Pharmacogenomic insights in psychiatric care: uncovering novel actionability, allele-specific CYP2D6 copy number variation, and phenoconversion in 15,000 patients.

Pharmacogenomic testing has emerged as an aid in clinical decision making for psychiatric providers, but more data is needed regarding its utility in clinical practice and potential impact on patient care. In this cross-sectional study, we determined the real-world prevalence of pharmacogenomic actionability in patients receiving psychiatric care. Potential actionability was based on the prevalence of CYP2C19 and CYP2D6 phenotypes, including CYP2D6 allele-specific copy number variations (CNVs). Combined actionability additionally incorporated CYP2D6 phenoconversion and the novel CYP2C-TG haplotype in patients with available medication data. Across 15,000 patients receiving clinical pharmacogenomic testing, 65% had potentially actionable CYP2D6 and CYP2C19 phenotypes, and phenotype assignment was impacted by CYP2D6 allele-specific CNVs in 2% of all patients. Of 4114 patients with medication data, 42% had CYP2D6 phenoconversion from drug interactions and 20% carried a novel CYP2C haplotype potentially altering actionability. A total of 87% had some form of potential actionability from genetic findings and/or phenoconversion. Genetic variation detected via next-generation sequencing led to phenotype reassignment in 22% of individuals overall (2% in CYP2D6 and 20% in CYP2C19). Ultimately, pharmacogenomic testing using next-generation sequencing identified potential actionability in most patients receiving psychiatric care. Early pharmacogenomic testing may provide actionable insights to aid clinicians in drug prescribing to optimize psychiatric care.

Unveiling Discrepant and Rare Dihydropyrimidine Dehydrogenase (DPYD) Results Using an In-House Genotyping Test: A Case Series.

Fluoropyrimidine chemotherapy is a primary component of many solid tumor treatment regimens, particularly those for gastrointestinal malignancies. Approximately one-third of patients receiving fluoropyrimidine-based chemotherapies experience serious adverse effects. This risk is substantially higher in patients carrying DPYD genetic variants, which cause reduced fluoropyrimidine metabolism and inactivation (ie, dihydropyridine dehydrogenase [DPD] deficiency). Despite the known relationship between DPD deficiency and severe toxicity risk, including drug-related fatalities, pretreatment DPYD testing is not standard of care in the United States. We developed an in-house DPYD genotyping test that detects 5 clinically actionable variants associated with DPD deficiency, and genotyped 827 patients receiving fluoropyrimidines, of which 49 (6%) were identified as heterozygous carriers. We highlight 3 unique cases: (1) a patient with a false-negative result from a commercial laboratory that only tested for the c.1905 + 1G>A (*2A) variant, (2) a White patient in whom the c.557A>G variant (typically observed in people of African ancestry) was detected, and (3) a patient with the rare c.1679T>G (*13) variant. Lastly, we evaluated which DPYD variants are detected by commercial laboratories offering DPYD genotyping in the United States and found 6 of 13 (46%) did not test for all 5 variants included on our panel. We estimated that 20.4% to 81.6% of DPYD heterozygous carriers identified on our panel would have had a false-negative result if tested by 1 of these 6 laboratories. The sensitivity and negative predictive value of the diagnostic tests from these laboratories ranged from 18.4% to 79.6% and 95.1% to 98.7%, respectively. These cases underscore the importance of comprehensive DPYD genotyping to accurately identify patients with DPD deficiency who may require lower fluoropyrimidine doses to mitigate severe toxicities and hospitalizations. Clinicians should be aware of test limitations and variability in variant detection by commercial laboratories, and seek assistance by pharmacogenetic experts or available resources for test selection and result interpretation.

Toxic effects of mutant huntingtin in axons are mediated by its proline-rich domain.

Huntington's disease (HD) results from expansion of a polyglutamine tract (polyQ) in mutant huntingtin (mHTT) protein, but mechanisms underlying polyQ expansion-mediated toxic gain-of-mHTT function remain elusive. Here, deletion and antibody-based experiments revealed that a proline-rich domain (PRD) adjacent to the polyQ tract is necessary for mutant huntingtin (mHTT) to inhibit fast axonal transport and promote axonal pathology in cultured mammalian neurons. Further, polypeptides corresponding to subregions of the PRD sufficed to elicit the toxic effect on fast axonal transport, which was mediated by JNK kinases and involved PRD binding to one or more SH3-domain containing proteins. Collectively, these data suggested a mechanism whereby polyQ tract expansion in mHTT promotes aberrant PRD exposure and interactions of this domain with SH3 domain-containing proteins including some involved in activation of JNK kinases. In support, biochemical and immunohistochemical experiments linked aberrant PRD exposure to increased JNK activation in striatal tissues of the zQ175 mouse model and from post-mortem HD patients. Collectively, these findings support a critical role of PRD on mHTT toxicity, suggesting a novel framework for the potential development of therapies aimed to halt or reduce axonal pathology in HD.

Co-production and adaptation of a prison-based problem-solving workbook to support the mental health of patients housed within a medium- and low-secure forensic service.

INTRODUCTION: Problem-solving skills (PSS) help to provide a systematic approach to dealing with and managing complex problems. The overall aim of this study was to assess the acceptability and feasibility of developing and adapting a prison-based PSS  workbook for adults within a medium- and low-secure hospital. METHOD: We used the Medical Research Council framework in our participatory mixed methods study incorporating an adapted survey (to identify what types of problems people experience in secure hospitals), a series of three interactive workshops (to co-produce two case study examples for a workbook) and we gathered feedback from patients and hospital staff on the acceptability and feasibility of the workbook. Data from the survey were used to inform the case study examples, and the feedback from patients and hospital staff was descriptively summarised and the results consolidated. RESULTS: In total, 82 (51%) patients took part in the survey; 22 patients and 49 hospital staff provided feedback on the workbook. The survey results indicated that patients regularly experience problems while in the hospital. Patients reported problems relating to restrictions of freedom and boredom. The workshops produced two case studies for the workbooks, with mainly positive patient and staff feedback. More work is required to improve the visual representation of the characters in the case studies, the amount and content of the language and the mechanism of the intervention delivery. CONCLUSION: The adaptation process proved acceptable and feasible to both patients and staff. The co-production methodology for the workbook and feedback from patients and staff was an effective way of iteratively refining the materials to ensure that they were both meaningful and acceptable to staff and patients. Subsequent work is required to develop the workbook and evaluate the feasibility of the intervention delivery, recruitment rates, uptake and adherence to the PSS using a randomised controlled trial. PATIENT OR PUBLIC CONTRIBUTION: At each stage of the project consultation with patients and/or hospital staff was involved.

Pharmacogenetic and clinical predictors of voriconazole concentration in hematopoietic stem cell transplant recipients receiving CYP2C19-guided dosing.

CYP2C19-guided voriconazole dosing reduces pharmacokinetic variability, but many patients remain subtherapeutic. The aim of this study was to evaluate the effect of candidate genes and a novel CYP2C haplotype on voriconazole trough concentrations in patients receiving CYP2C19-guided dosing. This is a retrospective candidate gene study in allogeneic hematopoietic cell transplant (HCT) patients receiving CYP2C19-guided voriconazole dosing. Patients were genotyped for ABCB1, ABCG2, CYP2C9, CYP3A4, CYP3A5, and the CYP2C haplotype. Of 185 patients, 36% were subtherapeutic (of which 79% were normal or intermediate metabolizers). In all patients, CYP2C19 (p < 0.001), age (p = 0.018), and letermovir use (p = 0.001) were associated with voriconazole concentrations. In the subset receiving 200 mg daily (non-RM/UMs), CYP2C19 (p = 0.004) and ABCG2 (p = 0.015) were associated with voriconazole concentrations; CYP2C19 (p = 0.028) and letermovir use (p = 0.001) were associated with subtherapeutic status. CYP2C19 phenotype and letermovir use were significantly associated with subtherapeutic voriconazole concentrations and may be used to improve voriconazole precision dosing, while further research is needed to clarify the role of ABCG2 in voriconazole dosing.

Myelin biomarkers in the healthy adult brain: Correlation, reproducibility, and the effect of fiber orientation.

PURPOSE: We investigated the correlation, reproducibility, and effect of white matter fiber orientation for three myelin-sensitive MRI techniques: magnetization transfer ratio (MTR), inhomogeneous magnetization transfer ratio (ihMTR), and gradient and spin echo-derived myelin water fraction (MWF). METHODS: We measured the three metrics in 17 white and three deep grey matter regions in 17 healthy adults at 3 T. RESULTS: We found a strong correlation between ihMTR and MTR (r = 0.70, p < 0.001) and ihMTR and MWF (r = 0.79, p < 0.001), and a weaker correlation between MTR and MWF (r = 0.54, p < 0.001). The dynamic range in white matter was greatest for MWF (2.0%-27.5%), followed by MTR (14.4%-23.2%) and then ihMTR (1.2%-5.4%). The average scan-rescan coefficient of variation for white matter regions was 0.6% MTR, 0.3% ihMTR, and 0.7% MWF in metric units; however, when adjusted by the dynamic range, these became 6.3%, 6.1% and 2.8%, respectively. All three metrics varied with fiber direction: MWF and ihMTR were lower in white matter fibers perpendicular to B0 by 6% and 1%, respectively, compared with those parallel, whereas MTR was lower by 0.5% at about 40°, with the highest values at 90°. However, separating the apparent orientation dependence by white matter region revealed large dissimilarities in the trends, suggesting that real differences in myelination between regions are confounding the apparent orientation dependence measured using this method. CONCLUSION: The strong correlation between ihMTR and MWF suggests that these techniques are measuring the same myelination; however, the larger dynamic range of MWF may provide more power to detect small differences in myelin.

Modeling and targeting of erythroleukemia by hematopoietic genome editing.

Acute erythroid leukemia (AEL) is characterized by a distinct morphology, mutational spectrum, lack of preclinical models, and poor prognosis. Here, using multiplexed genome editing of mouse hematopoietic stem and progenitor cells and transplant assays, we developed preclinical models of AEL and non-erythroid acute leukemia and describe the central role of mutational cooperativity in determining leukemia lineage. Different combination of mutations in Trp53, Bcor, Dnmt3a, Rb1, and Nfix resulted in the development of leukemia with an erythroid phenotype, accompanied by the acquisition of alterations in signaling and transcription factor genes that recapitulate human AEL by cross-species genomic analysis. Clonal expansion during tumor evolution was driven by mutational cooccurrence, with clones harboring a higher number of founder and secondary lesions (eg, mutations in signaling genes) showing greater evolutionary fitness. Mouse and human AEL exhibited deregulation of genes regulating erythroid development, notably Gata1, Klf1, and Nfe2, driven by the interaction of mutations of the epigenetic modifiers Dnmt3a and Tet2 that perturbed methylation and thus expression of lineage-specific transcription factors. The established mouse leukemias were used as a platform for drug screening. Drug sensitivity was associated with the leukemia genotype, with the poly (ADP-ribose) polymerase inhibitor talazoparib and the demethylating agent decitabine efficacious in Trp53/Bcor-mutant AEL, CDK7/9 inhibitors in Trp53/Bcor/Dnmt3a-mutant AEL, and gemcitabine and bromodomain inhibitors in NUP98-KDM5A leukemia. In conclusion, combinatorial genome editing has shown the interplay of founding and secondary genetic alterations in phenotype and clonal evolution, epigenetic regulation of lineage-specific transcription factors, and therapeutic tractability in erythroid leukemogenesis.

Nonaqueous magnetization following adiabatic and selective pulses in brain: T1 and cross-relaxation dynamics.

Inversion pulses are commonly employed in MRI for T 1 -weighted contrast and relaxation measurements. In the brain, it is often assumed that adiabatic pulses saturate the nonaqueous magnetization. We investigated this assumption using solid-state NMR to monitor the nonaqueous signal directly following adiabatic inversion and compared this with signals following hard and soft inversion pulses. The effects of the different preparations on relaxation dynamics were explored. Inversion recovery experiments were performed on ex vivo bovine and porcine brains using 360-MHz (8.4 T) and 200-MHz (4.7 T) NMR spectrometers, respectively, using broadband rectangular, adiabatic, and sinc inversion pulses as well as a long rectangular saturation pulse. Analogous human brain MRI experiments were performed at 3 T using single-slice echo-planar imaging. Relaxation data were fitted by mono- and biexponential decay models. Further fitting analysis was performed using only two inversion delay times. Adiabatic and sinc inversion left much of the nonaqueous magnetization along B 0 and resulted in biexponential relaxation. Saturation of both aqueous and nonaqueous magnetization components led to effectively monoexponential T 1 relaxation. Typical adiabatic inversion pulses do not, as has been widely assumed, saturate the nonaqueous proton magnetization in white matter. Unequal magnetization states in aqueous and nonaqueous 1 H reservoirs prepared by soft and adiabatic pulses result in biexponential T 1 relaxation. Both pools must be prepared in the same magnetization state (e.g., saturated or inverted) in order to observe consistent monoexponential relaxation.

Target sequence data shed new light on the infrafamilial classification of Araceae.

PREMISE: Recent phylogenetic studies of the Araceae have confirmed the position of the duckweeds nested within the aroids, and the monophyly of a clade containing all the unisexual flowered aroids plus the bisexual-flowered Calla palustris. The main objective of the present study was to better resolve the deep phylogenetic relationships among the main lineages within the family, particularly the relationships between the eight currently recognized subfamilies. We also aimed to confirm the phylogenetic position of the enigmatic genus Calla in relation to the long-debated evolutionary transition between bisexual and unisexual flowers in the family. METHODS: Nuclear DNA sequence data were generated for 128 species across 111 genera (78%) of Araceae using target sequence capture and the Angiosperms 353 universal probe set. RESULTS: The phylogenomic data confirmed the monophyly of the eight Araceae subfamilies, but the phylogenetic position of subfamily Lasioideae remains uncertain. The genus Calla is included in subfamily Aroideae, which has also been expanded to include Zamioculcadoideae. The tribe Aglaonemateae is newly defined to include the genera Aglaonema and Boycea. CONCLUSIONS: Our results strongly suggest that new research on African genera (Callopsis, Nephthytis, and Anubias) and Calla will be important for understanding the early evolution of the Aroideae. Also of particular interest are the phylogenetic positions of the isolated genera Montrichardia, Zantedeschia, and Anchomanes, which remain only moderately supported here.

'Excessive and Unreasonable': The Relation Between Clinical Insight and Clinical Correlates and Treatment Outcomes in Obsessive-Compulsive Disorder Across the Life Course.

Individuals with mental disorders possess varying levels of clinical insight-the degree to which one understands that they are afflicted with a mental disorder and that their symptoms are manifestations of this psychopathology. Although clinical insight in OCD is thought to play an especially important role in determining various clinical characteristics and treatment outcomes, insight has not been sufficiently addressed developmentally, the importance of which this review will elucidate. Findings from this review suggest that clinical insight is typically associated with more complex cases and worse treatment outcomes across the life course, and also reveal nuances between pediatric and adult OCD cases with low insight. Implications of these findings, future research directions, and recommendations for the field are discussed.

Frontotemporal Lobar Dementia Mutant Tau Impairs Axonal Transport through a Protein Phosphatase 1γ-Dependent Mechanism.

Pathologic tau modifications are characteristic of Alzheimer's disease and related dementias, but mechanisms of tau toxicity continue to be debated. Inherited mutations in tau cause early onset frontotemporal lobar dementias (FTLD-tau) and are commonly used to model mechanisms of tau toxicity in tauopathies. Previous work in the isolated squid axoplasm model demonstrated that several pathogenic forms of tau inhibit axonal transport through a mechanism involving activation of protein phosphatase 1 (PP1). Here, we determined that P301L and R5L FTLD mutant tau proteins elicit a toxic effect on axonal transport as monomeric proteins. We evaluated interactions of wild-type or mutant tau with specific PP1 isoforms (α, ß, and γ) to examine how the interaction contributes to this toxic effect using primary rat hippocampal neurons from both sexes. Pull-down and bioluminescence resonance energy transfer experiments revealed selective interactions of wild-type tau with PP1α and PP1γ isoforms, but not PP1ß, which were significantly increased by the P301L tau mutation. The results from proximity ligation assays confirmed the interaction in primary hippocampal neurons. Moreover, expression of FTLD-linked mutant tau in these neurons enhanced levels of active PP1, also increasing the pausing frequency of fluorescently labeled vesicles in both anterograde and retrograde directions. Knockdown of PP1γ, but not PP1α, rescued the cargo-pausing effects of P301L and R5L tau, a result replicated by deleting a phosphatase-activating domain in the amino terminus of P301L tau. These findings support a model of tau toxicity involving aberrant activation of a specific PP1γ-dependent pathway that disrupts axonal transport in neurons.SIGNIFICANCE STATEMENT Tau pathology is closely associated with neurodegeneration in Alzheimer's disease and other tauopathies, but the toxic mechanisms remain a debated topic. We previously proposed that pathologic tau forms induce dysfunction and degeneration through aberrant activation of a PP1-dependent pathway that disrupts axonal transport. Here, we show that tau directly interacts with specific PP1 isoforms, increasing levels of active PP1. Pathogenic tau mutations enhance this interaction, further increasing active PP1 levels and impairing axonal transport in isolated squid axoplasm and primary hippocampal neurons. Mutant-tau-mediated impairment of axonal transport was mediated by PP1γ and a phosphatase-activating domain located at the amino terminus of tau. This work has important implications for understanding and potentially mitigating tau-mediated neurotoxicity in tauopathies.

Incorporating G6PD genotyping to identify patients with G6PD deficiency.

Glucose-6-phosphate-dehydrogenase (G6PD) deficiency is a common X-linked enzyme disorder associated with hemolytic anemia after exposure to fava beans or certain medications. Activity testing is the gold standard for detecting G6PD deficiency; however, this test is affected by various hematologic parameters. Clinical G6PD genotyping is now included in pharmacogenetic arrays and clinical sequencing efforts and may be reconciled with activity results. Patients (n = 1391) enrolled on an institutional pharmacogenetic testing protocol underwent clinical G6PD genotyping for 164 G6PD variants. An algorithm accounting for known interferences with the activity assay is proposed. We developed clinical decision support alerts to inform prescribers when high-risk medications were prescribed, warning of gene-drug interactions and recommending therapy alteration. Of 1391 patients with genotype results, 1334 (95.9%) patients were predicted to have normal G6PD activity, 30 (2.1%) were predicted to have variable G6PD activity and 27 (2%) were predicted to have deficient G6PD activity. Of the 417 patients with a normal genotype and an activity result, 415 (99.5%) had a concordant normal G6PD phenotype. Of the 21 patients with a deficient genotype and an activity result, 18 (85.7%) had a concordant deficient activity result. Genotyping reassigned phenotype in five patients with discordant genotype and activity results: three switched from normal to deficient, and two switched from deficient to normal. G6PD activity and genotyping are two independent testing methods that can be used in conjunction to assign a more informed G6PD phenotype than either method alone.

Revisiting the seven pillars of RDoC.

BACKGROUND: In 2013, a few years after the launch of the National Institute of Mental Health's Research Domain Criteria (RDoC) initiative, Cuthbert and Insel published a paper titled "Toward the future of psychiatric diagnosis: the seven pillars of RDoC." The RDoC project is a translational research effort to encourage new ways of studying psychopathology through a focus on disruptions in normal functions (such as reward learning or attention) that are defined jointly by observable behavior and neurobiological measures. The paper outlined the principles of the RDoC research framework, including emphases on research that acquires data from multiple measurement classes to foster integrative analyses, adopts dimensional approaches, and employs novel methods for ascertaining participants and identifying valid subgroups. DISCUSSION: To mark the first decade of the RDoC initiative, we revisit the seven pillars and highlight new research findings and updates to the framework that are related to each. This reappraisal emphasizes the flexible nature of the RDoC framework and its application in diverse areas of research, new findings related to the importance of developmental trajectories within and across neurobehavioral domains, and the value of computational approaches for clarifying complex multivariate relations among behavioral and neurobiological systems. CONCLUSION: The seven pillars of RDoC have provided a foundation that has helped to guide a surge of new studies that have examined neurobehavioral domains related to mental disorders, in the service of informing future psychiatric nosology. Building on this footing, future areas of emphasis for the RDoC project will include studying central-peripheral interactions, developing novel approaches to phenotyping for genomic studies, and identifying new targets for clinical trial research to facilitate progress in precision psychiatry.

The dynamic relationship between cancer and employment-related financial toxicity: an in-depth qualitative study of 21 Australian cancer survivor experiences and preferences for support.

BACKGROUND: People with a cancer diagnosis experience physical and emotional impacts that may affect employment. Alongside cancer care costs, reduced ability to generate an income is a key contributor to financial toxicity which is associated with poor emotional wellbeing, quality of life, treatment adherence and survival. This study aimed to explore people's experiences of changes to employment and their suggestions for how cancer survivors can be better supported. METHODS: Semi-structured telephone interviews were conducted with a purposive sample of 21 cancer survivors identified as part of a larger study of emotional distress. Purposive sampling was used to include a diverse group of people across age, gender, tumour type, self-reported financial difficulties and employment status. Interviews were inductively and iteratively coded by two independent coders and analysed using thematic analysis. RESULTS: There is a dynamic relationship between a person's cancer treatment and their employment. For some, employment was disrupted due to physical or emotional impacts of cancer, or workplace stigma and discrimination. Others continued to work at the detriment of their health. Participants wished they had been made aware earlier how cancer might impact their capacity to work, their finances and their health. There was a lack of knowledge on the financial supports that may be available to them. CONCLUSIONS: Healthcare professionals may have a role in minimising the financial impact of a cancer diagnosis through early assessment, communication of patients' potential work capacity and appropriate referrals to occupational therapy to aid return to work or financial planning. A robust government social support system specifically for households experiencing cancer is urgently required.

Magnetic resonance imaging study of the sciatic nerve variation in the pediatric gluteal region: Implications for the posterior approach of the sciatic nerve blockade.

INTRODUCTION: In pediatric patients, the sciatic nerve is one of the most commonly blocked peripheral nerves during orthopedic procedures of the lower limb. Ultrasound guidance is the current standard for a successful localization of the sciatic nerve in the gluteal region. Relevant anatomical landmarks are also used to determine the nerve location when ultrasound is not available or inadequate. However, reports have demonstrated paucity of information regarding the sciatic nerve location and variation in the hip throughout pediatric development. This imaging study aimed to document and analyze the relative morphometric relationship of the sciatic nerve in the pediatric gluteal region throughout development. METHODS: The location of the sciatic nerve in relation to bony landmarks was measured in 84 pediatric magnetic resonance imaging of patients aged 0.7-15.8 years. RESULTS: The sciatic nerve was identified medial to the most lateral point of greater trochanter at the level of ischial spine and the tip of coccyx. The strong positive correlation between sciatic nerve to landmark distances and age and stature demonstrated linear variation between sciatic nerve location with age and growth of children. To predict the nerve location in the gluteal region, regression equations using patient age were created, having implications for the posterior approach of the sciatic nerve blockade in children. Clinically significant differences were found between sexes, specifically in the older age group. CONCLUSION: Despite the small sample size of younger age group, this study is the first to document the morphometric changes of the sciatic nerve in the gluteal region across pediatric development and may be useful for providing confirmatory guidelines for nerve location when ultrasound is not accessible or cannot be utilized for practice.

Reducing Blood Culture and Antibiotic Usage in Neonates: Using Quality Improvement Science to Guide Implementation of a Neonatal Early-Onset Sepsis Calculator.

BACKGROUND: A maternal diagnosis of chorioamnionitis, based on maternal peripartum fever of 100.4°F alone, is commonly used as an indication for blood work and antibiotic treatment in newborns. New strategies such as the Kaiser Permanente early-onset sepsis (EOS) calculator have proven effective in identifying high-risk newborns and reducing unnecessary antibiotic administration. PURPOSE: Retrospective data from October 2017 to September 2018 from 297 well-appearing newborns ≥35 weeks' gestational age (GA) with maternal chorioamnionitis showed that 93.6% had blood work and 90.2% were treated with antibiotics. This was despite no culture-positive cases of sepsis. Our aim was to reduce by 50% blood work evaluation and antibiotic treatment within a 6-month period. METHODS: Using plan-do-study-act (PDSA) cycles, we adopted the Kaiser Permanente EOS calculator. We collected longitudinal data to track the outcomes after its implementation. RESULTS: In 423 newborns with maternal chorioamnionitis triaged with the EOS calculator from October 2018 to July 2020, the rates of blood culture and antibiotic treatment decreased from 93.6% to 26.7% and 90.2% to 12.3% (P < .0001). In the larger population of 6426 newborns ≥35 weeks' GA, the rate of blood culture and antibiotic treatment decreased from 12.8% to 5.8% and 9.9% to 2.5% (P < .0001). IMPLICATIONS FOR PRACTICE: The EOS calculator substantially and safely decreases blood work and antibiotic administration in asymptomatic newborns with maternal chorioamnionitis. IMPLICATIONS FOR RESEARCH: Our findings provide further evidence for the effectiveness and safety of the EOS calculator.Video abstract available athttps://journals.lww.com/advancesinneonatalcare/Pages/videogallery.aspx.

Cochlear implant outcomes in the very elderly.

PURPOSE: Managing hearing health in older adults has become a public health imperative, and cochlear implantation is now the standard of care for aural rehabilitation when hearing aids no longer provide sufficient benefit. The aim of our study was to compare speech performance in cochlear implant patients ≥80 years of age (Very Elderly) to a younger elderly cohort between ages 65-79 years (Less Elderly). MATERIALS AND METHODS: Data were collected from 53 patients ≥80 years of age and 92 patients age 65-79 years who underwent cochlear implantation by the senior author between April 1, 2017 and May 12, 2020. The primary outcome measure compared preoperative AzBio Quiet scores to 6-month post-activation AzBio Quiet results for both cohorts. RESULTS: Very Elderly patients progressed from an average AzBio Quiet score of 22% preoperatively to a score of 45% in the implanted ear at 6-months post-activation (p < 0.001) while the Less Elderly progressed from an average score of 27% preoperatively to 60% at 6-months (p < 0.001). Improvements in speech intelligibility were statistically significant within each of these cohorts (p < 0.001). Comparative statistics using independent samples t-test and evaluation of effect size using the Hedges' g statistic demonstrated a significant difference for average improvement of AzBio in quiet scores between groups with a medium effect size (p = 0.03, g = 0.35). However, when the very oldest patients (90+ years) were removed, the statistical difference between groups disappeared (p = 0.09). CONCLUSIONS: When assessing CI performance, those over age 65 are typically compared to younger patients; however, this manuscript further stratifies audiometric outcomes for older CI recipients in a single-surgeon, high-volume practice. Our data indicates that for speech intelligibility, patients between age 65-79 perform similarly to CI recipients 80-90 years of age and should not be dismissed as potential cochlear implant candidates.

Non-Time-Loss and Time-Loss Injuries in Secondary School Girls' Volleyball Athletes: A Report From the National Athletic Treatment, Injury, and Outcomes Network Surveillance Program.

CONTEXT: Volleyball is a popular sport with a risk of injury to the entire body. Insight into non-time-loss (NTL) and time-loss (TL) injuries is needed to inform seasonal injury trends that may lead to appropriate prevention and management strategies. This study provides a descriptive analysis of volleyball injuries among secondary school athletes. STUDY DESIGN: Descriptive epidemiology study. METHODS: Data were collected from 72 secondary schools, representing 135 team seasons of data from the National Athletic Treatment, Injury, and Outcomes Network Surveillance Program (2014-2015 to 2018-2019 academic years). Injury counts, injury rates (IR) per 1000 athlete exposures (AEs), and incidence rate ratios (IRR) were reported with 95% confidence intervals (CIs). RESULTS: In total, 529 injuries over 193,858 AEs for girls' volleyball were captured, producing an IR of 2.73/1000AEs (95% CI = 2.50-2.96). The overall IR was highest during the preseason compared with regular season (IRR = 1.31, 95% CI = 1.09-1.59). Overall IRs were higher in competition (IR: 3.56, 95% CI = 3.07-4.05) compared with practice (IR: 2.38, 95% CI = 2.12-2.64; IRR = 1.49, 95% CI = 1.25-1.79). Common body locations injured were ankle (n = 141, 26.7%; NTL: n = 56, 21.7%; TL: n = 85, 31.7%), knee (n = 61, 11.5%; NTL: n = 33, 12.8%, TL: n = 28, 10.5%), hand/wrist (n = 59, 11.2%; NTL: n = 32, 12.4%, TL: n = 27, 10.1%), and head/face (n = 62, 11.7%; NTL: n = 14, 5.4%; TL: n = 47, 17.5%). CONCLUSIONS: Volleyball IRs were highest in preseason and during competition. Most injuries affected the lower-extremity which is notable considering the high upper-extremity load in volleyball. Consideration of strategies to reduce injuries prior to the start of the formal sports season may be needed to help reduce the incidence of preseason injuries.

Temperature dependence and histological correlation of inhomogeneous magnetization transfer and myelin water imaging in ex vivo brain.

PURPOSE: The promise of inhomogeneous magnetization transfer (ihMT) as a new myelin imaging method was studied in ex vivo human brain tissue and in relation to myelin water fraction (MWF). The temperature dependence of both methods was characterized, as well as their correspondence with a histological measure of myelin content. Unfiltered and filtered ihMT protocols were studied by adjusting the saturation scheme to preserve or attenuate signal from tissue with short dipolar relaxation time T1D. METHODS: ihMT ratio (ihMTR) and MWF maps were acquired at 7 T from formalin-fixed human brain samples at 22.5 °C, 30 °C and 37 °C. The impact of temperature on unfiltered ihMTR, filtered ihMTR and MWF was investigated and compared to myelin basic protein staining. RESULTS: Unfiltered ihMTR exhibited no temperature dependence, whereas filtered ihMTR increased with increasing temperature. MWF decreased at higher temperature, with an increasing prevalence of areas where the myelin water signal was unreliably determined, likely related to a reduction in T2 peak separability at higher temperatures ex vivo. MWF and ihMTR showed similar per-sample correlation with myelin staining at room temperature. At 37 °C, filtered ihMTR was more strongly correlated with myelin staining and had increased dynamic range compared to unfiltered ihMTR. CONCLUSIONS: Given the temperature dependence of filtered ihMT, increased dynamic range, and strong myelin specificity that persists at higher temperatures, we recommend carefully controlled temperatures close to 37 °C for filtered ihMT acquisitions. Unfiltered ihMT may also be useful, due to its independence from temperature, higher amplitude values, and sensitivity to short T1D components. Ex vivo myelin water imaging should be performed at room temperature, to avoid fitting issues found at higher temperatures.

Loss of growth hormone signaling in the mouse germline or in adulthood reduces islet mass and alters islet function with notable sex differences.

In the endocrine pancreas, growth hormone (GH) is known to promote pancreatic islet growth and insulin secretion. In this study, we show that GH receptor (GHR) loss in the germline and in adulthood impacts islet mass in general but more profoundly in male mice. GHR knockout (GHRKO) mice have enhanced insulin sensitivity and low circulating insulin. We show that the total cross-sectional area of isolated islets (estimated islet mass) was reduced by 72% in male but by only 29% in female GHRKO mice compared with wild-type controls. Also, islets from GHRKO mice secreted ∼50% less glucose-stimulated insulin compared with size-matched islets from wild-type mice. We next used mice with a floxed Ghr gene to knock down the GHR in adult mice at 6 mo of age (6mGHRKO) and examined the impact on glucose and islet metabolism. By 12 mo of age, female 6mGHRKO mice had increased body fat and reduced islet mass but had no change in glucose tolerance or insulin sensitivity. However, male 6mGHRKO mice had nearly twice as much body fat, substantially reduced islet mass, and enhanced insulin sensitivity, but no change in glucose tolerance. Despite large losses in islet mass, glucose-stimulated insulin secretion from isolated islets was not significantly different between male 6mGHRKO and controls, whereas isolated islets from female 6mGHRKO mice showed increased glucose-stimulated insulin release. Our findings demonstrate the importance of GH to islet mass throughout life and that unique sex-specific adaptations to the loss of GH signaling allow mice to maintain normal glucose metabolism.NEW & NOTEWORTHY Growth hormone (GH) is important for more than just growth. GH helps to maintain pancreatic islet mass and insulin secretion throughout life. Sex-specific adaptations to the loss of GH signaling allow mice to maintain normal glucose regulation despite losing islet mass.