The Medication Possession Ratio as a Predictor of Longitudinal HIV-1 Viral Suppression.

BACKGROUND: Antiretroviral adherence is essential to achieve viral suppression and limit HIV-related morbidity and mortality; however, antiretroviral adherence thresholds to achieve viral suppression in clinical practice have not been fully characterized using administrative claims data. OBJECTIVE: The purpose of this study was to assess the relationship between medication adherence and viral suppression among adult persons with HIV/AIDS (PWH) receiving antiretroviral therapy (ART) for ≥6 months. METHODS: This historical cohort, real-world investigation assessed maintenance of viral load suppression and viral load area-under-the-curve (vAUC) in PWH ≥18 years of age based on ART adherence. A marginal effects model was used to determine the predicted probabilities of final plasma HIV-1 RNA <50 copies/mL or vAUC <1,000 copy-days/mL according to the medication possession ratio (MPR), estimated using a Jackknife model variance estimator and a delta-method for marginal effects standard error. Tests for statistical significance used a Sidák method to correct for multiple comparisons. RESULTS: The mean MPR for ART was 86.7% (95% CI: 85.0%-88.4%) for the 372 PWH included in the study. The marginal effects analysis indicated that an MPR ≥82% was associated with a predicted probability of viral suppression <50 copies/mL (P < 0.05). Significant predicted probabilities for vAUC <1,000 copy-days/mL were observed with an MPR ≥90% (P < 0.05). CONCLUSION AND RELEVANCE: Medication possession ratio as a proxy for drug exposure was significantly and consistently associated with viral suppression using a longitudinal measure of HIV viremia. These findings can aid clinicians in the clinical management of PWH and inform future studies of adherence-viral suppression relationships with contemporary antiretroviral regimens.

Pemphigus foliaceus in Arabian oryx (Oryx leucoryx).

Pemphigus foliaceus (PF) is an autoimmune acantholytic skin disease described in humans, dogs, cats, horses, goats, and sheep. From 2003 to 2016, six Arabian oryx (Oryx leucoryx) at the National Zoological Garden in Pretoria, South Africa, developed progressive, bilaterally symmetrical, hyperkeratotic skin lesions and pustules consistent with PF. Lesions were similar to those observed in domestic animals and primarily affected the pinnae, face and nasal planum, distal legs, and tail tip. Histological evaluation of suspect PF skin lesions in affected animals, evaluation of medical records for treatments received, causative agents in the diet and environment, and special stains for infectious organisms yielded no consistent inciting cause. The Arabian oryx is a species highly adapted to arid environments of the desert and has recently survived from a severe genetic bottleneck; both of these factors may have contributed to the development of PF in these animals.

Correlating Cystic Fibrosis Transmembrane Conductance Regulator Function with Clinical Features to Inform Precision Treatment of Cystic Fibrosis.

Rationale: The advent of precision treatment for cystic fibrosis using small-molecule therapeutics has created a need to estimate potential clinical improvements attributable to increases in cystic fibrosis transmembrane conductance regulator (CFTR) function. Objectives: To derive CFTR function of a variety of CFTR genotypes and correlate with key clinical features (sweat chloride concentration, pancreatic exocrine status, and lung function) to develop benchmarks for assessing response to CFTR modulators. Methods: CFTR function assigned to 226 unique CFTR genotypes was correlated with the clinical data of 54,671 individuals enrolled in the Clinical and Functional Translation of CFTR (CFTR2) project. Cross-sectional FEV1% predicted measurements were plotted by age at which measurement was obtained. Shifts in sweat chloride concentration and lung function reported in CFTR modulator trials were compared with function-phenotype correlations to assess potential efficacy of therapies. Measurements and Main Results: CFTR genotype function exhibited a logarithmic relationship with each clinical feature. Modest increases in CFTR function related to differing genotypes were associated with clinically relevant improvements in cross-sectional FEV1% predicted over a range of ages (6-82 yr). Therapeutic responses to modulators corresponded closely to predictions from the CFTR2-derived relationship between CFTR genotype function and phenotype. Conclusions: Increasing CFTR function in individuals with severe disease will have a proportionally greater effect on outcomes than similar increases in CFTR function in individuals with mild disease and should reverse a substantial fraction of the disease process. This study provides reference standards for clinical outcomes that may be achieved by increasing CFTR function.

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine.

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.

Sarcoid within the oral cavity of a horse.

Equine sarcoids are common skin tumors that are thought to be caused by cross-species infection by bovine papillomaviruses (BPV). A 16-year-old horse developed a 1cm diameter mandibular gingival mass opposite the right second premolar tooth (406) and a 2cm diameter mass close to the commissure of the lips on the same side of the mouth. The right cheek was diffusely thickened. Histology of the smaller mass revealed a proliferation of mesenchymal cells covered by hyperplastic epithelium that formed thick rete pegs. BPV2 DNA was amplified from the mass. Although the mass had been incompletely excised, there was no recurrence after 5 months. The histological features and detection of BPV2 DNA is consistent with a diagnosis of equine sarcoid. Sarcoids have not previously been reported in the oral cavity of horses. It is hypothesized that trauma to the mouth may have been important for sarcoid development. Additionally, different BPV types may have variable ability to infect the gingiva. While rare, sarcoids are a differential for an oral mass in a horse.

Creation and Administration of a Chiropractic Program Practical Classroom Preparticipation Screening Aimed to Prevent Student Injuries: A Descriptive Report.

Objective: The purpose of this descriptive report is to describe the development of a preparticipation risk assessment screening process for incoming students prior to participation in practical labs. Methods: A committee at the Palmer College of Chiropractic, Florida met to discuss a health history questionnaire, physical examination process, and course of action to have second-year students use their current knowledge to screen incoming students for possible clinical considerations of practice lab participation. The aim was to identify potential risk factors that may require application modification associated with performing and receiving adjustments and other hands-on lab activities within the curriculum. The preparticipation screening process, focused on general health and curriculum referenced chiropractic clinical considerations, and was created as an expansion of the existing informed consent procedures to screen incoming students prior to participating in palpation, technique, physical examination, and open adjusting labs in the chiropractic program. Any clinical considerations identified during the screening were referred to be fully evaluated by a third-year clinic intern and faculty-licensed chiropractor to maintain classroom safety standards for the students. Referred students were restricted from full classroom lab participation until recommendations from the clinic or outside licensed healthcare providers managing their concerns were received. Results: The program was implemented in April 2022. Eight out of the 48 students evaluated in the first group and 12 of the 81 in the second group had possible clinical considerations to participation and were referred appropriately for a full evaluation. In the third group, 35 out of 146 students with suspected clinical considerations to participation were identified. Of the 55 students referred out, all students are now actively participating in classroom activities. Fifteen have been cleared to return to classroom participation with no restrictions and the remaining 40 students have been released for participation with patient-specific restrictions as directed by their managing health care providers. Conclusion: The preparticipation screening process was implemented as all incoming students since the inception of the process have been screened, referred for evaluation when deemed appropriate, and cleared to participate in labs either with or without restrictions. This process has also demonstrated the possibility of identifying multiple clinical considerations for safe curricular participation while participating in doctor-patient simulated classroom activities. This process may be helpful for new students to recognize the patient history and examination procedures as an important aspect of a patient encounter prior to receiving treatment.

Effect of Intermittent vs. Continuous Energy Restriction on Visceral Fat: Protocol for The Healthy Diet and Lifestyle Study 2 (HDLS2).

Obesity in the United States and Western countries represents a major health challenge associated with an increased risk of metabolic diseases, including cardiovascular disease, hypertension, diabetes, and certain cancers. Our past work revealed a more pronounced obesity-cancer link in certain ethnic groups, motivating us to develop a tailored dietary intervention called the Healthy Diet and Lifestyle 2 (HDLS2). The study protocol is described herein for this randomized six-month trial examining the effects of intermittent energy restriction (5:2 Diet) plus the Mediterranean dietary pattern (IER + MED) on visceral adipose tissue (VAT), liver fat, and metabolic biomarkers, compared to a standard MED with daily energy restriction (DER + MED), in a diverse participant group. Using MRI and DXA scans for body composition analysis, as well as metabolic profiling, this research aims to contribute to nutritional guidelines and strategies for visceral obesity reduction. The potential benefits of IER + MED, particularly regarding VAT reduction and metabolic health improvement, could be pivotal in mitigating the obesity epidemic and its metabolic sequelae. The ongoing study will provide essential insights into the efficacy of these energy restriction approaches across varied racial/ethnic backgrounds, addressing an urgent need in nutrition and metabolic health research. Registered Trial, National Institutes of Health, ClinicalTrials.gov (NCT05132686).

A hospital at home case report: Prolonged amphotericin B therapy via elastomeric pump.

PURPOSE: Hospital at home is an alternative means of providing inpatient care for a patient requiring prolonged liposomal amphotericin B therapy. SUMMARY: Hospital at home is a unique care model that allows patients to receive inpatient hospital care within the comfort of their home and can be seen as an alternative care site for patients with complex treatment regimens that may require prolonged hospitalization. Hospital systems have increasingly begun incorporating hospital at home programs into their inpatient service lines. We present the case of a patient with disseminated histoplasmosis requiring a prolonged course of intravenous liposomal amphotericin B therapy. Because of the complex administration and stability of this medication, care is often provided in an inpatient setting. The Vanderbilt University Medical Center Hospital at Home team was able to coordinate resources and services to allow for this patient to receive acute hospital care at home and continue to receive amphotericin B infusion. CONCLUSION: This experience spotlights how hospital at home can be considered for patients requiring ongoing inpatient care for prolonged intravenous treatment courses.

Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial.

BACKGROUND: Insulin replacement in diabetes often requires prandial intervention to reach hemoglobin A1(c) (HbA1(c)) targets. OBJECTIVE: To test whether twice-daily exenatide injections reduce HbA1(c) levels more than placebo in people receiving insulin glargine. DESIGN: Parallel, randomized, placebo-controlled trial, blocked and stratified by HbA1(c) level at site, performed from October 2008 to January 2010. Participants, investigators, and personnel conducting the study were masked to treatment assignments. (ClinicalTrials.gov registration number: NCT00765817) SETTING: 59 centers in 5 countries. PATIENTS: Adults with type 2 diabetes and an HbA1(c) level of 7.1% to 10.5% who were receiving insulin glargine alone or in combination with metformin or pioglitazone (or both agents). INTERVENTION: Assignment by a centralized, computer-generated, random-sequence interactive voice-response system to exenatide, 10 µg twice daily, or placebo for 30 weeks. MEASUREMENTS: The primary outcome was change in HbA1(c) level. Secondary outcomes included the percentage of participants with HbA1(c) values of 7.0% or less and 6.5% or less, 7-point self-monitored glucose profiles, body weight, waist circumference, insulin dose, hypoglycemia, and adverse events. RESULTS: 112 of 138 exenatide recipients and 101 of 123 placebo recipients completed the study. The HbA1(c) level decreased by 1.74% with exenatide and 1.04% with placebo (between-group difference, -0.69% [95% CI, -0.93% to -0.46%]; P < 0.001). Weight decreased by 1.8 kg with exenatide and increased by 1.0 kg with placebo (between-group difference, -2.7 kg [CI, -3.7 to -1.7]). Average increases in insulin dosage with exenatide and placebo were 13 U/d and 20 U/d. The estimated rate of minor hypoglycemia was similar between groups. Thirteen exenatide recipients and 1 placebo recipient discontinued the study because of adverse events (P < 0.010); rates of nausea (41% vs. 8%), diarrhea (18% vs. 8%), vomiting (18% vs. 4%), headache (14% vs. 4%), and constipation (10% vs. 2%) were higher with exenatide than with placebo. LIMITATIONS: The study was of short duration. There were slight imbalances between groups at baseline in terms of sex, use of concomitant glucose-lowering medications, and HbA1(c) levels, and more exenatide recipients than placebo recipients withdrew because of adverse events. CONCLUSION: Adding twice-daily exenatide injections improved glycemic control without increased hypoglycemia or weight gain in participants with uncontrolled type 2 diabetes who were receiving insulin glargine treatment. Adverse events of exenatide included nausea, diarrhea, vomiting, headache, and constipation. PRIMARY FUNDING SOURCE: Alliance of Eli Lilly and Company and Amylin Pharmaceuticals.

A Better Disinfectant for Low-Resourced Hospitals? A Multi-Period Cluster Randomised Trial Comparing Hypochlorous Acid with Sodium Hypochlorite in Nigerian Hospitals: The EWASH Trial.

Environmental hygiene in hospitals is a major challenge worldwide. Low-resourced hospitals in African countries continue to rely on sodium hypochlorite (NaOCl) as major disinfectant. However, NaOCl has several limitations such as the need for daily dilution, irritation, and corrosion. Hypochlorous acid (HOCl) is an innovative surface disinfectant produced by saline electrolysis with a much higher safety profile. We assessed non-inferiority of HOCl against standard NaOCl for surface disinfection in two hospitals in Abuja, Nigeria using a double-blind multi-period randomised cross-over study. Microbiological cleanliness [Aerobic Colony Counts (ACC)] was measured using dipslides. We aggregated data at the cluster-period level and fitted a linear regression. Microbiological cleanliness was high for both disinfectant (84.8% HOCl; 87.3% NaOCl). No evidence of a significant difference between the two products was found (RD = 2%, 90%CI: -5.1%-+0.4%; p-value = 0.163). We cannot rule out the possibility of HOCl being inferior by up to 5.1 percentage points and hence we did not strictly meet the non-inferiority margin we set ourselves. However, even a maximum difference of 5.1% in favour of sodium hypochlorite would not suggest there is a clinically relevant difference between the two products. We demonstrated that HOCl and NaOCl have a similar efficacy in achieving microbiological cleanliness, with HOCl acting at a lower concentration. With a better safety profile, and potential applicability across many healthcare uses, HOCl provides an attractive and potentially cost-efficient alternative to sodium hypochlorite in low resource settings.

Caution advised in the use of CFTR modulator treatment for individuals harboring specific CFTR variants.

In December 2020, the U.S. Food and Drug Administration (FDA) expanded the list of CFTR variants approved for treatment with CFTR modulators drugs from 39 to 183. Clinicians should be aware that individuals harboring certain variants approved for treatment may not respond to or benefit from this therapy. After review, the expert panel leading the CFTR2 project identified four categories of variants that may not result in a clinical response to modulator treatment: 15 variants assigned as non CF-causing; 45 variants of unknown significance; six variants known or suspected to cause mis-splicing as their primary defect rather than an amino acid substitution; and eight variants known to occur together in cis with another deleterious variant not expected to lead to CFTR protein (nonsense or frameshift). The potential risks and benefits of CFTR modulator therapy should be considered carefully for individuals harboring these variants.

Autologous CD34+ Stem Cell Therapy Increases Coronary Flow Reserve and Reduces Angina in Patients With Coronary Microvascular Dysfunction.

BACKGROUND: Coronary microvascular dysfunction results in angina and adverse outcomes in patients with evidence of ischemia and nonobstructive coronary artery disease; however, no specific therapy exists. CD34+ cell therapy increases microvasculature in preclinical models and improves symptoms, exercise tolerance, and mortality in refractory angina patients with obstructive coronary artery disease. The objective of this research was to evaluate the safety, tolerability, and efficacy of intracoronary CD34+ cell therapy in patients with coronary microvascular dysfunction. METHODS: We conducted a 2-center, 20-participant trial of autologous CD34+ cell therapy (protocol CLBS16-P01; NCT03508609) in patients with ischemia and nonobstructive coronary artery disease with persistent angina and coronary flow reserve ≤2.5. Efficacy measures included coronary flow reserve, angina frequency, Canadian Cardiovascular Society angina class, Seattle Angina Questionnaire, SF-36, and modified Bruce exercise treadmill test obtained at baseline and 6 months after treatment. Autologous CD34+ cells (CLBS16) were mobilized by administration of granulocyte-colony stimulating factor 5µg/kg/day for 5 days and collected by leukapheresis. Participants received a single intracoronary left anterior descending infusion of isolated CD34+ cells in medium that enhances cell function. RESULTS: Coronary flow reserve improved from 2.08±0.32 at baseline to 2.68±0.79 at 6 months after treatment (P<0.005). Angina frequency decreased (P<0.004), Canadian Cardiovascular Society class improved (P<0.001), and quality of life improved as assessed by the Seattle Angina Questionnaire (P≤0.03, all scales) and SF-36 (P≤0.04, all scales). There were no cell-related serious adverse events. CONCLUSIONS: In this pilot clinical trial of microvascular angina, patients with ischemia and nonobstructive coronary artery disease receiving intracoronary infusion of CD34+ cell therapy had higher coronary flow reserve, less severe angina, and better quality of life at 6 months. The current study supports a potential therapeutic role for CD34+ cells in patients with microvascular angina. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03508609.

Concerns of newborn blood screening advisory committee members regarding storage and use of residual newborn screening blood spots.

OBJECTIVES: We assessed attitudes and opinions of members of newborn blood screening (NBS) advisory committees regarding the storage and secondary research use of residual specimens from NBS. METHODS: We conducted focus groups in 2008 and 2009 with NBS advisory committees (4 focus groups; n = 39 participants) in the Mountain States region (i.e., AZ, CO, MT, NM, NV, TX, UT, and WY). RESULTS: Participants identified several challenges to implementing policies for storage of and research on residual newborn blood specimens. Themes that emerged from the data were public health relevancy; improvement of parental knowledge; impact of enhanced parental involvement; concerns over ownership, privacy, and confidentiality; identification of secondary research uses; and role of advisory committees. CONCLUSIONS: Participants indicated that secondary uses of residual specimens entailed opportunities for improvements in NBS programs but also carried significant risks for their programs. Addressing concerns from stakeholders will be necessary for state-level adoption of national recommendations.

Pharmacotherapy considerations in transgender individuals living with human immunodeficiency virus.

Pharmacotherapy considerations are often a concern for transgender individuals who are living with human immunodeficiency virus (HIV) due to concerns for drug-drug interactions between their hormone and antiretroviral therapies. Many of the first-line therapies offered to patients for the management of HIV have reduced concerns for safety, resistance, and drug-drug interactions. In this review, we highlight common medications and important considerations for caring for transgender people living with HIV.

Ethical Issues in Genetics and Infectious Diseases Research: An Interdisciplinary Expert Review.

PURPOSE: Research in genetics and infectious diseases (ID) presents novel configurations of ethical, legal, and social issues (ELSIs) related to the intersection of genetics with public health regulations and the control of transmissible diseases. Such research includes work both in pathogen genetics and on the ways that human genetics affect responses to ID. This paper identifies and systematizes the unique issues at this intersection, based on an interdisciplinary expert review. BASIC PROCEDURES: This paper presents results of a formal issue-spotting exercise among twenty experts in public health, law and genomics, biobanking, genetic epidemiology, ID medicine and public health, philosophy, ethics and ID, ethics and genomics, and law and ID. The focus of the exercise was on the collection, storage, and sharing of genetic information relating to ID. MAIN FINDINGS: The issue-spotting exercise highlighted the following ELSIs: risks in reporting to government authorities, return of individual research results, and resource allocation - each taking on specific configurations based on the balance between public health and individual privacy/protection. PRINCIPAL CONCLUSIONS: The public health implications of interactions between genomics and ID frame considerations for equity and justice. In the context of the COVID-19 pandemic, these issues are especially pressing.

Papillary dermal elastosis: a unique elastic tissue disorder or an unusual manifestation of pseudoxanthoma elasticum-like papillary dermal elastolysis?

There are numerous acquired elastic tissue disorders, several of which present cutaneously with small yellow-to-white papules resembling plucked chicken skin. Differential diagnoses depend on the abnormalities within the network of elastic tissues. We report a case with distinct histologic features, which may represent a unique elastic tissue disorder or a variant of pseudoxanthoma elasticum-like papillary dermal elastolysis. Our patient's clinical presentation includes scattered 1-2 mm white-to-yellow papules without surface change on the upper back and neck region. Histology is characterized by foci of clumped, granular elastic tissue, which have replaced the oxytalan and elaunin fibers, alternating with foci of decreased concentrations of normal-appearing elastic fibers within the papillary dermis. Given its characteristics, we have termed this novel entity 'papillary dermal elastosis'.

Reliability of the Sedation-Agitation Scale between nurses and doctors.

This study determined the inter-rater reliability of the Sedation-Agitation Scale (SAS) when used by staff in a tertiary level general intensive care unit (ICU). The study was designed to answer the question in the 'real world', with minimum patient exclusion criteria, do nurses and doctors rate ICU patient's sedation levels using the SAS similarly? A convenient sample of 35 nursing and seven medical staff and a randomly selected sample of 69 patients were used. A nurse and a doctor rated each patient simultaneously using the SAS, with a systematic five-stage arousal process. The results showed that there was exact agreement between the nurses' and doctors' scores in 74% of assessments. The weighted kappa finding of 0.82 indicates very good agreement (reliability). The mean SAS scores recorded for nurses (2.33+/-1.21) and doctors (2.36+/-1.35) were similar. Intraclass correlations for single measures (r=.921, p<.001) and average measures (r=.959, p<.001) indicated individuals who completed multiple ratings did not introduce bias. Where there was a difference between the paired ratings, these were only one level of the SAS away from each other. This research indicates nurses and doctors rate patients' levels of sedation similarly using the SAS. It also provides support for the use of the instrument in general ICUs outside the USA. Research is now needed to determine the value of the SAS in guiding clinical decision-making related to sedation management.

Should Genetic Testing for Variants Associated with Influenza Infection Be Mandatory for Health Care Employees?

Scientists are beginning to understand more about the role of host genetics in individuals' responses to influenza virus exposure. This fictional case addresses a situation in which a health care organization proposes requiring all health care practitioners with direct patient care responsibilities to undergo mandatory genetic testing for genetic variants used to (1) predict individuals' responses to the influenza vaccine, (2) determine individual susceptibility to influenza infection, and (3) identify individuals at increased risk for severe disease. This commentary will discuss ethical and legal issues associated with use of genetic test results to determine employee work assignments during an influenza pandemic.