Evaluation of cure rate in patients with hepatitis C virus completing shortened courses of treatment.

BACKGROUND: Guidelines recommend treatment with direct-acting antivirals for a minimum duration of 8 weeks in all patients with hepatitis C virus. Minimizing treatment duration is desirable because of decreased cost and increased adherence. Studies with treatment durations of less than 8 weeks have conflicting data. OBJECTIVE: The purpose of this study was to evaluate the clinical efficacy of hepatitis C treatment in patients who did not complete the guideline-recommended duration of therapy. METHODS: This was a retrospective, observational case series of patients with hepatitis C virus treated with 7 weeks or less of direct-acting antivirals between November 1, 2017 and July 31, 2019 at a large, academic medical center. The primary end point was cure, defined as sustained virologic response at 12 weeks after the end of treatment. Secondary end points included average duration of therapy, direct-acting antiviral used, and reason for early discontinuation. RESULTS: Of the 472 patients treated, 13 met criteria for inclusion. Sustained virologic response was achieved in 61.5% of the patients. Two patients (15.3%) were not cured, and 3 patients (23.1%) were lost to follow-up. Median duration of therapy was 4 weeks. All patients who received at least 4 weeks of therapy and remained in care were cured. CONCLUSION: In situations in which patients inadvertently stop hepatitis C treatment early, there is still the possibility of cure. Further studies are needed to determine which patient population may benefit from a shorter duration of therapy.

Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype-phenotype spectrum and functional impact on GPI-anchored proteins.

Early infantile epileptic encephalopathy 38 (EIEE38, MIM #617020) is caused by biallelic variants in ARV1, encoding a transmembrane protein of the endoplasmic reticulum with a pivotal role in glycosylphosphatidylinositol (GPI) biosynthesis. We ascertained seven new patients from six unrelated families harboring biallelic variants in ARV1, including five novel variants. Affected individuals showed psychomotor delay, hypotonia, early onset refractory seizures followed by regression and specific neuroimaging features. Flow cytometric analysis on patient fibroblasts showed a decrease in GPI-anchored proteins on the cell surface, supporting a lower residual activity of the mutant ARV1 as compared to the wildtype. A rescue assay through the transduction of lentivirus expressing wild type ARV1 cDNA effectively rescued these alterations. This study expands the clinical and molecular spectrum of the ARV1-related encephalopathy, confirming the essential role of ARV1 in GPI biosynthesis and brain function.

A realist evaluation of loneliness interventions for older people.

INTRODUCTION: the aim of this study was to develop a programme theory to inform the design of loneliness interventions and guide any future evaluations. METHODS: we undertook a mixed-method evaluation, informed by the realist approach, of different approaches to loneliness in one health and social care system in the East Midlands, UK. We used a combination of documentary analysis, interviews/focus groups with service providers and users and quantitative analysis to develop an initial programme theory. RESULTS: common aims of local interventions included enhancing social connectivity, providing emotional support and advice/information; recurring interventions included social activities, emotional support, advice and information, lunch clubs, learning new skills and practical support. None were robustly evaluated.Fifty-six service user or providers were involved in interviews or focus groups, which highlighted the causes of loneliness, preferred services, access to services, thoughts about intervention configuration and desired outcomes from services.The themes emerging from the interviews/focus groups from both service provider and service user perspectives were combined with all of the previous emerging data to create an overarching programme theory. Statements were constructed to allow service providers to think about which interventions might be useful to achieve specific outcomes in different contexts. CONCLUSION: the causes and consequences of loneliness vary widely between individuals, so a personalised approach is required to identify the causes and potential solutions. This study provides some high-level principles that can help commissioners and providers to tailor interventions to the individual needs of service users.

Lofexidine versus clonidine for mitigation of opioid withdrawal symptoms: A systematic review.

OBJECTIVES: The U.S. Food and Drug Administration recently approved lofexidine, an α-2-adrenergic agonist, as the first non-opioid medication for mitigation of opioid withdrawal symptoms. Clonidine, an α-2-adrenergic agonist, historically was used off-label for this indication. This review aimed to evaluate the effectiveness of lofexidine versus clonidine for mitigation of opioid withdrawal symptoms and to discuss the current role of lofexidine in the management of patients at risk of experiencing opioid withdrawal. DATA SOURCES: MEDLINE/PubMed, EBSCO, and CENTRAL were searched using the terms "lofexidine," "clonidine," and "opioid withdrawal." STUDY SELECTION: The literature search included English-language studies involving administration and prescription of lofexidine and clonidine for the management of opioid withdrawal symptoms in adults. Data sources were searched to include articles published between October 1993 and May 2019. DATA EXTRACTION: Three independent reviewers analyzed the title and abstract of studies to identify studies involving comparisons of lofexidine with clonidine for mitigation of opioid withdrawal symptoms. Reviewers were initially blinded to the individual determinations. Results were then unblinded and discussed among reviewers. RESULTS: Of the 110 citations screened, 5 articles were included. One study demonstrated a statistically significant reduction in opioid withdrawal symptom severity with lofexidine compared with clonidine, whereas the other 4 studies showed no significant difference. Three studies reported the completion of opioid detoxification treatment, with no significant differences seen. In 1 study that compared lofexidine with placebo, lofexidine caused significant hypotension, bradycardia, and pupillary constriction. Three studies showed significant adverse effects of hypotension and symptoms of feeling unwell with clonidine compared with lofexidine. CONCLUSION: Lofexidine appears equivalent in efficacy to clonidine, with fewer adverse effects, and it may have a limited role in the management of opioid withdrawal symptoms. However, cost, detoxification venue, and value of other preferred treatment modalities may affect the comparative efficacy of lofexidine to other agents.

Models for pharmacist-delivered tobacco cessation services: a systematic review.

OBJECTIVES: To summarize delivery models of pharmacist-led tobacco cessation services. DATA SOURCES: Studies published from July 1, 2003, to April 1, 2019, describing pharmacist-led tobacco cessation services in the United States were identified via PubMed/MEDLINE and EBSCO searches. STUDY SELECTION: Studies were considered for inclusion if they met the following criteria: population, patients 18 years of age and older using tobacco products; intervention, pharmacist-led tobacco cessation services; comparator, not required; and outcome, tobacco cessation. We used a web-based tool, Rayyan QCRI, to assist with study selection. DATA EXTRACTION: We used a data extraction tool to collect article reference, study design, primary and secondary objectives, brief description of intervention, pharmacologic interventions, service model, business model, method to measure tobacco cessation, tobacco cessation rates, and other comments. RESULTS: A total of 16 articles were incorporated into this review. Most studies included were observational (87.5%). The pharmacy settings included ambulatory care (68.8%), community (25%), and managed care (6.3%). Service models described most frequently followed an appointment-based, individual, face-to-face session between the patient and pharmacist. Business models included grant funding (12.5%), fee-for-service (6.3%), value-based (6.3%), and free services (6.3%), but most studies (56.3%) did not address reimbursement. Cessation rates ranged from 3.98% to 77.14% and were predominantly measured through self-report (62.5%). The timing of follow-up varied from 1 to 6 months after program completion, but in some articles was not reported (37.5%). CONCLUSION: Pharmacists currently manage tobacco cessation services via an assortment of methods and can successfully assist patients in achieving abstinence. Gaps in the literature necessitate further guidance on consistent outcomes reporting, impact of service model on tobacco cessation, and economic data of business models. The profession will benefit from such information to further expand the pharmacists' role within tobacco cessation services.

Development and delivery of a pharmacist training program to increase naloxone access in Kentucky.

OBJECTIVE: To describe the development and delivery of a comprehensive training program for Kentucky pharmacists to enable dispensation of naloxone per protocol. PRACTICE DESCRIPTION: In May 2015, the Kentucky Board of Pharmacy (KBP) promulgated regulations outlining the requirements for pharmacists to initiate the dispensing of naloxone under a physician-approved protocol. The Advancing Pharmacy Practice in Kentucky Coalition, a partnership between Kentucky's Colleges of Pharmacy, KBP, and state and local pharmacists associations, developed and offered educational programming to fulfill this regulation. Pharmacists who completed the 90-minute program could apply to KBP for registration as a naloxone-certified pharmacist. The program consists of a 90-minute session covering naloxone access, opioid overdoses, the pharmacology and use of naloxone, protocol development, patient identification, and resources. Sessions were offered live and via webinar. Sessions have also been incorporated into the pharmacy curriculum at the 2 colleges of pharmacy in Kentucky. RESULTS: Between June 28, 2015, and June 1, 2016, a total of 1254 pharmacists and 348 student pharmacists completed training. Of those, 646 (52%) have applied to KBP and received naloxone-certified status. The program was well received, with 87% of learners ranking the usefulness of the information presented as excellent. Learners cited screening tips, protocol information, patient screening information, and education resources as information they will implement in their practice. CONCLUSION: The swift deployment of training to a wide variety of pharmacy professionals has resulted in a substantial number of naloxone-certified pharmacists across Kentucky. Through a coordinated training initiative involving all major pharmacy stakeholders, we reached many individuals rapidly, documenting the value of this approach for future training endeavors. This educational initiative may enhance pharmacy practice across Kentucky and the nation by expanding and educating on the role pharmacists can play in public health and overdose death prevention.

Changing interpretation of chromosomal microarray over time in a community cohort with intellectual disability.

Chromosomal microarray (CMA) is the first-line diagnostic test for individuals with intellectual disability, autism, or multiple congenital anomalies, with a 10-20% diagnostic yield. An ongoing challenge for the clinician and laboratory scientist is the interpretation of variants of uncertain significance (VOUS)-usually rare, unreported genetic variants. Laboratories differ in their threshold for reporting VOUS, and clinical practice varies in how this information is conveyed to the family and what follow-up is arranged. Workflows, websites, and databases are constantly being updated to aid the interpretation of VOUS. There is a growing literature reporting new microdeletion and duplication syndromes, susceptibility, and modifier copy number variants (CNVs). Diagnostic methods are also evolving with new array platforms and genome builds. In 2010, high-resolution arrays (Affymetrix 2.7 M Oligo and SNP, 50 kB resolution) were performed on a community cohort of 67 individuals with intellectual disability of unknown aetiology. Three hundred and one CNVs were detected and analyzed using contemporary resources and a simple scoring system. Thirteen (19%) of the arrays were assessed as potentially pathogenic, 4 (6%) as benign and 50 (75%) of uncertain clinical significance. The CNV data were re-analyzed in 2012 using the contemporary interpretative resources. There was a statistically significant difference in the assessment of individual CNVs (P < 0.0001). An additional eight patients were reassessed as having a potentially pathogenic array (n = 21, 31%) and several additional susceptibility or modifier CNVs were identified. This study highlights the complexity involved in the interpretation of CMA and uniquely demonstrates how, even on the same array platform, it can be subject to change over time.

Levomilnacipran: A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder.

OBJECTIVE: To provide a clinical overview of the antidepressant levomilnacipran. DATA SOURCES: Articles were identified by searching the MEDLINE, PubMed, Cochrane Library, and Clinicaltrials.gov databases through March 2014 using the keyword levomilnacipran. The manufacturer provided additional information from unpublished phase II and phase III trials. STUDY SELECTION AND DATA EXTRACTION: Any clinical trial conducted for at least 3 weeks and published in the English language was selected for review. Additional documentation, including the product dossier, package insert, pharmacokinetic studies, and poster presentations supplied by the manufacturer, was also evaluated. DATA SYNTHESIS: Levomilnacipran is the more potent enantiomer of milnacipran. It is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), dosed from 20 to 120 mg daily for the treatment of major depressive disorder (MDD). Efficacy and tolerability were established during 3 phase III randomized, double-blind placebo-controlled trials finding levomilnacipran to be significantly more efficacious than placebo in reduction of Montgomery-Åsberg Depression Rating Scale scores. It is not known whether this agent is more efficacious than other antidepressants because direct comparison studies have not been conducted as of the time of this review. CONCLUSIONS: Levomilnacipran demonstrates efficacy and tolerability for short-term treatment of MDD in adults. Available evidence does not strongly indicate that there is a specific subpopulation of patients who would benefit from levomilnacipran over currently available SNRIs. Full characterization of the agent's place in therapy alongside multiple other agents with similar mechanisms and efficacy requires trials with longer duration and active comparators.

Effects of age on metacognitive efficiency.

Humans have a capacity to become aware of thoughts and behaviours known as metacognition. Metacognitive efficiency refers to the relationship between subjective reports and objective behaviour. Understanding how this efficiency changes as we age is important because poor metacognition can lead to negative consequences, such as believing one is a good driver despite a recent spate of accidents. We quantified metacognition in two cognitive domains, perception and memory, in healthy adults between 18 and 84years old, employing measures that dissociate objective task performance from metacognitive efficiency. We identified a marked decrease in perceptual metacognitive efficiency with age and a non-significant decrease in memory metacognitive efficiency. No significant relationship was identified between executive function and metacognition in either domain. Annual decline in metacognitive efficiency after controlling for executive function was ∼0.6%. Decreases in metacognitive efficiency may explain why dissociations between behaviour and beliefs become more marked as we age.

Single-Cell Phenotyping of Extracellular Electron Transfer via Microdroplet Encapsulation.

Electroactive organisms contribute to metal cycling, pollutant removal, and other redox-driven environmental processes. Studying this phenomenon in high-throughput is challenging since extracellular reduction cannot easily be traced back to its cell of origin within a mixed population. Here, we describe the development of a microdroplet emulsion system to enrich EET-capable organisms. We validated our system using the model electroactive organism S. oneidensis and describe the tooling of a benchtop microfluidic system for oxygen-limited processes. We demonstrated enrichment of EET-capable phenotypes from a mixed wild-type and EET-knockout population. As a proof-of-concept application, bacteria were collected from iron sedimentation from Town Lake (Austin, TX) and subjected to microdroplet enrichment. We observed an increase in EET-capable organisms in the sorted population that was distinct when compared to a population enriched in a bulk culture more closely akin to traditional techniques for discovering EET-capable bacteria. Finally, two bacterial species, C. sakazakii and V. fessus not previously shown to be electroactive, were further cultured and characterized for their ability to reduce channel conductance in an organic electrochemical transistor (OECT) and to reduce soluble Fe(III). We characterized two bacterial species not previously shown to exhibit electrogenic behavior. Our results demonstrate the utility of a microdroplet emulsions for identifying putative EET-capable bacteria and how this technology can be leveraged in tandem with existing methods.

An evaluation of the EQUIP treatment programme with men who have intellectual or other developmental disabilities.

BACKGROUND: The Equipping Youth to Help One Another Programme (EQUIP) was designed for young offenders to address a developmental delay in moral reasoning, distorted cognitions and social skills. METHODS: The present authors undertook a single case series study and piloted an adapted version of the EQUIP programme with three men with intellectual disabilities and four men with a diagnosis of Asperger Syndrome, all of whom were detained in a medium-secure forensic unit for people with intellectual disabilities. Treatment was delivered over a 12-week period, and participants took part in four-one-hour sessions per week. RESULTS: The results suggested that treatment was successful at increasing moral reasoning ability, reducing distorted cognitions and improving ability to choose effective solutions to problems. However, treatment did not have a significant effect upon anger. CONCLUSIONS: The EQUIP programme is a promising treatment, but further research is needed to investigate its effectiveness with men with intellectual or other developmental disabilities.

Validation of an adaptation of Levenson's locus of control scale with adult male incarcerated sexual offenders.

This article examines the psychometric properties of an adaptation of Levenson's Locus of Control (LoC) measure that is used by the English and Welsh Prison Service as part of the psychometric assessment battery for sexual offenders participating in the Sex Offender Treatment Programme (SOTP). Reliability and validity analyses were conducted on a sample of 2,497 sexual offenders who had completed SOTP. Internal consistency, convergent validity, and relationship to socially desirable responding were investigated. Construct validity was assessed via exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). Test-retest reliability data were collected from an additional sample of 26 sexual offenders. The scale was found to have excellent internal consistency, good test-retest reliability, and weak to moderate convergent validity with measures of self-esteem, attachment styles, emotional loneliness, and social problem solving. There was a moderate correlation between the scale and socially desirable responding. EFA and CFA suggested that a four-factor solution provided an acceptable fit to the data, with the factors relating to constructs of chance, problem solving, powerful others, and internal control. The findings of the present study suggest that the adapted LoC Scale is a useful tool for assessing sexual offenders' locus of control.

Risk of lead exposure from wild game consumption from cross-sectional studies in Madre de Dios, Peru.

Background: Studies have shown elevated blood lead levels (BLL) in residents of remote communities in the Amazon, yet sources of lead exposure are not fully understood, such as lead ammunition consumed in wild game. Methods: Data was collected during two cross-sectional studies that enrolled 307 individuals in 26 communities. Regression models with community random effects were used to evaluate risk factors for BLLs, including diet, water source, smoking, sex, age, and indigenous status. The All-Ages Lead Model (AALM) from the Environmental Protection Agency (EPA) was used to estimate background and dose from wild game consumption. Findings: Indigenous status and wild game consumption were associated with increased BLLs. Indigenous participants had 2.52 µg/dL (95% CI: 1.95-3.24) higher BLLs compared to non-indigenous. Eating wild game was associated with a 1.41 µg/dL (95% CI: 1.20-1.70) increase in BLLs. Two or more portions per serving were associated with increased BLLs of 1.66 µg/dL (95% CI: 1.10-2.57), compared to smaller servings. Using the AALM, we estimate background lead exposures to be 20 µg/day with consumption of wild game contributing 500 µg/meal. Lastly, we found a strong association between BLLs and mercury exposure. Interpretation: Consumption of wild game hunted with lead ammunition may pose a common source of lead exposure in the Amazon. Communities that rely on wild game and wild fish may face a dual burden of exposure to lead and mercury, respectively.

Evaluation of the addressing substance-related offending (ASRO) program for substance-using offenders in the community: a reconviction analysis.

This article reports an evaluation of the Addressing Substance-Related Offending program in the English and Welsh Probation Service. Participants were 319 adult male offenders who had a history of substance use and were serving community sentences. A quasi-experimental design was used to compare the reconviction rates of offenders who completed the program, offenders who started but did not complete the program, and a comparison group of offenders who were not allocated to the program. Multivariate analysis showed that at one-year follow-up the completers had a significantly lower rate of reconviction and longer time to reconviction than the non-completers, and the non-completers had a significantly higher rate of reconviction and shorter time to reconviction than the comparison group. No differences were found in reconviction between the completers and comparison group.

Development of a reproducible method for monitoring SARS-CoV-2 in wastewater.

Monitoring the genetic signal of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through RNA titers in wastewater has emerged as a promising strategy for tracking community-scale prevalence of coronavirus disease 2019 (COVID-19). Although many studies of SARS-CoV-2 in wastewater have been conducted around the world, a uniform procedure for concentrating the virus in wastewater is lacking. The goal of this study was to comprehensively evaluate how different methods for concentrating the suspended solids in wastewater affect the associated SARS-CoV-2 RNA signal and the time required for processing samples for wastewater-based epidemiology efforts. We additionally consider the effects of sampling location in the wastewater treatment train (i.e., following preliminary or primary treatment), pasteurization, and RNA extraction method. Comparison of the liquid phase to suspended solids obtained via centrifugation or vacuum filtration suggests that the RNA signal of SARS-CoV-2 preferentially occurs in the solids. Therefore, we assert that the recovery of SARS-CoV-2 from wastewater should focus on suspended solids. Our data indicate that the measured SARS-CoV-2 signal is higher among samples taken from the primary clarifier effluent, as opposed to those taken after preliminary treatment. Additionally, we provide evidence that sample pasteurization at 60 °C for 90 min reduces the SARS-CoV-2 signal by approximately 50-55%. Finally, the results indicate that a magnetic bead approach to RNA extraction leads to a higher SARS-CoV-2 signal than does a silica membrane approach.

Frailty and Social Isolation: Comparing the Relationship between Frailty and Unidimensional and Multifactorial Models of Social Isolation.

Objective: The aim of the study was to compare uni- and multidimensional models of social isolation to improve the specificity of determining associations between social isolation and frailty. Methods: The study included participants aged ≥60 years from the English Longitudinal Study of Ageing assessed for social isolation and frailty (frailty index and Fried phenotype) over a 4-year period. Factor analysis assessed whether social isolation was multidimensional. Multiple regression analysis was used to assess specificity in associations between social isolation and frailty over time. Results: Social isolation comprises social isolation from nuclear family, other immediate family, and wider social networks. Over time, social isolation from a wider social network predicted higher frailty index levels, and higher frailty index and Fried phenotype levels predicted greater social isolation from a wider social network. Discussion: Social isolation is multidimensional. The reciprocal relationship between social isolation from wider social networks and accumulating frailty deficits, and frailty as a clinical syndrome influencing social isolation from social networks is discussed.

The Write Stuff: The Development of a Medical Writing Pharmacy Residency Elective.

THE PROBLEM: Effective medical writing requires a mastery of many skills including those of data interpretation, literature evaluation, written communication, and leadership. A number of these skills are considered educational goals and objectives for residents by the American Society of Health-System Pharmacists, yet preceptors and residents oftentimes face challenges in gaining competency, confidence, and success in medical writing. INNOVATION: A structured yet individualized plan for medical writing, including idea creation, peer reviewing, manuscript preparation, and team management for post-graduate year two pharmacy residents was implemented as an elective learning experience. RESULTS: Feedback from residents participating in the elective was positive. Each of the two residents who participated produced a manuscript that was subsequently published. CONCLUSION: Though data is limited by number of residents that have completed this learning experience, this longitudinally designed elective has potential benefits and barriers to execution that should be considered, but may be an excellent opportunity to develop critical skills in scholarly endeavors for residents and preceptors alike.

Impact of Intersession Course Remediation on NAPLEX/PCOA Scores in an Accelerated Doctor of Pharmacy Program.

Objective. To compare Pharmacy Curriculum Outcomes Assessment (PCOA) scaled scores and North American Pharmacist Licensure Examination (NAPLEX) pass rates in students who completed a two-week intersession remediation or repeated a course with the scaled scores and pass rates of students who did not require any form of didactic remediation and did not have to repeat a course. Methods. Data examined for this study included NAPLEX/PCOA scores, NAPLEX pass/fail status, and remediation history for students at one college of pharmacy. Students from the graduating classes of 2016, 2017, and 2018 were organized into four groups: non-remediation, one course remediation and no repeats, more than one course remediation and no repeats, and one or more course repeats. Differences were analyzed using linear regression, logistic regression, and Pearson correlations. Results. The PCOA scores for students in the remediation groups were significantly lower than scores for students in the non-remediation groups, with a reduction of 37.8 to 50.9 points from the expected non-remediators' score. The NAPLEX scores for students who remediated more than one course or repeated one or more courses were 16-20 points lower compared to students who did not remediate. The likelihood of a student failing the NAPLEX was also not significantly lower for students who remediated one course but was significantly lower for other remediation groups. Conclusion. Although single course remediation in this curricular model appears to have minimal impact on NAPLEX outcomes and may be an acceptable intervention for many students, additional support and interventions may be warranted for students who qualify for remediation in multiple courses and/or for repeating a course.

Intersession Remediation to Minimize Attrition in a Three-Year Pharmacy Program.

Objective. To describe an intersession remediation process in an accelerated three-year Doctor of Pharmacy (PharmD) program and to determine if the remediation process reduced attrition rates, including program withdrawals, progression to advanced pharmacy practice experiences (APPEs), and on-time graduation rates. Methods. Attrition was defined as dismissal, withdrawal, leave of absence, and/or change in graduation date. Progression data from students who matriculated between 2008 to 2016, with data available through spring 2017, were analyzed for number of course failures and successful intersession remediation. Other factors such as pharmacy year (first or second year), course subject, and course repeats were evaluated to characterize successful remediation attempts and identify elements that foster student success. Results. Of the 812 matriculated students across the time period analyzed, 18% (n=146) failed at least one didactic course (defined as course average <69.5%). Overall, 74.7% (n=109) of the students who failed a course remediated, with 75.2% (n=82) of those able to remediate being successful, remaining on-time for graduation. If students who remediated were instead required to repeat coursework, the college attrition rate would have averaged over 10 percentage points higher for the time period analyzed than the actual rate of 13.4%. Conclusion. Our study demonstrated that the majority of students who qualified for remediation were successful and graduated on time. Further studies in this area are needed to fully elucidate the effect of remediation processes on learning and retention of knowledge and skills.