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Declines in lysosomal acidification and function with aging are observed in organisms ranging from yeast to humans. V-ATPases play a central role in organelle acidification and V-ATPase activity is regulated by reversible disassembly in many different settings. Using the yeast Saccharomyces cerevisiae as a replicative aging model, we demonstrate that V-ATPases disassemble into their V 1 and V 0 subcomplexes in aging cells, with release of V 1 subunit C (Vma5) from the lysosome-like vacuole into the cytosol. Disassembly is observed after ≥5 cell divisions and results in overall vacuole alkalinization. Caloric restriction, an established mechanism for reversing many age-related outcomes, prevents V-ATPase disassembly in older cells and preserves vacuolar pH homeostasis. Reversible disassembly is controlled in part by the activity of two opposing and conserved factors, the RAVE complex and Oxr1. The RAVE complex promotes V-ATPase assembly and a rav1 Δ mutant shortens replicative lifespan; Oxr1 promotes disassembly and an oxr1 Δ mutation extends lifespan. Importantly, the level of Rav2, a key subunit of the RAVE complex, declines in aged cells. These data indicate that reduced V-ATPase assembly contributes to the loss of lysosome acidification with age, which affects replicative lifespan., Competing Interests: Conflict of interest: The authors declare that they have no conflicts of interest with the contents of this article.

Objective: This study aimed to illustrate the effect of malaria infection on red blood cell parameters in children and evaluate the diagnostic relevance of haematological parameters in predicting malaria., Methods: The studies were identified through databases like PubMed, Google Scholar, and Scopus to retrieve related articles. Fourteen studies were selected by literature search based on inclusion and exclusion criteria, and a meta-analysis on different red blood cell parameters was performed., Results: Haematocrit, haemoglobin concentration, and RBC count show statistically significant findings with p values of (<0.00001), (p<0.00001) and (p=0.0004), respectively. Other parameters like MCV, MCH, and MCHC show statistically non-significant results with p values of 0.21, 0.36, and 0.63, respectively., Conclusion: Considering the above findings, the combination of haemoglobin concentration, haematocrit, and RBC counts could be used as reliable parameters to predict the presence of infection and included in the diagnostic strategy for malaria in children., Competing Interests: Declaration of competing interest 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, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematological malignancy with limited treatment options and poor prognosis. This case report presents the clinical course and management of a 62-year-old man with BPDCN in a resource-limited setting. The patient presented with constitutional symptoms and abnormal complete blood count findings. Initial treatment was performed with an acute lymphoblastic leukemia-based chemotherapy regimen, and the patient achieved complete remission, but the disease recurred 7 months after the initial diagnosis was confirmed in April 2022. The subsequent therapy was not effective, and the patient died during treatment. This case highlights the challenges in managing BPDCN and the need for further research to improve outcomes.

Aim: To generate a landscape of the current knowledge in the interventional management and outcomes of purulent skin and soft tissue infections., Design: This study is a scoping review., Methods: Electronic searches were undertaken using CINAHL, Medline, Cochrane Library, British Nursing Index, Science Direct, the National Health Service knowledge and library hub, ClinicalTrials.gov, and MedNar. The population, concept, context framework, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews were utilised, supporting a rigorous appraisal and synthesis of literature. Data Sources . The initial search and synthesis of literature were completed in January 2022 with repeat searches completed in March 2022 and July 2023. There were no imposed chronological parameters placed on the returned literature., Results: Nineteen papers were reviewed. Incision and drainage with primary closure, needle aspiration, loop drainage, catheter drainage, and suction drainage are viable adjuncts or alternatives to the traditional surgical management of skin and soft tissue abscesses., Conclusion: Despite the empirically favourable alternatives to the incision and drainage technique demonstrated, this does not appear to be driving a change in clinical practice. Future research must now look to mixed and qualitative evidence to understand the causative mechanisms of incision and drainage and its ritualistic practice. Implications . Ritual surgical practices must be challenged if nurses are to improve the treatment and management of this patient group. This will lead to further practice innovation. Impact : This study explored the challenges posed to patients, clinicians, nurses, and stakeholders, resulting from the ritualistic practice of the incision and drainage technique in purulent skin or soft tissue abscesses. Empirically and holistically viable alternatives were identified, impacting all identified entities and recommending a wider holistic study. Reporting Method . Adherence to EQUATOR guidance was achieved through the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2023 Liam Stout et al.)

Inflammatory biomarkers; C-reactive protein (CRP), Interleukin 6 (IL-6), and tumor necrosis factor- alpha (TNF-α) play a very crucial role in disease pathogenesis. Studies conducted earlier showed the associativity of these biomarkers with malaria severity. Meta-analysis of individual biomarkers was done in many studies, while in a few others, all these candidates were estimated, but the findings were inconclusive. Therefore, a systematic review and meta-analyses were performed to evaluate differences in biomarkers mentioned above in complicated and uncomplicated malaria patients. Studies focussed on CRP, IL-6, and TNF-α with quantitative data on complicated and uncomplicated malaria patients were searched on PubMed, Scopus, and Google Scholar. The quality of the studies selected for this review was checked following Newcastle-Ottawa Scale guidelines. The standard mean difference and confidence interval of biomarkers in the targeted groups were calculated using the random effects model. Egger's test and funnel plot asymmetry were performed to assess the publication bias. Thirteen studies that qualified the inclusion criteria were considered for this meta-analysis. CRP levels were higher in complicated malaria patients than uncomplicated ones (P < 0.00001, pooled SMD: 0.90 mg/L, 95 % CI: 0.51 to 1.30 mg/L, I 2 : 80 %, six studies). IL-6 levels were elevated in complicated cases (P < 0.00001, pooled SMD: 0.89 pg/ml, 95 % CI: 0.66 to 1.12, I 2 : 99 %, four studies) and TNF-α also showed an increase in severe complicated patients (P < 0.00001, pooled SMD: 1.18 pg/ml, 95 % CI: 1 to 1.36, I 2 : 99 %, six studies). In most of the included studies, CRP, IL-6, and TNF-α were higher in complicated malaria patients. Nevertheless, the results of a few studies were not convincing. Due to the lack of specificity in all individual biomarkers, none had adequate diagnostic accuracy. Considering the role of pro-inflammatory cytokines in the CRP activation pathway in malaria progression, the combination of these biomarkers should be used in monitoring the disease severity., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The International Council of Cardiovascular Prevention and Rehabilitation developed an International Cardiac Rehabilitation (CR) Registry (ICRR) to support CR programs in low-resource settings to optimize care provision and patient outcomes. This study assessed implementation of the ICRR, site data steward experience with on-boarding and data entry, and patient acceptability. Multimethod observational pilot involves (I) analysis of ICRR data from three centers (Iran, Pakistan, and Qatar) from inception to May 2022, (II) focus group with on-boarded site data stewards (also from Mexico and India), and (III) semistructured interviews with participating patients. Five hundred sixty-seven patients were entered. Based on volumes at each program, 85.6% of patients were entered in ICRR. 99.3% patients approached consented to participate. The average time to enter data at pre- and follow-up assessments by source was 6.8-12.6 min. Of 22 variables preprogram, completion was 89.5%. Among patients with any follow-up data, of four program-reported variables, completion was 99.0% in program completers and 51.5% in none; of 10 patient-reported variables, completion was 97.0% in program completers and 84.8% in none. The proportion of patients with any follow-up data was 84.8% in program completers, with 43.6% of noncompleters having any data entered other than completion status. Twelve data stewards participated in the focus group. Main themes were valuable on-boarding process, data entry, process of engaging patients, and benefits of participation. Thirteen patients were interviewed. Themes were good understanding of the registry, positive experience providing data, and value of lay summary and eagerness for annual assessment. Feasibility and data quality of ICRR were demonstrated., (© The Author(s) 2023. Published by Oxford University Press on behalf of International Society for Quality in Health Care.)

Background: Due to the differences in size and invasiveness when compared to non-giant macroadenomas (nGPAs), giant pituitary adenomas (GPAs) are considerably harder to resect. This study aimed to differentiate GPAs from nGPAs, based on the presenting complaints, surgical approaches, peri- and postoperative outcomes., Methods: We retrospectively analyzed cases of pituitary macroadenomas that underwent surgical resection at a tertiary care hospital. GPAs were tumors greater than 4 cm in the largest dimension, while nGPAs were tumors smaller than 4 cm. 55 GPA patients and 70 nGPA patients from 2006 to 2017 were included. Demographic, perioperative, and post-operative outcomes were evaluated. Group comparisons for continuous variables were made using an independent t-test/Mann Whitney U test and categorical data was analyzed on Chi-square/Fisher exact test; a p-value of < 0.05 was considered significant., Results: Visual deterioration was the most common complaint, reported by 61.4% of nGPA patients and 81.8% of GPA patients. The mean extent of gross total resection was 47.1% in nGPA patients and 18.2% in GPA patients (p = 0.001). After surgery, tumor recurrence was seen in 1.4% of nGPA patients and 18.2% of GPA patients (p = 0.001). First re-do surgery was required in 5.7% of nGPA patients and 25.5% of GPA patients (p = 0.004)., Conclusion: Compared to nGPAs, GPAs are more likely to present with a higher number of preoperative symptoms, and lesser chances of gross total tumor resection. GPAs are also associated with a higher rate of recurrence, which results in more follow-up procedures. Larger, multi-center longitudinal studies need to be done to validate these findings., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background No scoring system is available to predict the extent of resection of giant pituitary adenomas (GPAs) based on magnetic resonance imaging (MRI) parameters. We developed a novel AKU Giant Pituitary Adenoma (AGPA) score and assessed the predictive ability of the scoring system concerning the extent of resection of GPAs. Methodology We retrospectively collected data of patients presenting with GPAs and used our scoring system to assess the surgical resection of these tumors. The Lundin-Pederson (ABC/2) method was used to calculate the pre- and post-resection tumor volume. The relationship between the extent of resection and the AGPA score was assessed using linear regression. The AGPA score considered the tumor's extension into various planes. The maximum total score was 9. Results The scoring system was applied to 45 patients with GPA who underwent surgical resection. The mean resected tumor volume (%) was 82.0 ± 16.7, and the overall mean AGPA score was 4.2 ± 0.8. The pairwise correlation between the resected tumor volume and the overall AGPA scores showed a strong inverse association (r = -0.633, p < 0.001). A significant difference was detected between the estimated scores of 3 and 5 and 4 and 5 (p < 0.001). Conclusions AGPA score is inversely related to the extent of the tumor to be resected, which would help surgeons predict the amount of tumor resection possible as well as predict the difficulty of surgery and plan optimal preoperative patient counseling. In addition, it can predict if staging and a transcranial approach are required., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Enam et al.)

Community health worker (CHW) programs are essential for expanding health services to many areas of the world and improving uptake of recommended behaviors. One of these programs, called Accredited Social Health Activists (ASHA), was initiated by the government of India in 2005 and now has a workforce of about 1 million. ASHAs primarily focus on improving maternal and child health but also support other health initiatives. Evaluations of ASHA efficacy have found a range of results, from negative, to mixed, to positive. Clarity in forming a general impression of ASHA efficacy is hindered by the use of a wide range of evaluation criteria across studies, a lack of comparison to other sources of behavioral influence, and a focus on a small number of behaviors per study. We analyze survey data for 1,166 mothers from Bihar, India, to assess the influence of ASHAs and eight other health influencers on the uptake of 12 perinatal health behaviors. We find that ASHAs are highly effective at increasing the probability that women self-report having practiced biomedically-recommended behaviors. The ASHA's overall positive effect is larger than any of the nine health influencer categories in our study (covering public, private, and community sources), but their reach needs to be more widely extended to mothers who lack sufficient contact with ASHAs. We conclude that interactions between ASHAs and mothers positively impact the uptake of recommended perinatal health behaviors. ASHA training and program evaluation need to distinguish between individual-level and program-level factors in seeking ways to remove barriers that affect the reach of ASHA services., Competing Interests: The authors declare that no competing interests exist for this manuscript., (Copyright: © 2022 Burger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The timely reporting of adverse drug reactions (ADRs) could improve pharmacovigilance (PV) in a healthcare system. However, in almost all healthcare systems barriers exist that lead to the underreporting of ADRs. The objective of this study was to identify the barriers and facilitators regarding PV activities from the point of view of healthcare professionals (HCPs) in Lahore, Pakistan. A cross-sectional questionnaire-based survey was conducted between September 2018 to January 2019. The data was collected through convenience sampling of physicians, pharmacists, and nurses at tertiary care public hospitals in Lahore. A total of 384 questionnaires were distributed, and 346 HCPs responded to the survey. Over 62% percent of physicians and 54.8% of nurses agreed that they did not know how to report an ADR in their workplace. About 43.2% of pharmacists and 40.1% of nurses disagreed that they were not aware of the need for ADR reporting. Furthermore, 41.6% of nurses identified a lack of financial reimbursement and 51.8% highlighted a lack of support from a colleague as a reason that could lead to the underreporting of ADR. The majority of participants, including 69.6% physicians, 48.6% pharmacists, and 55.3% nurses identified the lack of knowledge about the existence of a national PV centre. Extra time for ADR reporting, incentives, continuous medical education, reminders, and availability of an online ADR reporting system was classed as the facilitators and were agreed upon by the majority of HCPs., Competing Interests: The authors have declared that no competing interests exist.

Background and objective Systemic lupus erythematosus (SLE) is one of the most devastating systemic autoimmune connective tissue diseases. There is a paucity of prospective data on Pakistani SLE patients, and in this prospective study, we aimed to investigate the disease course, clinical outcomes, and the predictors of poor outcomes in a random population-based cohort of newly diagnosed SLE patients (diagnosed within the last one year). Methods This was a prospective observational study carried out in the rheumatology department of the Fatima Memorial Hospital, Lahore. Lupus patients are regularly reviewed in our dedicated lupus clinic every one to three months. For the purpose of this study, a focus group of newly diagnosed patients (diagnosed within the last one year) attending our lupus clinic was identified and prospectively followed up for 12 months. A wide range of demographical and clinical parameters was recorded. The association of clinical variables with the progressive disease was determined using univariate and multivariate logistic regressions. Results Prospective data of 89 newly diagnosed SLE patients regularly attending our dedicated lupus clinic were reviewed. During the study period, (January 2021 through January 2022), these patients had multiple visits overall - median: five, minimum: three, and maximum: nine visits [interquartile range (IQR) 4-7]. All 89 patients had completed one year of follow-up. Of note, 46% of the cohort was noted to have an ongoing active disease during the majority of visits in the study period. On multiple logistic regression analysis, there was a significant association between ongoing active disease ("progressors") and low education status [odds ratio (OR): 2.81, 95% confidence interval (CI): 1.01-7.76, p=0.046], stress at home (OR: 5.8, 95% CI: 2.13-15.8, p=0.001), and hematologic manifestations (OR: 3.0, 95% CI: 1.08-8.32, p=0.03). Conclusions Almost half of our cohort of lupus patients demonstrated active disease manifestations throughout the one-year prospective follow-up, and these were found to be associated with low education status, stress at home, and hematological manifestations., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Ullah et al.)

Objective: To scrutinise the research proposals of medical residents fo inadequacies in writing dissertation synopsis., Methods: The analytical cross-sectional study was conducted at the regional centre of the College of Physicians and Surgeon Pakistan, Islamabad, Pakistan, and comprised synopsis from January t June 2020 of postgraduate residents attached wit different hospitals in Rawalpindi and Islamabad. For evaluation purposes, an institutional checklist was used that had domains: general, epidemiological, statistical, and bibliographical review. These were assessed by a single epidemiologist Data was analysed using SPSS 21., Results: Of the 400 research proposals, 224(56%) were submitted by male and 176(44%) by female residents. Also, 208(52% proposals were submitted by residents at public-sector hospitals, a 114(28.5%) by those at private-sector hospitals, while 78(19.5%) were from military hospitals. Significant association of errors was found with training institutions, speciality an duration of training (p<0.05). No gender difference was seen (p>0.05)., Conclusions: Majority of the research proposals lacke correcunderstanding of all the concepts related to research. Difference in research writing skills across specialties and trainin institutions may be related to the lack of availability o research assistance and good mentorship.

Aims We aimed to assess the level of non-adherence and poor illness perception among rheumatoid arthritis (RA) patients. Additionally, we examined their associations with clinical indicators and outcomes. Methods This was a cross-sectional study conducted using data collected at the time of patient enrolment in the Pakistan Registry of Rheumatic Diseases (PRIME) registry. A wide range of clinical variables was studied. To measure adherence, we used the Urdu version of the General Medication Adherence Scale (GMAS), which has recently been validated in RA patients. A Brief Illness Perception Questionnaire (BIPQ) was used to measure illness perception. Results The data of consecutive 320 RA patients were reviewed. Thirty-six percent of the cohort (n=116) was noted to have non-adherence. On multiple logistic regression analysis, a significant association of non-adherence was noted with moderate-to-severe stress (odds ratio {OR}: 1.85, confidence interval {CI}: 1.04-3.2), DAS-28 scores (OR: 1.83, CI: 1.52-2.21), Health Assessment Questionnaire (HAQ) scores (OR: 1.77, CI: 1.07-2.92), and deformed joint counts (OR: 1.30, CI: 1.15-1.46). Additionally, non-adherence due to "patient behavior" had a significant association with the male gender (OR: 0.48, CI: 0.26-0.87), unemployment (OR: 1.82, CI: 1.07-3.10), and stress at home (OR: 2.17, CI: 1.35-3.49). Twenty-six percent of the cohort (n=86) was noted to have the most negative illness perception, and on multiple logistic regression analysis, it was significantly associated with male gender (OR: 0.24, CI: 0.11-0.53), age of onset of arthritis (OR: 0.96, CI: 0.94-0.99), and worse HAQ scores (OR: 3.7, CI: 2.2-6.1). Conclusions Important adverse factors contributing to non-adherence and negative illness perception highlighted in this study were stress at home, female gender, and younger age of patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Hashmi et al.)

Background: Epilepsy is one of the most common but manageable neurological disorder. The relation between epilepsy, sleep, and health-related quality of life (HRQoL) in culturally distinct environment of Pakistan remains unclear. The purpose of this study was to determine prevalence and predictors of excessive daytime sleepiness (EDS), poor sleep quality (SQ), and to analyze their association with HRQoL in people with epilepsy (PWE)., Methods: A study was conducted among PWE attending two tertiary care hospitals of Islamabad and Rawalpindi, Pakistan. The EDS, SQ, and HRQoL were evaluated by Urdu versions of Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and Quality of Life in Epilepsy-31 (QOLIE-31)., Results: The study included 200 PWE and 51 healthy controls with mean (SD) ages of 33.1 ± 13.9, 32.9 ± 10.9, and a disease duration of 5.01 ± 6.17, respectively. The majority of the respondents (n = 130, 65%) had poor seizure control, and most of these (n = 88, 68%) were on combination antiepileptic drug (AED) therapy. In comparison to controls, a higher number of PWE had EDS by ESS (score ≥ 11, 10% vs. 40%, p-value 0.00), and poor SQ by PSQI (score > 5, 9% vs. 71%, p-value 0.00). A multiple logistic regression analysis reveals that the factors significantly associated with EDS were: female gender; increasing age; seizure control; duration of epilepsy; and combination AED therapy. A second multiple binary logistic regression analysis suggests that factors significantly associated with poor SQ were: increasing age; female gender; poor seizure control; and combination therapy. The Hierarchical multivariate analysis suggests that poor seizure control, EDS, and poor SQ were significant predictors of low HRQoL., Conclusion: The findings suggest high prevalence of EDS and poor SQ in PWE in Pakistan. A significant negative association exists between sleep complaints and HRQoL. During routine clinical consultations, awareness about sleep hygiene practices must be provided to enhance HRQoL., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Peripheral vascular diseases have a significant impact on functional quality of life. Previous research has demonstrated the complex, limiting and costly economic implications of these conditions such as lower limb ulceration chronicity and ischaemic amputation. These complex, limb and life threatening conditions demand the development of novel interventions with objective research as part of that development. Hence, a novel intermittent negative pressure medical device in the form of a wearable boot (FlowOx™) was developed. As part of the development process, this study aimed to explore patient and clinician opinions of the boot., Methods: A qualitative approach was used to collect patient and clinician experiences in Norway. An advisory group informed the semi-structured questions used in seven patient interviews and one clinician focus group (n = 5). The data were recorded digitally and transcribed verbatim. Patient and clinician data were analysed as distinct groups using a thematic process., Results: Data analysis resulted in five themes from the patients which gave insight into; the impact of the disease process; practicalities of using the boot, positive experiences of use; perceived outcomes; reflecting on use. Six themes were created from the clinicians. These gave insight into; ideal outcomes and how to measure them; ways to potentially use the boot; using research in healthcare; positives of the device; observed effects and next steps; potential improvements to the device., Conclusion: This study provides insight into the experiences and opinions of FlowOx™. Patients and clinicians were positive about the device due to its ease of use. Those patients with peripheral arterial disease experienced significantly more benefit, especially for ischaemic ulceration than those with a chronic venous condition. Clinicians placed value on the patient reported outcomes in the treatment decision-making process. This preliminary study into experiences of FlowOx™ use provides valuable feedback that will inform design modification and ongoing research into implementation points and prospective user groups. FlowOx™ demonstrates potential as a conservative therapy offering users a convenient, home use, self-care management solution for improving symptomatic peripheral arterial disease and quality of life., (© 2021. The Author(s).)

Objective: To assess the seroprevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Oman and longitudinal changes in antibody levels over time within the first 11 months of the coronavirus disease 2019 (COVID-19) pandemic., Methods: This nationwide cross-sectional study was conducted as a four-cycle serosurvey using a multi-stage stratified sampling method from July to November 2020. A questionnaire was used and included demographics, history of acute respiratory infection and list of symptoms, COVID-19 contact, previous diagnosis or admission, travel history and risk factors., Results: In total, 17,457 participants were surveyed. Thirty percent were female and 66.3% were Omani. There was a significant increase in seroprevalence throughout the study cycles, from 5.5% (4.8-6.2%) in Cycle 1 to 22% (19.6-24.6%) in Cycle 4. There was no difference in seroprevalence between genders, but significant differences were found between age groups. There was a transition of seroprevalence from being higher in non-Omanis than Omanis in Cycle 1 [9.1% (7.6-10.9%) vs 3.2% (2.6-3.9%)] to being higher in Omanis than non-Omanis in Cycle 4 [24.3% (21.0-27.9%) vs 16.8% (14.9-18.9%)]. There was remarkable variation in the seroprevalence of SARS-CoV-2 according to governorate. Close contacts of people with COVID-19 had a 96% higher risk of having the disease [adjusted odds ratio (AOR) 1.96, 95% confidence intervals (CI) 1.64-2.34]. Labourers had 58% higher risk of infection compared with office workers (AOR 1.58, 95% CI 1.04-2.35)., Conclusion: This study showed a wide variation in the spread of SARS-CoV-2 across governorates in Oman, with higher estimated seroprevalence in migrants in the first two cycles. Prevalence estimates remain low and are insufficient to provide herd immunity., Competing Interests: Conflict of interest statement None declared., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

It is an elegant albeit limited study reporting effects of pre op LVEF on long term results in patients with RHD undergoing DVR. Study includes 146 patients out of 201 who underwent DVR in the study period. Although all had some improvement immediate post op, those with preserved ejection fraction (EF) and smaller left ventricles regardless of type of prostheses used, surgical techniques (partial or full Subvalvular Apparatus Preservation), had more sustained improvement after 3-4 years than those with lower EF and more dilation. It can be partially explained by more prevalence of aortic insufficiency in patients with pre op lower EF <50 and dilation (average left ventricular end systolic dimension 49 vs. 32 mm in EF >50). There are myocardial factors which also play a part, those with abnormal left ventricle (LV) function have more extensive loss of myofibrils either due to disproportion of mitochondria-to-myofibril ratio or myofibrillar degeneration exhibiting the extent RHD involves myocardium. Structural adaptation may not all be just a result of hemodynamic abnormalities in these patients. The recommendation that surgical intervention should occur before the LV starts to dilate or EF drops is well founded and would be impactful in the developing world, an estimated 250,000 deaths occur annually worldwide and 10.5 million disability adjusted life years due to RHD, mostly in young people., (© 2021 Wiley Periodicals LLC.)

The sustainable financial behavior and financial well-being have been a key concern among the developing societies; thereby encompassing the various psychological factors which play a role in influencing individual's positive financial behavior and financial well-being, this study is conducted. Research focusing on the psychological aspect of human financial behavior and well-being is scarce, focusing more on the cognitive side such as financial literacy and numeracy. The aim of this research study is to find the role played by the non-cognitive factors such as self-esteem, self-control, optimism and deliberative thinking, in forming the financial behavior and financial well-being of the young adults. A sample of 429 university students from public and private sector was collected via an online and field survey using purposive sampling technique. The survey contained measures for demographics, self-esteem, optimism, deliberative thinking, self-control, general financial behavior and financial well-being. SPSS and PLS-SEM tools were used for the exploration of the relationships among dependent and independent variables. The results of PLS path analysis demonstrate that among the non-cognitive factors, self-control and deliberative thinking show a significant association with both financial behavior, and financial security. Self-esteem plays no significant role in forming the financial behavior of the young adults when all the variables are taken together but it exhibits a significant association with financial well-being (financial security and financial anxiety). Optimism on the other hand exhibits no significant association with both financial behavior and financial well-being (financial security and financial anxiety). The results of this study complement the previous studies and also put forth new outcomes. This research is unique as it is the first of its kind conducted in a consumption-oriented economy like Pakistan. In addition to the previous studies which have often established the link of self-esteem with general well-being, this study goes further by analyzing the association between self-esteem and financial well-being and by the identification of the role played by non-cognitive factors like self-esteem, optimism, deliberative thinking and self-control together on the financial behavior and financial well-being of the individuals using PLS-SEM approach., Competing Interests: The authors have declared that no competing interests exist.

Aerobic glycolysis in cancer cells, also known as the 'Warburg effect', is driven by hyperactivity of lactate dehydrogenase A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is unclear whether a dedicated intracellular protein also regulates its activity. Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. A flexible loop within the amino terminus of FLCN controls movement of the LDHA active-site loop, tightly regulating its enzyme activity and, consequently, metabolic homeostasis in normal cells. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Treatment of these cells with a decapeptide derived from the FLCN loop region causes cell death. Our data suggest that the glycolytic shift of cancer cells is the result of FLCN inactivation or dissociation from LDHA. Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background Community pharmacists' role in the primary health care, patient-centered services, beyond traditional dispensing services is well established in the developed world. However, this role is not fully established in low-middle-income countries including Pakistan. Objective To explore community pharmacists' perspectives and preparedness about practice change and associated facilitators and barriers to extended services. Setting A study was conducted involving community pharmacists of Lahore, Pakistan. Method Two phased studies were conducted using mixed-method sequential design. The first phase involved qualitative semi-structured face-to-face interviews with the community pharmacists, while the second phase constituted a questionnaire-based cross-sectional study. Main outcome measure Pharmacists' perspectives about extended pharmacy services, facilitators, barriers and preparedness for the practice change. Results For the first phase, pharmacists were purposively sampled and the saturation yielded a final sample size of fifteen pharmacists (N = 15). The thematic content analysis yielded four distinct themes; (1) current practices and familiarity with extended pharmacy services (2) practice gap between Pakistan and the developed countries (3) facilitators and the preparedness, and (4) barriers towards its implementation and provision. The second part was a questionnaire-based cross-sectional phase, where a total of 348 community pharmacists were approached, while only 242 responded, yielding a response rate of 69.5%. The triangulation of qualitative and quantitative data identified several barriers such as; shortage of pharmacists, lack of knowledge and skills, poor collaboration with general practitioners, failure of customers to pay for extended services. Facilitators and preparedness for the provision of extended pharmacy services were; access to patient notes, follow-up, separate counselling areas, accreditation of specific services and sufficient resources. Conclusion This study's findings call for the implementation and enforcement of Punjab Drug Sale Rules 2007 to facilitate the practice change and provision of comprehensive pharmacy services in Punjab, Pakistan. There is a need for additional laws to define community pharmacists' roles, uniform job description, training, new funding model, separate area, and accreditation of extended pharmacy services in Pakistan., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.)

Objectives: The study aimed to assess the knowledge, attitude and practices (KAP) of HCPs regarding the use of probiotics in different health conditions and to identify various barriers that are associated with their use., Methods: A cross-sectional study was conducted on 405 HCPs by using a validated self- administered questionnaire for assessing their KAP towards probiotic use. The study data were analysed using descriptive statistics, χ 2 test and binary logistic regression (BLR)., Results: Among the 405 participants, only 15.1 % of HCPs had good knowledge, while 15.6% had acceptable practices and 89.1% had a positive attitude towards probiotics. The professional position of HCPs was significantly associated with knowledge (p=0.001) and practice (p=0.001). Among all the HCPs, the pharmacists showed a significant association with good knowledge (p=0.016) and good practices (p=0.024) by using BLR. The lack of knowledge about probiotics was a major barrier to the utilisation of probiotics., Conclusions: The poor knowledge and practices regarding the use of probiotics have been seen in the current study. While the participants showed a positive attitude towards the utilisation of probiotics. To transform HCPs' positive attitude to their practices and to create awareness regarding probiotic use focused training programmes should be initiated by professional health organisations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The current study aims to assess the beliefs of the general public in Pakistan towards conspiracy theories, acceptance, willingness to pay, and preference for the COVID-19 vaccine. A cross-sectional study was conducted through an online self-administered questionnaire during January 2021. The Chi-square test or Fisher exact test was utilized for statistical data analysis. A total of 2158 respondents completed the questionnaire, among them 1192 (55.2%) were male with 23.87 (SD: ±6.23) years as mean age. The conspiracy beliefs circulating regarding the COVID-19 vaccine were believed by 9.3% to 28.4% of the study participants. Among them, 1040 (48.2%) agreed to vaccinate on its availability while 934 (43.3%) reported the Chinese vaccine as their preference. The conspiracy beliefs of the participants were significantly associated with acceptance of the COVID-19 vaccine. The existence of conspiracy beliefs and low vaccine acceptance among the general population is a serious threat to successful COVID-19 vaccination.

Patients diagnosed with metastatic renal cell carcinoma (RCC) have ∼12% chance for 5-year survival. The integrity of the extracellular matrix (ECM) that surrounds tumor cells influences their behavior and, when disturbed, it could facilitate local invasion and spread of tumor cells to distant sites. The interplay between von Hippel-Lindau/hypoxia inducible factor signaling axis and activated kinase networks results in aberrant ECM and tumor progression. Matrix metalloproteinases (MMPs) are proteolytic enzymes implicated in ECM remodeling, tumor angiogenesis, and immune cell infiltration. Understanding the cross-talk between kinase signaling and ECM proteolysis in RCC could provide insights into developing drugs that interfere specifically with the process of invasion. In this review, we discuss changes in the MMPs/ECM axis in RCC, prominent kinase signaling pathways implicated in MMPs induction, and comment on emerging extracellular regulatory networks that modulate MMPs activity., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Health-related quality of life (HRQoL) is considered to be the fourth 90 of UNAIDS 90-90-90 target to monitor the effects of combination antiretroviral therapy (ART). ART has significantly increased the life expectancy of people living with HIV/AIDS (PLWHA). However, the impact of chronic infection on HRQoL remains unclear, while factors influencing the HRQoL may vary from one country to another. The current study aimed to assess HRQoL and its associated factors among PLWHA receiving ART in Pakistan., Methods: A cross-sectional descriptive study was conducted among PLWHA attending an ART centre of a tertiary care hospital in Islamabad, Pakistan. HRQoL was assessed using a validated Urdu version of EuroQol 5 dimensions 3 level (EQ-5D-3L) and its Visual Analogue Scale (EQ-VAS)., Results: Of the 602 patients included in the analyses, 59.5% (n = 358) reported no impairment in self-care, while 63.1% (n = 380) were extremely anxious/depressed. The overall mean EQ-5D utility score and visual analogue scale (EQ-VAS) score were 0.388 (SD: 0.41) and 66.20 (SD: 17.22), respectively. Multivariate linear regression analysis revealed that the factors significantly associated with HRQoL were: female gender; age  > 50 years; having primary and secondary education;  > 1 year since HIV diagnosis; HIV serostatus AIDS-converted; higher CD 4 T lymphocytes count; detectable viral load; and increased time to ART., Conclusions: The current findings have shown that PLWHA in Pakistan adherent to ART had a good overall HRQoL, though with significantly higher depression. Some of the factors identified are amenable to institution-based interventions while mitigating depression to enhance the HRQoL of PLWHA in Pakistan. The HRQoL determined in this study could be useful for future economic evaluation studies for ART and in designing future interventions.

Introduction: Like many other countries, Pakistan's healthcare system is divided into the public and the private sector. According to some studies and the mindset of many Pakistani people, private hospitals provide better services than government hospitals., Purpose: The paucity of research studies compelled us to compare the understanding of prescription among outpatients of the government and private hospitals since the understanding of prescription by the patient is an important patient care indicator according to WHO., Method: A cross sectional study was conducted by virtue of convenience sampling. The study included 365 patients; 182 from the government sector and 183 from the private sector. The study was conducted over a period of 3 months. A structured questionnaire was prepared to gather data that was analyzed using SPSS Version 22.0., Results: Patients from both government and private hospitals got no counseling while only 45.9% of the government hospital patients and 65.9% of private hospital patients were satisfied with the counseling they received. Our study concluded that the role of a pharmacist must be extended besides dispensing only, in counseling and educating patients to reduce the burden on the physicians and hospitals as well., Conclusion: It was concluded that although the patients of private hospitals scored somewhat better at answering the questions than the government hospital patients but they failed to hit the benchmark. Their slightly better results were attributed to higher education levels and better socioeconomic status rather than better services of the hospital., (Copyright © 2021 FECA. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: The excessive consumption of antibiotics is a significant contributor to antimicrobial resistance, especially in children. Children are often advised antibiotics for viral infections. In developing countries, drugstores are a prime source of easy access to nonprescription antibiotics. Moreover, in Pakistan, their irrational use is an "everyday routine". The study, therefore, aimed to evaluate the dispensing of nonprescription antibiotics to children., Methods: Using pediatric acute diarrhea and acute upper respiratory infection as disease scenarios, a simulated client, cross-sectional study was conducted in Lahore, Pakistan, to explore the antibiotics' ease of availability at both categories of drugstores (pharmacies and medical stores) from November 1st, 2019 to January 31st, 2020. Chi-square ( χ 2 ) test was used to compare the differences in practices of different categorical variables. Multivariable logistic regression was applied to analyze the association of various factors with antibiotics dispensing., Results: Antibiotics were dispensed without prescription in 456 (59%) of 773 simulated visits out of which 425 (93.2%) were dispensed on the advice of the drugstore staff. A qualified pharmacist was available in only 164 (21.2%) cases. Of the 386 visits for acute diarrhea and 387 for acute upper respiratory infection, nonprescription antibiotic dispensing occurred in 259 (67.1%) and 197 (50.9%) visits, respectively. There were considerable differences (p-value <0.05) in the practices and antibiotics dispensing between each disease scenario presented. Moreover, antibiotics were less commonly dispensed at pharmacist-supervised drugstores compared to unsupervised ones., Conclusion: Overall, inappropriate dispensing practices were prevalent to a large extent at the drugstores, and antibiotics were effortlessly obtainable without prescription. The quality of the services provided, especially by the non-pharmacist staff, was also not satisfactory. Therefore, the Drug Regulating Authority of Pakistan must enforce strict implementation of drug laws at the drugstores without delay, especially in major cities to help curb the felonious use of antibiotics., Competing Interests: The authors declare that they have no competing interests., (© 2021 Malik et al.)

Background: Reliable Health-Related Quality of Life (HRQoL) assessment will be useful in identifying health issues and in identifying health care actions. Due to the lack of a psychometrically valid tool in Urdu, we aim to translate and examine the psychometric and cross-cultural adaptation of WHOQOL HIV Bref among people living with HIV/AIDS (PLWHA) in Pakistan., Methods: The standard forward-backwards translation technique was used to convert English version of the WHOQOL HIV Bref into Urdu. After cognitive debriefing, final Urdu version of instrument was developed. Based on the principle of at least 5 subjects for each item, a sample of 182 patients was used using a universal random sampling technique from the Pakistan Institute of Medical Sciences, Islamabad. The Cronbach's alpha and intra-class correlation coefficients (ICC) were estimated to assess internal validity and reliability of the translated version. Exploratory factor analysis was carried out to determine the factor structure and independent associations between the instrument domains and CD-4T-cell count were assessed using multivariable linear regression RESULTS: High Cronbach alpha 0.93 was found for all WHOQOL HIV Bref facets. The test-retest reliability demonstrated a statistically significant ICC ranged from 0.88 to 0.98 (p < 0.001). In known group validity, lower CD-4 lymphocytes count was significantly related to poor scores for all six domains (p < 0.001). Similarly, symptomatic subjects had significantly lower scores compared to asymptomatic subjects on the physical, psychological, social relationship and independence domains (p < 0.05). Statistically significant positive correlation of all six domains of instrument with CD4 cells count (p < 0.001), exhibiting patients with higher CD-4 cells will have higher mean scores of all domains. Factor analysis revealed 5 domains, including physical health, psychological health, social relationship, environmental, and spiritual health. Multivariable linear regression analysis reported; only physical, psychological health and environment health domains were found significantly associated with higher CD-4 lymphocytes count (Beta = 0.121, p < 0.001, Beta = 0.103, p = 0.002, and Beta = 0.032, p = 0.032)., Conclusion: Findings suggested that the Urdu version of WHOQOL HIV Bref is a psychometrically valid and culturally well-adapted HRQoL measurement tool for PLWHA in Pakistan.

Background: Critical limb ischaemia is a severe stage of lower limb peripheral artery disease which can lead to tissue loss, gangrene, amputation and death. FlowOx™ therapy is a novel negative-pressure chamber system intended for home use to increase blood flow, reduce pain and improve wound healing for patients with peripheral artery disease and critical limb ischaemia., Methods: A Markov model was constructed to assess the relative cost-effectiveness of FlowOx™ therapy compared to standard care in lower limb peripheral artery disease patients with intermittent claudication or critical limb ischaemia. The model used data from two European trials of FlowOx™ therapy and published evidence on disease progression. From an NHS analysis perspective, various FlowOx™ therapy scenarios were modelled by adjusting the dose of FlowOx™ therapy and the amount of other care received alongside FlowOx™ therapy, in comparison to standard care., Results: In the base case analysis, consisting of FlowOx™ therapy plus nominal care, the cost estimates were £12,704 for a single dose of FlowOx™ therapy per annum as compared with £15,523 for standard care. FlowOx™ therapy patients gained 0.27 additional quality adjusted life years compared to standard care patients. This equated to a dominant incremental cost-effectiveness ratio per QALY gained. At the NICE threshold WTP of £20,000 and £30,000 per QALY gained, FlowOx™ therapy in addition to standard care had a 0.80 and 1.00 probability of being cost-effectiveness respectively., Conclusions: FlowOx™ therapy delivered as a single annual dose may be a cost-effective treatment for peripheral artery disease. FlowOx™ therapy improved health outcomes and reduced treatment costs in this modelled cohort. The effectiveness and cost-effectiveness of FlowOx™ therapy is susceptible to disease severity, adherence, dose and treatment cost. Research assessing the impact of FlowOx™ therapy on NHS resource use is needed in order to provide a definitive economic evaluation., Competing Interests: HH is employed by Otivio AS with funding from The Research Council of Norway (grant no. 285758). Otivio AS has the commercial rights to the INP technology used in this study. The authors alone are responsible for the content and writing of the paper. We adhere fully to PLOS ONE policies on sharing data and materials.

Background: Spontaneous reporting of adverse drug reactions (ADRs) is a method of monitoring the safety of drugs and is the basic strategy for the post-marketing surveillance of the suspected drugs. Despite its importance, there is very little reporting of ADRs by healthcare professionals. The present study has evaluated the knowledge, attitude and practices of health care professionals (HCPs) regarding pharmacovigilance activities in Lahore, Pakistan., Methods: A cross-sectional questionnaire-based survey was employed, and a convenience sampling was opted to collect the data among physicians, pharmacists and nurses working in tertiary care public hospitals of Lahore, Pakistan from September 2018 to January 2019., Results: Of the 384 questionnaires distributed, 346 health care professionals responded to the questionnaire (90.10% response rate). Most participants had good knowledge about ADR reporting, but pharmacist had comparatively better knowledge than other HCPs regarding ADR (89.18%) pharmacovigilance system (81.08%), its centres (72.97%) and function (91.89%). Most of the participants exhibited positive attitude regarding ADR reporting, such as 49.1% of physicians (P < 0.05), 70.2% pharmacists and 76.1% nurses showed a positive attitude that they are the most important HCPs to report an ADR. About 64.3% of physicians (P < 0.05) emphasized that consulting other colleagues is important before reporting an ADR. Of all, 77.7% physicians, 75.7% pharmacists and 68% of nurses had positive attitude that ADR reporting is a professional obligation and 67.6% of the pharmacists stated that they have reported ADRs in their workplace and 77.2% nurses have verbally reported ADRs to the concerned personnel or department., Conclusion: Among all HCPs, pharmacists had better knowledge about ADR reporting and pharmacovigilance. All HCPs had positive attitude and inclination towards ADR reporting. The discrepancies were observed in the practices related to ADR reporting, whereas most of the participants including physicians and nurses did not report any ADR. Based on the above, strategies are needed to educate, train, and empower the HCPs in the domain of pharmacovigilance.

Background and Purpose: Over the past few decades, the focus of pharmacy practice has been shifted from the classical role of drug dispenser to pharmacotherapy expert. Pharmacists now are more often involved in the patient care process by addressing the drug-related needs of the patients and this patient-centered approach is known as pharmaceutical care (PC). The present study was conducted to assess the attitude of pharmacy undergraduate students toward PC and various contributing factors that influence their preference towards it., Method and Instrument: A descriptive cross-sectional study was conducted in 422 undergraduate pharmacy students by using a simple random sampling method. A pre-validated and self-reported Pharmaceutical Care Attitude Scale (PCAS) was used for assessing a student's attitude towards PC., Results: Amongst the 422 undergraduate students, the majority were males (68.2%) and 70.4% were between the age group of 20 and 25 years. The students studying in third, fourth, and fifth year (final year) were 140 (33.2%), 142 (33.6%), and 140 (33.2%), respectively. Overall participant showed a positive attitude toward the PC. Professional year showed significant influence on professional duties (PD) (p<0.001) and age was significantly associated with return on efforts (ROE) (p<0.001) and professional benefits (PB) (p<0.001)., Conclusion: Most of the participants showed a positive attitude toward PC and showed motivation to practice it. To promote PC practice in Pakistan, the government along with other professional bodies like Pakistan Pharmacists Association (PPA) should work together in collaboration with global health agencies to develop a well-structured advanced healthcare system in which there is a defined role of PC practice., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Hussain et al.)

Introduction: With the increase in the incidence rate of COVID-19, healthcare professionals (HCPs) being at the frontline of the outbreak response are at higher risk of getting exposure and suffering from the infection. The present study aimed to evaluate the knowledge, attitude, and precautionary practices of HCPs towards COVID-19., Methodology: The current study was a descriptive, cross-sectional, online study directed to the HCPs working in a metropolitan city of Karachi, during February 2020 and March 2020 using a self-administered questionnaire. A systematic random sampling approach was adopted., Results: A total of 286 completed surveys were incorporated in the investigation with a response rate of 74.28%. The median (interquartile range, IQR) knowledge score was 18.79 (17.64-19.57). Physicians were found to be more knowledgeable (OR: 1.32, 95% CI: 0.17-4.26, p = 0.003) as compared to other HCPs. Similarly, the HCPs working in private work settings (OR: 1.94, 95% CI: 1.54-2.79, p=0.001), having more experience (OR = 1.82; 95% CI = 1.64-2.78; p < 0.005) were found to be more well-informed than HCPs working in public sector (OR = 0.81; 95% CI = 0.63-0.72; p = 0.004). The correlation between the knowledge and attitude of respondents was found to be significantly correlated (correlation coefficient: 0.13, p < 0.005)., Conclusions: The findings of the study revealed that HCPs were well conversant and have an optimistic attitude towards COVID-19. Further contemplates are required to evaluate the understanding of HCPs at a national level so that viable mediations could be planned to combat this pandemic., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2020 Sadia Shakeel, Hina Rehman, Mohammad Azmi Hassali, Faraz Hashmi.)

Developed countries have established pharmacovigilance systems to monitor the safety of medicines. However, in the developing world, drug monitoring and reporting are facing enormous challenges. The current study was designed to explore the challenges related to the understanding and practices of physicians in reporting adverse drug reactions in Lahore, Pakistan. Through the purposive sampling technique, 13 physicians were interviewed. All interviews were audio-recorded, transcribed verbatim, and analyzed for a thematic content analysis. The thematic content analysis yielded six major themes: (1) Familiarity with medication safety and adverse drug reaction (ADR) concept, (2) Knowledge about pharmacovigilance activities, (3) Practices related to ADR reporting, (4) Barriers impeding ADR reporting, (5) Acknowledgement of the pharmacist's role, and (6) System change needs. The majority of the physicians were unaware of the ADR reporting system; however, they were ready to accept practice changes if provided with the required skills and training. A lack of knowledge, time, and interest, a fear of legal liability, poor training, inadequate physicians' and other healthcare professionals' communication, and most importantly lack of a proper reporting system were reported as barriers. The findings based on emerging themes can be used to establish an effective pharmacovigilance system in Pakistan. Overall, physicians reported a positive attitude towards practice changes, provided the concerned authorities support and take interest in this poorly acknowledged but most needed component of the healthcare system., Competing Interests: The authors declare no conflict of interest.

Aims: This article examines the outputs of pharmaceutical education with the development of the pharmacy profession and how that affects pharmaceutical innovation. It also discusses different models of collaboration between the academic and pharmaceutical industry in order to achieve a healthy collaboration between the stakeholders., Methods: The perspective, experiences and insights of educators from various backgrounds, origin and educational levels were sought regarding the role of pharmacy education in providing pharmaceutical research and development workforce., Results: Many countries around the world are currently undertaking major reforms in pharmacy education due to the changing landscape of health and healthcare delivery. These reforms must be accompanied by robust systems to assure that the quality of educational structures, processes and outcomes will produce competent pharmacy graduates in the future. It is also considered imperative that pharmacy academic institutions should establish collaboration with the drug development units, the pharmaceutical industry and government agencies for sustainability and positive research outcomes., Conclusion: Shortcomings in pharmacy curricula need to be addressed and the authors have proposed the 'TARGET' approach for the development of integrated pharmacy curriculum to substantially contribute to pharmaceutical research and development.

The extracellular molecular chaperone heat shock protein 90 (eHSP90) stabilizes protease client the matrix metalloproteinase 2 (MMP2), leading to tumor cell invasion. Although co-chaperones are critical modulators of intracellular HSP90:client function, how the eHSP90:MMP2 complex is regulated remains speculative. Here, we report that the tissue inhibitor of metalloproteinases-2 (TIMP2) is a stress-inducible extracellular co-chaperone that binds to eHSP90, increases eHSP90 binding to ATP, and inhibits its ATPase activity. In addition to disrupting the eHSP90:MMP2 complex and terminally inactivating MMP2, TIMP2 loads the client to eHSP90, keeping the protease in a transient inhibitory state. Secreted activating co-chaperone AHA1 displaces TIMP2 from the complex, providing a "reactivating" mechanism for MMP2. Gene knockout or blocking antibodies targeting TIMP2 and AHA1 released by HT1080 cancer cells modify their gelatinolytic activity. Our data suggest that TIMP2 and AHA1 co-chaperones function as a molecular switch that determines the inhibition and reactivation of the eHSP90 client protein MMP2., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The prevalence of unused medications in homes has dramatically increased in recent decades, which has resulted in medication wastage. The aim of this study is to review the prevalence of unused medications in homes and to determine the reasons behind this disuse, so as to help reduce such wastage. The review also sheds light on current methods of disposal of unwanted medications. Here, using a narrative review, we provide an overview of the issues of unused medications, medication wastage, and methods of disposal. We conducted an extensive literature search focusing on subject-related keywords, as given in the methods section below. A search was undertaken through indexing services available in the library of the authors' institution. Full-text papers concerned with the prevalence of unused medications in homes, written in English language between 1992 and 2018, were retrieved and reviewed. Twenty-five related studies performed in different world regions were reviewed and included. The public, healthcare providers, and governments are all accused of promoting medication wastage in different ways, and thus, they need to be targeted to solve the problem. It was also noticed that the prevalence of unused medications is high in many countries. Non-steroidal anti-inflammatory drugs are among the most frequently wasted medications, and most of the public just dispose of their expired medications in the trash or toilet. Non-adherence, death, and medication change are among the main causes of medication accumulation and consequent wastage. A lack of policies to return unwanted medications in some countries, as well as public unawareness, carelessness, or illiteracy, are reasons for improper disposal of unused medications that may lead to adverse economic and environmental impacts. Various mitigation strategies (e.g., smart medicine cabinet) have emerged to reduce medication wastage. Joint work among the public, healthcare providers, and various governmental and private organizations is needed to adequately address the issue of medication wastage.

Introduction: Health care services use surveys to assess patient satisfaction and identify areas for improvement. While it is important to assess patient satisfaction to ensure their needs are met, lengthy questionnaires with closed-ended questions often focus on areas that may be considered important by institutions rather than patients. Recently, focus has shifted toward patient and caregiver experience, which institutions address via appreciative inquiry. The aim of this initiative was the development of a patient experience survey (PES) for radiation therapy patients and caregivers which would allow them to express their opinions and priorities. This patient feedback would then be addressed through quality improvement (QI) projects geared toward improving the overall patient and caregiver experience in radiation therapy., Methods: A three-question minute survey was developed for use as a PES in the radiation therapy department of an academic oncology program located in a large metropolitan area. Feedback was obtained from patient education and person-centred care experts, as well as 10 radiation therapy patients. All feedback was incorporated to create the final PES; respondents rated their agreement on a five-point Likert scale with the statement "My overall experience in Radiation Therapy was great" and two open-ended questions allowed them to highlight departmental strengths and areas for improvement. An initial 3-month pilot was conducted where PESs were available on a self-serve basis to patients and caregivers in waiting areas and at radiation therapy treatment units. All responses were anonymous and completed surveys were returned via drop boxes. Descriptive statistics and thematic analysis were used to analyse responses., Results: A total of 86 surveys were returned. Of those, 80 (93%) responded to the Likert scale question with 83% agreeing or strongly agreeing that their experience in radiation therapy was great. Several strengths were identified by respondents including teamwork, professionalism, and knowledge. Areas identified for improvement included management of appointment delays and communication of delays to patients, as well as environmental improvements., Conclusions: Although most respondents reported a favourable experience, this pilot demonstrated the minute survey can identify areas for improvement that can be addressed through QI. Including the patient perspective in QI is evidenced to enhance its outcome and aligns with institutional, provincial, and national strategic goals of improving the quality of cancer care through patient engagement., (Copyright © 2018. Published by Elsevier Inc.)

Background: Medication safety is a major public health concern and there are well established pharmacovigilance programmes in developed countries. However, there is scarcity of literature on the issue in low and middle income countries. In this context, the current study was aimed to evaluate the knowledge, attitudes and practices of hospital pharmacists towards medication safety and ADR reporting in Lahore, Pakistan., Methods: A qualitative approach was used to conduct this study. A semi-structured interview guide was developed, 10 hospital pharmacists were recruited and interviewed through convenience sampling technique. All interviews were audio-taped, transcribed verbatim, and were then analyzed for thematic contents analysis., Results: Thematic content analysis of the interviews resulted in 6 major themes, including (1) Familiarity with medication safety & adverse drug reaction concept (2) Current system of practice and reporting of adverse drug reaction in hospital setting, (3) Willingness to accept the practice change (4) Barriers to adverse drug reaction reporting, (5) Policy change needs and (6) The recognition of the role. Majority of the hospital pharmacists were familiar with the concept of medication safety and ADR reactions reporting however they were unaware of the existence of national ADR reporting system in Pakistan. Several barriers hindering ADR reporting were identified including lack of awareness and training, communication gap between the hospitals and regulatory authorities., Conclusion: The study revealed that that hospital pharmacists were good in understanding of medication safety and ADR reporting; however they don't practice this in real sense. The readiness of the hospital pharmacist towards the practice change has indicated that they are all set to be actively involved in the provision of medication safety in hospital setting. Involvement of key stake holders from ministry of health, academia, pharmaceutical industry and healthcare professionals is warranted to promote safe and effective use of medicines., Competing Interests: The study was given the approval by Humans Ethics Committee (HEC), University College of Pharmacy, University of the Punjab, Lahore, Pakistan with reference no. HEC/PUCP/1943.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: An improved understanding of the structural and functional development of the paediatric foot is fundamental to a strong theoretical framework for health professionals and scientists. An infant's transition from sitting, through crawling and cruising, to walking is when the structures and function of the foot must adapt to bearing load. The adaptation of skin and other hard and soft tissue, and foot and gait biomechanics, during this time is poorly understood. This is because data characterising the foot tissue and loading pre-walking onset does not exist. Of the existing kinematic and plantar pressure data, few studies have collected data which reflects the real-life activities of infants with modern equipment., Methods: This is a longitudinal study and part of the Great Foundations Initiative, a collaborative project between the University of Brighton and the University of Salford, which is seeking to improve foot health in children. Two cohorts of 50 infants will be recruited at the two sites (University of Brighton, Eastbourne, UK and University of Salford, Salford, UK). Infants will be recruited when they first reach for their feet and attend four laboratory visits at milestones related to foot loading, with experienced independent walking being the final milestone. Data collection will include tissue characteristics (skin thickness, texture, elasticity, pH and tendon thickness and cross-sectional area), plantar pressures and kinematics captured during real world locomotion tasks., Discussion: This study will provide a database characterising the development of the infant foot as it becomes a weight bearing structure. The data will allow effective comparison and quantification of changes in structure and function due to maturation and loading by measuring pre and post established walking. Additional variables which impact on the development of the foot (gender, ethnicity and body weight) will also be factored into our analysis. This will help us to advance understanding of the determinants of foot development in early childhood., Competing Interests: Ethical approval for the studies has been gained and, as described, consent on behalf of participants will be obtained for the study.Consent for publication will be obtained from parents or their legal guardian of participants as part of the informed consent process.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Recognising structural and functional development of the paediatric foot is fundamental to ensuring a strong theoretical framework for health professionals and scientists. The transition of an infant from sitting to walking takes approximately 9 months and is when the structures and function of the foot must respond to the challenges of bearing load; becoming increasingly more essential for locomotion. Literature pertaining to the phase of development was searched. A narrative approach synthesised the information from papers written in English, with non-symptomatic infant participants up to the development stage of independent walking or two years of age. A range of literature was identified documenting morphological, physiological, neuromuscular and biomechanical aspects of the infant within this phase of development. The progression of variable gait to a regular pattern is documented within a range of studies focusing on neuromuscular control and ambulation development. However, methodological approaches may have compromised the external validity of such data. Additionally, limited consideration for the specific function and development of the foot is evident, despite its role as the primary site of weight bearing and interface with the floor. A lack of consideration of infants prior to ambulation (i.e. before cruising or walking) is also apparent which prevents a reference baseline being used effectively. This review also identifies future research priorities such that a comprehensive understanding of foot development from a non-weight bearing to a weight bearing structure during locomotor advancement can be gained., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Verrucae are a common foot skin pathology, which can in some cases persist for many years. Plantar verrucae can be unsightly and painful. There are a range of treatment options including needling., Objectives: The EVerT2 (Effective Verruca Treatments 2) trial aimed to evaluate the clinical and cost-effectiveness of the needling procedure for the treatment of plantar verrucae, relative to callus debridement., Methods: This single-centre randomized controlled trial recruited 60 participants (aged ≥ 18 years with a plantar verruca). Participants were randomized 1 : 1 to the intervention group (needling) or the control group (debridement of the overlying callus). The primary outcome was clearance of the index verruca at 12 weeks after randomization. Secondary outcomes included recurrence of the verruca, clearance of all verrucae, number of verrucae, size of the index verruca, pain and participant satisfaction at 12 and 24 weeks. A cost-effectiveness analysis was carried out from the National Health Service perspective over 12 weeks., Results: Sixty eligible patients were randomized (needling group n = 29, 48%; debridement group n = 31, 52%) and 53 were included in the primary analysis (needling n = 28, 97%; debridement n = 25, 81%). Clearance of the index verruca occurred in eight (15%) participants (needling n = 4, 14%; debridement n = 4, 16%; P = 0·86). The needling intervention costs were on average £14·33 (95% confidence interval 5·32-23·35) more per patient than for debridement., Conclusions: There is no evidence that the needling technique is more clinically or cost-effective than callus debridement. The results show a significant improvement in pain outcomes after needling compared with the debridement treatment alone., (© 2017 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor or vanilloid receptor 1 (VR1), is expressed in nociceptive neurons in the dorsal root ganglia (DRG) and participates in the transmission of pain. The present study investigated the underlying molecular mechanisms by which TRPV1 was regulated by nerve growth factor (NGF) signaling pathways in colonic hypersensitivity in response to colitis. We found that during colitis TRPV1 protein levels were significantly increased in specifically labeled colonic afferent neurons in both L1 and S1 DRGs. TRPV1 protein up-regulation in DRG was also enhanced by NGF treatment. We then found that TRPV1 protein up-regulation in DRG was regulated by activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway both in vivo and in vitro. Suppression of endogenous PI3K/Akt activity during colitis or NGF treatment with a specific PI3K inhibitor LY294002 reduced TRPV1 protein production in DRG neurons, and also reduced colitis-evoked TRPV1-mediated visceral hypersensitivity tested by hyper-responsiveness to colorectal distention (CRD) and von Frey filament stimulation of abdomen. Further studies showed that TRPV1 mRNA levels in the DRG were not regulated by either colitis or NGF. We then found that an up-regulation of the protein synthesis pathway was involved by which both colitis and NGF caused a PI3K-dependent increase in the phosphorylation level of eukaryotic translation initiation factor 4E-binding protein (4E-BP)1. These results suggest a novel mechanism in colonic hypersensitivity which involves PI3K/Akt-mediated TRPV1 protein, not mRNA, up-regulation in primary afferent neurons, likely through activation of the protein synthesis pathways., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To assess mid-luteal estradiol (E2) levels in poor and good responders and determine its effect on the outcome after intracytoplasmic sperm injection (ICSI)., Methods: The current study was carried out in females who underwent ICSI from June 2011 to September 2013 in "Islamabad Clinic Serving Infertile Couples". They were categorized into good and poor responders on the basis of female age ≤40 years, basal follicle stimulating hormone ≤12 mIU/ml, and antral follicle count >5, respectively. Their mid-luteal E2 measured on the day of embryo transfer was stratified into groups (A-E) on the basis of 20th, 40th, 60th and 80th percentile values. The outcome was categorized into non-pregnant with beta human chorionic Gonadotrophin (hCG) 5-25 m IU/ml, and clinical pregnancy with beta hCG>25 m IU/ml., Results: The conception rate was 12% (63/513) in poor responders and 72% (237/329) in good responders respectively. The mid-luteal E2 levels were higher in conception as compared to non-conception cycles (p<0.001) in good and poor responders., Conclusion: Maximum pregnancies in poor and good responders (53% and 98% respectively) with mid-luteal E2 levels above 80 th percentiles confirm the role of the increase in mid-luteal E2 for augmentation in conception rate of females after ICSI., Competing Interests: Declaration of interest: The authors declare that they have no conflict of interest.

Introduction: The objective of this study was to assess the clinical outcome of displaced proximal humerus fracture treated with a new locking blade nail., Materials and Methods: This prospective study included a series of 92 patients with acute fracture of the proximal humerus treated in one hospital level I trauma centre with locking blade nail between December 2010 and December 2013. According to the Neer classification, all fractures were two- to four-part fractures. Age adopted Constant score, DASH and visual analogue scores were used as outcome measures., Results: A total of 92 patients were enrolled in the study. However, 29 patients were excluded due to loss to follow-up and death. Ultimately, 63 patients were available for final follow-up and data analysis. The mean duration of follow-up was 22 months (range 16-48 months). On average at 1 year, all fractures had united. The mean weighted Constant score was 84.2 % and the median disabilities of the arm, shoulder and hand (DASH) score was 26, the range of elevation was 115 and range of abduction was 97. The head shaft angle was 130, and pain visual analogue was 1.6. We found that 5 of the 63 patients (8 %) demonstrated complications. Two patients (3 %) displayed secondary displacement and require device removal. Two patients (3 %) had impingement due to prominent metal work, and one patient had a superficial wound infection which was treated with a course of antibiotics., Conclusion: Our study shows excellent results with new locking blade nail for displaced proximal humerus fractures. We think the locking blade nail offers stiff triangular fixation of the head fragment and support of the medial calcar region to prevent secondary varus collapse., Level of Evidence: III., Competing Interests: Senior author (EM) is a consultant and receives royalties from Marquardt Medizintechnik Europe. The other author (F R H) has no interest, any financial gains, or relationship to any third party relating to this study. Ethical standards This study complies with the current laws of the country in which it was conducted.

Adiponectin exerts vasodilatory effects. Irbesartan, an angiotensin receptor blocker, possesses partial peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist activity and increases circulating adiponectin. This study explored the effect of irbesartan alone and in combination with adiponectin on blood pressure, renal hemodynamic excretory function, and vasoactive responses to angiotensin II and adrenergic agonists in spontaneously hypertensive rat (SHR). Irbesartan was given orally (30 mg/kg/day) for 28 days and adiponectin intraperitoneally (2.5 μg/kg/day) for last 7 days. Groups of SHR received either irbesartan or adiponectin or in combination. A group of Wistar Kyoto rats (WKY) served as controls. Metabolic data and plasma samples were taken on days 0, 21, and 28. In acute studies, the renal vasoconstrictor actions of angiotensin II (ANGII), noradrenaline (NA), phenylephrine (PE), and methoxamine (ME) were determined. SHR control rats had a higher mean blood pressure than the WKY (132 ± 7 vs. 98 ± 2 mmHg), lower plasma and urinary adiponectin, creatinine clearance, urine flow rate and sodium excretion, and oxidative stress markers compared to WKY (all P < 0.05) which were progressively normalized by the individual drug treatments and to a greater extent by combined treatment. Responses to intrarenal administration of NA, PE, ME, and ANGII were larger in SHR (P < 0.05) than WKY by 20-25 %. Irbesartan enhanced (P < 0.05) responses to NA and PE, while adiponectin blunted responses to all vasoconstrictors (all P < 0.05). Combined treatment in SHR further decreased the renal vascular responses to ANGII. These findings suggest that an interactive relationship may exist between PPAR-γ, alpha adrenoceptors, and ANGII in the renal vasculature of the SHR.