ninjaCap: A fully customizable and 3D printable headgear for fNIRS and EEG brain imaging.

Significance: Accurate sensor placement is vital for non-invasive brain imaging, particularly for functional near infrared spectroscopy (fNIRS) and diffuse optical tomography (DOT), which lack standardized layouts like EEG. Custom, manually prepared probe layouts on textile caps are often imprecise and labor-intensive. Aim: We introduce a method for creating personalized, 3D-printed headgear, enabling accurate translation of 3D brain coordinates to 2D printable panels for custom fNIRS and EEG sensor layouts, reducing costs and manual labor. Approach: Our approach uses atlas-based or subject-specific head models and a spring-relaxation algorithm for flattening 3D coordinates onto 2D panels, using 10-5 EEG coordinates for reference. This process ensures geometrical fidelity, crucial for accurate probe placement. Probe geometries and holder types are customizable and printed directly on the cap, making the approach agnostic to instrument manufacturers and probe types. Results: Our ninjaCap method offers 2.2±1.5 mm probe placement accuracy. Over the last five years, we have developed and validated this approach with over 50 cap models and 500 participants. A cloud-based ninjaCap generation pipeline along with detailed instructions is now available at openfnirs.org. Conclusions: The ninjaCap marks a significant advancement in creating individualized neuroimaging caps, reducing costs and labor while improving probe placement accuracy, thereby reducing variability in research.

BAP1 is required prenatally for differentiation and maintenance of postnatal murine enteric nervous system.

Epigenetic regulatory mechanisms are underappreciated, yet are critical for enteric nervous system (ENS) development and maintenance. We discovered that fetal loss of the epigenetic regulator Bap1 in the ENS lineage caused severe postnatal bowel dysfunction and early death in Tyrosinase-Cre Bap1fl/fl mice. Bap1-depleted ENS appeared normal in neonates; however, by P15, Bap1-deficient enteric neurons were largely absent from the small and large intestine of Tyrosinase-Cre Bap1fl/fl mice. Bowel motility became markedly abnormal with disproportionate loss of cholinergic neurons. Single-cell RNA sequencing at P5 showed that fetal Bap1 loss in Tyrosinase-Cre Bap1fl/fl mice markedly altered the composition and relative proportions of enteric neuron subtypes. In contrast, postnatal deletion of Bap1 did not cause enteric neuron loss or impaired bowel motility. These findings suggest that BAP1 is critical for postnatal enteric neuron differentiation and for early enteric neuron survival, a finding that may be relevant to the recently described human BAP1-associated neurodevelopmental disorder.

Hepatic HIF2 is a key determinant of manganese excess and polycythemia in SLC30A10 deficiency.

Manganese is an essential yet potentially toxic metal. Initially reported in 2012, mutations in SLC30A10 are the first known inherited cause of manganese excess. SLC30A10 is an apical membrane protein that exports manganese from hepatocytes into bile and from enterocytes into the lumen of the gastrointestinal tract. SLC30A10 deficiency results in impaired gastrointestinal manganese excretion, leading to manganese excess, neurologic deficits, liver cirrhosis, polycythemia, and erythropoietin excess. Neurologic and liver disease are attributed to manganese toxicity. Polycythemia is attributed to erythropoietin excess. The goal of this study was to determine the basis of erythropoietin excess in SLC30A10 deficiency. Here, we demonstrate that transcription factors hypoxia-inducible factor 1a (Hif1a) and 2a (Hif2a), key mediators of the cellular response to hypoxia, are both upregulated in livers of Slc30a10-deficient mice. Hepatic Hif2a deficiency corrected erythropoietin expression and polycythemia and attenuated aberrant hepatic gene expression in Slc30a10-deficient mice, while hepatic Hif1a deficiency had no discernible impact. Hepatic Hif2a deficiency also attenuated manganese excess, though the underlying cause of this is not clear at this time. Overall, our results indicate that hepatic HIF2 is a key determinant of pathophysiology in SLC30A10 deficiency and expand our understanding of the contribution of HIFs to human disease.

Rates of resistance and heteroresistance to newer ß-lactam/ß-lactamase inhibitors for carbapenem-resistant Enterobacterales.

Background: Heteroresistance (HR), the presence of antibiotic-resistant subpopulations within a primary isogenic population, may be a potentially overlooked contributor to newer ß-lactam/ß-lactamase inhibitor (BL/BLI) treatment failure in carbapenem-resistant Enterobacterales (CRE) infections. Objectives: To determine rates of susceptibility and HR to BL/BLIs ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam in clinical CRE isolates. Methods: The first CRE isolate per patient per year from two >500 bed academic hospitals from 1 January 2016 to 31 December 2021, were included. Reference broth microdilution (BMD) was used to determine antibiotic susceptibility, and population analysis profiling (PAP) to determine HR. Carbapenemase production (CP) was determined using the Carba NP assay. Results: Among 327 CRE isolates, 46% were Enterobacter cloacae, 38% Klebsiella pneumoniae and 16% Escherichia coli. By BMD, 87% to 98% of CRE were susceptible to the three antibiotics tested. From 2016 to 2021, there were incremental decreases in the rates of susceptibility to each of the three BL/BLIs. HR was detected in each species-antibiotic combination, with the highest rates of HR (26%) found in K. pneumoniae isolates with imipenem/relebactam. HR or resistance to at least one BL/BLI by PAP was found in 24% of CRE isolates and 65% of these had detectable CP. Conclusion: Twenty-four percent of CRE isolates tested were either resistant or heteroresistant (HR) to newer BL/BLIs, with an overall decrease of ∼10% susceptibility over 6 years. While newer BL/BLIs remain active against most CRE, these findings support the need for ongoing antibiotic stewardship and a better understanding of the clinical implications of HR in CRE.

Exploration of a Potential DOOR Endpoint for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia Using Six Registrational Trials for Antibacterial Drugs.

BACKGROUND: Desirability of outcome ranking (DOOR) is an innovative approach to clinical trial design and analysis that uses an ordinal ranking system to incorporate the overall risks and benefits of a therapeutic intervention into a single measurement. Here, we derived and evaluated a disease-specific DOOR endpoint for registrational trials for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP). METHODS: Through comprehensive examination of data from nearly 4,000 participants enrolled in six registrational trials for HABP/VABP submitted to the FDA between 2005-2022, we derived and applied a HABP/VABP specific endpoint. We estimated the probability that a participant assigned to the study treatment arm would have a more favorable overall DOOR or component outcome than a participant assigned to comparator. RESULTS: DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 48.3% to 52.9% and were not statistically different. There were no significant differences between treatment arms in the component analyses. Though infectious complications and serious adverse events occurred more frequently in ventilated participants compared to non-ventilated participants, the types of events were similar. CONCLUSIONS: Through a data-driven approach, we constructed and applied a potential DOOR endpoint for HABP/VABP trials. The inclusion of syndrome-specific events may help to better delineate and evaluate participant experiences and outcomes in future HABP/VABP trials and could help inform data collection and trial design.

Overreporting of adherence to hepatitis C direct-acting antiviral therapy and sustained virologic response among people who inject drugs in the HERO study.

BACKGROUND: Self-reported adherence to direct-acting antivirals (DAAs) to treat hepatitis C virus (HCV) among persons who inject drugs (PWID) is often an overreport of objectively measured adherence. The association of such overreporting with sustained virologic response (SVR) is understudied. This study among PWID aimed to determine a threshold of overreporting adherence that optimally predicts lower SVR rates, and to explore correlates of the optimal overreporting threshold. METHODS: This study analyzed per-protocol data of participants with adherence data (N = 493) from the HERO (Hepatitis C Real Options) study. Self-reported and objective adherence to a 12-week DAA regimen were measured using visual analogue scales and electronic blister packs, respectively. The difference (Δ) between self-reported and objectively measured adherence was calculated. We used the Youden index based on receiver operating characteristic (ROC) curve analysis to identify an optimal threshold of overreporting for predicting lower SVR rates. Factors associated with the optimal threshold of overreporting were identified by comparing baseline characteristics between participants at/above versus those below the threshold. RESULTS: The self-reported, objective, and Δ adherence averages were 95.1% (SD = 8.9), 75.9% (SD = 16.3), and 19.2% (SD = 15.2), respectively. The ≥ 25% overreporting threshold was determined to be optimal. The SVR rate was lower for ≥ 25% vs. < 25% overreporting (86.7% vs. 95.8%, p <.001). The factors associated with ≥ 25% Δ adherence were unemployment; higher number of days and times/day of injecting drugs; higher proportion of positive urine drug screening for amphetamine, methamphetamine, and oxycodone, and negative urine screening for THC (tetrahydrocannabinol)/cannabis. CONCLUSIONS: Self-reported DAA adherence was significantly greater than objectively measured adherence among PWID by 19.2%. Having ≥ 25% overreported adherence was associated with optimal prediction of lower SVR rates. PWID with risk factors for high overreporting may need to be more intensively managed to promote actual adherence.

Implementation of contact precautions for multidrug-resistant organisms in the post-COVID-19 pandemic era: An updated national Emerging Infections Network (EIN) survey.

OBJECTIVE: To understand how healthcare facilities employ contact precautions for patients with multidrug-resistant organisms (MDROs) in the post-coronavirus disease 2019 (COVID-19) era and explore changes since 2014. DESIGN: Cross-sectional survey. PARTICIPANTS: Emerging Infections Network (EIN) physicians involved in infection prevention or hospital epidemiology. METHODS: In September 2022, we sent via email an 8-question survey on contact precautions and adjunctive measures to reduce MDRO transmission in inpatient facilities. We also asked about changes since the COVID-19 pandemic. We used descriptive statistics to summarize data and compared results to a similar survey administered in 2014. RESULTS: Of 708 EIN members, 283 (40%) responded to the survey and 201 reported working in infection prevention. A majority of facilities (66% and 69%) routinely use contact precautions for methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) respectively, compared to 93% and 92% in 2014. Nearly all (>90%) use contact precautions for Candida auris, carbapenem-resistant Enterobacterales (CRE), and carbapenem-resistant Acinetobacter baumannii. More variability was reported for carbapenem-resistant Pseudomonas aeruginosa and extended-spectrum ß-lactamase-producing gram-negative organisms. Compared to 2014, fewer hospitals perform active surveillance for MRSA and VRE. Overall, 90% of facilities used chlorhexidine gluconate bathing in all or select inpatients, and 53% used ultraviolet light or hydrogen peroxide vapor disinfection at discharge. Many respondents (44%) reported changes to contact precautions since COVID-19 that remain in place. CONCLUSIONS: Heterogeneity exists in the use of transmission-based precautions and adjunctive infection prevention measures aimed at reducing MDRO transmission. This variation reflects a need for updated and specific guidance, as well as further research on the use of contact precautions in healthcare facilities.

Student Reflections on Learning in a Doctoral-Level Writing Course.

BACKGROUND: Programs to improve student writing have been deployed widely in nursing graduate education, but few operational indicators exist for measuring their value. PROBLEM: The challenge of measuring outcomes reflects the complexity of what transpires when graduate students write. Better understanding is needed of what it means to students to "learn" from writing support. APPROACH: A full-semester writing course was implemented in a nursing science PhD program. In formative course assessment activities, students identified problems in early drafts of their work, which they subsequently learned to detect and resolve. In this article, students report what was learned. CONCLUSION: Writing skills, like clinical skills, are intertwined with intellectual maturation and sense of professional identity. Writing, like clinical learning, requires an investment of time and labor far beyond what is typical in didactic approaches to classroom-based graduate education. Our experience suggests a need to reconceptualize writing pedagogy in nursing.

Optimal hepatitis C treatment adherence patterns and sustained virologic response among people who inject drugs: The HERO study.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) are highly effective for treating HCV infection even among people who inject drugs (PWID). Yet, little is known about patients' adherence patterns and their association with sustained virologic response (SVR) rates. We aimed to summarize various adherence patterns and determine their associations with SVR. METHODS: Electronic blister packs were used to measure daily adherence to once-a-day sofosbuvir/velpatasvir during the 12-week treatment period among active PWIDs. Blister pack data were available for 496 participants who initiated DAAs for whom SVR status was known. Adherence was summarized in multiple patterns, such as total adherent days, consecutive missed days, and early discontinuations. Thresholds for adherence patterns associated with >90% SVR rates were also determined. RESULTS: The overall SVR rate was 92.7%, with a median adherence rate of 75%. All adherence patterns indicating greater adherence were significantly associated with achieving SVR. Participant groups with ≥50% (>42/84) adherent days or <26 consecutive missed days achieved an SVR rate of >90%. Greater total adherent days during 9-12 weeks and no early discontinuation were significantly associated with higher SVR rates only in those with <50% adherence. Participants with first month discontinuation and ≥2 weeks of treatment interruption had low SVR rates, 25% and 85%, respectively. However, greater adherent days were significantly associated with SVR (adjusted odds ratio 1.10; 95% CI 1.04-1.16; p <0.001) even among participants with ≥14 consecutive missed days. CONCLUSIONS: High SVR rates can be achieved in the PWID population despite suboptimal adherence. Encouraging patients to take as much medication as possible, with <2 weeks consecutive missed days and without early discontinuation, was found to be important for achieving SVR. IMPACT AND IMPLICATIONS: People who inject drugs can be cured of HCV in >90% of cases, even with relatively low adherence to direct-acting antivirals, but early discontinuations and long treatment interruptions can significantly reduce the likelihood of achieving cure. Clinicians should encourage people who inject drugs who are living with HCV to adhere daily to direct-acting antivirals as consistently as possible, but if any days are interrupted, to continue and complete treatment. These results from the HERO study are important for patients living with HCV, clinicians, experts writing clinical guidelines, and payers. CLINICAL TRIAL NUMBER: NCT02824640.

The role of the hospital bed in hospital-onset Clostridioides difficile: A retrospective study with mediation analysis.

OBJECTIVE: To determine whether residing in a hospital bed that previously held an occupant with Clostridioides difficile increases the risk of hospital-onset C. difficile infection (HO-CDI). METHODS: In this retrospective cohort study, we used a real-time location system to track the movement of hospital beds in 2 academic hospitals from April 2018 to August 2019. We abstracted patient demographics, clinical characteristics, and C. difficile polymerase chain reaction (PCR) results from the medical record. We defined patients as being exposed to a potentially "contaminated" bed or room if, within the preceding 7 days from their HO-CDI diagnosis, they resided in a bed or room respectively, that held an occupant with C. difficile in the previous 90 days. We used multivariable logistic regression to determine whether residing in a contaminated bed was associated with HO-CDI after controlling for time at risk and requiring intensive care. We assessed mediation and interaction from a contaminated hospital room. RESULTS: Of 25,032 hospital encounters with 18,860 unique patients, we identified 237 cases of HO-CDI. Exposure to a contaminated bed was associated with HO-CDI in unadjusted analyses (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.4-2.31) and adjusted analyses (OR, 1.5; 95% CI, 1.2-2.0). Most of this effect was due to both mediation from and interaction with a contaminated hospital room. CONCLUSIONS: Residing in a hospital bed or room that previously had a patient with C. difficile increases the risk of HO-CDI. Increased attention to cleaning and disinfecting the healthcare environment may reduce hospital transmission of C. difficile.

Moving Beyond Mortality: Development and Application of a Desirability of Outcome Ranking (DOOR) Endpoint for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia.

BACKGROUND: Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are frequently caused by multidrug-resistant organisms. Patient-centered endpoints in clinical trials are needed to develop new antibiotics for HABP/VABP. Desirability of outcome ranking (DOOR) is a paradigm for the design, analysis, and interpretation of clinical trials based on a patient-centered, benefit-risk evaluation. METHODS: A multidisciplinary committee created an infectious diseases DOOR endpoint customized for HABP/VABP, incorporating infectious complications, serious adverse events, and mortality. We applied this to 2 previously completed, large randomized controlled trials for HABP/VABP. ZEPHyR compared vancomycin to linezolid and VITAL compared linezolid to tedizolid. For each trial, we evaluated the DOOR distribution and probability, including DOOR component and partial credit analyses. We also applied DOOR in subgroup analyses. RESULTS: In both trials, the HABP/VABP DOOR demonstrated similar overall clinical outcomes between treatment groups. In ZEPHyR, the probability that a participant treated with linezolid would have a more desirable outcome than a participant treated with vancomycin was 50.2% (95% confidence interval [CI], 45.1%--55.3%). In VITAL, the probability that a participant treated with tedizolid would have a more desirable outcome than a participant treated with linezolid was 48.7% (95% CI, 44.8%-52.6%). The DOOR component analysis revealed that participants treated with tedizolid had a less desirable outcome than those treated with linezolid when considering clinical response alone. However, participants with decreased renal function had improved overall outcomes with tedizolid. CONCLUSIONS: The HABP/VABP DOOR provided more granular information about clinical outcomes than is typically presented in clinical trials. HABP/VABP trials would benefit from prospectively using DOOR.

Effect of an initial specimen diversion device on blood-culture contamination rates and vancomycin usage: A quasi-experimental study.

Initial specimen diversion devices (ISDDs) are a potential solution for reducing blood-culture contamination rates. We report the implementation of an ISDD associated with a sustained reduction in blood-culture contamination rates for >18 months after implementation. We did not observe a clinically significant reduction in inpatient vancomycin usage.

Perinatal Telehealth: Meeting Patients Where They Are.

INTRODUCTION: Prior to the coronavirus disease 2019 (COVID-19) pandemic, studies of innovative telehealth perinatal care models showed similar clinical outcomes and perceived quality of care between groups receiving a combination of virtual video and in-person visits. However, these studies included primarily White, English-speaking participants, excluding those who were economically disenfranchised or did not speak English. The purpose of this qualitative study was to describe perinatal patients' and providers' experiences with telehealth during and after the acute phase of the COVID-19 pandemic to inform future utilization of telehealth to drive the delivery of high-quality, accessible, and equitable perinatal care to diverse communities. METHODS: This descriptive qualitative study included a purposive sample of 14 patients and 17 providers who received or provided perinatal care via telehealth in either a certified nurse-midwifery practice or the nurse-family partnership care model between March 2020 and April 2022. Maximum variation sampling offered a diverse population based on race, ethnicity, and rurality. Researchers conducted 2 rounds of semistructured interviews with a focus on understanding social and geographic context. RESULTS: Six themes were identified through inductive analysis: (1) unexpected advantages of telehealth, (2) patient empowerment, (3) providers' fear of adverse outcomes, (4) concern for equitable care, (5) strategies to enhance the telehealth experience, and (6) strategies to address access to perinatal telehealth. Patients appreciated the increased ease and reduced cost of accessing visits, which led to fewer missed appointments. Health care providers saw great opportunity in telehealth but expressed concerns about accessibility for patients with language barriers or limited resources. DISCUSSION: This study provides insight into priorities for continued telehealth utilization focused on providing equitable access to perinatal care. Rather than returning to practices from before the COVID-19 pandemic formed from longstanding routines and perceived limitations, providers are encouraged to capitalize on the rapid innovations in telehealth to build a more effective, equitable, and patient-centered approach to perinatal care.

Self-reported and measured adherence to hepatitis C direct-acting antiviral therapy and sustained virologic response among people who inject drugs: The HERO study.

BACKGROUND: Objective adherence measures, such as electronic blister pack (BP), for direct-acting antivirals (DAAs) for hepatitis C virus (HCV) treatment have high accuracy, but their use is limited in real practice settings. We examined the association of self-reported adherence using a visual analogue scale (VAS) with objective BP adherence and sustained virologic response (SVR) among people who inject drugs. METHODS: We conducted secondary analyses using a subset of participants (N = 493) from the per-protocol sample of the HERO study, a pragmatic randomized trial of HCV treatment interventions that used both VAS and BP to measure adherence to a 12-week sofosbuvir/velpatasvir DAA regimen. Multivariable mixed-effects regression models tested the association of self-report adherence level with longitudinal weekly objective adherence. Multivariable logistic regression tested the association of self-report adherence with SVR. RESULTS: The average VAS and BP adherences were 95.1 % (SD = 8.9 %) and 76.0 % (16.0 %), respectively, and the proportion of the participants achieving SVR was 92.9 %. The estimated adjusted mean objective adherence was significantly different (-16 %; 95 % CI: -22 %, -11 %, p < .001) between participants with 100 % and <80 % VAS adherence. The likelihood of SVR was significantly lower for those with <80 % VAS adherence [adjusted OR = 0.07; 95 % CI: 0.02, 0.24; p < .001] compared to those with 100 %. CONCLUSION: Self-reported adherence overestimated objective adherence. However, higher self-report adherence was significantly associated with higher objective adherence. Also, self-reported adherence ≥80 % was significantly associated with SVR. Thus, the self-report measure has utility as a monitoring tool for adherence during DAA treatment.

Cerebral folate deficiency: a treatable cause of late deterioration in epilepsy with developmental delay.

A 25-year-old woman with childhood-onset refractory epilepsy and developmental delay experienced a gradually progressive marked deterioration in mobility and seizure control, with language regression. Investigation identified a homozygous deletion within the contactin-associated protein-like 2 gene (CNTNAP2), underlying her early presentation, but also cerebral folate deficiency that most likely contributed to her later deterioration. Following antiseizure medication adjustment and treatment with folinic acid, she stabilised with improved seizure control and limited improvement in language and motor function; she has remained neurologically stable for more than a decade. That the previously observed neurological decline was halted by folinic acid replacement supports this being due to cerebral folate deficiency. Metabolic conditions are less well recognised in adults and can be under-diagnosed. They are potentially treatable and should be considered even in the presence of another cause, particularly when the presentation is not fully compatible.

Strategies for developing a successful career in academic medicine.

Academic medicine provides physicians an opportunity for long-term career satisfaction and fulfillment. However, despite the potential for great reward, academic careers can be challenging. To better define approaches to successfully navigate academic medicine, the Southern Society for Clinical Investigation sponsored a workshop titled 'Successful Careers in Academic Medicine' during the 2023 Southern Regional Meeting held in New Orleans; the critical elements of which are highlighted in the following summary. Participants discussed the benefits of an academic career, summarized strategies for negotiating a job, listed critical tools for career development, and discussed key concepts about planning and navigating the academic medicine promotion process. The information provides a roadmap for physicians to develop successful careers in academic medicine.

Sudden Shift to Telehealth in COVID-19: A Retrospective Cohort Study of Disparities in Use of Telehealth for Prenatal Care in a Large Midwifery Service.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic created disruption in health care delivery, including a sudden transition to telehealth use in mid-March 2020. The purpose of this study was to examine changes in the mode of prenatal care visits and predictors of telehealth use (provider-patient messaging, telephone visits, and video visits) during the COVID-19 pandemic among those receiving care in a large, academic nurse-midwifery service. METHODS: We conducted a retrospective cohort study of those enrolled for prenatal care in 2 nurse-midwifery clinics between 2019 and 2021 (n = 3172). Use outcomes included number and type of encounter: in-person and telehealth (primary outcome). Comparisons were made in frequency and types of encounters before and during COVID-19. A negative binomial regression was fit on the outcome of telehealth encounter count, with race/ethnicity, age, language, parity, hypertension, diabetes, and depression as predictors. RESULTS: When comparing pre-COVID-19 (before March 2020) with during COVID-19 (after March 2020), overall encounters increased from 15.9 to 19.5 mean number of encounters per person (P < .001). The increase was driven by telehealth encounters; there were no significant differences for in-person prenatal visit counts before and during the pandemic period. Direct patient-provider messaging was the most common type of telehealth encounter. Predictors of telehealth encounters included English as primary language and diagnoses of diabetes or depression. DISCUSSION: No differences in the frequency of in-person prenatal care visits suggests that telehealth encounters led to more contact with midwives and did not replace in-person encounters. Spanish-speaking patients were least likely to use telehealth-delivered prenatal care during the pandemic; a small, but significant, proportion of patients had no or few telehealth encounters, and a significant proportion had high use of telehealth. Integration of telehealth in future delivery of prenatal care should consider questions of equity, patient and provider satisfaction, access, redundancies, and provider workload.