Clinical efficacy of Azithromycin for COVID-19 management: A systematic meta-analysis of meta-analyses.

BACKGROUND: Azithromycin has been adopted as a component of the COVID-19 management protocol throughout the global healthcare settings but with a questionable if not downright unsubstantiated evidence base. OBJECTIVES: In order to amalgamate and critically appraise the conflicting evidence around the clinical efficacy of Azithromycin (AZO) vis a vis COVID-19 management outcomes, a meta-analysis of meta-analyses was carried out to establish an evidence-based holistic status of AZO vis a vis its efficacy as a component-in-use of the COVID-19 management protocol. METHODS: A comprehensive systematic search was carried out through PubMed/Medline, Cochrane and Epistemonikos with a subsequent appraisal of abstracts and full-texts, as required. The Quality of Reporting of Meta-analyses (QUOROM) checklist and the Assessment of Multiple Systematic Reviews (AMSTAR) methodology were adopted to assess the methodological quality of the included meta-analyses. Random-effects models were developed to calculate summarized pool Odds Ratios (with 95% confidence interval) for the afore determined primary and secondary outcomes. RESULTS: AZO, when compared with best available therapy (BAT) including or excluding Hydroxychloroquine, exhibited statistically insignificant reduction in mortality [(n= 27,204 patients) OR= 0.77 (95% CI: 0.51-1.16) (I2= 97%)], requirement of mechanical ventilation [(n= 14,908 patients) OR= 1.4 (95% CI: 0.58-3.35) (I2= 98%)], induction of arrhythmia [(n= 9,723 patients) OR= 1.21 (95% CI: 0.63-2.32) (I2= 92%)] and QTc prolongation (a surrogate for torsadogenic effect) [(n= 6,534 patients) OR= 0.62 (95% CI: 0.23-1.73) (I2= 96%)]. CONCLUSION: The meta-analysis of meta-analyses portrays AZO as a pharmacological agent that does not appear to have a comparatively superior clinical efficacy than BAT when it comes to COVID-19 management. Secondary to a very real threat of anti-bacterial resistance, it is suggested that AZO be discontinued and removed from COVID-19 management protocols.

Neuropharmacological evaluation of different species of Curcubitaceae seeds extract in experimental animals.

Major depressive disorders such as anxiety and depression is predominantly developed in the modern era due to stressful lifestyle and now become the second leading cause of disability. The purpose of the current investigation to evaluate and compared the neuropharmacological effects of three different varaities of Cucurbitaceae seeds including Cucumis Melo var. flexuosus, Cucumis melo var. reticulatus and Santa claus melons ethanol seed extract in experimental animals at three different doses, i.e. 25, 50 and 100mg/kg in animals after 60 days of oral administration. Afterward, various neuropharphamcological activities such as general behavior, phenobarbitone induced sleeping time and exploratory behavior (Elevated plus-maze and head dip test) and motor coordination by Rotarod test were assessed and compared with the control group. The extracts producing dose depended effects on central nervous system. The general behavior profile revealed significant depression at maximum doses. At maximum dose 100mg/kg of Cucumis reticulatus and Santa Claus, seed extracts significantly increases the number of entries in open arms. On the other hand, the Cucumis flexuosus seed extract significantly increases the frequency of numbers of head dips in mice. However, the lower doses of the extracts showed less significant results. The results suggested that all extracts at maximum doses produces anxiolytic effects without affecting the motor coordination in animals.

Postprandial Glycemic and Insulinemic Response by a Brewer's Spent Grain Extract-Based Food Supplement in Subjects with Slightly Impaired Glucose Tolerance: A Monocentric, Randomized, Cross-Over, Double-Blind, Placebo-Controlled Clinical Trial.

Dietary fiber exerts beneficial effects on human health reducing the risk factors of metabolic related diseases such as hyperglycemia, insulin resistance, and hypercholesterolemia. The aim of this study is to demonstrate the efficacy of a food supplement based on brewer's spent grain (BSG) extract in the reduction of postprandial glycemia and insulinemia in normoglycemic subjects. BSG was chemically characterized, revealing the presence of resistant starch (14.64 g/100 g), arabinoxylans (7.50 g/100 g), ß-glucans (1.92 g/100 g) and other soluble fibers (6.43 g/100 g), and bioaccessible ferulic acid (91.3 mg/100 g). For the clinical study, 40 normoglycemic subjects were randomized into two groups, 1 and 2 (n = 20), for a cross-over clinical design and received either BSG extract-based food supplement or placebo. Postprandial blood glucose values were significantly lower than corresponding values in the placebo group after 90 and 120 min, while at the baseline and in the first 60 min, the two glycemic curves overlapped substantially. This improved clinical outcome was corroborated by significant reductions in postprandial insulinemia. None of the subjects reported adverse effects. This study showed that the tested BSG extract-based food supplement improves glucose metabolism and insulinemic response in normoglycemic subjects with at most a mild insulin resistance.

The Efficacy of S-Adenosyl Methionine and Probiotic Supplementation on Depression: A Synergistic Approach.

Depression is a common and serious health issue affecting around 280 million people around the world. Suicidal ideation more frequently occurs in people with moderate to severe depression. Psychotherapy and pharmacological drugs are the mainstay of available treatment options for depressive disorders. However, pharmacological options do not offer complete cure, especially in moderate to severe depression, and are often seen with a range of adverse events. S-adenosyl methionine (SAMe) supplementation has been widely studied, and an impressive collection of literature published over the last few decades suggests its antidepressant efficacy. Probiotics have gained significant attention due to their wide array of clinical uses, and multiple studies have explored the link between probiotic species and mood disorders. Gut dysbiosis is one of the risk factors in depression by inducing systemic inflammation accompanied by an imbalance in neurotransmitter production. Thus, concomitant administration of probiotics may be an effective treatment strategy in patients with depressed mood, particularly in resistant cases, as these can aid in dysbiosis, possibly resulting in the attenuation of systemic inflammatory processes and the improvement of the therapeutic efficacy of SAMe. The current review highlights the therapeutic roles of SAMe and probiotics in depression, their mechanistic targets, and their possible synergistic effects and may help in the development of food supplements consisting of a combination of SAMe and probiotics with new dosage forms that may improve their bioavailability.

Evaluation of Susceptibility Testing Methods for Aztreonam and Ceftazidime-Avibactam Combination Therapy on Extensively Drug-Resistant Gram-Negative Organisms.

Carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CR-PA) producing metallo-ß-lactamases (MBLs) cause severe nosocomial infections with no defined treatment. The combination of aztreonam (ATM) with ceftazidime-avibactam (CZA) is a potential therapeutic option, but there is no approved, feasible testing method for use in clinical laboratories to assess the activity of two antimicrobials in combination. Here, we evaluate the performance of four ATM-CZA combination testing methods, as follows: broth disk elution (DE), disk stacking (DS), strip stacking (SS), and strip crossing (SX). We used 10 clinical, representative Enterobacterales and 6 P. aeruginosa isolates harboring MBL, Guiana extended-spectrum beta-lactamase (GES), or non-MBL enzymes. Four of these isolates were from clinical cases treated by ATM-CZA. All CRE producing NDM and CR-PA producing GES that were resistant to ATM and CZA alone were susceptible to the ATM-CZA combination. P. aeruginosa generating NDM or VIM remained resistant to ATM-CZA, likely due to non-ß-lactamase mechanisms, and all other isolates were susceptible to ATM or CZA alone. The most accurate, precise, and reproducible methods of low complexity were disc elution and both strip methods (SX and SS) using MIC test strips (MTS) , all with 100% sensitivity and specificity, followed by Etest with SX (95.83% sensitivity, 100% specificity) and SS (87.5% sensitivity, 100% specificity). DS had the lowest performance. DE is particularly valuable in low-resource settings that routinely use disks. MTS yielded higher categorical agreements by SX (94%) and SS (84%), relative to Etest by SX (90%) and SS (82%). P. aeruginosa results yielded the majority of the errors. These methods may allow laboratories to inform clinical decision making like combination therapy for severe infections caused by extensively drug-resistant Enterobacterales.

Effectiveness Of DIMCI Training In District Abbottabad, Khyber Pakhtunkhwa: An External Pilot Study.

BACKGROUND: Five million deaths per year in under-five children are reported to be due to preventable and treatable causes. IMCI strategy targets these causes through improvement in the case management skills of health care workers. The objectives of this study were to identify eligible clusters and identify & rectify any process, resources, and management-related issues for the main trial. METHODS: This study was conducted in two phases. Phase 1 was conducted for eligibility of Basic Health Units from which sample can be drawn for the main cluster randomized control trial. A single-page proforma was sent to all 54 BHUs of Abbottabad through registered mail service and replies received were analysed through SPSS-V25 and MS Excel-2016. Afterward a sample of 26 BHUs was drawn for the definitive trial. In phase 2, four BHUs were conveniently selected from the remaining sampling frame; one in the control arm while three in the intervention arm. From each BHU, a health care worker responsible for under-five consultations was trained; control arm in standard IMCI while intervention arm on distance learning IMCI. Ten observations in the form of cases managed were assessed at each BHU by a gold standard IMCI master trainer after a specific period. Descriptive summary measures and 95% CI were calculated using SPSS-V25. RESULTS: Out of 54 BHUs, 3 were nonrespondents while 36 were identified as an eligible sampling frame. The mean index of integrated assessment was found to be 0.90 and 0.89 for the control and intervention arm respectively. Discrepancies in filled forms were noted as 60% in control while 63.3% in intervention arm. CONCLUSIONS: Modifications in the plan for the main trial based on the findings of pilot study can ensure credibility and rigor in the definitive trial.

Engineering and expression of a human rotavirus candidate vaccine in Nicotiana benthamiana.

BACKGROUND: Human rotaviruses are the main cause of severe gastroenteritis in children and are responsible for over 500 000 deaths annually. There are two live rotavirus vaccines currently available, one based on human rotavirus serotype G1P[8], and the other a G1-G4 P[8] pentavalent vaccine. However, the recent emergence of the G9 and other novel rotavirus serotypes in Africa and Asia has prompted fears that current vaccines might not be fully effective against these new varieties. RESULTS: We report an effort to develop an affordable candidate rotavirus vaccine against the new emerging G9P[6] (RVA/Human-wt/ZAF/GR10924/1999/G9P[6]) strain. The vaccine is based on virus-like particles which are both highly immunogenic and safe. The vaccine candidate was produced in Nicotiana benthamiana by transient expression, as plants allow rapid production of antigens at lower costs, without the risk of contamination by animal pathogens. Western blot analysis of plant extracts confirmed the successful expression of two rotavirus capsid proteins, VP2 and VP6. These proteins assembled into VLPs resembling native rotavirus particles when analysed by transmission electron microscopy (TEM). Expression of the rotavirus glycoprotein VP7 and the spike protein VP4 was also tried. However, VP7 expression caused plant wilting during the course of the time trial and expression could never be detected for either protein. We therefore created three fusion proteins adding the antigenic part of VP4 (VP8*) to VP6 in an attempt to produce more appropriately immunogenic particles. Fusion protein expression in tobacco plants was detected by western blot using anti-VP6 and anti-VP4 antibodies, but no regular particles were observed by TEM, even when co-expressed with VP2. CONCLUSION: Our results suggest that the rotavirus proteins produced in N. benthamiana are candidates for a subunit vaccine specifically for the G9P[6] rotavirus strain. This could be more effective in developing countries, thereby possibly providing a higher overall efficacy for the existing vaccines. The production of rotavirus proteins in plants would probably result in lower manufacturing costs, making it more affordable for developing countries. Further investigation is required to evaluate the immunogenic potential of the VLPs and fusion proteins created in this study.

Quaternary Indolizidine and Indolizidone Iminosugars as Potential Immunostimulating and Glycosidase Inhibitory Agents: Synthesis, Conformational Analysis, Biological Activity, and Molecular Docking Study.

New quaternary indolizidine iminosugars, with hydroxymethyl group at the ring junction, namely, C-8a-hydroxymethyl-1-deoxycastanospermine congeners 1a, 2a, 3a and their 3-oxo analogs 1b, 2b, and 3b were synthesized by using intramolecular reductive aminocyclization/lactamization of d-mannose/D-glucose derived C5-γ-azido esters as a key step wherein both the rings of the indolizidine skeleton were built up in one pot following the cascade reaction pathway. The conformations ((5)C8 or (8)C5) of 1-3 were assigned on the basis of the (1)H NMR studies. All compounds were found to be potent inhibitors of various glycosidase enzymes with Ki and IC50 values in the micromolar/nanomolar concentration range and further substantiated by molecular docking studies. The effect of synthesized iminosugars 1-3 on the cytokine secretion of IL-4, IL-6, and IFN-γ was evaluated. All compounds were found to be TH1 bias increasing the TH1/TH2 cytokines ratio (IL-6 and IL-4) indicating their potency as immunostimulating agents. Our study suggests that immunomodulatory activity of indolizidine iminosugars can be tuned by minor structural/stereochemical alterations.

Perturbation of male sexual behavior in mice (Mus musculus) within a discrete range of perinatal bisphenol-A doses in the context of a high- or low-phytoestrogen diet.

Differentiation of masculine and feminine behavior in mammals depends on perinatal sex steroids. As bisphenol-A (BPA) can be estrogenic and anti-androgenic, we examined impacts of perinatal exposure upon adult sexual behavior and morphology of male mice. In Experiment 1, dams were fed either a high- or low-phytoestrogen diet and received daily oral doses of 0, 0.175, 1.75, or 17.5µg BPA from gestation day 10 through post-partum day 9. Male offspring from the high-phytoestrogen plus 17.5µg BPA condition showed reduced mass of vesicular-coagulating but not other male glands, and showed increased latency to insemination when paired with females. In Experiment 2, these procedures were replicated but with all animals fed the high-phytoestrogen diet and perinatal BPA doses of 0, 17.5, 175, or 1750µg/day. Adult masses of testes and male-accessory glands and levels of urinary steroids were not significantly affected. When males each encountered a sexually receptive female, there were fewer intromissions among those given 17.5 or 175µg and fewer ejaculations among those given 17.5µg, but the 1750µg dose had no effect. Perinatal BPA dosages thus influenced male sexual behavior non-monotonically, with impairment evident in a discrete dose range among males on a high-phytoestrogen diet.

Induced abortion in Pakistan: community-based research.

INTRODUCTION: This paper highlights the findings pertaining to profiles of abortion seekers, reasons for induced abortions and methods used, and treatment for post-abortion complications (PACs). METHODS: This paper is a review of community studies on induced abortion in Pakistan between 1969 and 2010, including the Induced Abortion Survey (IAS) 2010, in which the author took part. RESULTS: Findings from the review show that the profile of abortion seekers has remained by and large that of uneducated women aged over 30 with at least three children. A predominant reason for seeking abortion was contraceptive failure. Providers fall into both trained and untrained categories, yet complication rates are high even when women believe that they are going to safe providers in clinics or hospital settings. Dilation and curettage (D&C) (or evacuation) predominates among methods used while the use of folk methods may be on the decline. The IAS shows that women seek assistance for complications sooner than earlier studies have found. CONCLUSION: The review shows that despite a perceived stigma around the subject, community-level research is possible and further studies need to be done in other parts of the country. The paper concludes with suggestions for more community studies to explore these findings further and capture the diversity of the Pakistani context. It also suggests that advocacy and further research into the role of "semi-safe" providers be explored.

Light therapy for seasonal affective disorder in a clinical office setting.

OBJECTIVE: To determine predictors of response to light therapy (LT) for seasonal affective disorder, winter version, in a clinical office setting for patients with a spectrum of seasonality defined by the Seasonal Pattern Assessment Questionnaire (SPAQ). METHOD: A retrospective review was done of charts of 51 patients who had been treated with a 1-week light therapy intervention. Patient self-rated scales applied in a standard manner were used to measure clinical progress. The Beck Depression Inventory (BDI) with added atypical features was used as the primary outcome variable. Sleep patterns were analyzed and the effect of psychotropic medications on outcome was determined. Seven point scales were used to assess expected response and global response. The importance of having LT set up and available in an office setting was evaluated. Retrospective degree of disability was measured based on the SPAQ degree of problem. The severity of the depressive episode was determined based on BDI score at entry. RESULTS: Seasonality (how a patient's symptoms vary as a function of the season of the year), degree of disability based on the SPAQ, and severity of depressive episode at entry based on the BDI predicted response to LT. Greater severity at baseline based on BDI score predicted less chance of attaining full remission within 7 days of treatment compared with patients with lower severity scores at entry on the BDI. Sleep patterns relative to a fixed treatment time of 7 AM did not predict LT response. Light therapy was effective on its own, and the results were mixed as to whether adding LT to an existing antidepressant medication produced superior results. CONCLUSION: Degree of seasonality can be used as a predictor of response to LT and may be clinically useful when suggesting that patients consider a trial of LT.

Successful treatment of ligneous conjunctivitis with topical cyclosporine and heparin.

Ligneous conjunctivitis is a rare disease characterized by wood-like pseudomembranes developing on the ocular and extraocular mucosae. We present a case of ligneous conjunctivitis and cataracts in a 10-year-old boy with a positive family history of the disease and consanguinity. His condition was managed with topical cyclosporine, heparin, and steroids.

The onset of puberty in female mice as reflected in urinary steroids and uterine/ovarian mass: interactions of exposure to males, phyto-oestrogen content of diet, and ano-genital distance.

Development of puberty in female mice was examined in relationship with the ano-genital distance index (AGDI), phyto-oestrogen content of diet and exposure to males post weaning. Throughout gestation and post-natal development, females were exposed to a regular diet or a nutritionally similar diet deficient in phyto-oestrogens. After segregation at weaning on the basis of short or long AGDI, an indirect measure of in utero androgen exposure, females were housed alone or underneath two outbred adult males for 2 weeks. Female urinary samples were collected non-invasively throughout this exposure, then assayed for oestradiol, progesterone and creatinine. Females were then killed and uterine and ovarian mass was determined. Urinary oestradiol was substantially reduced in females raised on the phyto-oestrogen-free diet. Oestradiol levels were more dynamic over days in urine of male-exposed females, especially among those on the regular diet. Urinary progesterone was not strongly influenced by diet. Progesterone was more dynamic in urine of male-exposed females, and was generally elevated compared with levels in isolated females, the size of this effect dependent on AGDI, diet and whether the measure was adjusted for creatinine. Urinary creatinine was elevated by the phyto-oestrogen-free diet and reduced by male exposure, tending to decline over days in females exposed to males. Male exposure increased uterine and ovarian mass and was influenced by AGDI in interaction with diet and male exposure.

Onset of sexual maturation in female mice as measured in behavior and fertility: Interactions of exposure to males, phytoestrogen content of diet, and ano-genital distance.

Age of puberty was examined in female mice through non-invasive behavioral and fertility measures, in relationship to ano-genital distance, phytoestrogen content of diet, and exposure to males post-weaning. Throughout gestation and post-natal development, females were exposed to a regular diet or one that was nutritionally similar but deficient in phytoestrogens. After segregation at weaning on the basis of a short or long ano-genital distance index (AGDI), an indirect measure of in utero androgen exposure, females were housed alone or underneath two outbred adult males for two weeks. Subsequently, an outbred male was placed in the cage of each developing female, and mating behavior, escape attempts, biting gestures, and boxing postures were recorded. Next, females were monitored for the occurrence of a copulatory plug and allowed to bear young, with pregnancy and litters monitored up to weaning. Male-exposed females fed a regular diet were immediately sexually receptive when housed directly with males, and their conceptions occurred earlier than did those of other females. Subjects fed a diet deficient in phytoestrogens were least likely to show sexual receptivity. Male-exposed females with longer AGDI displayed more escape attempts in the presence of males, regardless of diet. Once inseminated, most females carried to term and the majority of pups survived until weaning. These data suggest that phytoestrogens and AGDI interact with exposure to males in determining age at onset of puberty.

In vitro genotoxicity of the West African anti-malarial herbal Cryptolepis sanguinolenta and its major alkaloid cryptolepine.

Cryptolepine (CLP), the major alkaloid of the West African anti-malarial herbal Cryptolepis sanguinolenta (Periplocaceae) is a DNA intercalator that exhibits potent toxicity to a variety of mammalian cells in vitro. We have hypothesized that the DNA intercalating properties of cryptolepine could trigger genetic damage in mammalian cells. The objective of the present study was therefore to assess the ability of both cryptolepine (CLP) and the traditional anti-malarial formulation, the aqueous extract from the roots (CSE) to induce mutation at the hprt locus and micronuclei (MN) formation in V79, a Chinese hamster fibroblast cell line commonly used in genetic toxicity studies. CSE at a high concentration (50 microg/ml) induced an apparent significant ten fold increase in mutant frequency compared to vehicle control (mean of 38 versus 4 mutant clones/10(6) surviving cells) but, this concentration of CSE was very toxic (<15% cell survival). CLP did not appear to be mutagenic in the dosage range used (up to 2.5 microM, equivalent to 1.1 microg/ml). However, after 24h treatment of V79 cells both CSE and CLP induced a dose-dependent increase in micronuclei of 4.15% and 6.43% (25 microg/ml CSE and 2.5 microM, equivalent to 1.1 microg/ml CLP, respectively) compared to 0.36% in vehicle control. These results show that treatment of mammalian cells with CSE and CLP can lead to DNA damage and we suggest that the routine use of CSE and the potential use of CLP derivatives in malaria chemotherapy could carry a genotoxic risk.

Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of Abeta42 in a manner which may have consequences for metal chelation therapy in Alzheimer's disease.

Metals are found associated with beta-pleated sheets of Abeta42 in vivo and may be involved in their formation. Metal chelation has been proposed as a therapy for Alzheimer's disease on the basis that it may safely dissolve precipitated Abeta peptides. We have followed fibrillisation of Abeta42 in the presence of an additional metal ion (Al(III), Fe(III), Zn(II), Cu(II)) over a period of 32 weeks and we have investigated the dissolution of these aged peptide aggregates in the presence of both desferrioxamine (DFO) and ethylenediaminetetraacetic acid (EDTA). Abeta42 either alone or in the presence of Al(III) or Fe(III) formed beta-pleated sheets of plaque-like amyloids which were dissolved upon incubation with either chelator. Zn(II) inhibited whilst Cu(II) prevented the formation of beta-pleated sheets of Abeta42and neither of these influences were affected by incubation of the aged peptide aggregates with either DFO or EDTA. Freshly prepared solutions of Abeta42 either alone or in the presence of added Al(III) or Fe(III) did not form beta-pleated amyloid in the presence of DFO when incubated for up to 8 weeks. EDTA did not prevent beta-pleated amyloid formation in the same treatments and promoted beta-pleated amyloid formation in the presence of either Zn(II) or Cu(II). The presence of significant concentrations of Al(III) and Fe(III) as contaminants of 'Abeta42 only' preparations suggested that both of these metals were involved in either triggering the formation or stabilising the structure of beta-pleated amyloid. If the formation of such amyloid is critical to the aetiology of AD then the chelation of Al(III) and Fe(III) may prove to be a protective mechanism whilst the chelation of Cu(II) and Zn(II) without also chelating Al(III) and Fe(III) might actually exacerbate the condition.

Epidemiology of cleft lip and cleft palate in Pakistan.

Clinical and epidemiologic studies of defined geographic populations can serve as a means of establishing data important for the diagnosis, treatment, and counseling of patients with cleft lip and cleft palate. Several descriptive epidemiologic studies have been carried out in many countries worldwide; however, no such study has ever been performed in Pakistan. Population-based data on the incidence of cleft lip and palate were obtained from birth registry information in northern Pakistan. A total of 117 cases from 61,156 live births reported were identified. The incidence for cleft lip and/or cleft palate was 1.91 per 1000 births (one per 523 births). Cleft lip alone (42 percent) was noted more frequently than isolated cleft palate (24 percent) and combined cleft lip and palate deformities (34 percent). Boys were more commonly affected by cleft lip and cleft lip with cleft palate, whereas girls predominated in the isolated cleft palate cases. Consanguineous marriages were observed in 32 percent of parents versus 18 percent in matched controls. Only 32 percent of cleft mothers received formal prenatal counseling, monthly examinations, and regular laboratory testing during the entirety of the pregnancy. Nutritional and vitamin supplements were given to only 28 percent of mothers of cleft children versus 59 percent in matched controls. Descriptive statistics were used to assess pertinent risk factors associated with cleft lip and palate. The acquisition of incidence and associated data has generated baseline information on the magnitude of cleft lip and cleft palate in Pakistan. It is hoped that this information can be used for appropriate resource use, cleft lip and cleft palate prevention programs, and counseling programs with Pakistan-specific data.