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Tenofovir disoproxil fumarate (TDF) is increasingly used in the highly active antiretroviral therapy (HAART) regimens of pregnant women, but limited data exist on the pregnancy pharmacokinetics of chronically dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum. Methods: International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P1026s is a prospective, nonblinded pharmacokinetic study of HIV-infected pregnant women that included a cohort receiving 300mg TDF once daily. Steady-state 24-hour pharmacokinetic profiles were measured at the second and third trimesters, postpartum, and in maternal and umbilical cord samples collected at delivery. Tenofovir was measured by liquid chromatography-mass spectrometry (LC-MS). The target area under the concentration versus time curve from time 0 to 24h post dose (AUC) was ≥1.99μg h/mL (nonpregnant historical control 10th percentile). Results: The median tenofovir AUC was decreased during the second (1.9μg h/mL) and third (2.4μg h/mL; P=0.005) trimesters versus postpartum (3.0μg h/mL). Tenofovir AUC exceeded the target for two of four women (50%) in the second trimester, 27 of 37 women [73%; 95% confidence interval (CI) 56%, 86%] in the third trimester, and 27 of 32 women (84%; 95% CI 67%, 95%) postpartum (P>0.05). Median second/third-trimester troughs were lower (39/54ng/mL) than postpartum (61ng/mL). Median third-trimester weight was greater for subjects below the target AUC versus those above the target (97.9 versus 74.2kg, respectively; P=0.006). The median ratio of cord blood to maternal concentrations was 0.88. No infants were HIV infected. Conclusions: This study found lower tenofovir AUC and troughs during pregnancy. Transplacental passage with chronic TDF use during pregnancy was high. Standard TDF doses appear to be appropriate for most HIV-infected pregnant women but therapeutic drug monitoring with dose adjustment should be considered in pregnant women with high weight (>90kg) or inadequate HIV RNA response.

Yellow nutsedge (Cyperus esculentus) is a troublesome weed in Switzerland. It reproduces mainly by tubers, but also by seeds. Dormant tubers in the soil cannot be controlled with herbicides. Pigs are known to reduce yellow nutsedge infestation levels by rooting up and consuming tubers. We hypothesized, that old pig breeds would especially be suited for yellow nutsedge control, as they search more actively for feed in the soil than modern pig breeds. A field trial with old pig breeds (Turopolje and Mangalica) was carried out in a field infested with yellow nutsedge (2019-2020). The pigs stayed in the field for 8 months. Infestation levels were determined before and after the trial by counting C. esculentus plants at 50 monitoring sites in the field. In addition, soil samples were taken before and after the experiment. The samples were placed in the greenhouse and emerging yellow nutsedge shoots were considered as a measure of the tuber bank in the soil. After 8 months of pig grazing in the field, we observed significantly less yellow nutsedge plants at the monitoring sites. Yellow nutsedge infestation levels i.e. the tuber bank was significantly reduced by 90%. This reduction is higher than the ones achieved in previous experiments and reported in the literature. Grazing of old pig breeds could be a non-chemical and an appealing approach for the public to considerably reduce yellow nutsedge infestation levels in affected fields.

Erdmandelgras (Cyperus esculentus) stellt ein großes Problem im Schweizer Gemüse- und Ackerbau dar. Mit dem Ziel, stark verseuchte Flächen zu sanieren, wurden an vier Standorten 3-jährige Schwarzbrache Streifenversuche (2018 bis 2020) auf landwirtschaftlichen Betrieben durchgeführt. Dabei wurden vier Versuchsvarianten verglichen: A. Wiederholte Bodenbearbeitung (BB), B. Wiederholte BB + einmalige Einarbeitung von Dual Gold (2 l/ha), C. Wiederholte BB + einmalige Anwendung von Equip Power (1,5 l/ha), D. Wiederholte BB + einmalige Anwendung von Monitor (25 g/ha). Die Landwirte konnten selbst auswählen, welche Geräte sie zur BB verwenden. Zur Bewertung der Wirkung wurden die Knöllchenzahlen pro Liter Erde zu Beginn des Versuchs (Ende 2017), nach einem Jahr Schwarzbrache (Ende 2018) und nach drei Jahren Schwarzbrache (Ende 2020) bestimmt. Nach drei Jahren Schwarzbrache gingen die Knöllchenzahlen auf allen vier Betrieben um durchschnittlich 75 % zurück. Es konnten keine statistisch signifikanten Unterschiede zwischen den Versuchsvarianten nachgewiesen werden, d.h. der Einsatz der Herbizide brachte keinen Zusatznutzen für die Reduzierung der Knöllchenzahl im Boden unter diesen Versuchsbedingungen.

In onions (Allium cepa) few herbicides are registered. Due to their erect leaf and plant structure, onions retain less herbicide after spraying than broadleaved weeds. Further, onion plants have a thicker plant cuticle. These differences allow a selective use of pelargonic acid in onions. The main aim of this study was to determine the selective dose at different crop growth stages. Five field trials were carried out. Three pelargonic acid containing products (1 SL- and 2 EC-formulations) were applied with a logarithmic sprayer. Dose range was 0 to 56 kg active substance (a.s.) ha-1. The growth stage varied between BBCH 10 and 16. Selectivity was rated visually. The products were selective at 7.2 and 8.3 kg a.s. ha-1 (BBCH 10-11), 6.1 and 8.9 kg a.s. ha-1 (BBCH 11-12), 8.5 and 20.7 kg a.s. ha-1 (BBCH 13) and 6.3 and 9.0 kg a.s. ha-1 (BBCH 14-16) for the SL- and EC-products respectively. Selectivity depended on growth stage and weather conditions. Important for selectivity is an intact cuticle, a rain-free, light-intense period before application. Pelargonic acid could become a component for sustainable weed control in onions. Due to its foliar activity, small weeds need to be targeted and several passes are required.

Yellow nutsedge (Cyperus esculentus) is a troublesome weed. It reproduces and spreads mainly via tubers, but also viable seeds are produced. The seeds are very small and have little resources stored. The seedlings are very fragile and look like grasses (poaceae). We hypothesized that C. esculentus plants originating from seeds are more susceptible to herbicides than plants originating from tubers. Cyperus esculentus plants grown from seeds in the greenhouse were treated with glyphosate, bentazone, bromoxynil, pelargonic acid and clethodim. Herbicide efficacy was rated and produced tubers were counted. None of the treatments achieved full control. Four weeks after application a growth reduction of 84% was observed in the glyphosate treatment, whereas bentazone reduced growth by 34% compared to the control. In the other treatments, growth reduction was < 15%. In the glyphosate and bentazone treatment, considerably fewer tubers were produced than in the control. Concluding, we could not confirm our hypothesis. Already 6 weeks after germination seedlings were well developed, tolerant to the sprayed herbicides, except for glyphosate and bentazone, and produced tubers. This implies, that already after a short time Cyperus esculentus stands originating from seeds pose the same problems as the ones originating from tubers.

This short essay reviews a specific aspect of Ennio Morricone’s work as a film music composer. The review is of personal character and analyses the expectation of the composer as a projection of the social conditions he lived in. The review invites controversial discussions and may show some ideas of the way how purposeful research can turn into culturally contributing subjectivity.

BackgroundIn the United States, there are lower rates of breastfeeding among African American mothers, particularly those who are younger women. Recent epidemiological studies have shown a strong association of more aggressive types of breast cancer (estrogen receptor negative) among African American women, with a higher risk in African American women who did not breastfeed their children. ObjectiveThis study aims to describe the process evaluation of recruitment and educational strategies to engage pregnant African American participants for a pilot study designed to determine whether social media messaging about breast cancer risk reduction through breastfeeding may positively influence breastfeeding rates. MethodsThis pilot study is conducted in collaboration with a local Women, Infants, and Children (WIC) organization and hospital and prenatal clinics of a local health care network. To engage African American women to enroll in the study, several methods and monitoring processes were explored, including WIC electronic text-based messages sent out to all phones of current WIC recipients (referred to as e-blasts); keyword responses to texts from flyers and posters in local community-based organizations, hospitals, and prenatal clinics; keyword responses using electronic links posted in established Facebook groups; and snowball recruitment of other pregnant women by current participants through Facebook. Once enrolled, participants were randomized to 2 study conditions: (1) an intervention group receiving messages about breast cancer risk reduction and breastfeeding or (2) a control group receiving breastfeeding-only messages. Data were obtained through electronic monitoring, SurveyMonkey, qualitative responses on Facebook, focus groups, and interviews. ResultsMore than 3000 text messages were sent and received through WIC e-blasts and keyword responses from flyers. A total of 472 women were recruited through WIC e-blast, and 161 responded to flyers and contacts through the local health care network, community-based organizations, Facebook, and friend referrals. A total of 633 women were assessed for eligibility to participate in the study. A total of 288 pregnant African American women were enrolled, consented, and completed presurvey assessments (102.8% of the goal), and 22 participants attended focus groups or interviews reporting on their experiences with Facebook and the educational messages. ConclusionsThis process evaluation suggests that using electronic, smartphone apps with social media holds promise for both recruitment and conduct of health education intervention studies for pregnant African American women. Providing messaging and resources through social media to reinforce and educate women about breastfeeding and potentially provide lactation support is intriguing. Convenience (for researchers and participants) is an attribute of social media for this demographic of women and worthy of further research as an educational tool. Trial RegistrationClinicalTrials.gov NCT03680235; https://clinicaltrials.gov/ct2/show/NCT03680235

The practice of parents and their young children co-sleeping is a topic of ongoing controversy and debate. Both physical and psychosocial risks and benefits have been attached to this practice. In this introduction to the special issue, we present the prevailing views about early sleep arrangements. We then discuss the organization of the special issue and highlight the contributions of each article. Together, this collection of original articles comprises a body of research that advances our understanding of co-sleeping in the context of social and physical environments. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

As chronic obesity in the United States increases to epidemic proportions, the need for sonography waiting areas and examination rooms to provide sufficient support for obese patients also increases. The purpose of the present study is to determine if these facilities are making the necessary changes to accommodate obese patients. Data were collected from 20 sonography facilities regarding the size of patient gowns, blood pressure cuffs, and size and weight tolerances of examination tables and waiting room chairs. The data were then compared to sizes that accommodate obese patients comfortably. Results show that sonography facilities are not accommodating obese patients. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: To determine whether there is a scientific basis for the routine use of contrast-enhanced computed tomography (CECT) in the evaluation of suspected deep neck infection (DNI). Study Design: We conducted a prospective, blinded comparison of clinical examination and CECT in DNI. Methods: Thirty-five consecutive patients with suspected DNI were prospectively assessed by clinical examination and CECT for the presence and extent of surgically drainable purulent collections. Before CECT a surgeon recorded clinical data and predicted the extent of infection. A head and neck neuroradiologist, blinded to the clinical evaluation, predicted the extent of infection based on CECT. Final outcome (the presence of a purulent collection) was determined at surgery or in long-term follow-up. The clinical and CECT findings were compared with the final outcome to determine the sensitivity, specificity, and accuracy of each modality. Results: Twenty patients had purulent drainable collections. The accuracy of clinical examination alone in identifying a drainable collection was 63%, the sensitivity was 55%, and the specificity was 73%. The accuracy of CECT alone was 77%, the sensitivity was 95%, and the specificity 53%. When CECT and clinical examination were combined, the accuracy in identifying a drainable collection was 89%, the sensitivity was 95%, and the specificity 80%. If fluid collections with volumes of 2 mL or greater on CECT were considered, the accuracy of CECT would have been 85%, the sensitivity 89%, and the specificity 80%. Conclusion: CECT and clinical examination are both critical components in the evaluation of suspected DNI. [ABSTRACT FROM AUTHOR]

Cyperus esculentus L. causes high yield losses in many crops worldwide. In Switzerland it was observed for the first time about 30 years ago. Since then it has become a serious weed in several regions - especially where vegetables are produced. Growing vegetables in heavily infested fields should be abandoned due to their low competitiveness and the lack of available, effective herbicides. Contrarily, in maize several herbicides with a partial effect on C. esculentus are registered. Thus, continuous cultivation of maize including the use of the most effective herbicides against C. esculentus could help reducing infestation levels in heavily infested fields. Field trials were carried out at two sites in maize during 2011 and 2012. Different herbicide combinations, hoeing and herbicide applications combined with hoeing were the applied treatments. Split application was compared with one single application of the same amount of product. The effect of an additional, late under leaf herbicide application was determined as well. Cyperus esculentus coverage was estimated in the fields in 2011. Plots were sampled in spring 2011, autumn 2011 and autumn 2012. The Number of C. esculentus sprouts germinated from the soil samples was determined under greenhouse conditions. The most effective herbicide combination of registered active ingredients was rimsulfuron and mesotrione. Smetolachlor was effective as well, especially if combined with mechanical weed control. Halosulfuron-methyl applied twice provided the best C. esculentus control. Split application tended to be more effective than a single application. Control of C. esculentus could be improved considerably with an additional herbicide application in late June (under leaf). The treatments with highest C. esculentus control determined in the field trials and combinations thereof are effective treatment options for C. esculentus control in maize. These findings indicate and confirm that maize cropped for several years with intensive weed control could successfully decrease C. esculentus infestation levels in farmers’ fields.

In spring 2011, two field trials on site-specific weed control in winter wheat and maize were carried out at Ihinger Hof research station of the University of Hohenheim. For the image acquisition, bi-spectral cameras were mounted on a vehicle. These cameras are able to take images free from disturbances by soil, mulch and stones. Images and the corresponding GPS-data were stored on-the-go. Afterwards, the images were analyzed by a weed recognition software. Weed infestation was mapped in consideration of weed species and weeds grouped according to their herbicide sensitivity. In order to simulate an online herbicide application, a onesided moving average of order five was used for the weed mapping. This kind of rearward calculation uses only the data of weed infestation which were already assessed behind or directly in the current position of the vehicle. The calculated weed distribution maps were checked by visual grid sampling. Herbicide application maps were generated by applying weed thresholds on the weed distribution maps. The herbicide application based on the maps was conducted by a multiple sprayer which allows the application of up to three herbicides independently from each other in a single pass across the field. Later on, the performance of the herbicide application was controlled again by visual grid sampling. Compared to a uniform herbicide application, the sitespecific weed control saved 83 % and 58 % herbicides respectively in winter wheat and 66 % in maize. The average efficacy of the site-specific herbicide application system in winter wheat was 70 % of the conventional herbicide application.

Rare donor programs are critically important for those patients with rare phenotypes who have produced the associated alloantibodies that necessitate the provision of rare blood components. We describe the American Rare Donor Program (ARDP) and its establishment, members, and policies. The specific phenotypes meeting the ARDP criteria for inclusion are described. Data on the number of rare donors registered by year, and the number of requests for rare blood components received and fulfilled over the 25 years of the program (1998-2023) are provided, along with a description of some notable cases and discussion of how the program supports patients with sickle cell disease., (© 2024 Margaret A. Keller et al., published by Sciendo.)

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is considered multifactorial with a number of predisposing gene polymorphisms known., Methods: The occurrence of MASLD in 7 and 10 year old siblings, one without classical risk factors and one with type 2 diabetes suggested a monogenic etiology and prompted next-generation sequencing. Exome sequencing was performed in the proband, both parents and both siblings. The impact of a likely disease-causing DNA variant was assessed on the transcript and protein level., Results: Two siblings have hepatomegaly, elevated serum transaminase activity, and steatosis and harbor a homozygous DECR1 splice-site variant, c.330+3A>T. The variant caused DECR1 transcript decay. Immunostaining demonstrated lack of DECR1 in patient liver., Conclusions: These patients may represent the first individuals with DECR1 deficiency, then defining within MASLD an autosomal-recessive entity, well corresponding to the reported steatotic liver disease in Decr1 knockout mice. DECR1 may need to be considered in the genetic work-up of MASLD., (© 2024. The Author(s).)

Many parasitoids alter their reproductive behaviour in response to the quality of encountered hosts. They make adaptive decisions concerning whether to parasitise a potential host, the number of eggs laid on an accepted host, and the allocation of sex to their offspring. Here we present evidence that Goniozus jacintae Farrugia (Hymenoptera: Bethylidae), a gregarious ectoparasitoid of larval tortricids, adjusts its reproductive response to the size and developmental stage of larvae of the light brown apple moth (LBAM), Epiphyas postvittana (Walker) (Lepidoptera: Tortricidae). Goniozus jacintae parasitises instars 3-6 of LBAM, but most readily parasitises the later, larger, instars. Brood sizes were bigger on larger hosts and brood sex ratios were female biased (proportion of males = 0.23) with extremely low variance (never >1 male in a brood at emergence), perhaps the most precise of all studied bethylids. Host size did not influence brood development time, which averaged 19.64 days, or the body size of male offspring. However, the size of females was positively correlated with host size and negatively correlated with brood size. The sizes of individual males and females were positively related to the average amount of host resource available to individuals within each brood, suggesting that adult body size is affected by scramble competition among feeding larvae. Average brood sizes were: 3rd instar host, 1.3 (SE ± 0.075); 4th instar, 2.8 (SE ± 0.18); 5th instar, 4.7 (SE ± 0.23); 6th instar, 5.4 (SE ± 0.28). The largest brood size observed was 8 individuals (7 females, 1 male) on the 6th instar of LBAM. These results suggest that later instars would give the highest yield to optimise mass-rearing of G. jacintae if used for augmentative biological pest control.

This case report showcases an extraordinary collaboration to support the transfusion needs of a patient with a rare phenotype and long-standing anemia due to gastrointestinal bleeding. This report describes the Immunohematology Reference Laboratory testing and logistics of rare blood provision over an 11-year period, as well as a summary of the hematologic, gastroenterologic, and surgical interventions. This case illustrates how a strong collaboration among the clinical team, laboratory, blood center, and the rare donor community facilitated successful management of this patient's anemia until the patient could receive life-changing treatment., (© 2024 Gavin Patch et al., published by Sciendo.)

This extraordinary case showcases the identification of a rare anti-En a specificity that was assisted by DNA-based red blood cell antigen typing and collaboration between the hospital blood bank in the United States, the home blood center in Qatar, the blood center Immunohematology Reference Laboratory, as well as the American Rare Donor Program (ARDP) and the International Society for Blood Transfusion (ISBT) International Rare Donor Panel. En a is a high-prevalence antigen, and blood samples from over 200 individuals of the extended family in Qatar were crossmatched against the patient's plasma with one compatible En(a-) individual identified. The ISBT International Rare Donor Panel identified an additional donor in Canada, resulting in a total of two En(a-) individuals available to donate blood for the patient., (© 2024 Stella T. Chou et al., published by Sciendo.)

Importance: For their proliferation within red blood cells, malaria parasites depend on a functional electron transport chain (ETC) within their mitochondrion, which is the target of several antimalarial drugs. Here, we have used gene disruption to identify a patatin-like phospholipase, Pf PNPLA2, as important for parasite replication and mitochondrial function in Plasmodium falciparum . Parasites lacking Pf PNPLA2 show defects in their ETC and become hypersensitive to mitochondrion-targeting drugs. Furthermore, Pf PNPLA2-deficient parasites show differences in the composition of their cardiolipins, a unique class of phospholipids with key roles in mitochondrial functions. Finally, we demonstrate that parasites devoid of Pf PNPLA2 have a defect in gametocyte maturation, underlining the importance of a functional ETC for parasite transmission to the mosquito vector., Competing Interests: The authors declare no conflict of interest.

A person who has achieved the Specialist in Blood Banking (SBB) certification is a medical laboratory scientist who receives advanced training in blood banking and transfusion medicine and has passed an examination given by the American Society for Clinical Pathology. There are several pathways or "eligibility routes" to qualify for the examination to obtain SBB certification, with the most common route involving enrollment in a Commission on Accreditation of Allied Health Education Programs-accredited SBB program. The goal of this study was to compile information about the current accredited SBB programs in the United States and SBB exam statistics for purposes of assessing changes in the programs and detecting trends in SBB exam takers and pass rates. SBB program coordinators were surveyed about qualitative and quantitative aspects of their programs. Current data, changes over time, and nationally available data were tabulated for comparison. This information may be helpful for all medical laboratory scientists interested in considering further studies and certification in blood banking and transfusion medicine., (© 2023 G.M. Meny et al., published by Sciendo.)

The anti-apoptotic function of Bcl-xL in the heart during ischemia/reperfusion is diminished by K-Ras-Mst1-mediated phosphorylation of Ser14, which allows dissociation of Bcl-xL from Bax and promotes cardiomyocyte death. Here we show that Ser14 phosphorylation of Bcl-xL is also promoted by hemodynamic stress in the heart, through the H-Ras-ERK pathway. Bcl-xL Ser14 phosphorylation-resistant knock-in male mice develop less cardiac hypertrophy and exhibit contractile dysfunction and increased mortality during acute pressure overload. Bcl-xL Ser14 phosphorylation enhances the Ca2+ transient by blocking the inhibitory interaction between Bcl-xL and IP3Rs, thereby promoting Ca2+ release and activation of the calcineurin-NFAT pathway, a Ca2+-dependent mechanism that promotes cardiac hypertrophy. These results suggest that phosphorylation of Bcl-xL at Ser14 in response to acute pressure overload plays an essential role in mediating compensatory hypertrophy by inducing the release of Bcl-xL from IP3Rs, alleviating the negative constraint of Bcl-xL upon the IP3R-NFAT pathway., (© 2023. Springer Nature Limited.)

Purpose: Open science is a collection of practices that seek to improve the accessibility, transparency, and replicability of science. Although these practices have garnered interest in related fields, it remains unclear whether open science practices have been adopted in the field of communication sciences and disorders (CSD). This study aimed to survey the knowledge, implementation, and perceived benefits and barriers of open science practices in CSD., Method: An online survey was disseminated to researchers in the United States actively engaged in CSD research. Four-core open science practices were examined: preregistration , self-archiving , gold open access , and open data. Data were analyzed using descriptive statistics and regression models., Results: Two hundred twenty-two participants met the inclusion criteria. Most participants were doctoral students (38%) or assistant professors (24%) at R1 institutions (58%). Participants reported low knowledge of preregistration and gold open access. There was, however, a high level of desire to learn more for all practices. Implementation of open science practices was also low, most notably for preregistration, gold open access, and open data (< 25%). Predictors of knowledge and participation, as well as perceived barriers to implementation, are discussed., Conclusion: Although participation in open science appears low in the field of CSD, participants expressed a strong desire to learn more in order to engage in these practices in the future. Supplemental Material and Open Science Form: https://doi.org/10.23641/asha.21569040.

Alkylglycerol monooxygenase (AGMO) and plasmanylethanolamine desaturase (PEDS1) are enzymes involved in ether lipid metabolism. While AGMO degrades plasmanyl lipids by oxidative cleavage of the ether bond, PEDS1 exclusively synthesizes a specific subclass of ether lipids, the plasmalogens, by introducing a vinyl ether double bond into plasmanylethanolamine phospholipids. Ether lipids are characterized by an ether linkage at the sn-1 position of the glycerol backbone and they are found in membranes of different cell types. Decreased plasmalogen levels have been associated with neurological diseases like Alzheimer's disease. Agmo-deficient mice do not present an obvious phenotype under unchallenged conditions. In contrast, Peds1 knockout mice display a growth phenotype. To investigate the molecular consequences of Agmo and Peds1 deficiency on the mouse lipidome, five tissues from each mouse model were isolated and subjected to high resolution mass spectrometry allowing the characterization of up to 2013 lipid species from 42 lipid subclasses. Agmo knockout mice moderately accumulated plasmanyl and plasmenyl lipid species. Peds1-deficient mice manifested striking changes characterized by a strong reduction of plasmenyl lipids and a concomitant massive accumulation of plasmanyl lipids resulting in increased total ether lipid levels in the analyzed tissues except for the class of phosphatidylethanolamines where total levels remained remarkably constant also in Peds1 knockout mice. The rate-limiting enzyme in ether lipid metabolism, FAR1, was not upregulated in Peds1-deficient mice, indicating that the selective loss of plasmalogens is not sufficient to activate the feedback mechanism observed in total ether lipid deficiency., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

BCL-2-like protein 1 (BCL2L1) is a key component of cell survival and death mechanisms. Its dysregulation and altered ratio of splicing variants associate with pathologies. However, isoform-specific loss-of-function analysis of BCL2L1 remains unexplored. Here we show the functional impact of genetically inhibiting Bcl-x short-isoform (Bcl-xS) in vivo . Bcl-xS is expressed in most tissues with predominant expression in the spleen and blood cells in mice. Bcl-xS knockout (KO) mice show no overt abnormality until 3 months of age. Thereafter, KO mice develop cardiac hypertrophy with contractile dysfunction and splenomegaly by 6 months. Cardiac fibrosis significantly increases in KO, but the frequency of apoptosis is indistinguishable despite cardiomyopathy. The Akt/mTOR and JNK/cJun signaling are upregulated in male KO heart, and the JNK/cJun is activated with increased Bax expression in KO spleen. These results suggest that Bcl-xS may be dispensable for development but is essential for maintaining the homeostasis of multiple organs., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Advances in reproductive health technologies such as noninvasive prenatal testing (NIPT) are changing the landscape of prenatal care and maternal health. NIPT, made clinically available in the United States (US) in 2011, is a screening test that utilizes cell-free DNA (cfDNA) to detect for aneuploidies and genetic characteristics in fetal DNA. In September 2020, the American College of Obstetricians and Gynecologists (ACOG) recommended NIPT for all pregnant patients regardless of age or risk factors. We examined peer-reviewed, empirical studies published from January 2011 to February 2022, assessing NIPT studies with patient perspectives in the US and what is known about how empirical studies include Black women. Our scoping review draws from PubMed (with advanced MeSH search options) and Scopus databases for advanced scoping review, with 33 articles meeting our criteria. Empirical studies on NIPT show patient perceptions range across five themes: 1) accuracy / safety, 2) return of results, 3) patient knowledge, 4) informed consent, and 5) perceptions among minoritized groups (with perceptions of race and gender as a social demographic intersection). Additionally, among the 15 studies that included that Black woman in their study sample, none measured the perceptions of Black women with genetic conditions. Bridging this knowledge gap is critical because NIPT is becoming increasingly accessible across the nation and is being developed to screen for additional genetic conditions, such as sickle cell disease. Ultimately, NIPT researchers need to go to greater lengths to examine the patient perspectives of Black women with and without genetic conditions., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Long-term disease control in multiple myeloma (MM) is typically an unmet medical need, and most patients experience multiple relapses. Fluorescence in situ hybridization (FISH) is the standard technique to detect chromosomal abnormalities (CAs), which are important to estimate the prognosis of MM and the allocation of risk adapted therapies. In advanced stages, the importance of CAs needs further investigation. From 148 MM patients, two or more paired samples, at least one of which was collected at relapse, were analyzed by FISH. Using targeted next-generation sequencing, we molecularly investigated samples harboring relapse-associated CAs. Sixty-one percent of the patients showed a change in the cytogenetic profile during the disease course, including 10% who acquired high-risk cytogenetics. Amp(1q) (≥4 copies of 1q21), driven by an additional increase in copy number in patients who already had 3 copies of 1q21, was the most common acquired CA with 16% affected patients. Tetraploidy, found in 10% of the samples collected at the last time-point, was unstable over the course of the disease and was associated with TP53 lesions. Our results indicate that cytogenetic progression is common in relapsed patients. The relatively high frequency of amp(1q) suggests an active role for this CA in disease progression., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

On the basis of findings that cultured rat hepatocytes secrete lipoprotein with a high plasmalogen content and the occurrence of this lipid in human serum, it has been suggested that hepatocytes play a role in the supply of plasmalogens to tissues. We tested this hypothesis in a mouse with a hepatocyte-specific defect in peroxisomes, an organelle essentially required for plasmalogen biosynthesis. We analyzed plasmalogens in lipid extracts of forebrain, liver and five further tissues and in plasma by reaction with dansylhydrazine in hydrochloric acid, which cleaves the vinyl ether of plasmalogens and forms a fluorescent dansylhydrazone, which we quantified by reversed phase high performance liquid chromatography. Reaction with dansylhydrazine in acetic acid was used to quantify free aldehydes as a control. Our results show normal levels of plasmalogens in plasma and in all tissues examined, including forebrain and the liver, irrespective of the inactivation of hepatic peroxisomes. None of the selected ether lipids analyzed by mass spectrometry in plasma and liver was decreased in the mice deficient in liver peroxisomes. In contrast, we found three plasmenylcholine species which were even significantly increased in the livers of these animals. Quantification of mRNA expression of plasmalogen biosynthetic enzymes revealed particularly low expression of fatty acyl-CoA reductase, the key regulatory enzyme of plasmalogen biosynthesis, in liver, with and without hepatic peroxisome deficiency. Our results do not support the suggested role of hepatocytes in supplying plasmalogens to tissues., Competing Interests: Declarations of interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Under the ISBT, the Working Party (WP) for Red Cell Immunogenetics and Blood Group Terminology is charged with ratifying blood group systems, antigens and alleles. This report presents the outcomes from four WP business meetings, one located in Basel in 2019 and three held as virtual meetings during the COVID-19 pandemic in 2020 and 2021., Materials and Methods: As in previous meetings, matters pertaining to blood group antigen nomenclature were discussed. New blood group systems and antigens were approved and named according to the serologic, genetic, biochemical and cell biological evidence presented., Results: Seven new blood group systems, KANNO (defined numerically as ISBT 037), SID (038), CTL2 (039), PEL (040), MAM (041), EMM (042) and ABCC1 (043) were ratified. Two (039 and 043) were de novo discoveries, and the remainder comprised reported antigens where the causal genes were previously unknown. A further 15 blood group antigens were added to the existing blood group systems: MNS (002), RH (004), LU (005), DI (010), SC (013), GE (020), KN (022), JMH (026) and RHAG (030)., Conclusion: The ISBT now recognizes 378 antigens, of which 345 are clustered within 43 blood group systems while 33 still have an unknown genetic basis. The ongoing discovery of new blood group systems and antigens underscores the diverse and complex biology of the red cell membrane. The WP continues to update the blood group antigen tables and the allele nomenclature tables. These can be found on the ISBT website (http://www.isbtweb.org/working-parties/red-cell-immunogenetics-and-blood-group-terminology/)., (© 2022 International Society of Blood Transfusion.)

Multifunctional proteins are challenging as it can be difficult to confirm pathomechanisms associated with disease-causing genetic variants. The human 17β-hydroxysteroid dehydrogenase 10 (HSD10) is a moonlighting enzyme with at least two structurally and catalytically unrelated functions. HSD10 disease was originally described as a disorder of isoleucine metabolism, but the clinical manifestations were subsequently shown to be linked to impaired mtDNA transcript processing due to deficient function of HSD10 in the mtRNase P complex. A surprisingly large number of other, mostly enzymatic and potentially clinically relevant functions have been attributed to HSD10. Recently, HSD10 was reported to exhibit phospholipase C-like activity towards cardiolipins (CL), important mitochondrial phospholipids. To assess the physiological role of the proposed CL-cleaving function, we studied CL architectures in living cells and patient fibroblasts in different genetic backgrounds and lipid environments using our well-established LC-MS/MS cardiolipidomic pipeline. These experiments revealed no measurable effect on CLs, indicating that HSD10 does not have a physiologically relevant function towards CL metabolism. Evolutionary constraints could explain the broad range of reported substrates for HSD10 in vitro. The combination of an essential structural with a non-essential enzymatic function in the same protein could direct the evolutionary trajectory towards improvement of the former, thereby increasing the flexibility of the binding pocket, which is consistent with the results presented here., (© 2022. The Author(s).)

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

The importance of identifying variant alleles among blood donors is significant to the safety of transfusion for recipients. Molecular methods have become more prominent in the routine process of antigen typing donor units. Some variant antigens cannot be detected using only serologic methods. Molecular testing allows the determination of nucleotide sequences that are used to predict a phenotype. Antigens of the Kell blood group system are known for being highly immunogenic and causing adverse reactions upon antibody formation. A female white blood donor who typed Kp(b-) using serologic methods on multiple donations since 2005 was the subject of a typing discrepancy investigation. Routine genotyping using a commercial genotyping kit (HemoID DQS Panel; Agena Bioscience, San Diego, CA) predicted the donor to type Kp(a+b+). Investigation of the discrepancy between these two results identified a rare single nucleotide variant in the KEL gene at nucleotide position c.948G>T that alters amino acid residue 316 from tryptophan (Trp) to cysteine (Cys). After discovery of the novel allele, adsorption and elution studies were performed to see if there was weakened Kp b expression. The elution studies yielded negative results, which indicated that Kp b is not expressed. The KEL transcripts expressed by the donor were determined using cDNA analysis, and the predicted amino acid sequence of the novel allele was modeled to investigate the impact of the amino acid sequence on the structure of the KEL polypeptide. Both SWISS-MODEL and Robetta software were used to evaluate the impact of the p.Trp316Cys on the three-dimensional protein structure. There was no conformational change noted with SWISS-MODEL, whereas the Robetta software showed a significant conformational change compared with the normal Kp(b+) reference sequence. Because the donor is homozygous for variants associated with k and Js b expression, it was not possible to determine whether the novel allele is associated with loss of Kp b only or loss of all Kell antigens., (© 2022 S. Yearout et al., published by Sciendo.)

Description Disability is extremely common in the United States with 26% of adults identifying as having some type of disability. Oftentimes, people with disabilities need to access health care services frequently in order to receive adequate care and support. However, despite this need, medical students receive limited, if any, education about people with disabilities and how to appropriately provide medical care and interact with them. This lack of education exacerbates health care disparities experienced by people with disabilities. This article highlights these disparities as well as the history of disability and health care. Current advancements in medical education regarding people with disabilities are reviewed with suggestions for medical schools looking to improve or begin programming focused on people with disabilities. By covering the history and current difficulties experienced by people with disabilities accessing health care, as well as the best practices for educating medical students, this article takes steps to fill an important gap in the literature., Competing Interests: Conflicts of Interest The author declares she has no conflicts of interest., (© 2022 HCA Physician Services, Inc. d/b/a Emerald Medical Education.)

Background: Crosstalk between neoplastic and stromal cells fosters prostate cancer (PCa) progression and dissemination. Insight in cell-to-cell communication networks provides new therapeutic avenues to mold processes that contribute to PCa tumor microenvironment (TME) alterations. Here we performed a detailed characterization of PCa tumor endothelial cells (TEC) to delineate intercellular crosstalk between TEC and the PCa TME., Methods: TEC isolated from 67 fresh radical prostatectomy (RP) specimens underwent multi-omic ex vivo characterization as well as orthogonal validation of both TEC functions and key markers by immunohistochemistry (IHC) and immunofluorescence (IF). To identify cell-cell interaction targets in TEC, we performed single-cell RNA sequencing (scRNA-seq) in four PCa patients who underwent a RP to catalogue cellular TME composition. Targets were cross-validated using IHC, publicly available datasets, cell culture expriments as well as a PCa xenograft mouse model., Results: Compared to adjacent normal endothelial cells (NEC) bulk RNA-seq analysis revealed upregulation of genes associated with tumor vasculature, collagen modification and extracellular matrix remodeling in TEC. PTGIR, PLAC9, CXCL12 and VDR were identified as TEC markers and confirmed by IF and IHC in an independent patient cohort. By scRNA-seq we identified 27 cell (sub)types, including endothelial cells (EC) with arterial, venous and immature signatures, as well as angiogenic tip EC. A focused molecular analysis revealed that arterial TEC displayed highest CXCL12 mRNA expression levels when compared to all other TME cell (sub)populations and showed a negative prognostic role. Receptor-ligand interaction analysis predicted interactions between arterial TEC derived CXCL12 and its cognate receptor CXCR4 on angiogenic tip EC. CXCL12 was in vitro and in vivo validated as actionable TEC target by highlighting the vessel number- and density- reducing activity of the CXCR4-inhibitor AMD3100 in murine PCa as well as by inhibition of TEC proliferation and migration in vitro., Conclusions: Overall, our comprehensive analysis identified novel PCa TEC targets and highlights CXCR4/CXCL12 interaction as a potential novel target to interfere with tumor angiogenesis in PCa., (© 2022. The Author(s).)

Little is known about the physiological role of alkylglycerol monooxygenase (AGMO), the only enzyme capable of cleaving the 1-O-alkyl ether bond of ether lipids. Expression and enzymatic activity of this enzyme can be detected in a variety of tissues including adipose tissue. This labile lipolytic membrane-bound protein uses tetrahydrobiopterin as a cofactor, and mice with reduced tetrahydrobiopterin levels have alterations in body fat distribution and blood lipid concentrations. In addition, manipulation of AGMO in macrophages led to significant changes in the cellular lipidome, and alkylglycerolipids, the preferred substrates of AGMO, were shown to accumulate in mature adipocytes. Here, we investigated the roles of AGMO in lipid metabolism by studying 3T3-L1 adipogenesis. AGMO activity was induced over 11 days using an adipocyte differentiation protocol. We show that RNA interference-mediated knockdown of AGMO did not interfere with adipocyte differentiation or affect lipid droplet formation. Furthermore, lipidomics revealed that plasmalogen phospholipids were preferentially accumulated upon Agmo knockdown, and a significant shift toward longer and more polyunsaturated acyl side chains of diacylglycerols and triacylglycerols could be detected by mass spectrometry. Our results indicate that alkylglycerol catabolism has an influence not only on ether-linked species but also on the degree of unsaturation in the massive amounts of triacylglycerols formed during in vitro 3T3-L1 adipocyte differentiation., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Crohn's disease (CD) globally emerges with Westernization of lifestyle and nutritional habits. However, a specific dietary constituent that comprehensively evokes gut inflammation in human inflammatory bowel diseases remains elusive. We aimed to delineate how increased intake of polyunsaturated fatty acids (PUFAs) in a Western diet, known to impart risk for developing CD, affects gut inflammation and disease course. We hypothesized that the unfolded protein response and antioxidative activity of glutathione peroxidase 4 (GPX4), which are compromised in human CD epithelium, compensates for metabolic perturbation evoked by dietary PUFAs., Methods: We phenotyped and mechanistically dissected enteritis evoked by a PUFA-enriched Western diet in 2 mouse models exhibiting endoplasmic reticulum (ER) stress consequent to intestinal epithelial cell (IEC)-specific deletion of X-box binding protein 1 (Xbp1) or Gpx4. We translated the findings to human CD epithelial organoids and correlated PUFA intake, as estimated by a dietary questionnaire or stool metabolomics, with clinical disease course in 2 independent CD cohorts., Results: PUFA excess in a Western diet potently induced ER stress, driving enteritis in Xbp1 -/-IEC and Gpx4 +/-IEC mice. ω-3 and ω-6 PUFAs activated the epithelial endoplasmic reticulum sensor inositol-requiring enzyme 1α (IRE1α) by toll-like receptor 2 (TLR2) sensing of oxidation-specific epitopes. TLR2-controlled IRE1α activity governed PUFA-induced chemokine production and enteritis. In active human CD, ω-3 and ω-6 PUFAs instigated epithelial chemokine expression, and patients displayed a compatible inflammatory stress signature in the serum. Estimated PUFA intake correlated with clinical and biochemical disease activity in a cohort of 160 CD patients, which was similarly demonstrable in an independent metabolomic stool analysis from 199 CD patients., Conclusions: We provide evidence for the concept of PUFA-induced metabolic gut inflammation which may worsen the course of human CD. Our findings provide a basis for targeted nutritional therapy., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)