloleucel, which are discussed in detail in current review. Recently two more drugs got approval i.e., brexucabtagene ciloleucel and lisocabtagene maraleucel, both are directed against CD19, similar to tisagenlecleucel. CAR-T cell therapy is approved for management of Acute Lymphoblastic Leukaemia, Chronic Lymphocytic Leukaemia and lymphoma. CAR-T cell persistence responsible for effectiveness and safety concerns are barriers for their wide application among patients. Growth factor receptors and cluster of differentiation are new drugs targets that are being explored as effective immunotherapy against cancers., Competing Interests: None

Context: Interpretation of dexamethasone suppression test (DST) may be influenced by dexamethasone absorption and metabolism and by the altered cortisol binding., Objective: We aimed to determine the normal ranges of free cortisol during DST in participants without adrenal disorders and to identify the population of patients where post-DST free cortisol measurements add value to the diagnostic workup., Design and Setting: Cross-sectional study conducted in a tertiary medical center., Participants: Adult volunteers without adrenal disorders (n = 168; 47 women on oral contraceptive therapy [OCP], 66 women not on OCP, 55 men) and patients undergoing evaluation for hypercortisolism (n = 196; 16 women on OCP)., Measurements: Post-DST dexamethasone and free cortisol (mass spectrometry) and total cortisol (immunoassay)., Main Outcome Measures: Reference range for post-DST free cortisol, diagnostic accuracy of post-DST total cortisol., Results: Adequate dexamethasone concentrations (≥0.1 mcg/dL) were seen in 97.6% volunteers and 96.3% patients. Only 25.5% of women volunteers on OCP had abnormal post-DST total cortisol (>1.8 mcg/dL). In volunteers, the upper post-DST free cortisol range was 48 ng/dL in men and women not on OCP, and 79 ng/dL in women on OCP. When compared with post-DST free cortisol, diagnostic accuracy of post-DST total cortisol was 87.3% (95% CI, 81.7-91.7); all false-positive results occurred in patients with post-DST cortisol between 1.8 and 5 mcg/dL. OCP use was the only factor associated with false-positive results (21.1% vs 4.9%, P = 0.02)., Conclusions: Post-DST free cortisol measurements are valuable in patients with optimal dexamethasone concentrations and post-DST total cortisol between 1.8 and 5 mcg/dL., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Antimicrobial Resistance (AMR) is significant challenge humanity faces today, with many patients losing their lives every year due to AMR. It is more widespread and has shown a higher prevalence in low- and middle-income countries (LMICs) due to lack of awareness and other associated reasons. WHO has suggested some crucial guidelines and specific strategies such as antimicrobial stewardship programs taken at the institutional level to combat AMR. Creating awareness at the grassroots level can help to reduce the AMR and promote safe and effective use of antimicrobials. Control strategies in curbing AMR also comprise hygiene and sanitation as microbes travel from contaminated surroundings to the human body surface. As resistance to multiple drugs increases, vaccines can play a significant role in curbing the menace of AMR. This article summarizes the current surveillance practices and applied control measures to tackle the hostility in these countries with particular reference to the role of antimicrobial stewardship programs and the responsibilities of regulatory authorities in managing the situation., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: COVID-19 pandemic led to increased self-medication of antimicrobials, vitamins, and immune boosters among the common people and consuming without prescription can lead to adverse consequences including antimicrobial resistance., Methods: A cross-sectional study was conducted on community pharmacies in Jodhpur, India. They were inquired regarding the prescription and increased sales (<25%, 25-50%, 50--75%, or 75--100%) of various medicines (Hydroxychloroquine, Azithromycin, Ivermectin, and Vitamin C) during the COVID-19 pandemic. Logistic regression analysis was conducted to assess the relationship between requests for certain COVID-19 medications and an increase in their sale., Results: A total of 204 pharmacies took part, and 88.23% reported patients to approach them without prescriptions. Most of the pharmacies revealed that <25% of patients came without prescription. The majority came for azithromycin (68%) and vitamin C (92%). Increased sales of the four targeted medications were seen by 85.92% of pharmacies compared to last year. A majority (51.5%) reported <25% increased sales of azithromycin, but no change in the sale of hydroxychloroquine and ivermectin. However, 39.6% reported >75% increase in vitamin C sales., Conclusion: There was an increase in the demand for COVID-19 medications without prescription. This study was unable to detect a significant increase in sales of antimicrobials, which is encouraging., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Family Medicine and Primary Care.)

Purpose of Review: Irrational use of antimicrobials has been reported in paediatric population during the COVID-19 time period. This may lead to potential development of antimicrobial resistance and increased morbidity and mortality among this vulnerable population. The purpose of this review is to ascertain the impact of COVID-19 pandemic on antimicrobial resistance among paediatrics and the possible strategies to minimize the menace of antimicrobial resistance., Recent Findings: Recent findings indicate that the COVID-19 pandemic has direct as well as indirect impact on the development of antimicrobial resistance among paediatric population., Summary: This review article shows the impact of COVID-19 on the development of antimicrobial resistance and strategies to prevent it with special reference to antimicrobial stewardship programmes among paediatric population., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022.)

Context: Hyperglycemia is a common complication of Cushing syndrome (CS)., Objective: We aimed to determine the impact of curative procedure on hyperglycemia and its management in patients with CS., Methods: This retrospective longitudinal cohort study took place 2000 to 2019 in a referral center among adults with endogenous CS and hyperglycemia. Main outcome measures included glycated hemoglobin A 1c (HbA1c), intensity of hyperglycemia therapy, and improvement of hyperglycemia., Results: In 174 patients with CS (pituitary in 106, ectopic in 25, adrenal in 43), baseline median HbA 1c was 6.9% (range, 4.9-13.1), with 41 (24%) patients not on any therapy for hyperglycemia, 93 (52%) on oral medications, and 64 (37%) on insulin (median daily units of 58; range, 10-360). Following CS remission, at the end of follow-up (median 10.5 months), 37 (21%) patients demonstrated resolution of hyperglycemia, 82 (47%) demonstrated improvement, and 55 (32%) had no change or worsening in hyperglycemia. At the end of follow-up, HbA 1c decreased by 0.84% ( P  < .001) and daily insulin dose decreased by a mean of 30 units ( P  < .001). Biochemical hypercortisolism severity score (severe vs moderate/mild: odds ratio [OR] of 2.4 [95% CI, 1.1-4.9]), and CS subtype (nonadrenal vs adrenal: OR of 2.9 [95% CI, 1.3-6.4]), but not type of hyperglycemia (diabetes vs prediabetes: OR of 2.1 [0.9-4.9]) were associated with hyperglycemia improvement at the end of follow-up., Conclusion: Two-thirds of patients with CS and hyperglycemia demonstrate resolution or improvement of hyperglycemia after a curative procedure. Close monitoring during CS recovery is needed to ensure appropriate therapy modification., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Suboptimal glycemic control is associated with maternal and neonatal morbidity and mortality in pregnancy complicated by type 1 diabetes (T1D). Prospective analysis of continuous glucose monitoring (CGM) metrics, insulin pump settings, and insulin delivery can better characterize the changes in glycemic levels and insulin use throughout pregnancy with T1D. Materials and Methods: Prescribed parameters, insulin delivery, carbohydrate intake, and CGM data for 25 pregnant women with T1D from three U.S. sites were collected. Participants enrolled before 17 weeks gestation and used personal insulin pumps and study CGM. Mean daily total, basal, and bolus insulin doses (units/kg), CGM time in range (TIR: 63-140 mg/dL), and pump-entered carbohydrates were analyzed for every 2-week gestational interval. Linear mixed-effects regression models were used to evaluate changes across gestational ages compared to 12-14 weeks. Results: Basal insulin was higher during weeks 6-12 and 24-40. Daily bolus and total insulin were higher during weeks 20-40. Pump parameters were adjusted to intensify insulin therapy from 22 weeks onward. Average TIR across pregnancy was 59% ± 14%. Between 18 and 30 weeks, TIR was significantly lower, and time above range was significantly higher compared to the reference biweek. Time below target was lower between 22 and 34 weeks. Seven participants achieved >70% recommended TIR for pregnancy. Participants with maternal complications or infant neonatal intensive care unit admissions had lower TIR. Conclusion: While insulin dosing changed significantly with advancing gestation, most participants did not achieve >70% TIR. Customized anticipatory pump setting adjustments and automated systems aimed toward the designated TIR are needed to improve outcomes for this population. NCT03761615.

Context: While adrenal adenomas have been linked with cardiovascular morbidity in convenience samples of patients from specialized referral centers, large-scale population-based data are lacking., Objective: To determine the prevalence and incidence of cardiometabolic disease and assess mortality in a population-based cohort of patients with adrenal adenomas., Design: Population-based cohort study., Setting: Olmsted County, Minnesota, USA., Patients: Patients diagnosed with adrenal adenomas without overt hormone excess and age- and sex-matched referent subjects without adrenal adenomas., Main Outcome Measure: Prevalence, incidence of cardiometabolic outcomes, mortality., Results: (Adrenal adenomas were diagnosed in 1004 patients (58% women, median age 63 years) from 1/01/1995 to 12/31/2017. At baseline, patients with adrenal adenomas were more likely to have hypertension [adjusted odds ratio (aOR) 1.96, 95% CI 1.58-2.44], dysglycemia (aOR 1.63, 95% CI 1.33-2.00), peripheral vascular disease (aOR 1.59, 95% CI 1.32-2.06), heart failure (aOR 1.64, 95% CI 1.15-2.33), and myocardial infarction (aOR 1.50, 95% CI 1.02-2.22) compared to referent subjects. During median follow-up of 6.8 years, patients with adrenal adenomas were more likely than referent subjects to develop de novo chronic kidney disease [adjusted hazard ratio (aHR) 1.46, 95% CI 1.14-1.86], cardiac arrhythmia (aHR 1.31, 95% CI 1.08-1.58), peripheral vascular disease (aHR 1.28, 95% CI 1.05-1.55), cardiovascular events (aHR 1.33, 95% CI 1.01-1.73), and venous thromboembolic events (aHR 2.15, 95% CI 1.48-3.13). Adjusted mortality was similar between the 2 groups., Conclusion: Adrenal adenomas are associated with an increased prevalence and incidence of adverse cardiometabolic outcomes in a population-based cohort., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

COVID-19 infection originated in Wuhan, China in December 2019 and crippled human health globally in no time. The public health emergency required urgent efforts to develop and test the efficacy and safety of vaccines to combat the COVID-19 pandemic. The emergency use approval has been granted to COVID-19 vaccines before the completion of conventional phases of clinical trials. However, there is no comprehensive review of safety data reported from the vaccine trials, which is critical information to inform the policies in order to improve uptake of COVID-19 vaccines and mitigate the risk aversion perceived due to the COVID-vaccine side effects. This study aims to systematically review and synthesize the evidence on the safety data from the published COVID-19 vaccine trials. This study followed PRISMA guidelines. We searched three major electronic databases (PubMed, Embase, and Google Scholar) for published studies between Dec 2019 and 2020. Eligible study designs were randomized trials and pre-and post-intervention evaluations. Descriptive findings of included studies were reported stratified by target population, setting, outcomes, and overall results. From PubMed, Embase, WHO database, and Google Scholar screened titles and abstracts, 11 studies were identified in this review. Most of the reactions reported were mild to moderate whereas a few with severe intensity. All reactions resolved within 3-4 days. The commonly reported local adverse events were pain at the site of injection, swelling, and redness. The systemic reactions included fever, fatigue, myalgia, and headache. Some trials also reported laboratory derangements  like decreased hemoglobin, increased bilirubin, altered SGOT and SGPT. None of these alterations were clinically manifested and were self-limiting. Few clinical trials reported serious adverse events, but they were unrelated to vaccination. This systematic review indicates that COVID-19 vaccines can be safe with no serious adverse events. However, long-term post-marketing surveillance data, particularly in high-risk vulnerable populations (elderly and those with co-morbidities, pregnant women, and children) is warranted to ensure the safety of COVID-19 vaccines., (© Association of Clinical Biochemists of India 2021.)

Introduction: Prevalence rates for diabetes mellitus continue to rise, which, coupled with increasing costs of complications, has appreciably increased expenditure in recent years. Poor glycaemic control including hypoglycaemia enhances complication rates and associated morbidity, mortality and costs. Consequently, this needs to be addressed. Whilst the majority of patients with diabetes have type-2 diabetes, a considerable number of patients with diabetes require insulin to help control their diabetes. Long-acting insulin analogues were developed to reduce hypoglycaemia associated with insulin and help improve adherence, which can be a concern. However, their considerably higher costs have impacted on their funding and use, especially in countries with affordability issues. Biosimilars can help reduce the costs of long-acting insulin analogues thereby increasing available choices. However, the availability and use of long-acting insulin analogues can be affected by limited price reductions versus originators and limited demand-side initiatives to encourage their use. Consequently, we wanted to assess current utilisation rates for long-acting insulin analogues, especially biosimilars, and the rationale for patterns seen, across multiple Asian countries ranging from Japan (high-income) to Pakistan (lower-income) to inform future strategies., Methodology: Multiple approaches including assessing utilization and prices of insulins including biosimilars among six Asian countries and comparing the findings especially with other middle-income countries., Results: Typically, there was increasing use of long-acting insulin analogues among the selected Asian countries. This was especially the case enhanced by biosimilars in Bangladesh, India, and Malaysia reflecting their perceived benefits. However, there was limited use in Pakistan due to issues of affordability similar to a number of African countries. The high use of biosimilars in Bangladesh, India and Malaysia was helped by issues of affordability and local production. The limited use of biosimilars in Japan and Korea reflects limited price reductions and demand-side initiatives similar to a number of European countries., Conclusions: Increasing use of long-acting insulin analogues across countries is welcomed, adding to the range of insulins available, which increasingly includes biosimilars. A number of activities are needed to enhance the use of long-acting insulin analogue biosimilars in Japan, Korea and Pakistan.

With an increasing frequency of infectious disease outbreaks, the COVID-19 pandemic causing mortality around the world and the threat of similar future events looming large, mankind is faced with the herculean task of counteracting such threats with the best possible strategies and public health decisions. It is key that such decisions should be guided by previous examples of similar health emergencies. Here we review some of the significant infectious disease outbreaks, including epidemics and pandemics occurring worldwide in the past including their impact at population and global levels, unique challenges presented by each and the measures taken by authorities worldwide as well as the crucial lessons each epidemic or pandemic provided. This review highlights that throughout history measures such as contact tracing, quarantine and isolation have been incredibly effective in limiting an outbreak in its severity, thus ensuring accurate information flow to the public is as essential as limiting the spread of misinformation. With global populations rising, surveillance for emerging and re-emerging pathogens will play an immense role in preventing future epidemics or pandemics. And finally that even though for novel strains or pathogens, although vaccines are thought to be an irreplaceable defense, but their development and distribution in time to curb an epidemic has seldom been witnessed and remains an important challenge for the future. Hence, we conclude that looking at these past examples not only highlights the important knowledge gained for the strategies to devise, but also the mistakes that can be avoided in the way forward., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Family Medicine and Primary Care.)

Background: Diabetes mellitus rates continue to rise, which coupled with increasing costs of associated complications has appreciably increased global expenditure in recent years. The risk of complications are enhanced by poor glycaemic control including hypoglycaemia. Long-acting insulin analogues were developed to reduce hypoglycaemia and improve adherence. Their considerably higher costs though have impacted their funding and use. Biosimilars can help reduce medicine costs. However, their introduction has been affected by a number of factors. These include the originator company dropping its price as well as promoting patented higher strength 300 IU/ml insulin glargine. There can also be concerns with different devices between the manufacturers. Objective: To assess current utilisation rates for insulins, especially long-acting insulin analogues, and the rationale for patterns seen, across multiple countries to inform strategies to enhance future utilisation of long-acting insulin analogue biosimilars to benefit all key stakeholders. Our approach: Multiple approaches including assessing the utilisation, expenditure and prices of insulins, including biosimilar insulin glargine, across multiple continents and countries. Results: There was considerable variation in the use of long-acting insulin analogues as a percentage of all insulins prescribed and dispensed across countries and continents. This ranged from limited use of long-acting insulin analogues among African countries compared to routine funding and use across Europe in view of their perceived benefits. Increasing use was also seen among Asian countries including Bangladesh and India for similar reasons. However, concerns with costs and value limited their use across Africa, Brazil and Pakistan. There was though limited use of biosimilar insulin glargine 100 IU/ml compared with other recent biosimilars especially among European countries and Korea. This was principally driven by small price differences in reality between the originator and biosimilars coupled with increasing use of the patented 300 IU/ml formulation. A number of activities were identified to enhance future biosimilar use. These included only reimbursing biosimilar long-acting insulin analogues, introducing prescribing targets and increasing competition among manufacturers including stimulating local production. Conclusions: There are concerns with the availability and use of insulin glargine biosimilars despite lower costs. This can be addressed by multiple activities., Competing Interests: MW and JR work for HTA Consulting and MH works for Square Toiletries Limited. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Godman, Haque, Leong, Allocati, Kumar, Islam, Charan, Akter, Kurdi, Vassalo, Bakar, Rahim, Sultana, Deeba, Khan, Alam, Jahan, Kamal, Hasin, Munzur-E-Murshid, Nahar, Haque, Dutta, Abhayanand, Kaur, Rwegerera, Nascimento, Dias Godói, Irfan, Amu, Matowa, Acolatse, Incoom, Sefah, Acharya, Opanga, Njeri, Kimonge, Kwon, Bae, Khuan, Abubakar, Sani, Khan, Hussain, Saleem, Malande, Piloya-Were, Gambogi, Hernandez Ortiz, Alutuli, Kalungia, Hoxha, Marković-Peković, Tubic, Petrova, Tachkov, Laius, Harsanyi, Inotai, Jakupi, Henkuzens, Garuoliene, Gulbinovič, Wladysiuk, Rutkowski, Mardare, Fürst, McTaggart, MacBride-Stewart, Pontes, Zara, Tagoe, Banzi, Wale and Jakovljevic.)

Objective: Several small studies reported increased prevalence and incidence of asymptomatic vertebral fractures in patients with non-functioning adrenal adenomas and adenomas with mild autonomous cortisol secretion. However, the risk of symptomatic fractures at vertebrae, and at other sites remains unknown. Our objective was to determine the prevalence and incidence of symptomatic site-specific fractures in patients with adrenal adenomas., Design: Population-based cohort study, Olmsted County, Minnesota, USA, 1995-2017., Methods: Participants were the patients with adrenal adenoma and age/sex-matched referent subjects. Patients with overt hormone excess were excluded. Main outcomes measures were prevalence and incidence of bone fractures., Results: Of 1004 patients with adrenal adenomas, 582 (58%) were women, and median age at diagnosis was 63 years (20-96). At the time of diagnosis, patients had a higher prevalence of previous fractures than referent subjects (any fracture: 47.9% vs 41.3%, P = 0.003, vertebral fracture: 6.4% vs 3.6%, P = 0.004, combined osteoporotic sites: 16.6% vs 13.3%, P = 0.04). Median duration of follow-up was 6.8 years (range: 0-21.9 years). After adjusting for age, sex, BMI, tobacco use, prior history of fracture, and common causes of secondary osteoporosis, patients with adenoma had hazard ratio of 1.27 (95% CI: 1.07-1.52) for developing a new fracture during follow up when compared to referent subjects., Conclusions: Patients with adrenal adenomas have higher prevalence of fractures at the time of diagnosis and increased risk to develop new fractures when compared to referent subjects.

Background: Generics are low-cost alternatives of the existing approved branded drugs. The aim of this work was to study knowledge and perception about generic drugs among the doctors practicing in government and private healthcare sectors., Methods: A cross-sectional study was conducted with a prevalidated questionnaire. Physicians working in government and private healthcare sectors were asked to fill the survey form after obtaining written informed consent. Descriptive analysis was used., Results: Of 240, 11.6% of primary care physicians could identify all the correct statements regarding generic drugs and 57% physicians agreed or strongly agreed that doctors should prescribe only generic drugs. Substandard quality (24.4%) and less effectiveness (35.6%) of generics was cited major reason for low use. Majority (76.1%) believed that patients will accept substitution of branded with generics but 21% either did not or rarely inform patients regarding generics. Only 11.7% considered generics has low efficacy as compared to branded drugs but majority (57.4%) denied the interchangeability of generics. Majority were aware about the Jan Aushadhi scheme (79.3%) and Indian Medical Council Act (Professional conduct, Etiquette and Ethics) (76.8%). For personal use, 45.6% preferred generics. Around 44% agreed/strongly agreed for pharmacist's right to substitute branded drugs with generics but private practicing physicians opted against it., Conclusion: Knowledge and acceptance of generic drugs is still low amongst the doctors. Efforts need to be done increase the awareness and acceptability., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Family Medicine and Primary Care.)

Objectives : Remdesivir has shown promise in the management of patients with COVID-19 although recent studies have shown concerns with its effectiveness in practice. Despite this there is a need to document potential adverse drug events (ADEs) to guide future decisions as limited ADE data available before the COVID-19 pandemic. Methods : Interrogation of WHO VigiBase® from 2015 to 2020 coupled with published studies of ADEs in COVID-19 patients. The main outcome measures are the extent of ADEs broken down by factors including age, seriousness, region and organ. Results : A total 1086 ADEs were reported from the 439 individual case reports up to July 19, 2020, in the VigiBase®, reduced to 1004 once duplicates were excluded. Almost all ADEs concerned COVID-19 patients (92.5%), with an appreciable number from the Americas (67.7%). The majority of ADEs were from males > 45 years and were serious (82.5%). An increase in hepatic enzymes (32.1%), renal injury (14.4%), rise in creatinine levels (11.2%), and respiratory failure (6.4%) were the most frequently reported ADEs. Conclusions : Deterioration of liver and kidney function are frequently observed ADEs with remdesivir; consequently, patients should be monitored for these ADEs. The findings are in line with ADEs included in regulatory authority documents.

Background: Generic drugs are low-cost alternatives to branded drugs. The government of India is encouraging physicians to prescribe the generics to decrease out-of-pocket expenditure of health care. Looking at India's low-prescription on generic drugs, it is crucial to analyze the factors responsible for it. A patient's unawareness may be an important factor; hence, it should be evaluated systematically., Objectives: This study was designed with the aim of assessing knowledge and perception of generics among patients visiting the outpatient department of primary care physicians at the Patan city of Gujarat., Material and Methods: A trained research associate visited the OPDs of various general practitioners to collect the data. A prevalidated questionnaire was administered to these patients. The data was analyzed with the help of statistical software. Descriptive statistics were used to analyze the data., Results: Among 345 patients, only 33.6% reportedly heard about generics. Of these only a few patients (<13%) had used the generic drugs in past. The majority (>60%) believed that generics are safe. Those who were not willing to take generics reported efficacy as the major concern. Out of various factors that may affect knowledge of generic drugs, young age (OR = 5.3) and education (Primary (OR = 8.01), Secondary (OR = 6.19), and Higher secondary (OR = 3.07) were statistically significant., Conclusion: Awareness about the generic drugs was low among the patients visiting the primary care physician. The young age and primary and secondary education levels were significantly associated with the awareness regarding generics., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Journal of Family Medicine and Primary Care.)

Background: Adrenal tumours are commonly encountered in clinical practice, but epidemiological data mainly originate from referral centres. We aimed to determine incidence, prevalence, and rates of malignancy and hormone excess in patients with adrenal tumours in a standardised geographically well defined population., Methods: In this retrospective population-based cohort study we assessed the standardised incidence rate of adrenal tumours in all patients with tumours who lived in Olmsted County, MN, USA, from Jan 1, 1995, to Dec 31, 2017. The Rochester Epidemiology Project infrastructure, which links medical records across all health-care providers for the entire population of Olmsted County since 1966, was used to allow researchers to identify individuals with specific diagnoses, surgical interventions, and other procedures, and to locate their medical records, which were then used in the analysis. Incidence rates and prevalence were standardised for age and sex according to the 2010 US Population., Findings: An adrenal tumour was diagnosed in 1287 patients (median age 62 years; 713 (55·4%) were women; and 13 (1·0%) were children). Standardised incidence rates increased from 4·4 (95% CI 0·3-8·6) per 100 000 person-years in 1995 to 47·8 (36·9-58·7) in 2017, mainly because of the incidental discovery of adenomas less than 40 mm in diameter in patients older than 40 years. Prevalence of adrenal tumours in 2017 was 532 per 100 000 inhabitants, ranging from 13 per 100 000 in children (aged <18 years) to 1900 per 100 000 in patients older than 65 years. 111 (8·6%) of 1287 patients were diagnosed with malignancy (96 [7·5%] of whom has metastases), 14 (1·1%) with phaeochromocytoma, and 53 (4·1%) with overt steroid hormone excess. Malignancy was more common in children (62%) versus those older than 18 years (8%; p<0·0001), tumours discovered during cancer-staging or follow-up (43% vs 3% for incidentalomas; p<0·0001), tumours more than 40 mm in diameter (34% vs 6% for tumours <20 mm; p<0·0001), tumours with unenhanced CT attenuation of 30 Hounsfield units or more (20% vs 1% for <20 Hounsfield units; p<·0001), and bilateral masses (16% vs 7% for unilateral, p=0·0004)., Interpretation: Adrenal tumour standardised incidence rates increased 10 times from 1995 to 2017. Population-based data revealed lower rates of malignancy, phaeochromocytoma, and overt steroid hormone excess than previously reported., Funding: National Institutes of Health., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Primary aldosteronism is a major cause of secondary hypertension. Its two principal forms are bilateral adrenal hyperplasia (BAH) and aldosterone-producing adenoma (APA) whose differentiation is clinically pivotal. There is a major clinical need for a reliable and easily accessible diagnostic biomarker for case identification and subtyping. Circulating microRNAs were shown to be useful as minimally invasive diagnostic markers. Our aim was to determine and compare the circulating microRNA expression profiles of adenoma and hyperplasia plasma samples, and to evaluate their applicability as minimally invasive markers. Methods: One hundred and twenty-three samples from primary aldosteronism patients were included. Next-generation sequencing was performed on 30 EDTA-anticoagulated plasma samples (discovery cohort). Significantly differently expressed miRNAs were validated by real-time reverse transcription-qPCR in an independent validation cohort (93 samples). Results: We have found relative overexpression of miR-30e-5p, miR-30d-5p, miR-223-3p , and miR-7-5p in hyperplasia compared to adenoma by next-generation sequencing. Validation by qRT-PCR confirmed significant overexpression of hsa-miR-30e-5p, hsa-miR-30d-5p , and hsa-miR-7-5p in hyperplasia samples. Regarding the microRNA expressional variations, adenoma is more heterogeneous at the miRNA level compared to hyperplasia. Conclusion: Three microRNAs were significantly overexpressed in hyperplasia samples compared to adenoma samples, but their sensitivity and specificity values are not good enough for introduction to clinical practice., (Copyright © 2019 Decmann, Nyírö, Darvasi, Turai, Bancos, Kaur, Pezzani, Iacobone, Kraljevic, Kastelan, Parasiliti-Caprino, Maccario, Nirschl, Heinrich, Reincke, Patócs and Igaz.)

Background: Current therapy for Type 1 diabetes (T1D) is characterized by significant glucose variability (GV). Pancreas transplantation (PT) is performed in certain T1D patients with and without end-stage renal disease. To date, GV has been examined to a limited extent after PT., Methods: We investigated GV using continuous glucose monitoring (CGM) 3-6 weeks after PT., Results: Eleven patients had simultaneous kidney pancreas transplantation (SPK), nine pancreas after kidney (PAK), and six pancreas transplantation alone (PTA). Mean CGM showed no difference between SPK, 126.5 ± 13.9, PAK 119.9 ± 12.8, and PTA 131.1 ± 29 mg/dL (P value .6). Percentage of time in range (TIR, 70-180 mg/dL) was 92% for SPK, 93.4% in PAK, and 88.5% in PTA with only 0.3%, 1.5%, and 0.3% of time <70 mg/dL. Percentage >180 mg/dL was 7.9% for SPK, 4.9% PAK, and 11% in PTA. Other measures of GV were similar in the three cohorts. In six patients, CGM was performed before and after PT and improved significantly. GV was also better compared with a matched cohort of T1D patients., Conclusions: All 3 types of PT resulted in excellent glucose control 3-6 weeks post-procedure. CGM outcomes represent an important objective outcome after PT., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Importance: Large studies investigating long-term outcomes of patients with bilateral pheochromocytomas treated with either total or cortical-sparing adrenalectomies are needed to inform clinical management., Objective: To determine the association of total vs cortical-sparing adrenalectomy with pheochromocytoma-specific mortality, the burden of primary adrenal insufficiency after bilateral adrenalectomy, and the risk of pheochromocytoma recurrence., Design, Setting, and Participants: This cohort study used data from a multicenter consortium-based registry for 625 patients treated for bilateral pheochromocytomas between 1950 and 2018. Data were analyzed from September 1, 2018, to June 1, 2019., Exposures: Total or cortical-sparing adrenalectomy., Main Outcomes and Measures: Primary adrenal insufficiency, recurrent pheochromocytoma, and mortality., Results: Of 625 patients (300 [48%] female) with a median (interquartile range [IQR]) age of 30 (22-40) years at diagnosis, 401 (64%) were diagnosed with synchronous bilateral pheochromocytomas and 224 (36%) were diagnosed with metachronous pheochromocytomas (median [IQR] interval to second adrenalectomy, 6 [1-13] years). In 505 of 526 tested patients (96%), germline mutations were detected in the genes RET (282 patients [54%]), VHL (184 patients [35%]), and other genes (39 patients [7%]). Of 849 adrenalectomies performed in 625 patients, 324 (52%) were planned as cortical sparing and were successful in 248 of 324 patients (76.5%). Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5% of patients treated with attempted cortical-sparing adrenalectomy. A third of patients with adrenal insufficiency developed complications, such as adrenal crisis or iatrogenic Cushing syndrome. Of 377 patients who became steroid dependent, 67 (18%) developed at least 1 adrenal crisis and 50 (13%) developed iatrogenic Cushing syndrome during median (IQR) follow-up of 8 (3-25) years. Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy. In contrast, 33 patients (13%) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median (IQR) of 8 (4-13) years, all of which were successfully treated with another surgery. Cortical-sparing surgery was not associated with survival. Overall survival was associated with comorbidities unrelated to pheochromocytoma: of 63 patients who died, only 3 (5%) died of metastatic pheochromocytoma., Conclusions and Relevance: Patients undergoing cortical-sparing adrenalectomy did not demonstrate decreased survival, despite development of recurrent pheochromocytoma in 13%. Cortical-sparing adrenalectomy should be considered in all patients with hereditary pheochromocytoma.

Acute pancreatitis (AP) associated with intravenous administration of propofol has been described with unknown causal relation. We therefore assessed this causality in a systematic review. Multiple databases were searched on 16 August 2017; studies were appraised and selected by two reviewers based on a priori criteria. Propofol causality was evaluated with the Naranjo scale and Badalov classification. We identified 18 studies from 11 countries with a total of 21 patients, and the majority had adequate methodological quality. The median age was 35 years (range, 4-77) and 10 (48%) were males. Overall, propofol was administrated in 8 patients as sedative along with induction/maintenance of anesthesia in 13 patients; median dose was 200 mg, with intermediate latency (1-30 days) in 14 (67%). Serum triglycerides were >1000 mg/dL in four patients. Severe AP was observed in four patients (19%). AP recurrence occurred in one out of two patients who underwent rechallenge. Mortality related to AP was 3/21(14%). Propofol was the probable cause of AP according to the Naranjo scale in 19 patients (89%). Propofol-induced AP has a probable causal relation and evidence supports Badalov class Ib. Hypertriglyceridemia is not the only mechanism by which propofol illicit AP. Propofol-induced AP was severe in 19% of patients with a mortality rate related to AP of 14%. Future research is needed to delineate whether this risk is higher if combined with other procedures that portend inherent risk of pancreatitis such as endoscopic retrograde cholangiopancreatography.

Background & Aims: Acute liver failure caused by hepatitis E virus genotype 3 and 4 has been rarely described. Because of the presence of a short golden therapeutic window in patients with viral acute liver failure from other causes, it is possible that early recognition and treatment might reduce the morbidity and mortality. We performed a systematic review and pooled analysis of acute liver failure caused by hepatitis E virus genotype 3 and 4., Methods: Two reviewers appraised studies after searching multiple databases on June 12th, 2017. Appropriate tests were used to compare hepatitis E virus genotype 3 vs 4, suspected vs confirmed genotypes, hepatitis E virus-RNA positive vs negative, and to discern important mortality risk factors., Results: We identified 65 patients, with median age 58 years (range: 3-79), and a male to female ratio of 1.2:1. The median bilirubin, ALT, AST and alkaline phosphatase (expressed by multiplication of the upper limit of normal) levels were 14.8, 45.3, 34.8 and 1.63 respectively. Antihepatitis E virus IgG, antihepatitis E virus IgM and hepatitis E virus-RNA were positive in 84%, 91% and 86% of patients respectively. The median interval from symptoms onset to acute liver failure was 23 days, and 16 patients underwent liver transplantation. Final outcome was reported in 58 patients and mortality was 46%. Age was a predictor of poor prognosis in multivariate analysis. No important differences were found between patients infected with genotype 3 vs 4, patients with confirmed vs suspected genotypes, or patients with positive vs negative RNA., Conclusion: Acute liver failure caused by hepatitis E virus genotype 3 and 4 is rare, similar between genotypes, occurs commonly in middle-aged/elderly patients and has a very high mortality. Age is predictive of poor prognosis in multivariate analysis., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Four commercially available intragastric balloons have been used for the management of obesity and underwent randomized controlled trials (RCTs), and we aimed to compare them using a network meta-analysis approach., Methods: Several databases were queried from inception to May 26, 2017, and we included RCTs enrolling patients treated with Orbera, Heliosphere, ReShape Duo, and Obalon compared with another balloon, sham, or open-label control group. Two investigators independently abstracted data. A random effects frequentist network meta-analysis and relative ranking of agents using surface under the cumulative ranking probabilities were performed., Results: We included 15 trials at low risk of bias (only two were head-to-head). Compared to control groups, the two fluid-filled devices were associated with significant outcome (% total body weight loss) at 6 months: Orbera, 6.72% (95% CI, 5.55, 7.89) and ReShape Duo 4% (95% CI 2.69, 5.31). Only one of the two gas-filled devices was associated with significant outcome at 6 months: Obalon 3.3% (95% CI 2.30, 4.30), and not the second: Heliosphere 6.71% (95% CI - 0.82, 14.23). Fluid-filled devices had the highest likelihood of superiority in achieving the outcome at 6 months (96.8%) and at 12 months (96.6%). The quality of evidence was high for comparisons against control., Conclusions: Fluid-filled balloons are more likely to produce weight loss compared to gas-filled balloons or lifestyle intervention. However, they may be associated with a higher rate of intolerance and early removal. This information will aid clinicians in device selection and engaging patients in shared decision-making.

Background: Globally, there have been tremendous efforts by regulatory authorities to make clinical trials safer by making stringent clinical trial regulations. Despite this, we witnessed several tragic events. TGN1412 and BIA 10-2474 phase I trials are infamous trails in which healthy volunteers either succumbed to severe adverse effects or faced irreversible impairments of the test drug. Such afflictions in clinical trials are not only turbulent to the image of pharmaceutical industry but it also conveys dispiriting message for clinical trial participants., Objective: To make clinical trials safer for participants, some regulatory changes are warranted., Methods: Some stipulated measures to improve safety of clinical trial participants include inclusion of patients instead of healthy volunteers in phase I clinical trials, all compounds which are used for first time in humans should be considered as high risk compounds, amendments in first in human clinical trial design to N of 1 randomized control trial in place of 6+2 design with the sequential dosing of subjects both within and between cohorts and the individual patient pharmacokinetic and pharmacodynamic data should be used to calculate sequential dosing. Besides these, there should be appropriate process for systematic risk assessment involving the use of statistical techniques to select pertinent risk factors with high predictive values of studies or sites that may be procumbent to non-compliance., Conclusion: Inclusion of above mentioned measures in clinical trials are bound to make them safer and may help in pacifying the insecurity that has emerged among humans to participate in clinical trials., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Rhinofacial conidiobolomycosis (RFC) is an uncommon subcutaneous fungal infection producing painless swelling with grotesque deformity of the face. Although there are case reports and small case series; there are very few prospective studies evaluating treatment outcome and long-term follow-up., Objective: To evaluate the safety and efficacy of combination of itraconazole (200 mg twice daily) and saturated solution of potassium iodide (SSKI) in patients with RFC., Methods: Ten patients of RFC were studied over a period of 5 years. Diagnosis was confirmed by clinical, histopathological, and microbiological evaluation. Conidiobolus was cultured in four cases and in the rest of the cases, the histopathology was suggestive of RFC. They were treated with itraconazole (200 mg twice daily) and SSKI and followed up for a minimum of 1 year after stopping treatment., Results: The mean age was 38.7 years and the mean duration of symptoms was 22.4 months. Males were predominantly involved (9 : 1). Seven patients responded to the combination treatment, five had complete resolution and two had good improvement (50-75%); however, in two patients the response was minimal (<25% regression of the swelling) and one patient did not show any improvement after 6 months of treatment., Conclusion: Combination of itraconazole and SSKI is an effective treatment modality for RFC with relatively faster onset of action, low relapse rates, and minimal adverse effects. It can be considered as first-line treatment in patients with RFC., (© 2015 The International Society of Dermatology.)

We previously reported the presence of vascular endothelial growth factor (VEGF) in testicular cells, and high concentrations of VEGF have been measured in semen, although its role in male reproduction remains obscure. In the present study we focus on understanding the mechanism of VEGF production by mouse Leydig cells cultured in vitro. Production of VEGF protein in medium by testicular cells was markedly increased by the addition of hCG in a time- and dose-dependent manner. Gonadotropin-stimulated VEGF production was mediated by cAMP-dependent protein kinase A (PKA), as evidenced by the effect of hCG being mimicked by 8Br-cAMP and being abolished in the presence of a PKA-specific inhibitor, H-89. Protein kinase C was not involved, as evidenced by phorbol 12-myristate 13-acetate having no influence on VEGF production by Leydig cells. In addition to hCG, atrial natriuretic peptide was also able to stimulate VEGF production, suggesting that cGMP is able to cross-activate PKA. A specific Src kinase inhibitor, PP2, could completely block the stimulatory effects of both gonadotropin and 8Br-cAMP on VEGF production by Leydig cells, implying an involvement of the Src kinase pathway. Furthermore, addition of U0126, an inhibitor of MEK 1/2, abolished the increase in VEGF production stimulated by both hCG and 8Br-cAMP. A similar inhibitory effect was observed by the addition of SB203580, a p38 mitogen-activated protein kinase inhibitor. Thus, in conclusion, Leydig cells are able to produce VEGF by a process under gonadotropic control, and PKA plays a key role in this process. Downstream of PKA, it appears that both MEK 1/2 and Src kinase-dependent pathways are involved, although further research will be necessary to determine the precise link between PKA and other kinases involved.