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Chakkarin Burudpakdee,1,2 Zeba M Khan,3 Smeet Gala,1 Merena Nanavaty,1 Satyin Kaura3 1Market Access Solutions, LLC, Raritan, NJ, USA; 2University of North Carolina at Charlotte, Charlotte, NC, USA; 3Celgene Corporation, Summit, NJ, USA Objectives: Patient adherence and persistence is important to improve outcomes in chronic conditions, including inflammatory and immunologic (I&I) diseases. Patient programs that aim at improving medication adherence or persistence play an essential role in optimizing care. This meta-analysis assessed the effectiveness of patient programs in the therapeutic area of I&I diseases.Methods: A global systematic literature review was conducted with inclusion criteria of: patient programs in I&I diseases; published in English language between January 2008 and September 2013; and reporting measures of adherence or persistence, including medication possession ratio >80% and persistence rate. A meta-analysis was performed using a random effects model. Subgroup analyses based on the type of program was performed whenever feasible.Results: Of 67 studies reviewed for eligibility, a total of 17 studies qualified for inclusion in the meta-analysis. Overall, patient programs increased adherence (odds ratio [OR]=2.48, 95% confidence interval [CI]=1.68–3.64, P

Objectives: To review studies of patient compliance/persistence with cardiovascular or antidiabetic medication published since the year 2000; to compare the methods used to measure compliance/persistence across studies; to compare reported compliance/persistence rates across therapeutic classes and to assess whether compliance/persistence correlates with clinical outcomes.Methods: English language papers published between January 2000 and November 2005 investigating patient compliance/persistence with cardiovascular or antidiabetic medication were identified through searches of the MEDLINE and EMBASE databases. Definitions and measurements of compliance/persistence were compared across therapeutic areas using contingency tables.Results: Of the 139 studies analysed, 32% focused on hypertension, 27% on diabetes and 13% on dyslipidaemia. The remainder covered coronary heart disease and cardiovascular disease (CVD) in general. The most frequently reported measure of compliance was the 12-month medication possession ratio (MPR). The overall mean MPR was 72%, and the MPR did not differ significantly between treatment classes (range: 67-76%). The average proportion of patients with an MPR of >80% was 59% overall, 64% for antihypertensives, 58% for oral antidiabetics, 51% for lipid-lowering agents and 69% in studies of multiple treatments, again with no significant difference between treatment classes. The average 12-month persistence rate was 63% and was similar across therapeutic classes. Good compliance had a positive effect on outcome in 73% of the studies examining clinical outcomes.Conclusions: Non-compliance with cardiovascular and antidiabetic medication is a significant problem, with around 30% of days 'on therapy' not covered by medication and only 59% of patients taking medication for more than 80% of their days 'on therapy' in a year. Good compliance has a positive effect on clinical outcome, suggesting that the management of CVD may be improved by improving patient compliance. [ABSTRACT FROM AUTHOR]

Background. Workplace productivity evaluations often involve subjective assessments. This study was performed to develop and validate a new multidimensional instrument, the Health and Work Questionnaire (HWQ), for measuring workplace productivity and worker heath.Methods. In a prospective, non-randomized study, objective and subjective workplace productivity (measured with the HWQ) was assessed among 96 current, 94 former, and 104 non-smoking volunteer reservation agents at a US-based international airline.Results. Six HWQ sub-scales were identified from factor analyses: productivity, concentration/focus, supervisor relations, impatience/irritability, work satisfaction, and non-work satisfaction. Non-smokers (individuals who had never smoked) had higher scores on all scales. The HWQ scale scores all correlated significantly with the objective measure 'Time Lost'; two of the scales correlated significantly with the summary objective performance measure. Magnitudes of the significant correlations were modest (0.12 to 0.22).Conclusions. The HWQ may be useful for evaluating the impact of interventions on workplace productivity. Additional validation research on the HWQ is recommended before use as a primary measure in studies of worker productivity. [ABSTRACT FROM AUTHOR]

In this month's column, the authors evaluate the cost effectiveness of oseltamivir and zanamivir, compared with standard care, for the treatment of influenza. Using efficacy data from randomized, placebo-controlled clinical trials, a cost-effectiveness model was constructed. In an influenza-positive patient population, the cost per symptomfree day was $16 for zanamivir-treated patients compared with $39 for oseltamivir-treated patients. Considering a hypothetical drug budget of $100,000, 919 additional patients could be treated with zanamivir than with oseltamivir. Treatment with zanamivir would result in a gain of 1,714 symptom-free days and 52 fewer influenza-related complications than if oseltamivir were used. [ABSTRACT FROM AUTHOR]

Background: Older adults are more likely to suffer from the adverse effects of digoxin. Studies have described the inappropriate use of digoxin in various populations. The objective of this study was to determine the correlates of inappropriate digoxin use in older heart failure patients.Methods: We studied older hospitalized heart failure patients with documented left ventricular (LV) function evaluation and electrocardiography. Digoxin use was considered inappropriate if patients had preserved LV systolic function (ejection fraction greater > or =40%) or if they had no atrial fibrillation (AF). We compared baseline patient characteristics by indication for digoxin and tested statistical significance using Pearson's chi-square analysis and Student's t tests. Using logistic regression, we determined the correlates of inappropriate use and initiation of digoxin.Results: Subjects (N = 603) had a mean age of 79 (+/-7) years; 59% were women, and 18% were African American. A total of 376 patients (62%) were discharged on digoxin, and 223 (37%) had no indication for its use. Half of the patients without an indication for digoxin received the drug. Of 132 patients without an indication and not already on digoxin, 38 (29%) were initiated on it. After adjustment for various patient and care characteristics, prior digoxin use (adjusted odds ratio [OR] 11.47, 95% confidence interval [CI] 5.72-23.02) and pulse > or =100/min (adjusted OR 2.33, 95% CI 1.10-4.94) were associated with inappropriate digoxin use. Pulse > or =100/min was also associated with inappropriate initiation of the drug (adjusted OR 2.95, 95% CI 1.28-6.78).Conclusions: Inappropriate use of digoxin was common and was associated with prior use. Tachycardia was associated with inappropriate use and initiation. Electrocardiography and echocardiography should be performed in all older heart failure patients. Digoxin therapy should not be initiated or continued in patients without any evidence of LV systolic dysfunction or chronic AF. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the cost-effectiveness of a single-pill combination (SPC) of perindopril/amlodipine/indapamide versus its free equivalent combination (FEC) in adults with hypertension in Italy., Methods: A Markov model was developed to perform a cost-utility analysis with a lifetime horizon and an Italian healthcare payer's perspective. In the model, the additional effect of the SPC on blood pressure level compared with the FEC was translated into a decreased risk of cardiovascular events and CKD, which was modeled via Framingham risk algorithms. Difference in persistence rates of SPC and FEC were modeled via discontinuation rates., Results: A perindopril/amlodipine/indapamide SPC is associated with lower cost and better health outcomes compared to its FEC. Over a lifetime horizon, it is associated with a 0.050 QALY gain and cost savings of €376, resulting from lower cardiovascular event rates. In the alternative scenario, where different approach for modeling impact of adherence was considered, incremental gain of 0.069 QALY and savings of €1,004 were observed. Results were robust to sensitivity and scenario analyses, indicating that use of this SPC is a cost-effective strategy., Conclusions: The findings indicate that a perindopril/amlodipine/indapamide SPC is a cost-saving treatment option for hypertension in Italy, compared to its FEC.

Backgroud: Socioeconomic status (SES) plays a vital role in determining vaccination uptake and attitudes. Vaccine hesitancy varies among different communities, yet knowledge of vaccine attitudes among Asian-Americans is limited., Objective: This study aims to investigate the relationship between SES and vaccine attitudes among Asian-Americans in the State of New Jersey (NJ)., Methods: Asian-Americans aged ≥ 18 years living in NJ were included (N = 157). SES was measured by education level, employment type, employment status, and household income. The primary outcomes were vaccine hesitancy, reluctance, and confidence for COVID-19, influenza, and pneumococcal vaccines. Descriptive and inferential statistics were performed. Multivariable logistic regression was used to identify associations between SES and vaccine hesitancy while controlling for confounders such as age, gender, birthplace, and religion., Results: Among 157 participants, 12.1% reported vaccine hesitancy. There was no statistically significant association between vaccine hesitancy and education level (p = 0.68), employment status (p = 1), employment type (p = 0.48), and household income (p = 0.15). Multivariable logistic regression modeling confirmed that none of the SES predictor variables were associated with vaccine hesitancy. However, as exploratory finding, gender was found to be a significant predictor, with males having lower odds of vaccine hesitancy than females (Adjusted OR = 0.14; p < 0.05). Confidence in influenza and pneumococcal vaccines increased during the pandemic, from 62.34% to 70.13% and from 59.2% to 70.51%, respectively. For the COVID-19 vaccine, 73.1% of participants reported having "a lot of confidence" in taking vaccine., Conclusion: Most sampled Asian-Americans in NJ have high confidence in taking COVID-19 vaccines, and there is no significant association between vaccine hesitancy and SES., (© 2024. The Author(s).)

Introduction: Suboptimal medication adherence is common among patients with cardiovascular diseases. We sought evidence on non-pharmacological interventions used to support adherence for patients with hypertension and/or dyslipidemia., Methods: We searched MEDLINE, EMBASE, MEDLINE In-Process, ClinicalTrials.gov, EUCTR, and conference proceedings from July 2011 to July 2021 to identify trials evaluating effects of health education, phone reminders, or digital interventions on medication adherence or persistence of adult patients with hypertension and/or dyslipidemia. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool v2., Results: Of 64 studies, 62 used health education approaches (e.g. educational interviews, motivational meetings, advice from physicians, and mobile health content), 16 phone reminders (e.g. text reminders, electronic pill-box linked reminders, bi-directional text messaging), and 10 digital applications as interventions (e.g., various self-management applications). All studies assessed medication adherence; only two persistence. Overall, 30 studies (83%) assessing health education approaches alone and 25 (78%) combined with other strategies, 12 (75%) phone reminders and eight studies (80%) digital applications combined with other strategies reported improved medication adherence. Two studies assessing health education approaches reported improved persistence., Conclusions: Our findings indicate non-pharmacological interventions may positively impact adherence. Therefore, 'beyond the pill' approaches could play a role in preventing cardiovascular diseases.

Objectives: Hypertension is a leading cause of death and disease burden followed by dyslipidemia. Their asymptomatic nature leads to low adherence and persistence to treatments. A systematic literature review (SLR) investigated the impact of single-pill-combinations (SPC) compared to free-equivalent combination (FEC) on adherence, persistence, clinical outcomes, healthcare resource utilization (HCRU), and patient-reported outcomes, in patients with hypertension, dyslipidemia, or both., Methods: MEDLINE, MEDLINE-IN-PROCESS, Embase, and Cochrane were searched from inception until 11 May 2021, for studies comparing SPC against FEC in patients with hypertension and/or dyslipidemia. Patient characteristics, study design, therapies, measures of adherence or persistence, clinical outcomes, and follow-up were extracted., Results: Among 52 studies identified in the SLR, 27 ( n  = 346,030 patients) were included in the meta-analysis. SPCs were associated with significantly improved adherence compared with FEC, as assessed through medication-possession-ratio ≥80% (odds ratio (OR) 0.42, p  < 0.01) and proportion of days covered ≥80% (OR 0.45, p  < 0.01). SPC also improved persistence (OR 0.44, p  < 0.01) and systolic blood pressure (SBP) reduction (mean difference -1.50, p  < 0.01) compared with the FEC., Conclusions: SPC use resulted in significantly improved adherence, persistence, and SBP levels compared with FEC in patients with hypertension. The findings support SPC use in reducing the burden of hypertension and dyslipidemia.

Glioblastoma (GBM) is the most common and malignant type of primary brain tumor. Even after surgery and chemoradiotherapy, residual GBM cells can infiltrate the healthy brain parenchyma to form secondary tumors. To mitigate GBM recurrence, we recently developed an injectable hydrogel that can be crosslinked in the resection cavity to attract, collect, and ablate residual GBM cells. We previously optimized a thiol-Michael addition hydrogel for physical, chemical, and biological compatibility with the GBM microenvironment and demonstrated CXCL12-mediated chemotaxis can attract and entrap GBM cells into this hydrogel. In this study, we synthesize hydrogels under conditions mimicking GBM resection cavities and assess feasibility of histotripsy to ablate hydrogel-encapsulated cells. The results showed the hydrogel synthesis was bio-orthogonal, not shear-thinning, and can be scaled up for injection into GBM resection mimics in vitro. Experiments also demonstrated ultrasound imaging can distinguish the synthetic hydrogel from healthy porcine brain tissue. Finally, a 500 kHz transducer applied focused ultrasound treatment to the synthetic hydrogels, with results demonstrating precise histotripsy bubble clouds could be sustained in order to uniformly ablate red blood cells encapsulated by the hydrogel for homogeneous, mechanical fractionation of the entrapped cells. Overall, this hydrogel is a promising platform for biomaterials-based GBM treatment., Competing Interests: Declarations Conflict of interest ZMK, SSV, and EV are inventors on a pending patent related to this work. Dr. Eli Vlaisavljevich also has research and financial relationships with HistoSonics Inc. The authors declare no other conflicts of interest or competing financial interests., (© 2024. The Author(s).)

The RAS-mitogen-activated protein kinase (MAPK) pathway includes KSR, RAF, MEK and the phospho-regulatory sensor 14-3-3. Specific assemblies among these components drive various diseases and likely dictate efficacy for numerous targeted therapies, including allosteric MEK inhibitors (MEKi). However, directly measuring drug interactions on physiological RAS-MAPK complexes in live cells has been inherently challenging to query and therefore remains poorly understood. Here we present a series of NanoBRET-based assays to quantify direct target engagement of MEKi on MEK1 and higher-order MEK1-bound complexes with ARAF, BRAF, CRAF, KSR1 and KSR2 in the presence and absence of 14-3-3 in living cells. We find distinct MEKi preferences among these complexes that can be compiled to generate inhibitor binding profiles. Further, these assays can report on the influence of the pathogenic BRAF-V600E mutant on MEKi binding. Taken together, these approaches can be used as a platform to screen for compounds intended to target specific complexes in the RAS-MAPK cascade., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: We aimed to summarize evidence on the effect of poor medication adherence on clinical outcomes and health resource utilization (HRU) among patients with hypertension and/or dyslipidemia., Areas Covered: A systematic review of studies reporting clinical outcomes and HRU for patients by status of adherence to antihypertensives and/or lipid-lowering medications was searched using Embase, MEDLINE, and MEDLINE In-Process and supplemented by manual searches of conference abstracts. In total, 45 studies were included, with most being retrospective observational studies ( n  = 36). Patients with poor adherence to antihypertensives and lipid-lowering medications compared with those with good adherence showed less reduction of blood pressure (BP) and low-density lipoprotein cholesterol (LDL-c) after 6-12 months follow-up (∆ systolic BP: 1.2 vs. -4.5 mmHg; ∆LDL-c: -14.0 to -18.9 vs. -34.1 to -42.0 mg/dL). Poor adherence was also significantly associated with a higher risk of cardiovascular events (HR: 1.1-1.9) and mortality (HR: 1.4-1.8) in patients with hypertension and dyslipidemia and increased HRU (i.e. outpatient visits, risk of cardiovascular-related and all-cause hospitalization, annual inpatient days, total health-care costs)., Expert Opinion: Poor adherence is associated with poor clinical outcomes and increased HRU, highlighting the need to enhance medication adherence in patients with hypertension and/or dyslipidemia.

Background: Heart failure is a chronic disease linked with significant morbidity and mortality, and uncontrolled resting heart rate is a risk factor for adverse outcomes. This systematic literature review aimed to assess the efficacy, safety, and patient-reported outcomes (PROs) of ivabradine in patients with heart failure (HF) with reduced ejection fraction (HFrEF) in randomized controlled trials (RCTs) and observational studies. Methods: We searched electronic databases from their inception to July 2021 to include studies that reported on efficacy, safety, or PROs of ivabradine in patients with HFrEF. Results: Of 1947 records screened, 51 RCTs and 6 observational studies were identified. Ivabradine on top of background therapy demonstrated a significant reduction in composite outcomes including hospitalization for HF or cardiovascular death. In addition, observational studies suggested that ivabradine was associated with a significant reduction in mortality. Across all studies, ivabradine use on top of background therapy was associated with greater reductions in heart rate, improved EF, and improved health-related quality of life (QoL) and comparable risk of total adverse events compared to those treated with background therapy alone. Conclusions: Ivabradine on top of background therapy is beneficial for heart rate, hospitalization risk for HF, mortality, EF, and patients' QoL. Moreover, these benefits were achieved with no significant increase in the overall risk of total adverse events., Competing Interests: The authors declare that they have a conflict of interest. Briere Jean Baptiste is an employee of Servier, and Zeba M. Khan was a paid consultant for Servier International at the time of the study. Elzbieta Olewinska, Fatma Khrouf, and Mateusz Nikodem are employees of Putnam PHMR, which received funding from Servier to conduct the study. However, this funding did not influence the design, conduct, or reporting of the research presented in this manuscript., (© 2023 Putnam PHMR. Published by Informa UK Limited, trading as Taylor & Francis Group.)

Competing Interests: None.

Introduction Traditionally, injuries have often been perceived as random and inevitable 'accidents'. However, in the current context, both intentional and unintentional injuries are preventable. Among these, neck injuries can be particularly complex, encompassing homicidal, suicidal, or accidental causes. Despite extensive research on the different modes and patterns of cut-throat injuries in the general population, this study aims to look deeper into this phenomenon within a unique context. Our investigation is centered in the Eastern part of India, among a tribal-dominated population who live with their traditional culture. Method In this prospective observational study, 50 cut-throat patients were included, who reported to the emergency department and then were referred to the ENT department. Parameters such as age, sex, anatomical location, mode of cut-throat injury, prior substance abuse, psychiatric issues, socioeconomic level, and length of hospital stay were considered for analysis. Results The majority (n=40, 80%) of patients belonged to tribal communities and most were young adults. Cut-throat injuries were predominantly caused by suicide (n=36, 72%) and homicide (n=12, 24%). Among tribals, 85% (n=34) of the cases were suicidal. Among suicidal cases, 86.11% (n=31) had a history of substance abuse while 22.22% (n=8) had a history of psychiatric illnesses. Conclusion In Eastern India, among the tribal-dominated population, suicide emerges as the predominant mode of cut-throat injuries, which is notably distinct from patterns observed in the general population of developing countries. These were often associated with substance abuse. Future interventions and public health efforts in these regions should consider these factors in the development of targeted strategies aimed at prevention and support for at-risk individuals., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Anas et al.)

The study aimed to prepare and characterize biodegradable sustained-release beads of letrozole (LTZ) for treating cancerous disease. The ionotropic gelation method was used for the preparation and calcium chloride (CaCl 2 ) was used as a gelating agent, while chitosan (CTS) and sodium alginate (NaAlg) as biodegradable polymeric matrices in the blend hydrogel beads. The beads were characterized for their size, surface morphology, drug entrapment efficiency, drug-polymer interaction and crystallinity using different analytic techniques, including optical microscopy, Scanning Electron Microscopy (SEM), UV-spectroscopy, Fourier-transform Infrared Spectroscopy (FTIR), Thermo gravimetric Analysis (TGA), Differential Scanning Calorimetry (DSC) and X-ray Diffraction Analysis (XRD) respectively. In vitro swelling studies were also applied to observe the response of these polymeric networks against different pH (at 1.2, 6.8 and 7.4 pH). The results from TGA and DSC exhibited that the components in the formulation possess better thermal stability. The XRD of polymeric networks displays a minor crystalline and significant amorphous nature. The SEM micrographs revealed that polymeric networks have uneven surfaces and grooves. Better swelling and in vitro outcomes were achieved at a high pH (6.8,7.4), which endorsed the pH-responsive characteristics of the prepared beads. Hence, beads based on chitosan and sodium alginate were successfully synthesized and can be used for the controlled release of letrozole.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. β-Catenin (CTNNB1)-mutated HCC represents 30% of cases of the disease with no precision therapeutics available. Using chemical libraries derived from clinical multi-kinase inhibitor (KI) scaffolds, we screened HCC organoids to identify WNTinib, a KI with exquisite selectivity in CTNNB1-mutated human and murine models, including patient samples. Multiomic and target engagement analyses, combined with rescue experiments and in vitro and in vivo efficacy studies, revealed that WNTinib is superior to clinical KIs and inhibits KIT/mitogen-activated protein kinase (MAPK) signaling at multiple nodes. Moreover, we demonstrate that reduced engagement on BRAF and p38α kinases by WNTinib relative to several multi-KIs is necessary to avoid compensatory feedback signaling-providing a durable and selective transcriptional repression of mutant β-catenin/Wnt targets through nuclear translocation of the EZH2 transcriptional repressor. Our studies uncover a previously unknown mechanism to harness the KIT/MAPK/EZH2 pathway to potently and selectively antagonize CTNNB1-mutant HCC with an unprecedented wide therapeutic index., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Human interventions and rapid changes in land use adversely affect the adequate distribution of water resources. A research study was conducted to quantify the gap between demand and supply for irrigation water in Multan, Pakistan, which may lead to sustainable water management. Two remotely sensed images (Landsat 8 OLI and Landsat 5 TM) were downloaded for the years 2010 and 2020, and supervised classification method was performed for the selected land use land cover (LULC) classes and basic framework. During the evaluation, the kappa coefficient was found in the ranges of 0.83-0.85, and overall accuracy was found to be more than 80% which indicated a substantial agreement between the classified maps and the ground truth data for both years and seasons. The LULC maps showed that urbanization has increased by 49% during the last decade (2010-2020). Reduction in planting areas for wheat (9%), cotton (24%), and orchards (46%) was observed. An increase in planting areas for rice (92%) and sugarcane (63%) was observed. The changing LULC pattern may be related to variation in water demand and supply for irrigation. The irrigation water demand has decreased by 370.2 Mm 3 from 2010 to 2020, due to the reduction in agricultural land and an increase in urbanization. Available irrigation water supply (canals/rainfall) was estimated as 2432 Mm 3 for the year 2020 which was 26% less than that of total irrigation water demand (3281 Mm 3 ). The findings also provide the database for sustainable water management and equitable distribution of water in the region., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Glioblastoma (GBM), characterized by high infiltrative capacity, is the most common and deadly type of primary brain tumor in adults. GBM cells, including therapy-resistant glioblastoma stem-like cells (GSCs), invade the healthy brain parenchyma to form secondary tumors even after patients undergo surgical resection and chemoradiotherapy. New techniques are therefore urgently needed to eradicate these residual tumor cells. A thiol-Michael addition injectable hydrogel for compatibility with GBM therapy is previously characterized and optimized. This study aims to develop the hydrogel further to capture GBM/GSCs through CXCL12-mediated chemotaxis. The release kinetics of hydrogel payloads are investigated, migration and invasion assays in response to chemoattractants are performed, and the GBM-hydrogel interactions in vitro are studied. With a novel dual-layer hydrogel platform, it is demonstrated that CXCL12 released from the synthetic hydrogel can induce the migration of U251 GBM cells and GSCs from the extracellular matrix microenvironment and promote invasion into the synthetic hydrogel via amoeboid migration. The survival of GBM cells entrapped deep into the synthetic hydrogel is limited, while live cells near the surface reinforce the hydrogel through fibronectin deposition. This synthetic hydrogel, therefore, demonstrates a promising method to attract and capture migratory GBM cells and GSCs responsive to CXCL12 chemotaxis., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Objectives: To assess the knowledge of medical doctors about osteonecrosis who prescribe radiotherapy and bisphosphonates and dentists who receive these patients with such risk factors., Methods: This cross sectional multicenter study was carried out from 15 th October 2021 to 20 th November 2021 in different set-ups of Pakistan. A validated and piloted questionnaire was sent to dental and non-dental doctors working in different set-ups of Pakistan through email. All data was analyzed in SPSS version 22 with p value <0.05 being significant., Results: A total of 400 completed responses were received. Only 58% and 67% of the participants were actively educating their patients regarding the hazards of bisphosphonate and radiotherapy, respectively whereas only 45% of the medical doctors referred their patients to dentists before prescribing bisphosphonates and/or radiotherapy. Although the medical doctors had a statistically better knowledge of the definition of osteonecrosis, overall both the dental and non-dental doctors performed poorly regarding answering the questions pertaining to definition, clinical features and risk factors. The dental doctors also showed a poor performance for more technical and in depth questions that was statistically related to lesser work experience, working in a tertiary care facility and previous exposure to such patients., Conclusion: The inadequate awareness of dentists and physicians about the prevention and management of osteonecrosis of jaw is alarming. Efforts should be undertaken to raise the knowledge of dentists and physicians in this regard., (Copyright: © Pakistan Journal of Medical Sciences.)

Met encodes a receptor tyrosine kinase (MET) that is expressed during development and regulates cortical synapse maturation. Conditional deletion of Met in the nervous system during embryonic development leads to deficits in adult contextual fear learning, a medial prefrontal cortex (mPFC)-dependent cognitive task. MET also regulates the timing of critical period plasticity for ocular dominance in primary visual cortex (V1). However, the underlying circuitry responsible remains unknown. Therefore, this study determines the broad expression patterns of MET throughout postnatal development in mPFC and V1 projection neurons (PNs), providing insight into similarities and differences in the neuronal subtypes and temporal patterns of MET expression between cortical areas. Using a transgenic mouse line that expresses green fluorescent protein (GFP) in Met + neurons, immunofluorescence and confocal microscopy were performed to visualize MET-GFP + cell bodies and PN subclass-specific protein markers. Analyses reveal that the MET expression is highly enriched in infragranular layers of mPFC, but in supragranular layers of V1. Interestingly, temporal regulation of the percentage of MET + neurons across development not only differs between cortical regions but also is distinct between lamina within a cortical region. Further, MET is expressed predominantly in the subcerebral PN subclass in mPFC, but the intratelencephalic PN subclass in V1. The data suggest that MET signaling influences the development of distinct circuits in mPFC and V1 that underlie subcerebral and intracortical functional deficits following Met deletion, respectively., (© 2022 The Authors. The Journal of Comparative Neurology published by Wiley Periodicals LLC.)

The repetitive nature and complexity of some medically relevant genes poses a challenge for their accurate analysis in a clinical setting. The Genome in a Bottle Consortium has provided variant benchmark sets, but these exclude nearly 400 medically relevant genes due to their repetitiveness or polymorphic complexity. Here, we characterize 273 of these 395 challenging autosomal genes using a haplotype-resolved whole-genome assembly. This curated benchmark reports over 17,000 single-nucleotide variations, 3,600 insertions and deletions and 200 structural variations each for human genome reference GRCh37 and GRCh38 across HG002. We show that false duplications in either GRCh37 or GRCh38 result in reference-specific, missed variants for short- and long-read technologies in medically relevant genes, including CBS, CRYAA and KCNE1. When masking these false duplications, variant recall can improve from 8% to 100%. Forming benchmarks from a haplotype-resolved whole-genome assembly may become a prototype for future benchmarks covering the whole genome., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Glioblastoma multiforme (GBM) is an aggressive primary brain cancer and although patients undergo surgery and chemoradiotherapy, residual cancer cells still migrate to healthy brain tissue and lead to tumor relapse after treatment. New therapeutic strategies are therefore urgently needed to better mitigate this tumor recurrence. To address this need, we envision after surgical removal of the tumor, implantable biomaterials in the resection cavity can treat or collect residual GBM cells for their subsequent eradication. To this end, we systematically characterized a poly(ethylene glycol)-based injectable hydrogel crosslinked via a thiol-Michael addition reaction by tuning its hydration level and aqueous NaHCO 3 concentration. The physical and chemical properties of the different formulations were investigated by assessing the strength and stability of the polymer networks and their swelling behavior. The hydrogel biocompatibility was assessed by performing in vitro cytotoxicity assays, immunoassays, and immunocytochemistry to monitor the reactivity of astrocytes cultured on the hydrogel surface over time. These characterization studies revealed key structure-property relationships. Furthermore, the results indicated hydrogels synthesized with 0.175 M NaHCO 3 and 50 wt% water content swelled the least, possessed a storage modulus that can withstand high intracranial pressures while avoiding a mechanical mismatch, had a sufficiently crosslinked polymer network, and did not degrade rapidly. This formulation was not cytotoxic to astrocytes and produced minimal immunogenic responses in vitro. These properties suggest this hydrogel formulation is the most optimal for implantation in the resection cavity and compatible toward GBM therapy. STATEMENT OF SIGNIFICANCE: Survival times for glioblastoma patients have not improved significantly over the last several decades, as cancer cells remain after conventional therapies and form secondary tumors. We characterized a biodegradable, injectable hydrogel to reveal structure-property relationships that can be tuned to conform the hydrogel toward glioblastoma therapy. Nine formulations were systematically characterized to optimize the hydrogel based on physical, chemical, and biological compatibility with the glioblastoma microenvironment. This hydrogel can potentially be used for adjuvant therapy to glioblastoma treatment, such as by providing a source of molecular release for therapeutic agents, which will be investigated in future work. The optimized formulation will be developed further to capture and eradicate glioblastoma cells with chemical and physical stimuli in future research., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ZMK, SSV, TEL, and EV are inventors on a pending patent related to this work. The authors declare no other conflicts of interest or competing financial interests., (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Objectives: To analyze the systems and tools involved in assessment of skill procurement and demonstrating workplace skills in postgraduate medical training., Methods: This cross-sectional survey was carried out by enrolling trainee doctors currently working in Medical, Surgical, Dental and Allied specialties of the country by sending a validated and piloted questionnaire through email. Data collection was done from 20 th April to 20 th May 2021. Data was analysed using SPSS v. 21.0., Results: A total of 351 completed responses were received from 10 major cities of the country. Multiple aspects of entry-into-training, in-training and end-of-training evaluation showed poor correlation with the required training goals. A comparison of assessment for entry-into-supervised training (FCPS-I) versus independent practice (FCPS-II) showed a dismal situation regarding assessing affective skills like leadership, teamwork, coping with pressure and self-awareness. The concept of maintaining portfolios was completely alien to the trainees and the assessment tools used for demonstrating workplace skills were outdated. The lack of a continuous, periodic and balanced assessment (65%); detailed feedback (61.5%); fair exams (59%); variability in scoring system (58%) and professionalism of the examiners (57.5%) were the most frequently selected perceived flaws in the assessment system by the participants., Conclusion: There are multiple lacunae regarding competency-based assessment systems in our training programs and a massive scope for improvement. Assessment systems should be implemented as continuous process of learning, self-reflection, feedback and revalidation throughout the training tenure at regular and multiple points., (Copyright: © Pakistan Journal of Medical Sciences.)

Electroresponsive hydrogels possess a conducting material component and respond to electric stimulation through reversible absorption and expulsion of water. The high level of hydration, soft elastomeric compliance, biocompatibility, and enhanced electrochemical properties render these hydrogels suitable for implantation in the brain to enhance the transmission of neural electric signals and ion transport. This review provides an overview of critical electroresponsive hydrogel properties for augmenting electric stimulation in the brain. A background on electric stimulation in the brain through electroresponsive hydrogels is provided. Common conducting materials and general techniques to integrate them into hydrogels are briefly discussed. This review focuses on and summarizes advances in electric stimulation of electroconductive hydrogels for therapeutic applications in the brain, such as for controlling delivery of drugs, directing neural stem cell differentiation and neurogenesis, improving neural biosensor capabilities, and enhancing neural electrode-tissue interfaces. The key challenges in each of these applications are discussed and recommendations for future research are also provided., (© 2021 Wiley-VCH GmbH.)

Background: The distressing COVID-19 pandemic has had a substantial impact on public mental health, and the importance of food and nutrients in several aspects of mental health has been recognized. People in isolation or quarantine suffer from severe stress, anger, panic attack, and anxiety., Scope and Approach: Although, people who have improved and progressed through medications or vaccines have reduced anxiety levels to some extent yet the efficacy of these measures, in the long run, remains a question. The review depicts that such negative emotional reactions were particularly higher in elderly individuals in the first wave than in other phases. The emotional and behavioral response to the COVID-19 pandemic is multifactorial. From different research studies, it has been found that stress scores were considerably higher for those engaging in unhealthy eating practices. This factor relies not only on external components but on personal and innate ones as well. In the present pandemic, the sustainable development of the food system would have been a major issue; this should be carefully restored to avoid a food crisis in the future., Key Findings and Conclusions: Changes in mind-body interactions are triggered by psychosocial stresses such as interpersonal loss and social rejection. Physiological response (in terms of psychological stress) in COVID-19 affected patients varies due to individual physical health status. This review explores the relationship between nutrition and mental health as what we eat and think is interlinked with the gut-brain-axis. The role of dietary components along with the Mediterranean diet, DASH diet and use of psychobiotics in improving psychological distress in pandemic induced stress, anxiety and depression has also been discussed., (© 2022 Elsevier Ltd. All rights reserved.)

Industrial revolution and rapid population growth are responsible for alteration of land into different settlements. These changes may lead to change in land use (LU) and land cover (LC). The LULC changes have impact on hydrological regimes including streams flow pattern and allocated irrigation water (water allocation through Warabandi system). The present study aimed to identify the LULC changes and settlement impact on allocated water using the unsupervised classification and normalized difference vegetation index (NDVI) of Landsat images for the years of 1990 to 2020 in Multan District. The accuracy assessment and Kappa coefficient were also investigated to evaluate quality of results derived from the classified images. The results show that the reduction in waterbody, spare, and dense vegetation was -7.6, -1.7, and -30.7%, respectively. The settlements, barren, and crop lands have increased to 25.2, 10.1, and 4.6%, respectively, from 1990 to 2020. The values of kappa coefficient (0.84-0.85) showed very good level of classification. In addition, the volume of water loss due to change of LULC from waterbody into settlements, barren land, crop land, spare, and dense vegetation was found approximately 472, 44, 133, 54, and 85 m 3 , respectively, in last 30 years. This volume of water is not reaching equitably to the farming community because of the LU and LC changes and urban settlements. The results indicated that remotely sensed image interpretation technique may be a useful for reallocation of water among farmers in an equitable and efficient way., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Pseudokinases often operate through functionally related enzymes and receptors. A prime example is the pseudokinase KSR (Kinase Suppressor of RAS), which can act as both an amplifier and inhibitor of members in the RAS-MAPK (Mitogen Activated Protein Kinase) signaling pathway. KSR is structurally related to the active RAF kinases over multiple domains; moreover, the pseudokinase domain of KSR forms physical and regulatory complexes with both RAF and MEK through distinct interfaces. Characterization of small molecule interactions on KSR has been used to uncover novel chemical tools and understand the mechanism of action of clinical drugs. Here, we elaborate on assays and structural methods for measuring binding at orthosteric and interfacial binding sites on KSR. These distinct small molecule pockets provide therapeutic paths for targeting KSR1 and KSR2 pseudokinases in disease, including in RAS and RAF mutant cancers., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To investigate patient perspective of telephone consultations (TCs) in gynaecology and identify which patients benefit most from a telemedicine system., Design: Service evaluation., Setting: Gynaecology outpatient services at a tertiary referral hospital., Population: Patients who received a TC during May and June 2020., Methods: Postal questionnaire combining three validated tools: QQ-10, Patient Enablement Index (PEI) and National Health Service Friends and Family Test (NHS-FFT). Quantitative data and free text responses were analysed., Main Outcome Measures: Responses to QQ-10, PEI and NHS-FFT., Results: In total, 1307 patients were contacted and 504 patients responded (39%). Most (89%) described their experience as 'Very good' or 'Good' (NHS-FFT). Positive themes from responses included 'convenience', 'effectiveness' and 'equivalent care'. QQ-10 responses demonstrated a high Value score of 79 (0-100) and a low Burden score of 15. PEI scores suggested that most patients felt better or much better able to understand and cope with their condition following TC. The majority of patients (77%) would 'Strongly agree' or 'Mostly agree' to a repeat TC. Regarding patient outcomes, 21% were discharged and 71% required follow up. Menopause, fertility and endometriosis follow-up clinic patients benefited most from TC. Gynaecology-oncology patients found TC least acceptable., Conclusion: We report a large questionnaire survey of patient experience of TC in gynaecology. Telemedicine is convenient, acceptable and effective for conducting care in selected groups. TC can support patients in communicating intimate symptoms., Tweetable Abstract: Telephone consultations are a convenient, acceptable and effective medium for conducting patient care in gynaecology., (© 2021 John Wiley & Sons Ltd.)

Dental caries is a multifactorial disease mainly caused by cariogenic bacteria commonly found in the oral cavity. Dental caries may cause demineralization of the tooth, cavitation, hypersensitivity, pulp inflammation, and even tooth loss if left untreated. Saliva secreted in the oral cavity can serve as a tool for identification of biomarkers for early detection of diseases. In the present study, differential expression of salivary proteins from 33 dental caries patients was compared with 10 control subjects. The unstimulated saliva was analyzed by 12% SDS-PAGE and two-dimensional gel electrophoresis. Gelatin and casein zymography was performed to check for protease activity. Also, salivary IgAs from both groups were compared by sandwich ELISA technique. Dental caries patient's saliva showed decreased caseinolytic and increased gelatinolytic activity probably due to metalloproteases and cathepsins. Mean salivary levels of sIgA were also significantly higher ( p < 0.018) in dental caries saliva samples. The 2D electrophoresis profile of both the groups showed regions on gel with visually detectable alterations in protein expression. The present study is among the few initial studies in the locality for identification of protein differences in saliva from dental caries patients and has demonstrated a good potential to identify alterations. However, a large population-based analysis is required to validate these findings to be translated as a tool for indicative applications., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2021 Zaid Majeed Khan et al.)

Despite release of the GRCh38 human reference genome more than seven years ago, GRCh37 remains more widely used by most research and clinical laboratories. To date, no study has quantified the impact of utilizing different reference assemblies for the identification of variants associated with rare and common diseases from large-scale exome-sequencing data. By calling variants on both the GRCh37 and GRCh38 references, we identified single-nucleotide variants (SNVs) and insertion-deletions (indels) in 1,572 exomes from participants with Mendelian diseases and their family members. We found that a total of 1.5% of SNVs and 2.0% of indels were discordant when different references were used. Notably, 76.6% of the discordant variants were clustered within discrete discordant reference patches (DISCREPs) comprising only 0.9% of loci targeted by exome sequencing. These DISCREPs were enriched for genomic elements including segmental duplications, fix patch sequences, and loci known to contain alternate haplotypes. We identified 206 genes significantly enriched for discordant variants, most of which were in DISCREPs and caused by multi-mapped reads on the reference assembly that lacked the variant call. Among these 206 genes, eight are implicated in known Mendelian diseases and 53 are associated with common phenotypes from genome-wide association studies. In addition, variant interpretations could also be influenced by the reference after lifting-over variant loci to another assembly. Overall, we identified genes and genomic loci affected by reference assembly choice, including genes associated with Mendelian disorders and complex human diseases that require careful evaluation in both research and clinical applications., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The study described here examined the effects of cavitation nuclei characteristics on histotripsy. High-speed optical imaging was used to compare bubble cloud behavior and ablation capacity for histotripsy generated from intrinsic and artificial cavitation nuclei (gas-filled microbubbles, fluid-filled nanocones). Results showed a significant decrease in the cavitation threshold for microbubbles and nanocones compared with intrinsic-nuclei controls, with predictable and well-defined bubble clouds generated in all cases. Red blood cell experiments showed complete ablations for intrinsic and nanocone phantoms, but only partial ablation in microbubble phantoms. Results also revealed a lower rate of ablation in artificial-nuclei phantoms because of reduced bubble expansion (and corresponding decreases in stress and strain). Overall, this study demonstrates the potential of using artificial nuclei to reduce the histotripsy cavitation threshold while highlighting differences in the bubble cloud behavior and ablation capacity that need to be considered in the future development of these approaches., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)