Depression and HIV Care-seeking Behaviors in a Population-based Sample in North West Province, South Africa.

Depression is associated with key HIV-related prevention and treatment behaviors in sub-Saharan Africa. We aimed to identify the association of depressive symptoms with HIV testing, linkage to care, and ART adherence among a representative sample of 18-49 year-olds in a high prevalence, rural area of South Africa. Utilizing logistic regression models (N = 1044), depressive symptoms were inversely associated with reported ever HIV testing (AOR 0.92, 95% CI 0.85-0.99; p = 0.04) and ART adherence (AOR 0.82, 95% CI: 0.73-0.91; p < 0.01) among women. For men, depressive symptoms were positively associated with linkage to care (AOR: 1.21, 95% CI: 1.09-1.34; p < 0.01). Depression may adversely impact ART adherence for HIV-positive women and reduce the likelihood of HIV testing for women not aware of their HIV status which, in settings with high HIV prevalence, carries severe consequences. For HIV-positive men, findings suggest that depression may encourage help-seeking behavior, thereby impacting their health system interactions. These findings underscore the need for health-care settings to factor mental health, such as depression, into their programs to address health-related outcomes, particularly for women.

RESUMEN: La depresión está asociada con conductas clave de prevención y tratamiento relacionadas con el VIH en África subsahariana. Nuestro objetivo fue identificar la asociación de los síntomas depresivos con los resultados relacionados con el VIH entre una muestra representativa de personas de 18 a 49 años en Sudáfrica. Utilizando modelos de regresión logística (N = 1044), los síntomas depresivos se asociaron inversamente con los que se informaron que habían probado de VIH alguna vez (AOR 0,92, IC del 95%: 0,85 a 0,99; p = 0,04) y la adherencia al TAR (AOR 0,82, IC del 95%: 0,73 a 0,91; p < 0,01) entre las mujeres. Para los hombres, los síntomas depresivos se asociaron positivamente con la vinculación con cuidado (AOR: 1,21, IC del 95%: 1,09­1,34; p < 0,01). La depresión puede tener un impacto adverso en la adherencia al TAR para las mujeres VIH-positivas y reducir la probabilidad de que las mujeres se hagan la prueba del VIH. Para los hombres VIH-positivos, los resultados sugieren que la depresión fomente una conducta de búsqueda de ayuda, afectando así sus interacciones con el sistema de salud. Estos resultados subrayan la necesidad de que los que proveen servicios médicos tengan en cuenta la salud mental en sus programas que abordan los resultados relacionados con la salud.

Challenges and opportunities from using abortion harm reduction and value clarification and attitude transformation engagements for safe abortion advocacy in Uganda.

BACKGROUND: From 2018, the International Federation of Gynecologists and Obstetricians (FIGO) implemented the Advocating Safe Abortion project to support national obstetrics and gynecology (Obs/gyn) societies from ten member countries to become leaders of Sexual and Reproductive Health and Rights (SRHR). We share experiences and lessons learnt about using value clarification and attitude transformation (VCAT) and abortion harm reduction (AHR) as strategies for our advocacy engagements. METHODS: The advocacy goal of ending abortion-related deaths followed predefined pathways from an extensive needs assessment prior to the project. These pathways were strengthening capacity of the Obs/gyn society as safe abortion advocates; establishing a vibrant network of partners; transforming social and gender norms; raising awareness of the legal and policy environment regarding abortion, and promoting the generation and use abortion data for evidence-informed policy and practice. Our advocacy targeted multiple stakeholders including media, policy makers judicio-legal, political and religious leaders, health workers and the public. RESULTS: During each engagement, facilitators required audiences to identify what roles they can play along the continuum of strategies that can reduce maternal death from abortion complications. The audiences acknowledged abortion complications as a major problem in Uganda. Among the root causes for the abortion context, audiences noted absence of an enabling environment for abortion care, which was characterized by low awareness about the abortion laws and policy, restricted abortion laws, cultural and religious beliefs, poor quality of abortion care services and abortion stigma. CONCLUSION: VCAT and AHR were critical in enabling us to develop appropriate messages for different stakeholders. Audiences were able to recognize the abortion context, distinguish between assumptions, myths and realities surrounding unwanted pregnancy and abortion; recognize imperative to address conflict between personal and professional values, and identify different roles and values which inform empathetic attitudes and behaviors that mitigate abortion harms. The five pathways of the theory of change reinforced each other. Using the AHR model, we delineate strategies and activities which stakeholders could use to end abortion deaths. VCAT enables critical reflection of views, beliefs and values versus professional obligations and responsibilities, and promotes active attitude and behavior change and commitment to end abortion-related deaths.

Physical activity, sedentary behaviour and colorectal cancer risk in the UK Biobank.

This corrects the article DOI: 10.1038/bjc.2017.85.

Engaging HIV-positive clients in care: acceptability and mechanisms of action of a peer navigation program in South Africa.

Antiretroviral therapy (ART) could curtail the HIV epidemic, but its impact is diminished by low uptake. We developed a peer navigation program to enhance engagement in HIV care, ART adherence, and behavioral prevention. In preparation for a randomized controlled trial, the program was piloted over four months at two primary health clinics in South Africa's North West Province. Newly diagnosed, HIV-positive clients met regularly with navigators to address barriers to care, adherence, and prevention. To assess program acceptability and feasibility and characterize the mechanisms of action, we surveyed 25 clients who completed navigation services and conducted interviews with 10 clients, four navigators, and five clinic providers. Clients expressed near universal approval for the program and were satisfied with the frequency of contact with navigators. HIV stigma emerged as a primary driver of barriers to care. Navigators helped clients overcome feelings of shame through education and by modeling how to live successfully with HIV. They addressed discrimination fears by helping clients disclose to trusted individuals. These actions, in turn, facilitated clients' care engagement, ART adherence, and HIV prevention efforts. The findings suggest peer navigation is a feasible approach with potential to maximize the impact of ART-based HIV treatment and prevention strategies.

Methylomics of gene expression in human monocytes.

DNA methylation is one of several epigenetic mechanisms that contribute to the regulation of gene expression; however, the extent to which methylation of CpG dinucleotides correlates with gene expression at the genome-wide level is still largely unknown. Using purified primary monocytes from subjects in a large community-based cohort (n = 1264), we characterized methylation (>485 000 CpG sites) and mRNA expression (>48K transcripts) and carried out genome-wide association analyses of 8370 expression phenotypes. We identified 11 203 potential cis-acting CpG loci whose degree of methylation was associated with gene expression (eMS) at a false discovery rate threshold of 0.001. Most of the associations were consistent in effect size and direction of effect across sex and three ethnicities. Contrary to expectation, these eMS were not predominately enriched in promoter regions, or CpG islands, but rather in the 3' UTR, gene bodies, CpG shores or 'offshore' sites, and both positive and negative correlations between methylation and expression were observed across all locations. eMS were enriched for regions predicted to be regulatory by ENCODE (Encyclopedia of DNA Elements) data in multiple cell types, particularly enhancers. One of the strongest association signals detected (P < 2.2 × 10(-308)) was a methylation probe (cg17005068) in the promoter/enhancer region of the glutathione S-transferase theta 1 gene (GSTT1, encoding the detoxification enzyme) with GSTT1 mRNA expression. Our study provides a detailed description of the epigenetic architecture in human monocytes and its relationship to gene expression. These data may help prioritize interrogation of biologically relevant methylation loci and provide new insights into the epigenetic basis of human health and diseases.

Barriers to preventing unintended pregnancies and sexually transmitted infections as experienced by women in Fort Dauphin, southeast Madagascar.

OBJECTIVES: As part of a broader investigation into maternal and child health, this study aimed to explore barriers to preventing unintended pregnancies and sexually transmitted infections (STIs) for women in southeast Madagascar, in order to inform the development of interventions by a local non-governmental organisation. METHODS: A year-long mixed methods study was conducted. Qualitative information was obtained from 246 participants through focus groups, single-event and serial qualitative interviews. Quantitative data was collected through a closed-ended questionnaire with a sample of 373 women of reproductive age. Data was analysed using pre-determined and emerging themes. RESULTS: Family planning and sexual health services are not well integrated into other health services, nor routinely offered. Barriers to contraceptive use include actual or perceived side effects of hormonal methods, inaccurate information from health providers, and lack of support from partners or family members. STI prevalence is high, concurrent sexual relationships are common, and condom use is limited. CONCLUSIONS: Women's ability to prevent unintended pregnancies and STIs could be improved through measures aiming to dispel misconceptions about eligibility for and perceived risks of hormonal contraceptives, increase support for family planning among partners and families, and reframe the socio-cultural meaning of condom use in sexual relationships.

Mice with mutations in Fas and Fas ligand demonstrate increased herpetic stromal keratitis following corneal infection with HSV-1.

HSV-1 infection of the cornea leads to a potentially blinding immunoinflammatory lesion of the cornea, termed herpetic stromal keratitis. It has also been shown that one of the factors limiting inflammation of the cornea is the presence of Fas ligand (FasL) on corneal epithelium and endothelium. In this study, the role played by FasL expression in the cornea following acute infection with HSV-1 was determined. Both BALB/c and C57BL/6 (B6) mice with HSV-1 infection were compared with their lpr and gld counterparts. Results indicated that mice bearing mutations in the Fas Ag (lpr) displayed the most severe disease, whereas the FasL-defective gld mouse displayed an intermediate phenotype. It was further demonstrated that increased disease was due to lack of Fas expression on bone marrow-derived cells. Of interest, although virus persisted slightly longer in the corneas of mice bearing lpr and gld mutations, the persistence of infectious virus in the trigeminal ganglia was the same for all strains infected. Further, B6 mice bearing lpr and gld mutations were also more resistant to virus-induced mortality than were wild-type B6 mice. Thus, neither disease nor mortality correlated with viral replication in these mice. Collectively, the findings indicate that the presence of FasL on the cornea restricts the entry of Fas(+) bone marrow-derived inflammatory cells and thus reduces the severity of HSK.

Mycobacterium tuberculosis lipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b.

Contact of Mycobacterium tuberculosis (M.tb) with the immune system requires interactions between microbial surface molecules and host pattern recognition receptors. Major M.tb-exposed cell envelope molecules, such as lipomannan (LM), contain subtle structural variations that affect the nature of the immune response. Here we show that LM from virulent M.tb (TB-LM), but not from avirulent Myocobacterium smegmatis (SmegLM), is a potent inhibitor of TNF biosynthesis in human macrophages. This difference in response is not because of variation in Toll-like receptor 2-dependent activation of the signaling kinase MAPK p38. Rather, TB-LM stimulation leads to destabilization of TNF mRNA transcripts and subsequent failure to produce TNF protein. In contrast, SmegLM enhances MAPK-activated protein kinase 2 phosphorylation, which is critical for maintaining TNF mRNA stability in part by contributing microRNAs (miRNAs). In this context, human miRNA miR-125b binds to the 3' UTR region of TNF mRNA and destabilizes the transcript, whereas miR-155 enhances TNF production by increasing TNF mRNA half-life and limiting expression of SHIP1, a negative regulator of the PI3K/Akt pathway. We show that macrophages incubated with TB-LM and live M.tb induce high miR-125b expression and low miR-155 expression with correspondingly low TNF production. In contrast, SmegLM and live M. smegmatis induce high miR-155 expression and low miR-125b expression with high TNF production. Thus, we identify a unique cellular mechanism underlying the ability of a major M.tb cell wall component, TB-LM, to block TNF biosynthesis in human macrophages, thereby allowing M.tb to subvert host immunity and potentially increase its virulence.

Maternal health practices, beliefs and traditions in southeast Madagascar.

Contextualising maternal health in countries with high maternal mortality is vital for designing and implementing effective health interventions. A research project was therefore conducted to explore practices, beliefs and traditions around pregnancy, delivery and postpartum in southeast Madagascar. Interviews and focus groups were conducted with 256 pregnant women, mothers of young children, community members and stakeholders; transcripts were analysed to identify and explore predetermined and emerging themes. A questionnaire was also conducted with 373 women of reproductive age from randomly selected households. Data was analysed using STATA. Results confirmed high local rates of maternal mortality and morbidity and revealed a range of traditional health care practices and beliefs impacting on women's health seeking behaviours. The following socio-cultural barriers to health were identified: 1) lack of knowledge, 2) risky practices, 3) delays seeking biomedical care, and 4) family and community expectations. Recommendations include educational outreach and behaviour change communications targeted for women, their partners and family, increased engagement with traditional midwives and healers, and capacity building of formal health service providers.

Perineal repair performed by midwives in Australia: A cross-sectional survey study of education and practice.

PROBLEM: Perineal repair is generally not a widely practiced skill amongst Australian midwives, the reasons for this are uncertain and may result in technique variations. BACKGROUND: Many birthing women experience perineal tears that require suturing. As midwives attend the majority of vaginal births, they would be ideally placed to undertake perineal repair. AIM: To describe the current level of midwifery perineal repair skill acquisition, knowledge, techniques and utilization by Australian midwives. METHODS: An online survey was distributed to Australian College of Midwives members and shared via social media. Data on demographics, suturing techniques, reasons why midwives did or did not suture and barriers to skill acquisition were collected. Descriptive statistics were calculated for all variables including percentages, mean, standard deviation, median and range as appropriate. FINDINGS: 375 completed surveys were received between April and May 2023. 197 midwives indicated current suturing practice and 178 did not suture. Contributing to continuity of care was the most common motivating factor. The use of a continuous suturing technique for all layers of a perineal injury was reported by the majority of suturing midwives. There was greater variation in the management of labial tears. Low numbers of skilled midwives to support attaining competency and high workloads were the main barriers to attaining suturing skills. DISCUSSION: Australian midwives view perineal suturing as a valid midwifery skill that can contribute to continuity of care. Largely organisational barriers exist to skill development and greater utilisation. CONCLUSION: Perineal repair should be prioritised as a fundamental midwifery skill.

Professional societies of obstetrics and gynecology as agents of change in sexual and reproductive health: FIGO's 10-country safe abortion advocacy project in Africa and Latin America.

In 2019, FIGO started implementing its abortion project focusing on advocacy. The Advocacy for Safe Abortion (ASA) Project was conducted in partnership with 10 national professional societies of obstetrics and gynecology in Latin America and Africa. The project aimed to strengthen national societies, support them to be leaders in sexual and reproductive health, and enable them to obtain context-specific advocacy goals that improve access to safe abortion. Innovative monitoring and evaluation methodology enabled tracking of outcomes, consideration of their contribution to success, and cross-country evaluation. The project saw success through some key strategies: institutional capacity strengthening; enhanced work through collaborations; training to increase knowledge and reduce abortion-related stigma with a broad array of stakeholders; and generation and use of evidence to influence decision-makers. This article describes the project and methodology used and provides tangible examples of how societies have been agents of change in their countries and of the need for such important work to continue.

Transcutaneous auricular vagus nerve stimulation may benefit from the addition of N-acetylcysteine to facilitate motor learning in infants of diabetic mothers failing oral feeds.

Objective: This study aims to determine if pretreating with enteral N-acetylcysteine (NAC) improves CNS oxidative stress and facilitates improvement in oromotor skills during transcutaneous auricular nerve stimulation (taVNS) paired with oral feedings in infants of diabetic mothers (IDMs) who are failing oral feeds. Methods: We treated 10 IDMs who were gastrostomy tube candidates in an open-label trial of NAC and taVNS paired with oral feeding. NAC (75 or 100 mg/kg/dose) was given by nasogastric (NG) administration every 6 h for 4 days, then combined with taVNS paired with 2 daily feeds for another 14 days. NAC pharmacokinetic (PK) parameters were determined from plasma concentrations at baseline and at steady state on day 4 of treatment in conjunction with magnetic resonance spectroscopic (MRS) quantification of CNS glutathione (GSH) as a marker of oxidative stress. We compared increases in oral feeding volumes before and during taVNS treatment and with a prior cohort of 12 IDMs who largely failed to achieve full oral feeds with taVNS alone. Results: NAC 100 mg/kg/dose every 6 h NG resulted in plasma [NAC] that increased [GSH] in the basal ganglia with a mean of 0.13 ± 0.08 mM (p = 0.01, compared to baseline). Mean daily feeding volumes increased over 14 days of NAC + taVNS compared to the 14 days before treatment and compared to the prior cohort of 12 IDMs treated with taVNS alone. Seven IDMs reached full oral feeds sufficient for discharge, while three continued to have inadequate intake. Conclusion: In IDM failing oral feeds, NAC 100 mg/kg/dose every 6 h NG for 4 days before and during taVNS paired with oral feeding increased CNS GSH, potentially mitigating oxidative stress, and was associated with improving functional feeding outcomes compared to taVNS alone in a prior cohort. This represents a novel approach to neuromodulation and supports the concept that mitigation of ongoing oxidative stress may increase response to taVNS paired with a motor task.

Antiviral Prescribing Among Patients at an Ambulatory Cancer Center With Laboratory-Confirmed Influenza.

Among 133 cancer outpatients diagnosed with influenza between 2016 and 2018, 110 (83%) were prescribed oseltamivir. Among 109 with a known symptom onset date, 53% presented for care and 31% were prescribed oseltamivir within 48 hours. Patient/provider education and rapid diagnostics are needed to improve early oseltamivir use among cancer patients with influenza.

Hostilities faced by people on the frontlines of sexual and reproductive health and rights: a scoping review.

Frontline workers for sexual and reproductive health and rights (SRHR) provide life-changing and life-saving services to millions of people every year. From accompanying the pregnant, delivering babies and caring for the newborn to supporting those subjected to sexual violence; from treating debilitating infections to expanding contraceptive choices; from enabling access to safe abortion services to countering homophobia: all over the world frontline SRHR carers and advocates make it possible for so many more to experience dignity in sex, sexuality and reproduction. Yet they are also subjected to hostility for what they do, for whom they provide care, for where they work and for the issues they address. From ostracistion and harassment in the workplace to verbal threats and physical violence, hostilities can extend even into their private lives. In other words, as SRHR workers seek to fulfil the human rights of others, their own human rights are put at risk. Yet, as grave as that is, it is a reality largely undocumented and thus also underestimated. This scoping review sets out to marshal what is known about how hostilities against frontline SRHR workers manifest, against whom, at whose hands and in which contexts. It is based on review of six sources: peer-reviewed and grey literature, news reports, sector surveys, and consultations with sector experts and, for contrast, literature issued by opposition groups. Each source contributes a partial picture only, yet taken together, they show that hostilities against frontline SRHR workers are committed the world over-in a range of countries, contexts and settings. Nevertheless, the narratives given in those sources more often treat hostilities as 'one-off', exceptional events and/or as an 'inevitable' part of daily work to be tolerated. That works in turn both to divorce such incidents from their wider historical, political and social contexts and to normalise the phenomena as if it is an expected part of a role and not a problem to be urgently addressed. Our findings confirm that the SRHR sector at large needs to step-up its response to such reprisals in ways more commensurate with their scale and gravity.

Sulforaphane induced NRF2 activation in obese pregnancy attenuates developmental redox imbalance and improves early-life cardiovascular function in offspring.

In adverse pregnancy a perturbed redox environment is associated with abnormal early-life cardiovascular development and function. Previous studies have noted alterations in the expression and/or activity of Nuclear Factor E2 Related Factor 2 (NRF2) and its antioxidant targets during human gestational diabetic (GDM) pregnancy, however to our knowledge the functional role of NRF2 in fetal 'priming' of cardiovascular dysfunction in obese and GDM pregnancy has not been investigated. Using a murine model of obesity-induced glucose dysregulated pregnancy, we demonstrate that NRF2 activation by maternal sulforaphane (SFN) supplementation normalizes NRF2-linked NQO1, GCL and CuZnSOD expression in maternal and fetal liver placental and fetal heart tissue by gestational day 17.5. Activation of NRF2 in utero in wild type but not NRF2 deficient mice improved markers of placental efficiency and partially restored fetal growth. SFN supplementation was associated with reduced markers of fetal cardiac oxidative stress, including Nox2 and 3-nitrotyrosine, as well as attenuation of cardiac mass and cardiomyocyte area in male offspring by postnatal day 52 and improved vascular function in male and female offspring by postnatal day 98. Our findings are the first to highlight the functional consequences of NRF2 modulation in utero on early-life cardiovascular function in offspring, demonstrating that activation of NRF2 affords cardiovascular protection in offspring of pregnancies affected by redox dysregulation.

Mycobacterium tuberculosis activates human macrophage peroxisome proliferator-activated receptor gamma linking mannose receptor recognition to regulation of immune responses.

Mycobacterium tuberculosis enhances its survival in macrophages by suppressing immune responses in part through its complex cell wall structures. Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor superfamily member, is a transcriptional factor that regulates inflammation and has high expression in alternatively activated alveolar macrophages and macrophage-derived foam cells, both cell types relevant to tuberculosis pathogenesis. In this study, we show that virulent M. tuberculosis and its cell wall mannose-capped lipoarabinomannan induce PPARgamma expression through a macrophage mannose receptor-dependent pathway. When activated, PPARgamma promotes IL-8 and cyclooxygenase 2 expression, a process modulated by a PPARgamma agonist or antagonist. Upstream, MAPK-p38 mediates cytosolic phospholipase A(2) activation, which is required for PPARgamma ligand production. The induced IL-8 response mediated by mannose-capped lipoarabinomannan and the mannose receptor is independent of TLR2 and NF-kappaB activation. In contrast, the attenuated Mycobacterium bovis bacillus Calmette-Guérin induces less PPARgamma and preferentially uses the NF-kappaB-mediated pathway to induce IL-8 production. Finally, PPARgamma knockdown in human macrophages enhances TNF production and controls the intracellular growth of M. tuberculosis. These data identify a new molecular pathway that links engagement of the mannose receptor, an important pattern recognition receptor for M. tuberculosis, with PPARgamma activation, which regulates the macrophage inflammatory response, thereby playing a role in tuberculosis pathogenesis.

The tibetan uterotonic zhi byed 11: mechanisms of action, efficacy, and historical use for postpartum hemorrhage.

Objective. To explore evidence for the traditional Tibetan medicine, Zhi Byed 11 (ZB11), for use as a uterotonic. Methods. The eleven ingredients in ZB11 were chemically analyzed by mass spectroscopy. A review was conducted of Western allopathic literature for scientific studies on ZB11's individual components. Literature from Tibetan and other traditional paradigms were reviewed. Results. Potential mechanisms of action for ZB11 as a uterotonic include laxative effects, a dose-dependant increase in smooth muscle tissue peristalsis that may also affect the uterus smooth muscle, and chemical components that are prostaglandin precursors and/or increase prostaglandin synthesis. A recent RCT demonstrated comparable efficacy to misoprostol in reducing severe postpartum hemorrhage (PPH) (>1000 mL) and greater effect than placebo. Historical and anecdotal evidence for ZB11 and its ingredients for childbirth provide further support. Discussion. ZB11 and its ingredients are candidates for potentially effective uterotonics, especially in low-resource settings. Further research is warranted to understand the mechanisms of action and synergy between ingredients.

Health-related quality of life among pregnant women with and without depression in Hubei, China.

The role of prenatal depression on physical and mental health among women in mainland China has not been previously investigated. The aim of this research was to (a) calculate the prevalence of depression during pregnancy, (b) explore the relationship between depression sample characteristics and quality of life and (c) identify predictors of physical and mental health among pregnant women. This study was designed as a cross-sectional and exploratory survey. A total of 454 pregnant women participated in the study between December 2009 and June 2010 in central China. The data was collected using the Medical Outcomes Study short form 36 v2 and the Edinburgh Postnatal Depression Scale. Participants were recruited at outpatient departments of obstetrics and gynecology. Findings show that almost 40% of pregnant women experience prenatal depression. Depression was significantly associated with physical and mental health-related quality of life (HRQoL). Depression, increased age, higher gestational age, being employed and married were significant predictors of lower physical HRQoL. Depression, lower BMI and having an unintended pregnancy were significant predictors of lower mental HRQoL. Prenatal depression is very common in women from mainland China. Depressed women suffer from impaired physical and mental health; prenatal depression has a negative impact on women's HRQoL. We recommend that antenatal services integrate screening for depression into routine antenatal care.

Integrated Osteopathic-Neurologic Examinations With Musculoskeletal Treatment: The ONE Approach.

The global burden of neurologic disorders is a leading cause of disability and death worldwide and has increased the demand for treatments and rehabilitation. Our proposed integrated osteopathic-neurologic examination (ONE) provides the physician with expanded diagnostic and point-of-care treatment modalities while allowing the physician to make a more tangible effect in patient care. By incorporating the osteopathic structural somatic examination with the complete neurologic evaluation, somatic dysfunction, occurring as a consequence or independent of neurologic injury, can be identified and treated using osteopathic manipulative techniques at time of visit. Using the proposed integrated examination, the physician can determine the interplay between structural and neurologic findings to identify patterns of change that coincide with more specific diagnoses and the chronicity of a condition. Tangible benefits from the ONE approach translate to more accurate clinical assessment and enhanced patient and physician satisfaction.

Voriconazole in Hematopoietic Stem Cell Transplantation and Cellular Therapies: Real-World Usage and Therapeutic Level Attainment at a Major Transplantation Center.

Voriconazole (VCZ) was one of the first mold-active triazoles available; however, its current use among high-risk hematology populations is unknown as the uptake of posaconazole (PCZ) and isavuconazole (ISZ) increases. We evaluated the usage and therapeutic level attainment of VCZ in hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell (CAR-T) therapy patients at our cancer center. Electronic medical records for all adult HCT or CAR-T patients with an order for VCZ, PCZ, or ISV between January 1, 2018, and June 30, 2020, were extracted. Clinical characteristics, VCZ indication, trough VCZ levels, and frequency of VCZ initiation from 6 months before to 6 months after HCT/CAR-T infusion in consecutive HCT/CAR-T recipients within the study period (infusion between July 1, 2018, and January 1, 2020) were assessed. The association between relevant clinical characteristics and the attainment of subtherapeutic or supratherapeutic levels was also evaluated. Of 468 patients prescribed mold-active triazoles, 256 (54.7%) were prescribed VCZ, 324 (69.2%) PCZ, and 60 (12.8%) ISZ; 152/468 (32.5%) treatment regimens were sequentially modified to alternate mold-active triazoles. Among consecutive HCT and CAR-T recipients at our center, evaluated 6 months pre- or post- HCT/ CAR-T, VCZ was commonly initiated before or after allogeneic HCT (102/381, 26.8%), with most use in the first 30 days after stem cell infusion (40/381, 10.5%); VCZ use was less common in autologous HCT (13/276, 4.7%) and CAR-T (10/153, 6.5%). Of 223 VCZ orders that met inclusion for analysis, indications included empiric treatment in 108/223 (48.4%), directed therapy in 25/223 (11.2%), primary prophylaxis in 69/223 (30.9%) and secondary prophylaxis in 21/223 (9.4%). Of 223 eligible VCZ patients, 144 (64.6%) had at least 1 VCZ level measured during the study period; 75/144 (52.1%) had a therapeutic VCZ level (1.0-5.5 mg/L) at the first measurement (median 2.8mg/L [range 0.1-13.5]) at a median of 6 days of therapy, with 26.4% subtherapeutic and 21.5% supratherapeutic; 46/88 (52.3%) were therapeutic at the second measurement (2.1mg/L [0.1-9.9]) at a median of 17 days of therapy; and 33/48 (68.8%) at the third (2.3mg/L [0.1-7.7]) at a median of 29 days. In multivariable analysis of factors associated with sub- or supratherapeutic levels (body mass index ≥30, concurrent omeprazole use, concurrent letermovir use, indication for VCZ, history/timeframe of HCT), the only significant association was lower odds of a supratherapeutic VCZ level among those undergoing HCT within the previous 30 days compared to those without a history of HCT. VCZ continues to remain an important option in the treatment and prevention of invasive fungal infections in an era when alternative oral mold-active triazoles are available. In spite of long-standing experience with VCZ prescribing, therapeutic level attainment remains a challenge.