Insulin sensitivity, body composition and bone mineral density after testosterone treatment in transgender youth with and without prior GnRH agonist therapy.

Background: 1.8% of youth identify as transgender; a growing proportion are transgender male (female sex, male gender identity). Many receive gonadotropin releasing hormone agonist (GnRHa) therapy to suppress endogenous puberty and/or will start testosterone to induce secondary sex characteristics that align with gender identity. Objectives: To determine the effects of 12 months of testosterone on cardiometabolic health among transgender youth, including insulin sensitivity, body composition, and bone mineral density and whether changes in outcomes differ based on prior GnRHa treatment. Methods: Participants (n = 19, baseline age 15.0 ± 1.0 years) were examined prior to and 12 months after testosterone therapy in a longitudinal observational study. Fasted morning blood draw, a 2-hour 75-gram oral glucose tolerance test, body composition and bone mineral density (dual-energy X-ray absorptiometry) were assessed at baseline and 12 months. Insulin sensitivity was estimated by HOMA-IR and Matsuda index. Changes were compared with mixed linear regression models evaluating time (baseline, 12 months), group (GnRHa treatment yes/no), and their interaction. Results: In the entire cohort, fasted insulin decreased (median [25,75 %ile]: -3 [-5, 0] mIU/L, p = 0.044) and 2-hour glucose increased (mean ± standard deviation): +18.5 ± 28.9 mg/dL, p = 0.013 from baseline after 12 months of testosterone therapy. There were no significant changes in HOMA-IR (p = 0.062) or Matsuda index (p = 0.096), nor by GnRHa status. Absolute (+6.2 [4.7, 7.5] kg, p = 0.016) and percent fat-free mass increased (+7.3 [5.4, 9.1] %, p = 0.003) and percent fat mass declined (-7.4 [-9.3, 5.3]%, p = 0.005) for the entire cohort. There were time*group interactions for absolute (p = 0.0007) and percent fat-free mass (p = 0.033). There were time*group interactions for bone mineral content (p = 0.006). Conclusions: Twelve months of testosterone in transgender adolescents resulted in changes in body composition and bone mineral density, with baseline differences between the +/-GnRHa group and convergence after 12 months. There were no changes in insulin sensitivity over time or between groups.

Phase II Trial Assessing Toxicity of Personalized Response-Based Radiation Treatment in Patients with Locally Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Local failure rates after treatment for locally advanced non-small-cell lung cancer (NSCLC) remain high. Efforts to improve local control with uniform dose-escalation or dose-escalation to mid-treatment PET-avid residual disease have been limited by heightened toxicity. This trial aimed to refine response-based adaptive radiation (RT) and minimize toxicity by incorporating FDG-PET and V/Q SPECT imaging mid-treatment. METHODS: 47 patients with Stage IIA-III unresectable NSCLC were prospectively enrolled in this single-institution trial (NCT02492867). Patients received concurrent chemoradiation with personalized response-based adaptive RT over 30 fractions incorporating V/Q SPECT and FDG-PET. The first 21 fractions (46.2Gy at 2.2 Gy/fraction) were delivered to the tumor while minimizing dose to SPECT-defined functional lung. The plan was then adapted for the final 9 fractions (2.2-3.8Gy/fraction) up to a total of 80.4Gy, based on mid-treatment FDG-PET tumor response to escalate dose to residual tumor while minimizing dose to SPECT-defined functional lung. Non-progressing patients received consolidative carboplatin/paclitaxel or durvalumab. The primary endpoint of the study was ≥ grade 2 lung and esophageal toxicities. Secondary endpoints included time to local progression, tumor response, and overall survival. RESULTS: At one year post-treatment, the rates of grade 2 and grade 3 pneumonitis were 21.3% and 2.1%, respectively, with no difference in pneumonitis rates among patients who received and did not receive adjuvant durvalumab (p=0.74). While there were no grade 3 esophageal-related toxicities, 66.0% of patients experienced grade 2 esophagitis. 1- and 2-year local control rates were 94.5% (95% CI, 87.4% - 100%) and 87.5% (95% CI, 76.7% - 100%), respectively. Overall survival was 82.8% (95% CI, 72.6% -94.4%) at 1 year and 62.3% (95% CI, 49.6%-78.3%) at 2 years. CONCLUSIONS: Response-based adaptive dose-escalation accounting for tumor change and normal tissue function during treatment provided excellent local control, comparable toxicity to standard chemoradiation, and did not increase toxicity with adjuvant immunotherapy.

Early Liver Transplant for Alcohol-associated Liver Disease Has Excellent Survival but Higher Rates of Harmful Alcohol Use.

BACKGROUND & AIMS: Early liver transplantation (LT) for alcohol-associated liver disease (ALD) has increased worldwide. Short-term outcomes have been favorable, but data on longer-term outcomes are lacking. METHODS: Single-center retrospective study of primary LT recipients between 2010 and 2020, with follow-up through July 1, 2022. Survival analysis was performed using log rank, Cox models, and Kaplan-Meier method. Cox models were created to identify variables associated with mortality; logistic regression to identify variables associated with post-LT alcohol use. RESULTS: Of 708 patients who underwent LT, 110 (15.5%) had ALD and abstinence <6 months prior to LT (ELT), 234 (33.1%) had ALD and alcohol abstinence >6 months (SLT), and 364 (51.4%) had non-ALD diagnoses. Median follow-up was 4.6 years (interquartile range, 2.6-7.3 years). ELT recipients were younger (P = .001) with median abstinence pre-LT of 61.5 days. On adjusted Cox model, post-LT survival was similar in ELT and SLT (hazard ratio [HR], 1.31; P = .30) and superior to non-ALD (HR, 1.68; P = .04). Alcohol use (40.9% vs 21.8%; P < .001) and harmful alcohol use (31.2% vs 16.0%; P = .002) were more common in ELT recipients. Harmful alcohol use was associated with post-LT mortality on univariate (HR, 1.69; P = .03), but not multivariable regression (HR, 1.54; P = .10). Recurrence of decompensated ALD trended toward more common in ELT (9.1% vs 4.4%; P = .09). Greater than 6 months pre-LT abstinence was associated with a decreased risk of harmful alcohol use (odds ratio, 0.42; P = .001), but not in a multivariable model (odds ratio, 0.71; P = .33). CONCLUSIONS: Patients who undergo ELT for ALD have similar or better survival than other diagnoses in the first 10 years after LT despite a higher incidence of post-LT alcohol use.

The association of gender-affirming hormone therapy duration and body mass index on bone mineral density in gender diverse adults.

Introduction: Feminizing and masculinizing gender-affirming hormone therapy (fGAHT, mGAHT) results in bone mineral density (BMD) maintenance or improvement over time in transgender and gender diverse (TGD) adults. Mostly European TGD studies have explored GAHT's impact on BMD, but the association of BMI and BMD in TGD adults deserves further study. Objective: To determine whether GAHT duration or BMI are associated with BMD and Z-scores among TGD young adults. Methods: Cross-sectional study of nonsmoking TGD adults aged 18-40 years without prior gonadectomy or gonadotropin-releasing hormone agonist (GnRHa) therapy taking GAHT for > 1 year. BMD and Z-scores were collected from dual-energy x-ray absorptiometry. Associations between femoral neck, total hip, and lumbar spine BMDs and Z-scores and the predictors, GAHT duration and BMI, were estimated using linear regression. Results: Among 15 fGAHT and 15 mGAHT, mean BMIs were 27.6 +/- standard deviation (SD) 6.4 kg/m2 and 25.3 +/- 5.9 kg/m2, respectively. Both groups had mean BMDs and Z-scores within expected male and female reference ranges at all three sites. Higher BMI among mGAHT was associated with higher femoral neck and total hip BMDs (femoral neck: ß = 0.019 +/- standard error [SE] 0.007 g/cm2, total hip: ß = 0.017 +/- 0.006 g/cm2; both p < 0.05) and Z-scores using male and female references. GAHT duration was not associated with BMDs or Z-scores for either group. Conclusions: Z-scores in young, nonsmoking TGD adults taking GAHT for > 1 year, without prior gonadectomy or GnRHa, and with mean BMIs in the overweight range, were reassuringly within the expected ranges for age based on male and female references. Higher BMI, but not longer GAHT duration, was associated with higher femoral neck and total hip BMDs and Z-scores among mGAHT. Larger, prospective studies are needed to understand how body composition changes, normal or low BMIs, and gonadectomy affect bone density in TGD adults.

Soybean MKK2 establishes intricate signalling pathways to regulate soybean response to cyst nematode infection.

Mitogen-activated protein kinase (MPK) cascades play central signalling roles in plant immunity and stress response. The soybean orthologue of MPK kinase2 (GmMKK2) was recently identified as a potential signalling node whose expression is upregulated in the feeding site induced by soybean cyst nematode (SCN, Heterodera glycines). To investigate the role of GmMKK2 in soybean-SCN interactions, we overexpressed a catabolically inactive variant referred to as kinase-dead variant (KD-GmMKK2) using transgenic hairy roots. KD-GmMKK2 overexpression caused significant reduction in soybean susceptibility to SCN, while overexpression of the wild-type variant (WT-GmMKK2) exhibited no effect on susceptibility. Transcriptome analysis indicated that KD-GmMKK2 overexpressing plants are primed for SCN resistance via constitutive activation of defence signalling, particularly those related to chitin, respiratory burst, hydrogen peroxide and salicylic acid. Phosphoproteomic profiling of the WT-GmMKK2 and KD-GmMKK2 root samples upon SCN infection resulted in the identification of 391 potential targets of GmMKK2. These targets are involved in a broad range of biological processes, including defence signalling, vesicle fusion, chromatin remodelling and nuclear organization among others. Furthermore, GmMKK2 mediates phosphorylation of numerous transcriptional and translational regulators, pointing to the presence of signalling shortcuts besides the canonical MAPK cascades to initiate downstream signalling that eventually regulates gene expression and translation initiation. Finally, the functional requirement of specific phosphorylation sites for soybean response to SCN infection was validated by overexpressing phospho-mimic and phospho-dead variants of two differentially phosphorylated proteins SUN1 and IDD4. Together, our analyses identify GmMKK2 impacts on signalling modules that regulate soybean response to SCN infection.

First report of root rot of strawberry caused by Fusarium cugenangense, a member of the F. oxysporum species complex, in Tennessee, USA.

Strawberry (Fragaria × ananassa Duch) in Tennessee is cultivated on plastic mulched beds annually, and production is limited primarily by multiple oomycete and fungal root rot pathogens that result in reduced vigor and black root rot disease symptoms. In early June 2018, plants (cv. Chandler) with reduced shoot vigor and size, and black, necrotic stunted roots were collected from Rhea County, TN. Roots and crowns of 10 plants were cut into 1-3 cm pieces and surface sterilized with 0.6% NaOCl, followed by 70% ethanol for 1 min each, and plated on water agar. White mycelia produced after 3 days were transferred to potato dextrose agar amended with 10 mg/liter rifampicin. After 10 days, fungal colonies were light purple on the surface and dark purple on the colony underside, later developing blue-black pigmentation on the underside. Microconidia on carnation leaf agar were ovoid to ellipsoid, aseptate or septate and 8.0 to 24.2 (13.7) × 3.0 to 4.5 (3.8) µm in size, macroconidia were 3 to 5 septate and falcate to almost straight and 33.7 to 52.8 (44.4) × 4.0 to 5.5 (4.9) µm in size (n=80); both conidia were produced on monophialides. Chlamydospores were globose and subglobose, formed terminally and intercalary on aerial, submerged, and surface mycelium, singly or in pairs and were abundantly produced in sucrose broth and on synthetic nutrient-poor agar (SNA) (diam. 7.6 µm). Morphology was consistent with Fusarium oxysporum (Leslie and Summerell, 2006) and F. cugenangense, a member of the F. oxysporum species complex, as described by Maryani et al. (2019). Fungal mycelia were used for PCR (Phire Plant Direct PCR Master Mix, Thermo Scientific, CA) and the translational elongation factor 1-α (EF1α) region was amplified with primers EF-1/EF-2 (O'Donnell et al., 1998), internal transcribed spacer (ITS) regions amplified with primers ITS1/ITS2 (White et al. 1990), and the RNA polymerase second largest subunit region (RPB2) with primer pairs 5f2/7cr and 7cf/11ar (O'Donnell et al., 2022). PCR products of isolate SC5 were sequenced, and sequences compared to all sequences in the FUSARIOID-ID database using polyphasic identification (Crous et al., 2021) with EF1α (GenBank Accession No. ON703236) and RPB2 (OR472390) sequences. The highest similarity (100%) was with isolates of F. cugenangense, including ex-type isolate InaCC F984 (99.94% similarity) (Maryani et al., 2019). F. cugenangense is closely related to F. callistephi and F. elaeidis, but both species lack chlamydospores, and F. elaeidis has polyphialides (Lombard et al, 2019). To satisfy Koch's postulates, healthy rooted strawberry plants produced in soilless media were transplanted into 4 plastic pots (1.2-liter) containing 5% (w/v) fungal inoculum (grown on barley grain) and mixed into the top 5-cm of peat-based soilless medium. Pots were incubated at 25°C and 50% RH in a growth chamber. Four pots without inoculum served as controls. The trial was repeated. Within 8 weeks, all inoculated plants had low vigor, with necrotic and stunted roots. Root sections of control and inoculated plants were plated, and the pathogen was re-isolated from diseased roots of all inoculated plants only and confirmed as F. cugenangense based on morphology and sequence analysis. To our knowledge, this is the first report of F. cugenangense, or any member of the F. oxysporum species complex, causing root rot of strawberry in Tennessee and could be an important component of the production-limiting black root rot disease complex of strawberry.

Impact of barriers and motivators on intention and confidence to undergo hereditary cancer genetic testing.

Genetic testing for hereditary cancer syndromes can provide lifesaving information allowing for individualized cancer screening, prevention, and treatment. However, the determinants, both barriers and motivators, of genetic testing intention are not well described. A survey of barriers and motivators to genetic testing was emailed to adult patients eligible for genetic testing based on cancer diagnosis who previously have not had genetic testing (n = 201). Associations between barriers/motivators with testing intention and confidence were examined first by correlation followed by multivariable linear regression model holding constant potential covariates. Seven barrier items from two domains (logistics and genetic testing knowledge) were found to significantly negatively correlate with genetic testing intention. Unexpectedly, three barrier items had significant positive correlation with genetic testing intention; these were related to family worry (passing a condition on to future generations) and testing knowledge (needing more information on the genetic testing process and what it has to offer). Ten barrier items had significant negative correlation with confidence to get a genetic test and encompassed four domains: stigma, insurance/genetic discrimination, knowledge, and cost. All motivator items were associated with intention to get a genetic test, while none were associated with confidence. Multivariable analysis yielded six total barriers (five from the knowledge domain, one from cost domain) and two motivators (relieved to know and treatment impact) that were significantly associated with genetic testing intention or confidence when controlling for demographic characteristics. These findings indicate the need for tailored interventions to amplify motivating factors and counter-message barriers to enhance patient motivation and confidence to undergo testing.

Recent Advances in Closed-Tube Barcoding for FastFish-ID.

FastFish-ID for rapid and accurate identification of fish species was conceived at Brandeis University based on pioneering work on Closed-Tube Barcoding (Rice et al., Mitochondrial DNA Part A 27(2):1358-1363, 2016; Sirianni et al., Genome 59:1049-1061, 2016). FastFish-ID was subsequently validated and commercialized at Thermagenix, Inc. using a portable device and high-precision PCR (Naaum et al., Food Res Int 141:110035, 2021). The motivation for these efforts was the pressing need for a technology that could be widely used throughout the seafood supply chain to combat IUU Fishing (Helyar et al., PLOS ONE 9, 2014) and overfishing (FAO, State of the World Fisheries and Aquaculture 2018. http://www.fao.org/documents/card/en/c/I9540EN/ , 2018), along with seafood fraud and mislabeling (Watson et al., Fish Fish 17:585-595, 2015). These destructive practices are wasting fish stocks, frustrating attempts to achieve seafood sustainability, endangering oceanic ecosystems, and causing consumers billions of dollars each year (Porterfield et al., Oceana: February, 2022). During the past three Covid19 pandemic years, EcologeniX, LLC has taken over further development and optimization of FastFish-ID. The present chapter provides an overview of the improvements introduced throughout the FastFish-ID process.

Recent Applications of FastFish-ID.

FastFish-ID via Closed-Tube barcoding is a portable platform for rapid and accurate identification of fish species that was conceived at Brandeis University, commercialized at Thermagenix, Inc., and further improved at Ecologenix, LLC (see Chap. 17 in this volume). This chapter focuses on the use of FastFish-ID for (1) identification of intraspecies variants, (2) quantitative use of FastFish-ID to measure the decay of fresh fish, and (3) use of FastFish-ID for the identification of dried and processed shark fins.

Examining the Impact of Layperson Rescuer Gender on the Receipt of Bystander CPR for Women in Cardiac Arrest.

BACKGROUND: Women who suffer a witnessed out-of-hospital cardiac arrest receive bystander cardiopulmonary resuscitation (CPR) less often than men. To understand this phenomenon, we queried whether there are differences in deterrents to providing CPR based on the rescuer's gender. METHODS: Participants were surveyed using a national crowdsourcing platform. Participants ranked the following 5 previously identified themes as reasons: rescuers are afraid to injure or hurt women; rescuers might have a misconception that women do not suffer cardiac arrest; rescuers are afraid to be accused of sexual assault or sexual harassment; rescuers have a fear of touching women or that their touch might be inappropriate; and rescuers think that women are faking it or being overdramatic. Participants were adult US residents able to correctly define CPR. Participants ranked the themes if the rescuer was gender unidentified, a man, and a woman, in variable order. RESULTS: In November 2018, 520 surveys were completed. The respondents identified as 42.3% women, 74.2% White, 10.4% Black, and 6.7% Hispanic. Approximately half (48.1%) of the cohort knew how to perform CPR, but only 7.9% had ever performed CPR. When the rescuer was identified as a man, survey participants ranked fear of sexual assault or sexual harassment and fear of touching women or that the touch might be inappropriate as the top reasons (36.2% and 34.0% of responses, respectively). Conversely, when the rescuer was identified as a woman, survey respondents reported fear of hurting or injuring as the top reason (41.2%). CONCLUSIONS: Public perceptions as to why women receive less bystander CPR than men were different based on the gender of the rescuer. Participants reported that men rescuers would potentially be hindered by fears of accusations of sexual assault/harassment or inappropriate touch, while women rescuers would be deterred due to fears of causing physical injury.

Disparate Outcomes, Biologic and Therapeutic Differences in Pediatric versus Adult Patients with Ewing Sarcoma.

INTRODUCTION: Ewing sarcoma (ES) is a small blue round cell sarcoma affecting a wide age spectrum. Clinical advances predominately stem from pediatric research consortia clinical trials. In most series, adults have poorer outcomes when compared to children. The aim of this study was to perform a detailed evaluation of factors potentially accounting for this difference. METHODS: A single institution retrospective chart review was conducted on patients with ES diagnosed from 2005 to 2015, identified using a free-text search engine with the keywords "Ewing sarcoma" as well as a corresponding pathologic database. Data were analyzed based on age, pediatric (age <18) and adult (age >18 years), using a multivariate analysis model. RESULTS: Eighty-eight ES patients (34 pediatric, 54 adult) were identified with a median age of 13 (range 3-18) and 31 (range 19-70) in their respective cohorts. Five-year overall survival (OS) was higher in pediatric patients (73.5% vs. 48.1%, p = 0.0213). By stage, 5-year OS in pediatric versus adult patients was 65% versus 20% (p = 0.0530) in metastatic (n = 32) and 68.1% versus 58.8% (p = 0.278) in localized (n = 56) patients. Lung-only metastases were present in 83% of metastatic pediatric patients versus 35% of adult metastatic patients. Pediatric patients received more cycles of first-line chemotherapy (13.8 vs. 11.4, p = 0.001), independent of stage. More cycles of chemotherapy correlated with improved OS (HR: 0.864, CI: 0.773-0.967) and progression-free survival (HR: 0.897, CI: 0.808-0.996). CONCLUSIONS: Outcome differences were most notable in patients with metastatic disease, although not statistically significant. Our series found differences in presentation between pediatric and adult populations with adult patients receiving fewer cycles of chemotherapy. This may suggest that both variations in underlying disease biology and potentially differences in treatment may account for outcome disparities.

A Phase II Trial of Pevonedistat and Docetaxel in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer.

BACKGROUND: Postimmunotherapy (IO) treatment options for stage IV non-small-cell lung cancer (NSCLC) remain limited. Docetaxel alone or in combination with ramucirumab remains a standard of care, but response rates and survival benefit are suboptimal. Cullin-RING ligases (CRL) catalyze degradation of tumor suppressor proteins and are overactivated in NSCLC. Neddylation, which is catalyzed by the NEDD8 activating enzyme (NAE), is required for the activation of CRLs. Pevonedistat, a first-in-class small molecule NAE inhibitor, exerted antitumor activity when combined with docetaxel in preclinical studies. METHODS: We conducted a phase II, single-arm, investigator-initiated study evaluating the efficacy of pevonedistat plus docetaxel in patients with relapsed/refractory stage IV NSCLC. Patients received docetaxel 75 mg/m2 on day 1 and pevonedistat 25 mg/m2 on days 1, 3 and 5 of a 21-day cycle. The primary endpoint was objective response rate (ORR). RESULTS: From March 5, 2018 to January 26, 2021, we enrolled 31 patients. The ORR was 22% (1 CR, 5 PR), median PFS was 4.1 months, and median OS was 13.2 months. The incidence of Grade ≥3 adverse events (AE) was 53% in patients (n = 30) who received at least 1 dose of both drugs, with the most frequent being neutropenia and AST/ALT elevation. One patient was taken off study for a Grade 4 transaminase elevation. There were no Grade 5 toxicities. CONCLUSION: Our data suggest that the combination of docetaxel and pevonedistat is safe and exerts activity in patients with relapsed NSCLC. These encouraging results suggest that the neddylation pathway is an antitumor pathway that should be further studied.

Communicating Patient Discharge Readiness: An Implementation Evaluation in an Inpatient Hospital Medicine Setting.

BACKGROUND: The progression of patients through a hospital from admission to discharge can be slowed by delays in patient discharge, increasing pressure on health care staff. We designed and piloted the Discharge Today tool, with the goal of improving the efficiency of patient discharge; however, adoption remained low. PURPOSE: To close this implementation gap, we deployed and evaluated a 4-part implementation strategy bundle. METHODS: We measured the success of implementation by evaluating validated implementation outcomes using both quantitative and qualitative methods, grounded in Normalization Process Theory. RESULTS: The implementation strategies used were effective for increasing use of the Discharge Today tool by hospital medicine physicians and advanced practice providers during both the active and passive implementation periods. CONCLUSIONS: While the implementation strategies used were effective, qualitative findings indicate that limitations in the functionality of the tool, alongside inconsistent use of the tool across clinical staff, continued to inhibit adoption.

Provider Perceptions of Oxygenation Strategies for Critically Ill Trauma Patients With and Without Moderate-to-Severe Traumatic Brain Injury.

BACKGROUND: Hypoxia and hyperoxia (pulse oximetry [SpO2] > 96%) are associated with increased mortality in critically ill patients. However, provider practices regarding oxygenation in traumatic brain injury (TBI) patients are unknown. This study assesses views on oxygenation of critically ill trauma patients with and without TBI and how this varies between Neurological ICU (NeuroICU) and Surgical-Trauma ICU (STICU) providers. METHODS: This is a cross-sectional survey of Level I trauma center's NeuroICU and STICU providers. We used Likert scales, yes-no questions, and multiple-choice case-based scenarios to characterize provider views on oxygenation with descriptive statistics to characterize responses. Significant differences regarding TBI and non-TBI patients or NeuroICU and STICU providers were determined using Fisher's exact test and a P-value of .05. RESULTS: A total of 83 providers initiated the survey, and 53 providers completed it. Most providers identified a threshold SpO2 < 92% for the administration of supplemental oxygen in critically ill TBI patients. A total of 9% of providers "somewhat or completely agreed" that they were more likely to give supplemental oxygen to a critically ill trauma patient with TBI than one without TBI and the same SpO2. A total of 48% of providers selected an SpO2 < 90% as the point at which supplemental oxygen should be initiated in patients without TBI, compared to 27% of providers in patients with TBI (P < .01). This threshold for supplemental oxygen use varied by provider type for non-TBI patients, but not for TBI patients (30% NeuroICU and 69% STICU providers selected SpO2 < 90% in non-TBI, P < .05; 30% NeuroICU and 35% STICU providers selected SpO2 < 90% in TBI, P = .85). CONCLUSIONS: Critical care providers at UCHealth University of Colorado Hospital approach the oxygenation of critically ill trauma patients with and without TBI differently. Specifically, critical care respondents accepted a different lower oxygen saturation threshold for TBI and non-TBI patients. NeuroICU and STICU respondents differed in their threshold for the down-titration of supplemental oxygen. Targeted education for critical care providers may reduce these discrepancies and optimize oxygen use.

Genetics of vegetarianism: A genome-wide association study.

A substantial body of evidence points to the heritability of dietary preferences. While vegetarianism has been practiced for millennia in various societies, its practitioners remain a small minority of people worldwide, and the role of genetics in choosing a vegetarian diet is not well understood. Dietary choices involve an interplay between the physiologic effects of dietary items, their metabolism, and taste perception, all of which are strongly influenced by genetics. In this study, we used a genome-wide association study (GWAS) to identify loci associated with strict vegetarianism in UK Biobank participants. Comparing 5,324 strict vegetarians to 329,455 controls, we identified one SNP on chromosome 18 that is associated with vegetarianism at the genome-wide significant level (rs72884519, ß = -0.11, P = 4.997 x 10-8), and an additional 201 suggestively significant variants. Four genes are associated with rs72884519: TMEM241, RIOK3, NPC1, and RMC1. Using the Functional Mapping and Annotation (FUMA) platform and the Multi-marker Analysis of GenoMic Annotation (MAGMA) tool, we identified 34 genes with a possible role in vegetarianism, 3 of which are GWAS-significant based on gene-level analysis: RIOK3, RMC1, and NPC1. Several of the genes associated with vegetarianism, including TMEM241, NPC1, and RMC1, have important functions in lipid metabolism and brain function, raising the possibility that differences in lipid metabolism and their effects on the brain may underlie the ability to subsist on a vegetarian diet. These results support a role for genetics in choosing a vegetarian diet and open the door to future studies aimed at further elucidating the physiologic pathways involved in vegetarianism.

Real world experience with conversion from valganciclovir to letermovir for cytomegalovirus prophylaxis: Letermovir reverses leukopenia and avoids mycophenolate dose reduction.

PURPOSE: Valganciclovir (VGC) is the gold-standard for cytomegalovirus (CMV) prophylaxis (PPX) after solid organ transplant (SOT). Letermovir (LTV) was recently approved in high-risk kidney transplant and has reduced myelosuppressive toxicity. Conversion from VGC to LTV may be pursued in the setting of leukopenia. It is unknown if this strategy is effective. METHODS: Adult patients receiving abdominal SOT were included if converted from VGC to LTV between January 1, 2018 and January 31, 2023. Primary objective was to describe the impact of LTV conversion as measured by WBC recovery, mycophenolate modification, and use of GCSF, and prophylaxis efficacy assessed by course completion and breakthrough DNAemia. Secondary objective was to evaluate rates of post-prophylaxis CMV. RESULTS: Seventy five SOT recipients met inclusion criteria. Mean change in WBC in response to LTV conversion by day 14 was +2.02 ± 2.52 k/uL. 75%(56/75) of the population did not require mycophenolate adjustment or had their dose increased after conversion. GCSF was required in 38.7%(29/75) prior to conversion; only 21.3%(16/75) of patients required GCSF after conversion. Early termination was uncommon, 14.7%(11/75) stopped due to lack of ongoing insurance approval, only one patient stopped due to adverse effects (1.3%). One patient had clinically significant breakthrough (1.3%) that was successfully managed with VGC. Incidence of post prophylaxis CMV was 40%. CONCLUSION: Withholding of VGC with LTV conversion may improve leukopenia without need for additional supportive measures. Most importantly, this strategy avoided additional mycophenolate modifications. In our study, LTV was associated with low rates of breakthrough. Post-prophylaxis CMV was similar to VGC prophylaxis.

Identification of PROK2 gene polymorphisms as predictors of methamphetamine use disorder risk and indicators of craving scale in the Chinese Han population.

Background: Methamphetamine use disorder (MUD) has become a global problem due to the highly addictive nature of methamphetamine. Earlier research have demonstrated that PROK2 functions as a compensatory and protective response against neurotoxic stress by stimulating astrocyte reactivity. The aim of our study was to evaluate the correlation between the PROK2 gene and both MUD risk susceptibility and craving scale in the Chinese Han population. Methods: A total of 5,282 participants (1,796 MUD patients and 3,486 controls) were recruited. Seven tag SNPs of the PROK2 gene were chosen and genotyped in the samples. Genetic association analyses were performed to capture the significant SNPs. To investigate the relationship between PROK2 levels and craving scores with the associated-SNP genotypes, we conducted a linear model. Results: SNP rs75433452 was significantly linked with MUD risk (p-value = 1.54 × 10-8), with the A allele being positively correlated with an increased risk of MUD. Moreover, the average serum level of PROK2 decreased when more copies of the A allele were presented in both MUD patients (p-value = 4.57 × 10-6) and controls (p-value = 1.13 × 10-5). Furthermore, the genotypes of SNP rs75433452 were strongly correlated with the craving scores in MUD patients (p-value = 4.05 × 10-4). Conclusion: Our study identified a significant association signal of the PROK2 gene with MUD risk susceptibility and methamphetamine craving scores in the Chinese Han population, providing potential valuable insights into the underlying mechanisms of METH dependence.

The collaborative study on the genetics of alcoholism: Genetics.

This review describes the genetic approaches and results from the family-based Collaborative Study on the Genetics of Alcoholism (COGA). COGA was designed during the linkage era to identify genes affecting the risk for alcohol use disorder (AUD) and related problems, and was among the first AUD-focused studies to subsequently adopt a genome-wide association (GWAS) approach. COGA's family-based structure, multimodal assessment with gold-standard clinical and neurophysiological data, and the availability of prospective longitudinal phenotyping continues to provide insights into the etiology of AUD and related disorders. These include investigations of genetic risk and trajectories of substance use and use disorders, phenome-wide association studies of loci of interest, and investigations of pleiotropy, social genomics, genetic nurture, and within-family comparisons. COGA is one of the few AUD genetics projects that includes a substantial number of participants of African ancestry. The sharing of data and biospecimens has been a cornerstone of the COGA project, and COGA is a key contributor to large-scale GWAS consortia. COGA's wealth of publicly available genetic and extensive phenotyping data continues to provide a unique and adaptable resource for our understanding of the genetic etiology of AUD and related traits.

The soybean immune receptor GmBIR1 regulates host transcriptome, spliceome, and immunity during cyst nematode infection.

BAK1-INTERACTING RECEPTOR LIKE KINASE1 (BIR1) is a negative regulator of various aspects of disease resistance and immune responses. Here, we investigated the functional role of soybean (Glycine max) BIR1 (GmBIR1) during soybean interaction with soybean cyst nematode (SCN, Heterodera glycines) and the molecular mechanism through which GmBIR1 regulates plant immunity. Overexpression of wild-type variant of GmBIR1 (WT-GmBIR1) using transgenic soybean hairy roots significantly increased soybean susceptibility to SCN, whereas overexpression of kinase-dead variant (KD-GmBIR1) significantly increased plant resistance. Transcriptome analysis revealed that genes oppositely regulated in WT-GmBIR1 and KD-GmBIR1 upon SCN infection were enriched primarily in defense and immunity-related functions. Quantitative phosphoproteomic analysis identified 208 proteins as putative substrates of the GmBIR1 signaling pathway, 114 of which were differentially phosphorylated upon SCN infection. In addition, the phosphoproteomic data pointed to a role of the GmBIR1 signaling pathway in regulating alternative pre-mRNA splicing. Genome-wide analysis of splicing events provided compelling evidence supporting a role of the GmBIR1 signaling pathway in establishing alternative splicing during SCN infection. Our results provide novel mechanistic insights into the function of the GmBIR1 signaling pathway in regulating soybean transcriptome and spliceome via differential phosphorylation of splicing factors and regulation of splicing events of pre-mRNA decay- and spliceosome-related genes.

Community perceptions of vaccine advocacy for children under five in rural Guatemala.

Historically, partnerships with community leaders (e.g., religious leaders, teachers) have been critical to building vaccination confidence, but leaders may be increasingly vaccine hesitant. In rural Guatemala, the extent of vaccine hesitancy among community leaders is unclear, as are their perceptions of advocacy for childhood vaccines. We sought to: (i) compare Guatemalan religious leaders' and community leaders' attitudes toward childhood vaccines, (ii) describe leaders' experiences and comfort with vaccination advocacy, and (iii) describe community members' trust in them as vaccination advocates. In 2019, we surveyed religious leaders, other community leaders, and parents of children under five in rural Guatemala. We recorded participant demographic information and assessed participant vaccine hesitancy regarding childhood vaccines. We analyzed data descriptively and via adjusted regression modeling. Our sample included 50 religious leaders, 50 community leaders, and 150 community members (response rate: 99%); 14% of religious leaders and community leaders were vaccine hesitant, similar to community members (P = 0.71). In the prior year, 47% of leaders had spoken about vaccines in their formal role; 85% felt responsible to do so. Only 28% of parents trusted politicians "a lot" for vaccine advice, versus doctors (72%; P < 0.01), nurses (62%; P < 0.01), religious leaders (49%; P < 0.01), and teachers (48%; P < 0.01). In this study, religious leaders and community leaders were willing but incompletely engaged vaccination advocates. Most community members trusted doctors and nurses a lot for vaccination advice; half trusted teachers and religious leaders similarly. Public health officials in rural Guatemala can complement efforts by doctors and nurses through partnerships with teachers and religious leaders to increase vaccination confidence and delivery.