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UnlabelledWe have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD).Study designThese analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine.ResultsPatients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5 to 31.8 g/day and of sodium phenylbutyrate ranging from 1.3 to 31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% to 5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r = 0.730, p < 0.001) or as total 24-hour excretion (r = 0.791 p

Objectives Risk-adjusted 30-day hospital readmission rate is a commonly used benchmark for hospital quality of care and for Medicare reimbursement. Persons living with HIV ( PLWH) may have high readmission rates. This study compared 30-day readmission rates by HIV status in a multi-state sample with planned subgroup comparisons by insurance and diagnostic categories. Methods Data for all acute care, nonmilitary hospitalizations in nine states in 2011 were obtained from the Healthcare Costs and Utilization Project. The primary outcome was readmission for any cause within 30 days of hospital discharge. Factors associated with readmission were evaluated using multivariate logistic regression. Results A total of 5 484 245 persons, including 33 556 (0.6%) PLWH, had a total of 6 441 695 index hospitalizations, including 45 382 (0.7%) among PLWH. Unadjusted readmission rates for hospitalizations of HIV-uninfected persons and PLWH were 11.2% [95% confidence interval ( CI) 11.2, 11.2%] and 19.7% (95% CI 19.3, 20.0%), respectively. After adjustment for age, gender, race, insurance, and diagnostic category, HIV infection was associated with 1.50 (95% CI 1.46, 1.54) times higher odds of readmission. Predicted, adjusted readmission rates were higher for PLWH within every insurance category, including Medicaid [12.9% (95% CI 12.8, 13.0%) and 19.1% (95% CI 18.4, 19.7%) for HIV-uninfected persons and PLWH, respectively] and Medicare [13.2% (95% CI 13.1, 13.3%) and 18.0% (95% CI 17.4, 18.7%), respectively], and within every diagnostic category. Conclusions HIV infection is associated with significantly increased readmission risk independent of demographics, insurance, and diagnostic category. The 19.7% 30-day readmission rate may serve as a preliminary benchmark for assessing quality of care of PLWH. Policy-makers may consider adjusting for HIV infection when calculating a hospital's expected readmission rate. [ABSTRACT FROM AUTHOR]

Abstract Retrenchment of government services has occurred across a wide range of sectors and regions. Care services, in particular, have been clawed away in the wake of fiscal policies of cost containment and neoliberal policies centred on individual responsibility and market autonomy. Such policies have included the deinstitutionalisation of care from hospitals and clinics, and early discharge from hospital, both of which are predicated on the notion that care can be provided informally within families and communities. In this paper we examine the post-birth "care crisis" that new mothers face in one region of Canada. Method The data are drawn from a larger study of social determinants of pregnant and new mothers' health in Victoria, Canada. Mixed methods interviews were conducted among a purposive sample of women at three points in time. This paper reports data on sample characteristics, length of stay in hospital and health service gaps. This data is contextualised via a more in-depth analysis of qualitative responses from Wave 2 (4-6 weeks postpartum). Results Out results show a significant portion of participants desired services that were not publically available to them during the post-birth period. Among those who reported a gap in care, the two most common barriers were: cost and unavailability of home care supports. Participants' open-ended responses revealed many positive features of the public health care system but also gaps in services, and economic barriers to receiving the care they wanted. The implications of these findings are discussed in relation to recent neoliberal reforms. Discussion & conclusions While Canada may be praised for its public provision of maternity care, mothers' reports of gaps in care during the early postpartum period and increasing use of private doulas is a worrying trend. To the extent that individual mothers or families rely on the market for care provision, issues of equity and quality of care are pivotal. This paper concludes with suggestions for further research on the impact of recent changes in post-birth care on new fathers and on inequities in pre and post-birth care in less-resourced regions of the world.

Abstract Background In clinical practice, physicians often need to change the antipsychotic medications they give to patients because of an inadequate response or the presence of unacceptable or unsafe side effects. However, there is a lack of consensus in the field as to the optimal switching strategy for antipsychotics, especially with regards to the speed at which the dose of the previous antipsychotic should be reduced. This paper assesses the short-term results of strategies for the discontinuation of olanzapine when initiating risperidone. Methods In a 6-week, randomized, open-label, rater-blinded study, patients with schizophrenia or schizoaffective disorder, on a stable drug dose for more than 30 days at entry, who were intolerant of or exhibiting a suboptimal symptom response to more than 30 days of olanzapine treatment, were randomly assigned to the following switch strategies (common risperidone initiation scheme; varying olanzapine discontinuation): (i) abrupt strategy, where olanzapine was discontinued at risperidone initiation; (ii) gradual 1 strategy, where olanzapine was given at 50% entry dose for 1 week after risperidone initiation and then discontinued; or (iii) gradual 2 strategy, where olanzapine was given at 100% entry dose for 1 week, then at 50% in the second week, and then discontinued. Results The study enrolled 123 patients on stable doses of olanzapine. Their mean age was 40.3 years and mean (± standard deviation (SD)) baseline Positive and Negative Syndrome Scale (PANSS) total score of 75.6 ± 11.5. All-cause treatment discontinuation was lowest (12%) in the group with the slowest olanzapine dose reduction (gradual 2) and occurred at half the discontinuation rate in the other two groups (25% in abrupt and 28% in gradual 1). The relative risk of early discontinuation was 0.77 (confidence interval 0.61–0.99) for the slowest dose reduction compared with the other two strategies. After the medication was changed, improvements at endpoint were seen in PANSS total score (-7.3; p < 0.0001) and in PANSS positive (-3.0; p < 0.0001), negative (-0.9; p = 0.171) and anxiety/depression (-1.4; p = 0.0005) subscale scores. Severity of movement disorders and weight changes were minimal. Conclusion When switching patients from olanzapine to risperidone, a gradual reduction in the dose of olanzapine over 2 weeks was associated with higher rates of retention compared with abrupt or less gradual discontinuation. Switching via any strategy was associated with significant improvements in positive and anxiety symptoms and was generally well tolerated. Trial registration ClinicalTrials.gov NCT00378183

HIV care continuum outcome disparities by health insurance status have been noted among people with HIV (PWH). We therefore examined associations between state Medicaid expansion and HIV outcomes in the United States. Adults (≥18 years) with ≥1 visit in NA-ACCORD clinical cohorts from 2012-2017 contributed person-time annually between first and final visit or death; in each calendar year, clinical retention was ≥2 completed visits > 90 days apart, antiretroviral therapy (ART) receipt was receipt of ≥3 antiretroviral agents, and viral suppression was last measured HIV-1 RNA < 200 copies/mL. CD4 at enrollment was obtained within 6 months of enrollment in cohort. Difference-in-difference (DID) models quantified associations between Medicaid expansion changes (by state of residence) and HIV outcomes. Across 50 states, 87 290 PWH contributed 325 113 person-years of follow-up. Medicaid expansion had a substantial positive effect on CD4 at enrollment (DID = 93.5, 95% CI: 52.9, 134 cells/mm 3 ), a small negative effect on proportions clinically retained (DID = -0.19, 95% CI: -0.037, -0.01), and no effects on ART receipt (DID = 0.001, 95% CI: -0.003, 0.005) or viral suppression (DID = -0.14, 95% CI: -0.34, 0.07). Medicaid expansion had a positive effect on CD4 at entry, suggesting more timely HIV testing and care linkage, but generally null effects on downstream HIV care continuum measures., Competing Interests: Conflicts of interest Please see ICMJE form(s) for author conflicts of interest. These have been provided as supplementary materials. K.N.A. reports service on the scientific review board for TrioHealth, Inc. and consultancy with the All of Us Research Program. P.F.R. reports consulting fees for advising on HIV care continuum and cardiometabolic outcome analyses from Gilead & Janssen. All other authors report no potential COIs., (© The Author(s) 2024. Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc.)

Background: Thirty-day hospital readmission measures quality of care, but there are limited data among people with HIV (PWH) and people without HIV (PWoH) in the era of universal recommendation for antiretroviral therapy. We descriptively compared 30-day all-cause, unplanned readmission risk between PWH and PWoH., Methods: A retrospective cohort study was conducted using the 2019 Nationwide Readmissions Database (2019/01/01-2019/12/31), an all-payer database that represents all US hospitalizations. Index (initial) admissions and readmissions were determined using US Centers for Medicare & Medicaid Services definitions. Crude and age-adjusted risk ratios (aRR) comparing the 30-day all-cause, unplanned readmission risk between PWH to PWoH were estimated using random effect logistic regressions and predicted marginal estimates. Survey weights were applied to all analyses., Findings: We included 24,338,782 index admissions from 18,240,176 individuals. The median age was 52(IQR = 40-60) years for PWH and 61(IQR = 38-74) years for PWoH. The readmission risk was 20.9% for PWH and 12.2% for PWoH (age-adjusted-RR:1.88 [95%CI = 1.84-1.92]). Stratified by age and sex, young female (age 18-29 and 30-39 years) PWH had a higher readmission risk than young female PWoH (aRR = 3.50 [95%CI = 3.11-3.88] and aRR = 4.00 [95%CI = 3.67-4.32], respectively). While the readmission risk increased with age among PWoH, the readmission risk was persistently high across all age groups among PWH. The readmission risk exceeded 30% for PWH admitted for hypertensive heart disease, heart failure, and chronic kidney disease., Interpretation: PWH have a disproportionately higher risk of readmission than PWoH, which is concerning given the aging profile of PWH. More efforts are needed to address readmissions among PWH., Funding: US National Institutes of Health., Competing Interests: KNA declares support from US National Institute of Health, Coursera, Trio Health, and International Workshop on HIV and Hepatitis C Observational databases. Other authors declare no potential conflicts of interest., (© 2024 The Author(s).)

Abstract: Among 8455 people engaged in HIV care in 4 US cities, 4925 (58%) had treponemal testing at care entry. Of the 4925 tested, 3795 (77%) had a nonreactive result and might benefit from the reverse algorithm for a future incident syphilis diagnosis. Furthermore, low-barrier treponemal testing as a first step in the reverse algorithm may increase syphilis screening and decrease time to treatment., Competing Interests: Conflict of Interest and Sources of Funding: The authors declare that they have no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript. The Center for AIDS Research Network of Integrated Clinical Systems is funded by NIH NIAID R24 AI067039., (Copyright © 2024 American Sexually Transmitted Diseases Association. All rights reserved.)

Long-chain fatty acid oxidation disorders (LC-FAODs) are a group of rare, inherited, metabolic disorders that can lead to a wide range of symptoms that predominantly affect organ systems with high energy needs, such as the heart, liver, skeletal muscle, and nervous system. Clinical management primarily consists of close attention to and monitoring of diet and activity and avoidance of prolonged fasting. In addition, patients and caregivers must be alert for signs of life-threatening metabolic decompensation. As a result, LC-FAODs can have significant and wide-ranging impacts on the lives of patients and their caregivers. This article describes the effects of LC-FAODs at different life stages and in the context of the North American healthcare system from the perspective of a group of patients, caregivers, and healthcare providers ( n  = 6). We explain how challenges and needs change throughout life. Following an early diagnosis, an adjustment phase occurs during which caregivers may feel overwhelmed by their new roles and deeply concerned for their children's futures. As children grow, they become more aware of the differences between themselves and their peers, and with increasing independence comes more responsibility for managing their own condition. Major life events, such as new employment and moving house, pose challenges for people of all ages. In addition, it may be difficult to find and connect with qualified and experienced healthcare providers; navigate the health insurance system; and educate and align primary, specialist, and emergency care providers. We propose several strategies to improve the care of patients with LC-FAODs, such as educating local healthcare teams, improving trust between patients/caregivers and healthcare providers, and raising awareness of the challenges faced by patients and caregivers across the different life stages., Competing Interests: E.S.B., J.B., T.S., and E.R. declare no conflicts of interest. D.G. is an employee and shareholder of Ultragenyx Pharmaceutical, Inc. S.A.B. declares no conflicts of interest., (© The Author(s) 2024.)

Background: Sitting at the bedside may improve patient-clinician communication; however, many clinicians do not regularly sit during inpatient encounters., Objective: To determine the impact of adding wall-mounted folding chairs inside patient rooms, beyond any impact from a resident education campaign, on the patient-reported frequency of sitting at the bedside by internal medicine resident physicians., Design, Setting, and Participants: Prospective, controlled pre-post trial between 2019 and 2022 (data collection paused 2020-2021 due to COVID-19) at an academic hospital in Baltimore, Maryland. Folding chairs were installed in two of four internal medicine units and educational activities were delivered equally across all units., Main Outcome and Measures: Patient-reported frequency of sitting at bedside, assessed as means on Likert-type items with 1 being "never" and 5 being "every single time." We also examined the frequency of other patient-reported communication behaviors., Results: Two hundred fifty six and 206 patients enrolled in the pre and post-intervention periods, respectively. The mean frequency of patient-reported sitting by resident physicians increased from 1.8 (SD 1.2) to 2.3 (1.2) on education-only units (absolute difference 0.48 [95% CI: 0.21-0.75]) and from 2.0 (1.3) to 3.2 (1.4) on units receiving chairs (1.16, [0.87-1.45]). Comparing differences between groups using ordered logistic regression adjusting for clustering within residents, units with added chairs had greater increases in sitting (odds ratio 2.05 [1.10-3.82]), spending enough time at the bedside (2.43 [1.32-4.49]), and checking for understanding (3.04 [1.44-6.39]). Improvements in sitting and other behaviors were sustained on both types of units., Conclusions: Adding wall-mounted folding chairs may help promote effective patient-clinician communication., (© 2024 The Authors. Journal of Hospital Medicine published by Wiley Periodicals LLC on behalf of Society of Hospital Medicine.)

There are limited studies regarding the attainment of the Accreditation Council for Genetic Counseling Practice-Based Competencies by genetic counseling students who complete clinical rotations in an in-person setting versus in a remote setting that incudes telephone and/or video patient encounters. This study explored the perceptions of 17 patient-facing genetic counselors who had served as supervisors for genetic counseling students regarding student attainment of practice-based competencies in in-person compared to remote rotations. Participants were recruited through an American Board of Genetic Counseling eblast and were required to have at least 2 years of clinical experience and experience providing genetic counseling supervision for at least one in-person rotation and one remote rotation. Four focus groups were created comprising genetic counselors from various practice disciplines. Discussion focused on potential differences and similarities in supervisor perceptions of student attainment of each clinical practice-based competency, and whether there were any concerns about students being able to attain each competency in remote rotations. Overall, participants discussed that genetic counseling students' attainment of clinical competencies through remote rotations was comparable to in-person rotations; however, 15 themes were identified illustrating differences reported by participants in how they observed these skills being performed by students in in-person versus remote clinical settings. The findings of this study highlight important considerations when developing a remote rotation, as well as ways in which certain clinical skills may be further enhanced through a combination of both in-person and remote clinical experiences. A noted limitation of remote rotations is that students have less of an opportunity to interact with other providers, and so may require other opportunities for interprofessionalism and to understand their role as part of a larger organization. Further study is required to elucidate differences between telephone and video clinics, as well as potential differences pertaining to various specialty areas of practice., (© 2024 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Background: Hospital readmission trends for persons with human immunodeficiency virus (PWH) in North America in the context of policy changes, improved antiretroviral therapy (ART), and aging are not well-known. We examined readmissions during 2005-2018 among adult PWH in NA-ACCORD., Methods: Linear risk regression estimated calendar trends in 30-day readmissions, adjusted for demographics, CD4 count, AIDS history, virologic suppression (<400 copies/mL), and cohort., Results: We examined 20 189 hospitalizations among 8823 PWH (73% cisgender men, 38% White, 38% Black). PWH hospitalized in 2018 versus 2005 had higher median age (54 vs 44 years), CD4 count (469 vs 274 cells/μL), and virologic suppression (83% vs 49%). Unadjusted 30-day readmissions decreased from 20.1% (95% confidence interval [CI], 17.9%-22.3%) in 2005 to 16.3% (95% CI, 14.1%-18.5%) in 2018. Absolute annual trends were -0.34% (95% CI, -.48% to -.19%) in unadjusted and -0.19% (95% CI, -.35% to -.02%) in adjusted analyses. By index hospitalization reason, there were significant adjusted decreases only for cardiovascular and psychiatric hospitalizations. Readmission reason was most frequently in the same diagnostic category as the index hospitalization., Conclusions: Readmissions decreased over 2005-2018 but remained higher than the general population's. Significant decreases after adjusting for CD4 count and virologic suppression suggest that factors alongside improved ART contributed to lower readmissions. Efforts are needed to further prevent readmissions in PWH., Competing Interests: Potential conflicts of interest. K. N. A. reports grants to their institution from NIH; royalties or licenses from Coursera; and consulting fees from NIH and TrioHealth. R. J. B. reports grants to their institution from NIH and support for travel from NIH. J. A. C. reports grants to their institution from NIH and payment or honoraria from Prime Education and Integritas Communications. H. M. C. reports grants to their institution from AHRQ, NIH, and ViiV Healthcare; and participation in a data and safety monitoring board (DSMB) or advisory board for Gilead Sciences, NIH Office of AIDS Research, and ViiV Healthcare. J. J. E. reports grants to their institution from NIH, ViiV Healthcare, Gilead Sciences, and Janssen; consulting fees from ViiV Healthcare, Gilead Sciences, and Merck & Co; and participation on a DSMB or advisory board for TAIMED. K. A. G. reports grants to their institution from the US Department of Defense, NIH, Mental Wellness Foundation, HealthNetwork Foundation, Bloomberg Philanthropies, Defense Health Agency, the State of Maryland, Octapharma, Moriah Fund, and National Center for Advancing Translational Sciences; consulting fees from Spark HealthCare, Teach for America, and Aspen Institute; and participation on a DSMB or advisory board for Pfizer. M. J. G. reports grants to their institution from NIH; and participation on a DSMB or advisor board for Merck & Co, Gilead Sciences, and ViiV Healthcare. B. C. H. reports grants to their institution from NIH. M. A. H. reports grants to their institution from NIH. M. Y. K. reports grants to their institution from Gilead Sciences and ViiV Healthcare; payment or honoraria to their institution from Practice Point Communications CME; leadership in the AIDS Clinical Trials Group (ACTG) Underrepresented Populations Committee (Vice Chair) with payments to their institution; and uncompensated leadership on the Being Alive San Diego Board (member). M. B. K. reports grants to their institution from NIH, ViiV Healthcare, AbbVie, and Gilead Sciences; and consulting fees from ViiV Healthcare, AbbVie, and Gilead Sciences. R. L. reports support for travel from CIHR. V. D. L. reports grants to their institution from CIHR; payment or honoraria from ViiV Healthcare; support for travel from the Conference on Retroviruses and Opportunistic Infections; and participation on a DSMB or advisory board for the Providence Health Care Ethics Board. R. D. M. reports grants to their institution from NIH. S. N. reports grants to their institution from NIH. A. N. reports grants to their institution from Gilead Sciences. P. F. R. reports grants to their institution from NIH and consulting fees from Gilead Sciences and Janssen. J. E. T. reports grants to their institution from the National Eye Institute and ACTG; consulting fees from Gilead Sciences, Canfield, and UpToDate; participation on a DSMB or advisory board for NEI and Tarsier; stock or stock options in Tarsier; and fees for serving as Editor-in-Chief for Ocular Immunology and Inflammation. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: US hospitals report data on many health care quality metrics to government and independent health care rating organizations, but the annual cost to acute care hospitals of measuring and reporting quality metric data, independent of resources spent on quality interventions, is not well known., Objective: To evaluate externally reported inpatient quality metrics for adult patients and estimate the cost of data collection and reporting, independent of quality-improvement efforts., Design, Setting, and Participants: Retrospective time-driven activity-based costing study at the Johns Hopkins Hospital (Baltimore, Maryland) with hospital personnel involved in quality metric reporting processes interviewed between January 1, 2019, and June 30, 2019, about quality reporting activities in the 2018 calendar year., Main Outcomes and Measures: Outcomes included the number of metrics, annual person-hours per metric type, and annual personnel cost per metric type., Results: A total of 162 unique metrics were identified, of which 96 (59.3%) were claims-based, 107 (66.0%) were outcome metrics, and 101 (62.3%) were related to patient safety. Preparing and reporting data for these metrics required an estimated 108 478 person-hours, with an estimated personnel cost of $5 038 218.28 (2022 USD) plus an additional $602 730.66 in vendor fees. Claims-based (96 metrics; $37 553.58 per metric per year) and chart-abstracted (26 metrics; $33 871.30 per metric per year) metrics used the most resources per metric, while electronic metrics consumed far less (4 metrics; $1901.58 per metric per year)., Conclusions and Relevance: Significant resources are expended exclusively for quality reporting, and some methods of quality assessment are far more expensive than others. Claims-based metrics were unexpectedly found to be the most resource intensive of all metric types. Policy makers should consider reducing the number of metrics and shifting to electronic metrics, when possible, to optimize resources spent in the overall pursuit of higher quality.

Background: Sitting at the bedside may strengthen physician-patient communication and improve patient experience. Yet despite the potential benefits of sitting, hospital physicians, including resident physicians, may not regularly sit down while speaking with patients., Objective: To examine the frequency of sitting by internal medicine residents (including first post-graduate year [PGY-1] and supervising [PGY-2/3] residents) during inpatient encounters and to assess the association between patient-reported sitting at the bedside and patients' perceptions of other physician communication behaviors. We also assessed residents' attitudes towards sitting., Design: In-person survey of patients and email survey of internal medicine residents between August 2019 and January 2020., Participants: Patients admitted to general medicine teaching services and internal medicine residents at The Johns Hopkins Hospital., Main Measures: Patient-reported frequency of sitting at the bedside, patients' perceptions of other communication behaviors (e.g., checking for understanding); residents' attitudes regarding sitting., Key Results: Of 334 eligible patients, 256 (76%) completed a survey. Among these 256 respondents, 198 (77%) and 166 (65%) reported recognizing the PGY-1 and PGY-2/3 on their care team, respectively, for a total of 364 completed surveys. On most surveys (203/364, 56%), patients responded that residents "never" sat. Frequent sitting at the bedside ("every single time" or "most of the time," together 48/364, 13%) was correlated with other positive behaviors, including spending enough time at the bedside, checking for understanding, and not seeming to be in a rush (p < 0.01 for all). Of 151 residents, 77 (51%) completed the resident survey; 28 of the 77 (36%) reported sitting frequently. The most commonly cited barrier to sitting was that chairs were not available (38 respondents, 49%)., Conclusions: Patients perceived that residents sit infrequently. However, sitting was associated with other positive communication behaviors; this is compatible with the hypothesis that promoting sitting could improve overall patient perceptions of provider communication., (© 2021. Society of General Internal Medicine.)

Background: Despite rising rates of syphilis among people with human immunodeficiency virus (HIV; PWH) in the United States, there is no optimal syphilis screening frequency or prioritization., Methods: We reviewed records of all PWH in care between 1 January 2014 and 16 November 2018 from 4 sites in the Centers for AIDS Research Network of Integrated Clinical Systems Cohort (CNICS; N = 8455). We calculated rates of syphilis testing and incident syphilis and used Cox proportional hazards models modified for recurrent events to examine demographic and clinical predictors of testing and diagnosis., Results: Participants contributed 29 568 person-years of follow-up. The rate of syphilis testing was 118 tests per 100 person-years (95% confidence interval [CI]: 117-119). The rate of incident syphilis was 4.7 cases per 100 person-years (95% CI: 4.5-5.0). Syphilis diagnosis rates were highest among younger cisgender men who have sex with men and transgender women, Hispanic individuals, people who inject drugs, and those with detectable HIV RNA, rectal infections, and hepatitis C., Conclusions: We identified PWH who may benefit from more frequent syphilis testing and interventions for syphilis prevention., Competing Interests: Potential conflicts of interest. K. C. reports investigator-initiated grant support from Gilead Sciences and serving on Gilead Sciences Medical Advisory Board, outside the submitted work. J. D. reports consulting fees from National Association of State and Territorial AIDS Directors and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Planned Parenthood Federation of America, outside the submitted work. E. C. reports unrelated research grants, funding paid to UC Regents, from Merck Sharp and Dohme and Gilead Science, outside the submitted work. H. M. C. reports funding from the National Institutes of Health (NIH), the Agency for Healthcare Research and Quality, and ViiV and participation on the NIH Office of AIDS Research Advisory Council, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The incidence of Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) is increasing in the United States; however, there are limited data on anatomic site-specific GC/CT among people with HIV (PWH)., Methods: We reviewed records of all PWH in care between January 1, 2014, and November 16, 2018, at 4 sites in the CFAR Network of Integrated Clinical Systems Cohort (CNICS; n = 8455). We calculated anatomic site-specific GC/CT testing and incidence rates and used Cox proportional hazards models modified for recurrent events to examine sociodemographic and clinical predictors of GC/CT testing and incidence at urogenital, rectal, and pharyngeal sites. We also calculated site-specific number needed to test (NNT) to detect a positive GC/CT test., Results: Of 8455 PWH, 2460 (29.1%) had at least yearly GC/CT testing at any anatomic site. The rates of urogenital, rectal, and pharyngeal GC were 1.7 (95% CI, 1.6-1.9), 3.2 (95% CI, 3.0-3.5), and 2.7 (95% CI, 2.5-2.9) infections per 100 person-years, respectively. The rates of urogenital, rectal, and pharyngeal CT were 1.9 (95% CI, 1.7-2.1), 4.3 (95% CI, 4.0-4.5), and 0.9 (95% CI, 0.8-1.0) infections per 100 person-years, respectively. PWH 16-39 years old experienced greater GC/CT rates at all anatomic sites, while men who have sex with men experienced greater rates of extragenital infections. NNTs for urogenital, rectal, and pharyngeal GC/CT were 20 (95% CI, 19-21), 5 (95% CI, 5-5), and 9 (95% CI, 8-9), respectively., Conclusions: Many PWH are not tested annually for GC/CT, and rates of GC/CT infection, particularly rates of extragenital infections, are high. We identified groups of PWH who may benefit from increased site-specific GC/CT testing., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Purpose: Mitochondrial trifunctional protein deficiency (TFPD) and isolated long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) are two related defects of fatty acid β -oxidation. While NBS has decreased mortality, morbidity remains significant. Additionally, the relationship of genotype to clinical outcome remains unclear. To better understand these issues, we collected natural history data for these conditions by reviewing seven years of retrospective data from 45 cases of TFPD or LCHADD in the Inborn Errors of Metabolism - Information System., Methods: Available data included age at database entry, last datapoint, and development of various complications. Data were analyzed by clinical assigned diagnosis (LCHADD or TFPD), subdivided by method of ascertainment (newborn screening-NBS, or other than by newborn screening-NNBS), then re-analyzed based on four genotype groups: homozygous c.1528GC (p.E510Q) (common LCHAD variant); heterozygous c.1528GC (p.E510Q), other HADHA variants; and HADHB variants., Results: Forty-five patients from birth to 34 years of age were analyzed by assigned diagnosis (30 LCHADD and 15 TFPD) and method of ascertainment. Thirty had further analysis by genotype (22 biallelic HADHA variants and 8 biallelic HADHB variants). With regards to maternal complications, retinopathy, cardiomyopathy and hypoglycemia, patients with biallelic HADHA variants (with or without the common LCHAD variant) manifest a traditional LCHADD phenotype, while those with HADHB gene variants more commonly reported neuromusculoskeletal type TFPD phenotype. While retinopathy, rhabdomyolysis and peripheral neuropathy tended to present later in childhood, many features including initial report of cardiomyopathy and hypoglycemia presented across a wide age spectrum., Conclusion: This study demonstrates the utility of genotypic confirmation of patients identified with LCHADD/TFPD as variants in the HADHA and HADHB genes lead to different symptom profiles. In our data, biallelic HAHDA variants conferred a LCHADD phenotype, regardless of the presence of the common LCHAD variant., (© 2022 The Authors.)

With the rapid increase in publicly available sequencing data, healthcare professionals are tasked with understanding how genetic variation informs diagnosis and affects patient health outcomes. Understanding the impact of a genetic variant in disease could be used to predict susceptibility/protection and to help build a personalized medicine profile. In the United States, over 3.8 million newborns are screened for several rare genetic diseases each year, and the follow-up testing of screen-positive newborns often involves sequencing and the identification of variants. This presents the opportunity to use longitudinal health information from these newborns to inform the impact of variants identified in the course of diagnosis. To test this, we performed secondary analysis of a 10-year natural history study of individuals diagnosed with metabolic disorders included in newborn screening (NBS). We found 564 genetic variants with accompanying phenotypic data and identified that 161 of the 564 variants (29%) were not included in ClinVar. We were able to classify 139 of the 161 variants (86%) as pathogenic or likely pathogenic. This work demonstrates that secondary analysis of longitudinal data collected as part of NBS finds unreported genetic variants and the accompanying clinical information can inform the relationship between genotype and phenotype., 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 © 2022 Wilhelm, Edick, Berry, Hartnett and Brower.)

Methionine synthase deficiency (cblG complementation group) is a rare inborn error of metabolism affecting the homocysteine re-methylation pathway. It leads to a biochemical phenotype of hyperhomocysteinemia and hypomethioninemia. The clinical presentation of cblG is variable, ranging from seizures, encephalopathy, macrocytic anemia, hypotonia, and feeding difficulties in the neonatal period to onset of psychiatric symptoms or acute neurologic changes in adolescence or adulthood. Given the variable and nonspecific symptoms seen in cblG, the diagnosis of affected patients is often delayed. Medical management of cblG includes the use of hydroxocobalamin, betaine, folinic acid, and in some cases methionine supplementation. Treatment has been shown to lead to improvement in the biochemical profile of affected patients, with lowering of total homocysteine levels and increasing methionine levels. However, the published literature contains differing conclusions on whether treatment is effective in changing the natural history of the disease. Herein, we present five patients with cblG who have shown substantial clinical benefit from treatment with objective improvement in their neurologic outcomes. We demonstrate more favorable outcomes in our patients who were treated early in life, especially those who were treated before neurologic symptoms manifested. Given improved outcomes from treatment of presymptomatic patients, cblG warrants inclusion in newborn screening., (© 2021 SSIEM.)

Background: Persons with human immunodeficiency virus (PWH) with persistently low CD4 counts despite efficacious antiretroviral therapy could have higher hospitalization risk., Methods: In 6 US and Canadian clinical cohorts, PWH with virologic suppression for ≥1 year in 2005-2015 were followed until virologic failure, loss to follow-up, death, or study end. Stratified by early (years 2-5) and long-term (years 6-11) suppression and lowest presuppression CD4 count <200 and ≥200 cells/µL, Poisson regression models estimated hospitalization incidence rate ratios (aIRRs) comparing patients by time-updated CD4 count category, adjusted for cohort, age, gender, calendar year, suppression duration, and lowest presuppression CD4 count., Results: The 6997 included patients (19 980 person-years) were 81% cisgender men and 40% white. Among patients with lowest presuppression CD4 count <200 cells/μL (44%), patients with current CD4 count 200-350 vs >500 cells/μL had aIRRs of 1.44 during early suppression (95% confidence interval [CI], 1.01-2.06), and 1.67 (95% CI, 1.03-2.72) during long-term suppression. Among patients with lowest presuppression CD4 count ≥200 (56%), patients with current CD4 351-500 vs >500 cells/μL had an aIRR of 1.22 (95% CI, .93-1.60) during early suppression and 2.09 (95% CI, 1.18-3.70) during long-term suppression., Conclusions: Virologically suppressed patients with lower CD4 counts experienced higher hospitalization rates and could potentially benefit from targeted clinical management strategies., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: To examine recent trends and differences in all-cause and cause-specific hospitalization rates by race, ethnicity, and gender among persons with HIV (PWH) in the United States and Canada., Design: HIV clinical cohort consortium., Methods: We followed PWH at least 18 years old in care 2005-2015 in six clinical cohorts. We used modified Clinical Classifications Software to categorize hospital discharge diagnoses. Incidence rate ratios (IRR) were estimated using Poisson regression with robust variances to compare racial and ethnic groups, stratified by gender, adjusted for cohort, calendar year, injection drug use history, and annually updated age, CD4+, and HIV viral load., Results: Among 27 085 patients (122 566 person-years), 80% were cisgender men, 1% transgender, 43% White, 33% Black, 17% Hispanic of any race, and 1% Indigenous. Unadjusted all-cause hospitalization rates were higher for Black [IRR 1.46, 95% confidence interval (CI) 1.32-1.61] and Indigenous (1.99, 1.44-2.74) versus White cisgender men, and for Indigenous versus White cisgender women (2.55, 1.68-3.89). Unadjusted AIDS-related hospitalization rates were also higher for Black, Hispanic, and Indigenous versus White cisgender men (all P < 0.05). Transgender patients had 1.50 times (1.05-2.14) and cisgender women 1.37 times (1.26-1.48) the unadjusted hospitalization rate of cisgender men. In adjusted analyses, among both cisgender men and women, Black patients had higher rates of cardiovascular and renal/genitourinary hospitalizations compared to Whites (all P < 0.05)., Conclusion: Black, Hispanic, Indigenous, women, and transgender PWH in the United States and Canada experienced substantially higher hospitalization rates than White patients and cisgender men, respectively. Disparities likely have several causes, including differences in virologic suppression and chronic conditions such as diabetes and renal disease., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: To assess the possible impact of antiretroviral therapy improvements, aging, and comorbidities, we examined trends in all-cause and cause-specific hospitalization rates among persons with HIV (PWH) from 2005 to 2015., Methods: In 6 clinical cohorts, we followed PWH in care (≥1 outpatient CD4 count or HIV load [VL] every 12 months) and categorized ICD codes of primary discharge diagnoses using modified Clinical Classifications Software. Poisson regression estimated hospitalization rate ratios for calendar time trends, adjusted for demographics, HIV risk factor, and annually updated age, CD4, and VL., Results: Among 28 057 patients (125 724 person-years), from 2005 to 2015, the median CD4 increased from 389 to 580 cells/µL and virologic suppression from 55% to 85% of patients. Unadjusted all-cause hospitalization rates decreased from 22.3 per 100 person-years in 2005 (95% confidence interval [CI], 20.6-24.1) to 13.0 in 2015 (95% CI, 12.2-14.0). Unadjusted rates decreased for almost all diagnostic categories. Adjusted rates decreased for all-cause, cardiovascular, and AIDS-defining conditions, increased for non-AIDS-defining infection, and were stable for most other categories., Conclusions: Among PWH with increasing CD4 counts and viral suppression, unadjusted hospitalization rates decreased for all-cause and most cause-specific hospitalizations, despite the potential effects of aging, comorbidities, and cumulative exposure to HIV and antiretrovirals., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Background: It is unknown whether gaining inpatient health care coverage had an effect on hospitalization rates among persons with HIV (PWH) after implementation of the Affordable Care Act in 2014., Methods: Hospitalization data from 2015 were obtained for 1634 adults receiving longitudinal HIV care at 3 US HIV clinics within the HIV Research Network. All patients were engaged in care and previously uninsured and supported by the Ryan White HIV/AIDS Program in 2013. We evaluated whether PWH who transitioned to either Medicaid or private insurance in 2014 tended to have a change in hospitalization rate compared with PWH who remained uncovered and Ryan White HIV/AIDS Program supported. Analyses were performed by negative binomial regression with robust standard errors, adjusting for gender, race/ethnicity, age, HIV risk factor, CD4 count, viral load, clinic site, and 2013 hospitalization rate., Results: Among PWH without inpatient health care coverage in 2013, transitioning to Medicaid [adjusted incidence rate ratio 1.26, (0.71, 2.23)] or to private insurance [0.48 (0.18, 1.28)] in 2014 was not associated with 2015 hospitalization rates, after accounting for demographics, HIV characteristics, and prior hospitalization rates. The factors significantly associated with higher hospitalization rates include age 55-64, CD4 <200 cells/µL, viral load >400 copies/mL, and 2013 hospitalization rate., Conclusions: Acquiring inpatient coverage was not associated with a change in hospitalization rates. These results provide some evidence to allay the concern that acquiring inpatient coverage would lead to increased inpatient utilization., Competing Interests: The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background/aims: Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age., Methods: This was an open-label study in UCD patients aged 0 - 2 months, consisting of an initiation/transition period (1 - 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter., Results: All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported., Conclusions: This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population., Competing Interests: Declaration of Competing Interest The authors have the following conflicts of interest: Colleen Canavan, Thomas Vescio, Teresa Kok, and Marty Porter are employees of, and have stock in, Horizon. None of the other authors have a financial interest in Horizon. For the following authors, payments were made by Horizon to their institutions for services provided in the conduct of the clinical studies upon which this report is based: Nicola Longo (University of Utah), George Diaz (Icahn School of Medicine at Mount Sinai), Uta Lichter-Konecki (Children's Hospital of Pittsburgh), Andreas Schulze (Hospital for Sick Children, Toronto), Robert Conway (Wayne State University), Shawn McCandless (University Hospitals of Cleveland and University of Colorado), Roberto Zori (University of Florida), Bryan Hainline (Indiana University School of Medicine), Nicholas Ah Mew (Children's National Medical Center), and Susan Berry (University of Minnesota). Nicola Longo, George Diaz, Uta Lichter-Konecki, Andreas Schulze, Robert Conway, Shawn McCandless, Roberto Zori, Bryan Hainline, and Susan Berry have served as Horizon advisory board members., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) is a fatty acid oxidation disorder in which the patient is unable to break down fats to produce energy. This disorder places children at risk for metabolic decompensation during periods of stress, such as routine childhood illnesses. The intent of this clinical report is to provide pediatricians with additional information regarding the acute clinical care of patients with MCADD. Although each patient with MCADD will still be expected to have a primary metabolic physician, the involvement of the primary care provider is crucial as well. Appropriate treatment of children with MCADD can lead to avoidance of morbidity and mortality., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

With an ever-increasing interest in secure and reliable free-space optical communication, upconversion detectors enabled through nonlinear optical processes are an attractive route to transmitting data as a mid-infrared signal. This spectral region is known to have a higher transmissivity through the atmosphere. In this work, we present an upconversion scheme for detection in the silicon absorption band using magnesium-oxide doped periodically poled lithium niobate to generate 21 mW of a 3.4 µm signal from commercial laser sources using a difference frequency generation process. Following a further nonlinear frequency conversion, via sum-frequency generation, the resulting signal at 809 nm is detected. We achieve >50 µW of signal and bit error rates of 10 -7 from a single-pass nonlinear conversion for both the transmitter and receiver systems without the need for additional optical amplifiers at the receiving end. The error rates due to potentially reduced laser powers at the receiver end are investigated and laser noise transfer through our system is discussed.

Mucopolysaccharidosis, type II (MPS II, MIM 309900) is a severe lysosomal storage disease with multisystem involvement. There is one product approved by the FDA, an enzyme replacement therapy, based on a phase III trial in older, attenuated MPS II individuals. Guidance on treatment of MPS II is lacking, not only in general, but for specific clinical situations. A previous systematic evidence-based review of treatment for MPS II demonstrated insufficient strength in all data analyzed to create a definitive practice guideline based solely on published evidence. The American College of Medical Genetics and Genomics (ACMG) Therapeutics Committee conducted a Delphi study to generate an MPS II clinical practice resource of the treatment for these individuals for the genetics community, based on the evidence-based review and subsequent literature. This report describes the process, including consensus development and areas where consensus could not be obtained due to lack of quality evidence. Recommendations from the Delphi process were generated, and areas were highlighted that need further study to help guide clinical care of these individuals.

Persons with HIV (PWH) are aging. The impact of aging on healthcare utilization is unknown. The objective of this study was to evaluate hospitalization rates and reasons stratified by age among PWH in longitudinal HIV care. Hospitalization data from 2014-2015 was obtained on all adults receiving HIV care at 14 diverse sites within the HIV Research Network in the United States. Modified clinical classification software from the Agency for Healthcare Research and Quality assigned primary ICD-9 codes into diagnostic categories. Analysis performed with multivariate negative binomial regression. Among 20,608 subjects during 2014-2015, all cause hospitalization rate was 201/1000PY. Non-AIDS defining infection (non-ADI) was the leading cause for admission (44.2/1000PY), followed by cardiovascular disease (CVD) (21.2/1000PY). In multivariate analysis of all-cause admissions, the incidence rate ratio (aIRR) increased with older age (age 18-29 reference): age 30-39 aIRR 1.09 (0.90,1.32), age 40-49 1.38 (1.16,1.63), age 50-59 1.58 (1.33,1.87), and age ≥ 60 2.14 (1.77,2.59). Hospitalization rates increased significantly with age for CVD, endocrine, renal, pulmonary, and oncology. All cause hospitalization rates increased with older age, especially among non-communicable diseases (NCDs), while non-ADIs remained the leading cause for hospitalization. HIV providers should be comfortable screening for and treating NCDs.

Periodically poled lithium niobate (PPLN) waveguides are a proven and popular means for efficient wavelength conversion. However, conventional PPLN waveguides typically have small mode field diameters (MFD) (≲6 µm) or significant insertion and/or propagation losses, limiting their ability to operate at multi-watt power levels. In this work we utilise zinc indiffused PPLN ridge waveguides that have a larger MFD, favourable pump/SHG modal overlap, and low insertion losses. Here for the first time, we have demonstrated continuous wave (CW) spectral narrowing from a PPLN waveguide, both with high efficiency and multi-watt second harmonic generation (SHG). 2.5 W of 780 nm has been produced by SHG of an amplified 1560 nm telecom laser with a device efficiency of 58% in a 4.0-cm long ridge waveguide. We have modelled conversion efficiency and applied experimentally measured waveguide parameters to show excellent agreement to the SHG spectra. Spectral narrowing of the full width half maximum (FWHM) of 35.7% has been measured as the nonlinear drive is increased. This work demonstrates that single-pass, multi-watt, CW SHG at 780 nm is feasible from our PPLN waveguide in the large conversion regime.

A blazed chirped Bragg grating in a planar silica waveguide device was used to create an integrated diffractive element for a spectrometer. The grating diffracts light from a waveguide and creates a wavelength dependent focus in a manner similar to a bulk diffraction grating spectrometer. An external imaging system is used to analyse the light, later device iterations plan to integrate detectors to make a fully integrated spectrometer. Devices were fabricated with grating period chirp rates in excess of 100 nm mm -1 , achieving a focal length of 5.5 mm. Correction of coma aberrations resulted in a device with a footprint of 20 mm×10 mm, a peak FWHM resolution of 1.8 nm, a typical FWHM resolution of 2.6 nm and operating with a 160 nm bandwidth centered at 1550 nm.

We present the design and characterization of a zinc-indiffused periodically poled lithium-niobate ridge waveguide for second-harmonic generation of ∼390 n m light from 780 nm. We use a newly developed, broadband near-infrared vertical external-cavity surface-emitting laser (VECSEL) to investigate the potential for lower-footprint nonlinear optical pump sources as an alternative to larger commercial laser systems. We demonstrate a VECSEL with an output power of 500 mW, containing an intracavity birefringent filter for spectral narrowing and wavelength selection. In this first demonstration of using a VECSEL to pump a nonlinear waveguide, we present the ability to generate 1 mW of ∼390 n m light with further potential for increased efficiency and size reduction.