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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

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.

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.)

Course-based undergraduate research experience (CURE) courses incorporate high-impact pedagogies that have been shown to increase undergraduate retention among underrepresented minorities and women. As part of the Building Infrastructure Leading to Diversity program at the University of Detroit Mercy, a CURE metagenomics course was established in the winter of 2019. Students investigated the bacterial community composition in a eutrophic cove in Lake Saint Clair (Harrison Township, MI, United States) from water samples taken in the summer and winter. The students created 16S rRNA libraries that were sequenced using next-generation sequencing technology. They used a public web-based supercomputing resource to process their raw sequencing data and web-based tools to perform advanced statistical analysis. The students discovered that the most common operational taxonomic unit, representing 31% of the prokaryotic sequences in both summer and winter samples, corresponded to an organism that belongs to a previously unidentified phylum. This result showed the students the power of metagenomics because the approach was able to detect unclassified organisms. Principal Coordinates Analysis of Bray-Curtis dissimilarity index data showed that the winter community was distinct from the summer community [Analysis of Similarities (ANOSIM) r = 0.59829, n = 18, and p < 0.001]. Dendrograms based on hierarchically clustered Pearson correlation coefficients of phyla were divided into a winter clade and a summer clade. The conclusion is that the winter bacterial population was fundamentally different from the summer population, even though the samples were taken from the same locations in a protected cove. Because of the small class sizes, qualitative as well as statistical methods were used to evaluate the course's impact on student attitudes. Results from the Laboratory Course Assessment Survey showed that most of the respondents felt they were contributing to scientific knowledge and the course fostered student collaboration. The majority of respondents agreed or strongly agreed that the course incorporated iteration aspects of scientific investigations, such as repeating procedures to fix problems. In summary, the metagenomics CURE course was able to add to scientific knowledge and allowed students to participate in authentic research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Baker, Alhassan, Asenov, Choi, Craig, Dastidar, Karim, Sheardy, Sloulin, Aggarwal, Al-Habib, Camaj, Cleminte, Hamady, Jaafar, Jones, Khan, Khoshaba, Khoshaba, Ko, Mashrah, Patel, Rajab and Tandon.)

Pseudokinases play important roles in signal transduction and cellular processes similar to those of catalytically competent kinases. However, pseudokinase pharmacological tractability and conformational space accessibility are poorly understood. Pseudokinases have only recently been suggested to adopt "inactive" conformations or interact with conformation-specific kinase inhibitors (e.g., type II compounds). In this work, the heavily substituted pseudokinase STRADα, which possesses a DFG → GLR substitution in the catalytic site that permits nucleotide binding while impairing divalent cation coordination, is used as a test case to demonstrate the potential applicability of conformation-specific, type II compounds to pseudokinase pharmacology. Integrated structural modeling is employed to generate a "GLR-out" conformational ensemble. Likely interacting type II compounds are identified through virtual screening against this ensemble model. Biophysical validation of compound binding is demonstrated through protein thermal stabilization and ATP competition. Localization of a top-performing compound through surface methylation strongly suggests that STRADα can adopt the "GLR-out" conformation and interact with compounds that comply with the standard type II pharmacophore. These results suggest that, despite a loss of catalytic function, some pseudokinases, including STRADα, may retain the conformational switching properties of conventional protein kinases.

Liquid exfoliated, 2-dimensional (2D), few layered graphene and molybdenum disulfide nanosheets (GNS and MNS) are size selected for EMI shielding application. Scanning electron microscopy (SEM) has confirmed the lateral dimensions increase (1-2 µm for GNS and MNS) with lowering centrifugation speed (1000 to 500 rpm). The micron size (~ 15 µm) restacked structures of GNS and MNS (L ~ 2 µm) over a nylon membrane have shown ~ 16 dB and ~ 6 dB EMI shielding effectiveness (1-8 GHz frequency), respectively. The enhanced EMI shielding effectiveness for GNS-500 may be credited to its high carrier mobility as well as high aspect ratio of nanosheets. The GNS-500 are further dispersed (0.3 wt.%) in thermoplastic polyurethane for their applicability as flexible EMI shielding material. The dielectric characteristics predicted an enhancement for the attenuation (200 MHz-1 GHz). The experimental results (1-8 GHz) suggested the maximum attenuation ~ 18 dB showing the composite applicability as a broadband EMI shielding material.

The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology 1 , and more recently in immunotherapy 2,3 and ageing 4 . However, many MEK inhibitors are limited owing to on-target toxicities 5-7 and drug resistance 8-10 . Accordingly, a molecular understanding of the structure and function of MEK within physiological complexes could provide a template for the design of safer and more effective therapies. Here we report X-ray crystal structures of MEK bound to the scaffold KSR (kinase suppressor of RAS) with various MEK inhibitors, including the clinical drug trametinib. The structures reveal an unexpected mode of binding in which trametinib directly engages KSR at the MEK interface. In the bound complex, KSR remodels the prototypical allosteric pocket of the MEK inhibitor, thereby affecting binding and kinetics, including the drug-residence time. Moreover, trametinib binds KSR-MEK but disrupts the related RAF-MEK complex through a mechanism that exploits evolutionarily conserved interface residues that distinguish these sub-complexes. On the basis of these insights, we created trametiglue, which limits adaptive resistance to MEK inhibition by enhancing interfacial binding. Our results reveal the plasticity of an interface pocket within MEK sub-complexes and have implications for the design of next-generation drugs that target the RAS pathway.

Background: The field of global health has grown with multiple different public and private stakeholders engaging in the effort to improve health outcomes for underserved populations around the world. There is, however, only limited published guidance on how to promote successful partnerships between academia and the biopharmaceutical industry., Objective: This analysis will provide a framework for developing successful partnerships around five central principles. This framework will then be applied to two representative pharmacy collaboration case studies focused on training and donations., Framework Description and Case Study Findings: Within the Academic Model Providing Access to Healthcare (AMPATH), successful collaborations between the biopharmaceutical industry philanthropic entities and academic partners have consistently prioritized 1) contextualization, 2) collaboration, 3) local priorities, 4) institutional commitment, and 5) integration. In the first case study, the application of this framework to clinical pharmacy training activities sponsored by Celgene and implemented by the Purdue Kenya Partnership has helped the program transition from an entirely donor dependent training program to a revenue generating, locally administered program which is now recognized and accredited by the Kenyan government. In the second case study, medication donations from Eli Lilly and Company have been converted from a traditional donation program in one Kenyan health facility to a replicable and sustainable supply chain model which has been expanded to more than 70 public sector facilities across western Kenya., Conclusion: Adherence to the five core principles of the proposed framework can help guide partnerships between academic institutions and the biopharmaceutical industry to advance healthcare services for underserved populations around the world. As large-scale government-based development agencies continue to primarily focus on specific disease states, biopharmaceutical industry-based collaborations can help initiate activities in underfunded therapeutic areas such as non-communicable diseases., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The present research was conducted to assess the feasibility of biological treatment of a typical wastewater (WW) stream in Multan, Pakistan, using daily trends of WW characteristics and to design a wastewater treatment (WWT) system for that stream. The pH (5.8-6.2), temperature (24-30 °C), biological oxygen demand (BOD 5 : 128-265 mg/L), ultimate BOD (BOD u : 227-438 mg/L), BOD/total Kjeldahl nitrogen (BOD 5 /TKN:5.9-11.2), BOD u /BOD 5 (1.6-2.0), carbonaceous BOD u /nitrogenous BOD u (CBOD u /NBOD u :1.6-2.8) of the WW was found to support the biological WWT. The inclusion of NBOD also indicated the need for nitrification-denitrification. The linear regression analysis of volatile suspended solids (VSS) with total suspended solids (TSS) indicated the high content of organic solids, which also made the WW suitable for biological treatment. The BOD/COD (chemical oxygen demand) <0.8 indicated the requirement for biomass acclimation. The major process units of the WWT system developed included a primary clarifier, cascade aeration, trickling filter, adsorption filter and chlorination contact tank. During the validation of design procedures, considerable removal of TSS (91%), TDS (46%), BOD 5 (88%), COD (87%) was observed over the 15 week operational period of the secondary WWT system. The WWT system developed was appropriate as a sustainable WWT system that consumed less energy and had lower operational costs.

Current research is based on an innovative approach of the fabrication of encapsulated sustainable, green, phytogenic magnetic nanoparticles (PMNPs), to inhibit the generation of secondary pollutants (Iron/Fe o ) during water treatment applications. These novel bio-magnetic membrane capsules (BMMCs) were prepared using two-step titration gel crosslink method, with polyvinyl alcohol and sodium alginate matrix as the model encapsulating materials to eliminate potentially toxic metals (Pb 2+ and Cd 2+ ) from water. The development of BMMCs was characterized by FTIR, XRD, XPS, SEM, VSM, TGA and EDX techniques. The effects of various operating parameters, adsorbent dose, contact time, solution pH, temperature, initial concentration of metals cations and co-existing ions were studied. The hysteresis loops have illustrated an excellent super-paramagnetic nature, demonstrating the smooth encapsulation of PMNPs without losing their magnetic properties. The maximum monolayer adsorptive capacities estimated at pH 6.5 by the Langmuir isotherm model were 548 and 610.67 mg/g for Pb 2+ and Cd 2+ , respectively. The novel BMMCs did not only control oxidation of PMNPs but also sustained the adsorptive removal over a wide range of pH (3-8), and the electrostatic interaction and ion-exchange were the core adsorption mechanisms. The BMMCs could easily be regenerated using 25% HNO 3 as an eluent for successful usage in seven repeated cycles. Therefore, the BMMCs as a material can be used as an excellent sorbent or composite material to remove toxic metals Pb 2+ and Cd 2+ , showing strong potential for improving water and wastewater treatment technologies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Treatment of toxic and emerging pollutants (T&EPs) is increasing the threats to the survival of conventional wastewater treatment (WWTs) technologies. The high installation and operational costs of advanced treatment technologies have shifted the research interest to the development of economical and reliable technology for management of T&EPs. Thus, recently biogenic nanoparticles (BNPs) fabricated using microbes/microorganisms are getting tremendous research interest due to their unique properties (i.e. high specific surface area, desired morphology, catalytic reactivity) for the biodegradation and biosorption of T&EPs. In addition, BNPs can be manufactured using metal contaminated water which indicates a hidden potential for resource recovery and utilization. Therefore, the present study discusses the adsorptive and catalytic performance of BNPs in the removal of T&EPs from water (W) and wastewater (WW). In addition, inspired by the superior performance of BNPs in advance WWT, a model of BNPs based WWT resource recovery and utilization process is also proposed. Finally, main issues i.e. mass production, leaching, poisoning/toxicity, regeneration, reusability and fabrication costs and process optimization are discussed which are main hinders in the transfer of BNPs based WWT technologies from laboratory to commercial scale., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Using diagnosis code-based algorithms is the primary method of identifying patient cohorts for retrospective studies; nevertheless, many databases lack reliable diagnosis code information., Objectives: To develop precise algorithms based on medication claims/prescriber visits (MCs/PVs) to identify psoriasis (PsO) patients and psoriatic patients with arthritic conditions (PsO-AC), a proxy for psoriatic arthritis, in Canadian databases lacking diagnosis codes., Methods: Algorithms were developed using medications with narrow indication profiles in combination with prescriber specialty to define PsO and PsO-AC. For a 3-year study period from July 1, 2009, algorithms were validated using the PharMetrics Plus database, which contains both adjudicated medication claims and diagnosis codes. Positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity of the developed algorithms were assessed using diagnosis code as the reference standard. Chosen algorithms were then applied to Canadian drug databases to profile the algorithm-identified PsO and PsO-AC cohorts., Results: In the selected database, 183,328 patients were identified for validation. The highest PPVs for PsO (85%) and PsO-AC (65%) occurred when a predictive algorithm of two or more MCs/PVs was compared with the reference standard of one or more diagnosis codes. NPV and specificity were high (99%-100%), whereas sensitivity was low (≤30%). Reducing the number of MCs/PVs or increasing diagnosis claims decreased the algorithms' PPVs., Conclusions: We have developed an MC/PV-based algorithm to identify PsO patients with a high degree of accuracy, but accuracy for PsO-AC requires further investigation. Such methods allow researchers to conduct retrospective studies in databases in which diagnosis codes are absent., (Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Magnetotactic bacteria (MTB) have started to be employed for the biosynthesis of magnetic nanoparticles, due to the rapidly increasing demand for nanoparticles in biomedical, biotechnology and environmental protection. MBT are the group of prokaryotes that have the ability to produce bio-magnetic minerals or bio-magnetic crystals of either magnetite (Fe 3 O 4 ) or greigite (Fe 3 S 4 ) in numerous shapes and size ranges, known as magnetosomes (MS). MS compel MTB to respond to the applied external magnetic field. However, it is extremely difficult to grow MTB and produce high yield of MS under artificial environmental conditions, thus creating a major hurdle to relocate MTB technology from laboratory scale to industrial or commercial level. Therefore, to best of our knowledge this review is the first attempt to highlight existing research developments about the laboratory scale and mass production of MS by MTB. Moreover, the optimum culture media and environmental conditions used for the cultivation of MTB were also considered. Finally, future research is encouraged for the improvement of MS yield which will result in the development of advanced nanotechnology/magnetotechnology., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Metastatic pancreatic cancer (mPC) is associated with low survival, with less than 10% of patients surviving 5 years. Recent therapies improve survival outcomes where few alternative therapies exist, but few economic analyses measure the value of survival gains attributable to new therapies., Objective: To estimate the value of survival gains in advanced or mPC attributable to the introduction of novel treatment regimens., Methods: Multivariate Cox proportional hazards models were used to estimate real-world survival gains associated with the introduction of gemcitabine (GEM) for patients diagnosed with stage IV or unstaged mPC in the Surveillance, Epidemiology, and End Results Program cancer registries. Then, evidence from clinical trials was used to evaluate the survival gains associated with nab-paclitaxel + gemcitabine (nP +GEM) and FOLFIRINOX (FFX) relative to GEM. The survival estimates and clinical trial evidence were used to calibrate an economic model and assess the cumulative value of survival gains in mPC to patients. Costs of treatment were calculated based on published cost-effectiveness studies., Results: We estimated that the introduction of GEM in 1996 was associated with a hazard ratio of 0.920 (P < 0.05) and an increase in median survival from 3.1 to 4.5 months. Results suggested that the value of survival gains attributable to GEM equaled about $71,000 per patient, while the value attributable to nP + GEM was an additional $56,700. Estimates for the value of survival gains per patient, net of total incremental lifetime treatment costs (drugs, adverse events, and other costs), were $50,294 for GEM and an additional $31,900 for nP + GEM. Clinical trials and cost-effectiveness studies reported an overall survival gain from FFX that was larger than, but statistically similar to, nP + GEM and had greater risk of adverse events and total incremental costs. We estimated that the total value of survival gains to mPC patients, net of total costs, associated with GEM was up to $47.6 billion, and the additional values attributable to nP+GEM and FFX were up to $39.0 billion and $26.3 billion, respectively., Conclusions: Historically, mPC patients have faced high disease burden and had few treatment options. Treatments introduced since 1996 have led to improved survival, with varying costs associated with treatment and adverse events. Accounting for total incremental costs, the majority of the value of survival gains from GEM and nP+GEM was retained by mPC patients, highlighting the value of innovation in settings where survival is low and few alternative therapies exist., Disclosures: Support for this research was provided by Celgene. Precision Health Economics was compensated by Celgene for work on this study. MacEwan is an employee of, and Yin is a consultant to, Precision Health Economics. Kaura and Khan are employees of Celgene. Study concept and design were contributed primarily by Yin and MacEwan, along with Kaura and Khan. MacEwan collected the data, and data interpretation was performed primarily by MacEwan and Yin, along with Kaura and Khan. The manuscript was written and revised by MacEwan, Yin, Kaura, and Khan.

Objectives: To measure the value of survival gains attributable to the introduction of 3 novel therapies for myelodysplastic syndromes (MDS)., Study Design: Retrospective study of patients diagnosed with MDS in the Surveillance, Epidemiology and End Results Program (SEER) registry, clinical trial evidence for MDS therapies, and claims data., Methods: We used multivariate Cox proportional hazards models to estimate the increase in survival associated with the introduction of the 3 new therapies for patients diagnosed with MDS from 2001 to 2011 in the SEER cancer registry. Increases in survival associated with the 3 novel therapies were estimated using retrospective survival analyses and published clinical trial evidence. MDS treatment costs were estimated using Ingenix claims data and used to calculate the share of the value of survival gains retained by patients., Results: We estimated that the introduction of these 3 therapies is associated with a hazard ratio of 0.901 (P <.10), and a 73% increase in median survival from 33 to 57 months. We estimated that for current and future MDS patients, these 3 therapies will generate over $193 billion in cumulative value through extensions in patient survival., Conclusions: This study demonstrates that the value of recently approved innovative therapies in MDS is large and that the value of survival gains in MDS far outweighs their costs.

Background: Since the early 2000s, treatment options for multiple myeloma have rapidly expanded, adding significant complexity to the management of this disease. To our knowledge, no systematic qualitative research on clinical decision-making in multiple myeloma has been published. We sought to characterize how physicians view and implement guidelines and incorporate novel approaches into patient care., Methods: We designed a semi-structured qualitative interview guide informed by literature review and an expert advisory panel. We conducted 60-minute interviews with a diverse sample of oncology physicians in the southeast United States. We used a constant comparative method to code and analyze interview transcripts. The research team and advisory panel discussed and validated emergent themes., Results: Participants were 13 oncologists representing 5 academic and 4 community practices. Academic physicians reported using formal risk-stratification schemas; community physicians typically did not. Physicians also described differences in eligibility criteria for transplantation; community physicians emphasized distance, social support, and psychosocial capacity in making decisions about transplantation referral; the academic physicians reported using more specific clinical criteria. All physicians reported using a maintenance strategy both for post-transplant and for transplant-ineligible patients; however, determining the timing of maintenance therapy initiation and the response were reported as challenging, as was recognition or definition of relapse, especially in terms of when treatment re-initiation is indicated., Conclusions: Practices reported by both academic and community physicians suggest opportunities for interventions to improve patient care and outcomes through optimal multiple myeloma management and therapy selection. Community physicians in particular might benefit from targeted education interventions about risk stratification, transplant eligibility, and novel therapies.

Background: Certain governmental agencies, patient advocacy organizations, and pharmaceutical manufacturers have implemented programs to assist patients in overcoming barriers to accessing healthcare. Recently, such programs have expanded their services, helping both uninsured and insured patients to navigate the complex healthcare system, and assisting with increasing out-of pocket costs and copays for the drugs. Objective: To better understand the effect of patient support programs on access to therapy for solid tumor malignancies, this study evaluated service use, case outcomes, and patient characteristics from a manufacturer-sponsored program in the United States. Methods: Sociodemographic characteristics, services use rates, and outcomes by case and insurance type were evaluated at the patient- and case-level in a random sample of patients prescribed nab-paclitaxel for solid tumor malignancies who enrolled in the Celgene Patient Support (CPS) program (April 2011-November 2013). Results: This analysis included 4566 patients (8134 cases); most patients were female (64.7%), aged <65 years (59.2%), in the South (53.9%), and treated in community settings (87.9%). Patients were primarily insured by Medicare (38.5%) or commercial plans (37.3%), or were uninsured (16.6%). Following benefits investigations for new patients entering the program (98.5%), CPS provided support to obtain free medicine (29.4%), appeal denial of coverage (15.0%), receive commercial co-payment assistance (8.1%), or obtain prior payer authorization (1.3%). Nab-paclitaxel was provided at no cost in 89.4% of cases where patients sought financial support; payer reimbursement was obtained in 63.2% of reimbursement appeals. Of commercially-insured patients who required assistance with co-payments and met financial criteria, 93.3% received a mean of $597 in co-payment support. Conclusion: The CPS program was successful in gaining access to therapy. Healthcare providers and both insured or uninsured patients accessed CPS for prior authorization/precertification, appeals support, and financial support through the Free Medication Program and the Commercial Co-Pay program.

Present investigation concern with combination of two drugs for the treatment of gout. One of these drug (naproxen sodium) is pain killer which is sustain their action within the body for 12 hours and the other drug (colchicine) is anti-gout, which release as conventional dosage. After oral administration naproxen will act as sustain release dosage and increase patient compliance about six batches of tablet were developed and evaluate .For the sustain release action polymers Methocel K4M and HPMCK15were used. These polymers were used in combination used with other inactive ingredients. Two methods were used for proration of final tablets. In 1st method only naproxen sodium granules were prepared which are sustained released. In second method these granules were mixed with colchicines powder and other all inactive ingredients. This method is easy and cost effective characterization of pallets and final tablets were performed. Final tablets were evaluated for all tests like appearance, friability, dissolution, hardness, assay, weight variation and in-vitro release study performed. The results obtained were satisfactory and complies with USP specification. Formulation containing combination of Methocel K4M and HPMC K15 showed good sustain release profile for 12 hours.

Introduction: There have been significant improvements in both treatment and screening efforts for many types of cancer over the past decade. However, the effect of these advancements on the survival of cancer patients is unknown, and many question the value of both new treatments and screening efforts., Methods: This study uses a retrospective analysis of SEER Registry data to quantify reductions in mortality rates for cancer patients diagnosed between 1997 and 2007. Using variation in trends in mortality rates by stage of diagnosis across cancer types, we use logistic regression to decompose separate survival gains into those attributable to advances in treatment versus advances in detection. We estimate the gains in survival due to gains in both treatment and detection overall and separately for 15 of the most common cancer types., Results: We estimate that 3-year cancer-related mortality of cancer patients fell 16.7% from 1997 to 2007. Overall, advances in treatment reduced mortality rates by approximately 12.2% while advances in early detection reduced mortality rates by 4.5%. The relative importance of treatment and detection varied across cancer types. Improvements in detection were most important for thyroid, prostate and kidney cancer. Improvements in treatment were most important for non-Hodgkins lymphoma, lung cancer and myeloma., Conclusion: Both improved treatment options and better early detection have led to significant survival gains for cancer patients diagnosed from 1997 to 2007, generating considerable social value over this time period.