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Abstract Breast cancer risks in older BRCA2 pathogenic variant carriers are understudied. Recent studies show a marked decline in the relative risk at older ages. We used data from two large studies to update the breast cancer risks in the BOADICEA model for BRCA2 carriers 60 years and older.

Abstract Human endogenous retroviruses (HERVs) are repetitive elements previously implicated in major psychiatric conditions, but their role in aetiology remains unclear. Here, we perform specialised transcriptome-wide association studies that consider HERV expression quantified to precise genomic locations, using RNA sequencing and genetic data from 792 post-mortem brain samples. In Europeans, we identify 1238 HERVs with expression regulated in cis, of which 26 represent expression signals associated with psychiatric disorders, with ten being conditionally independent from neighbouring expression signals. Of these, five are additionally significant in fine-mapping analyses and thus are considered high confidence risk HERVs. These include two HERV expression signatures specific to schizophrenia risk, one shared between schizophrenia and bipolar disorder, and one specific to major depressive disorder. No robust signatures are identified for autism spectrum conditions or attention deficit hyperactivity disorder in Europeans, or for any psychiatric trait in other ancestries, although this is likely a result of relatively limited statistical power. Ultimately, our study highlights extensive HERV expression and regulation in the adult cortex, including in association with psychiatric disorder risk, therefore providing a rationale for exploring neurological HERV expression in complex neuropsychiatric traits.

Abstract Human endogenous retroviruses (HERVs) are the germline embedded proviral fragments of ancient retroviral infections that make up roughly 8% of the human genome. Our understanding of HERVs in physiology primarily surrounds their non-coding functions, while their protein coding capacity remains virtually uncharacterized. Therefore, we applied the bioinformatic pipeline “hervQuant” to high-resolution ribosomal profiling of healthy tissues to provide a comprehensive overview of translationally active HERVs. We find that HERVs account for 0.1–0.4% of all translation in distinct tissue-specific profiles. Collectively, our study further supports claims that HERVs are actively translated throughout healthy tissues to provide sequences of retroviral origin to the human proteome.

Abstract Neuropsychiatric and neurodegenerative disorders are correlated with cellular stress. Macroautophagy (autophagy) may represent an important protective pathway to maintain cellular homeostasis and functionality, as it targets cytoplasmic components to lysosomes for degradation and recycling. Given recent evidence that some novel psychiatric treatments, such as the neuroactive steroid (NAS) allopregnanolone (AlloP, brexanolone), may induce autophagy, we stably transfected human embryonic kidney 293 (HEK) cells with a ratiometric fluorescent probe to assay NAS effects on autophagy. We hypothesized that NAS may modulate autophagy in part by the ability of uncharged NAS to readily permeate membranes. Microscopy revealed a weak effect of AlloP on autophagic flux compared with the positive control treatment of Torin1. In high-throughput microplate experiments, we found that autophagy induction was more robust in early passages of HEK cells. Despite limiting studies to early passages for maximum sensitivity, a range of NAS structures failed to reliably induce autophagy or interact with Torin1 or starvation effects. To probe NAS in a system where AlloP effects have been shown previously, we surveyed astrocytes and again saw minimal autophagy induction by AlloP. Combined with other published results, our results suggest that NAS may modulate autophagy in a cell-specific or context-specific manner. Although there is merit to cell lines as a screening tool, future studies may require assaying NAS in cells from brain regions involved in neuropsychiatric disorders.

Histone‐lysine N‐methyltransferase SETD2 (SETD2), the sole histone methyltransferase that catalyzes trimethylation of lysine 36 on histone H3 (H3K36me3), is often mutated in clear cell renal cell carcinoma (ccRCC). SETD2 mutation and/or loss of H3K36me3 is linked to metastasis and poor outcome in ccRCC patients. Epithelial‐to‐mesenchymal transition (EMT) is a major pathway that drives invasion and metastasis in various cancer types. Here, using novel kidney epithelial cell lines isogenic for SETD2, we discovered that SETD2 inactivation drives EMT and promotes migration, invasion, and stemness in a transforming growth factor‐beta‐independent manner. This newly identified EMT program is triggered in part through secreted factors, including cytokines and growth factors, and through transcriptional reprogramming. RNA‐seq and assay for transposase‐accessible chromatin sequencing uncovered key transcription factors upregulated upon SETD2 loss, including SOX2, POU2F2 (OCT2), and PRRX1, that could individually drive EMT and stemness phenotypes in SETD2 wild‐type (WT) cells. Public expression data from SETD2 WT/mutant ccRCC support the EMT transcriptional signatures derived from cell line models. In summary, our studies reveal that SETD2 is a key regulator of EMT phenotypes through cell‐intrinsic and cell‐extrinsic mechanisms that help explain the association between SETD2 loss and ccRCC metastasis.

Summary: Background: Endogenous retroelements (EREs), including human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs), comprise almost half of the human genome. Our previous studies of the interferome in the gut suggest potential mechanisms regarding how IFNb may drive HIV-1 gut pathogenesis. As ERE activity is suggested to partake in type 1 immune responses and is incredibly sensitive to viral infections, we sought to elucidate underlying interactions between ERE expression and gut dynamics in people living with HIV-1 (PLWH). Methods: ERE expression profiles from bulk RNA sequencing of colon biopsies and PBMC were compared between a cohort of PLWH not on antiretroviral therapy (ART) and uninfected controls. Findings: 59 EREs were differentially expressed in the colon of PLWH when compared to uninfected controls (padj

Objectives No large-scale randomized clinical trial investigations have evaluated the potential differential effectiveness of early interventions for post-traumatic stress disorder (PTSD) among injured patients from racial and ethnic minority backgrounds. The current investigation assessed whether a stepped collaborative care intervention trial conducted at 25 level I trauma centers differentially improved PTSD symptoms for racial and ethnic minority injury survivors.Methods The investigation was a secondary analysis of a stepped wedge cluster randomized clinical trial. Patients endorsing high levels of distress on the PTSD Checklist (PCL-C) were randomized to enhanced usual care control or intervention conditions. Three hundred and fifty patients of the 635 randomized (55%) were from non-white and/or Hispanic backgrounds. The intervention included care management, cognitive behavioral therapy elements and, psychopharmacology addressing PTSD symptoms. The primary study outcome was PTSD symptoms assessed with the PCL-C at 3, 6, and 12 months postinjury. Mixed model regression analyses compared treatment effects for intervention and control group patients from non-white/Hispanic versus white/non-Hispanic backgrounds.Results The investigation attained between 75% and 80% 3-month to 12-month follow-up. The intervention, on average, required 122 min (SD=132 min). Mixed model regression analyses revealed significant changes in PCL-C scores for non-white/Hispanic intervention patients at 6 months (adjusted difference −3.72 (95% CI −7.33 to –0.10) Effect Size =0.25, p

Abstract Efferent cholinergic signaling is a critical and targetable source of immunoregulation. The vagus nerve (VN) is the primary source of cholinergic signaling in the body, and partially innervates hepatic functionality through the liver-brain axis. Virus-induced disruption of cholinergic signaling may promote pathogenesis in hepatotropic and neurotropic viruses. Therefore, restoring VN functionality could be a novel therapeutic strategy to alleviate pathogenic inflammation in hepatotropic and neurotropic viral infections alike. In this minireview, we discuss the physiological importance of cholinergic signaling in maintaining liver-brain axis homeostasis. Next, we explore mechanisms by which the VN is perturbed by viral infections, and how non-invasive restoration of cholinergic signaling pathways with bioelectronic medicine (BEM) might ameliorate hepatic inflammation and neuroinflammation in certain viral infections.

Abstract Background Symptomatic COVID-19 and Long COVID, also referred to as post-acute sequelae of SARS-CoV-2 (PASC) or post-COVID conditions, have been widely reported in young, healthy people, but their prevalence has not yet been determined in student athletes. We sought to estimate the prevalence of reported COVID-19, symptomatic COVID-19, and Long COVID in college athletes in the United States attending 18 schools from spring 2020 to fall 2021. Methods We developed an online survey to measure the prevalence of student athletes who tested positive for COVID-19, developed Long COVID, and did not return to their sport during the relevant time period. We surveyed a convenience sample of 18 collegiate school administrators, representing about 7,000 student athletes. Of those schools surveyed, 16 responded regarding the spring 2020 semester, and 18 responded regarding the full academic year of fall 2020 to spring 2021 (both semesters). Results According to the survey responses, there were 9.8% of student athletes who tested positive for COVID-19 in spring 2020 and 25.4% who tested positive in the academic year of fall 2020 to spring 2021. About 4% of student athletes who tested positive from spring 2020 to spring 2021 developed Long COVID, defined as new, recurring, or ongoing physical or mental health consequences occurring 4 or more weeks after SARS-CoV-2 infection. Conclusions This study highlights that Long COVID occurs among young, healthy athletes and is a real consequence of COVID-19. Understanding the prevalence of Long COVID in this population requires longer follow-up and further study.

Abstract We generated single haplotype assemblies from a hinny hybrid which significantly improved the gapless contiguity for horse and donkey autosomal genomes and the X chromosomes. We added over 15 Mb of missing sequence to both X chromosomes, 60 Mb to donkey autosomes and corrected numerous errors in donkey and some in horse reference genomes. We resolved functionally important X-linked repeats: the DXZ4 macrosatellite and ampliconic Equine Testis Specific Transcript Y7 (ETSTY7). We pinpointed the location of the pseudoautosomal boundaries (PAB) and determined the size of the horse (1.8 Mb) and donkey (1.88 Mb) pseudoautosomal regions (PARs). We discovered distinct differences in horse and donkey PABs: a testis-expressed gene, XKR3Y, spans horse PAB with exons1–2 located in Y and exon3 in the X–Y PAR, whereas the donkey XKR3Y is Y-specific. DXZ4 had a similar ~ 8 kb monomer in both species with 10 copies in horse and 20 in donkey. We assigned hundreds of copies of ETSTY7, a sequence horizontally transferred from Parascaris and massively amplified in equids, to horse and donkey X chromosomes and three autosomes. The findings and products contribute to molecular studies of equid biology and advance research on X-linked conditions, sex chromosome regulation and evolution in equids.

5β-Dihydrosteroids are produced by the reduction of Δ4-3-ketosteroids catalyzed by steroid 5β-reductase (AKR1D1). By analogy with steroid 5α-reductase, genetic deficiency exists in AKR1D1 which leads to errors in newborn metabolism and in this case to bile acid deficiency. Also, like the 5α-dihydrosteroids (e.g., 5α-dihydrotestosterone), the 5β-dihydrosteroids produced by AKR1D1 are not inactive but regulate ligand access to nuclear receptors, can act as ligands for nuclear and membrane-bound receptors, and regulate ion-channel opening. For example, 5β-reduction of cortisol and cortisone yields the corresponding 5β-dihydroglucocorticoids which are inactive on the glucocorticoid receptor (GR) and provides an additional mechanism of pre-receptor regulation of ligands for the GR in liver cells. By contrast, 5β-pregnanes can act as neuroactive steroids at the GABAA and NMDA receptors and at low-voltage-activated calcium channels, act as tocolytic agents, have analgesic activity and act as ligands for PXR, while bile acids act as ligands for FXR and thereby control cholesterol homeostasis. The 5β-androstanes also have potent vasodilatory properties and work through blockade of Ca2+ channels. Thus, a preference for 5β-dihydrosteroids to work at the membrane level exists via a variety of mechanisms. This article reviews the field and identifies gaps in knowledge to be addressed in future research.

Background: Biomechanical analysis of the sagittal alignment of the lumbar spine and pelvis on radiographs is common in clinical practices including chiropractic, physical therapy, scoliosis-related thoraco-lumbo-sacral orthosis (TLSO) management, orthopedics, and neurosurgery. Of specific interest is the assessment of pelvic morphology and the relationship between angle of pelvic incidence, sacral slope, and lumbar lordosis to pain, disability, and clinical treatment of spine conditions. The current state of the literature on the reliability of common methods quantifying these parameters on radiographs is limited. Methods: The objective of this systematic review is to identify and review the available studies on the reliability of different methods of biomechanical analysis of sagittal lumbo-pelvic parameters used in clinical practice. Our review followed the recommendations of the preferred reporting items for systematic reviews and meta-analyses (PRISMA). The design of this systematic review was registered with PROSPERO (CRD42023379873). Results: The search strategy yielded a total of 2387 articles. A total of 1539 articles were screened after deduplication and exclusion by automation tools, leaving 473 full-text articles that were retrieved. After exclusion, 64 articles met the inclusion criteria. The preponderance of the evidence showed good to excellent reliability for biomechanical assessment of sagittal lumbo-pelvic spine alignment. Conclusions: The results of this systematic review of the literature show that sagittal radiographic analysis of spinal biomechanics and alignment of the human lumbo-pelvic spine is a reliable tool for aiding diagnosis and management in clinical settings.

Background Previous pandemics have had negative effects on mental health, but there are few data on children and adolescents who were receiving ongoing psychiatric treatment. Aims To study changes in emotions and clinical state, and their predictors, during the COVID-19 pandemic in France. Method We administered (by interview) the baseline Youth Self-Report version of the CoRonavIruS Health Impact Survey v0.3 (CRISIS, French translation) to 123 adolescent patients and the Parent/Caregiver version to evaluate 99 child patients before and during the first ‘lockdown’. For 139 of these patients who received ongoing treatment in our centre, treating physicians retrospectively completed longitudinal global ratings for five time periods, masked to CRISIS ratings. Results The main outcome measure was the sum of eight mood state items, which formed a single factor in each age group. Overall, this score improved for each age group during the first lockdown. Clinician ratings modestly supported this result in patients without intellectual disability or autism spectrum disorder. Improvement of mood states was significantly associated with perceived improvement in family relationships in both age groups. Conclusions Consistent with previous studies of clinical cohorts, our patients had diverse responses during the pandemic. Several factors may have contributed to the finding of improvement in some individuals during the first lockdown, including the degree of family support or conflict, stress reduction owing to isolation, limitations of the outcome measures and/or possible selection bias. Ongoing treatment may have had a protective effect. Clinically, during crises additional support may be needed by families who experience increased conflict or who care for children with intellectual disability.

Summary: Background: Clinical management of Asian BRCA1 and BRCA2 pathogenic variants (PV) carriers remains challenging due to imprecise age-specific breast (BC) and ovarian cancer (OC) risks estimates. We aimed to refine these estimates using six multi-ethnic studies in Asia. Methods: Data were collected on 271 BRCA1 and 301 BRCA2 families from Malaysia and Singapore, ascertained through population/hospital-based case-series (88%) and genetic clinics (12%). Age-specific cancer risks were estimated using a modified segregation analysis method, adjusted for ascertainment. Findings: BC and OC relative risks (RRs) varied across age groups for both BRCA1 and BRCA2. The age-specific RR estimates were similar across ethnicities and country of residence. For BRCA1 carriers of Malay, Indian and Chinese ancestry born between 1950 and 1959 in Malaysia, the cumulative risk (95% CI) of BC by age 80 was 40% (36%–44%), 49% (44%–53%) and 55% (51%–60%), respectively. The corresponding estimates for BRCA2 were 29% (26–32%), 36% (33%–40%) and 42% (38%–45%). The corresponding cumulative BC risks for Singapore residents from the same birth cohort, where the underlying population cancer incidences are higher compared to Malaysia, were higher, varying by ancestry group between 57 and 61% for BRCA1, and between 43 and 47% for BRCA2 carriers. The cumulative risk of OC by age 80 was 31% (27–36%) for BRCA1 and 12% (10%–15%) for BRCA2 carriers in Malaysia born between 1950 and 1959; and 42% (34–50%) for BRCA1 and 20% (14–27%) for BRCA2 carriers of the same birth cohort in Singapore. There was evidence of increased BC and OC risks for women from >1960 birth cohorts (p-value = 3.6 × 10−5 for BRCA1 and 0.018 for BRCA2). Interpretation: The absolute age-specific cancer risks of Asian carriers vary depending on the underlying population-specific cancer incidences, and hence should be customised to allow for more accurate cancer risk management. Funding: Wellcome Trust [grant no: v203477/Z/16/Z]; CRUK (PPRPGM-Nov20∖100002).

Pro-inflammatory changes contribute to multiple neuropsychiatric illnesses. Understanding how these changes are involved in illnesses and identifying strategies to alter inflammatory responses offer paths to potentially novel treatments. We previously found that acute pro-inflammatory stimulation with high (μg/ml) lipopolysaccharide (LPS) for 10-15 min dampens long-term potentiation (LTP) in the hippocampus and impairs learning. Effects of LPS involved non-canonical inflammasome signaling but were independent of toll-like receptor 4 (TLR4), a known LPS receptor. Low (ng/ml) LPS also inhibits LTP when administered for 2-4 h, and here we report that this LPS exposure requires TLR4. We also found that effects of low LPS on LTP involve the oxysterol, 25-hydroxycholesterol, akin to high LPS. Effects of high LPS on LTP are blocked by inhibiting synthesis of 5α-reduced neurosteroids, indicating that neurosteroids mediate LTP inhibition. 5α-Neurosteroids also have anti-inflammatory effects, and we found that exogenous allopregnanolone (AlloP), a key 5α-reduced steroid, prevented effects of low but not high LPS on LTP. We also found that activation of TLR2, TLR3 and TLR7 inhibited LTP and that AlloP prevented the effects of TLR2 and TLR7, but not TLR3. The enantiomer of AlloP, a steroid that has anti-inflammatory actions but low activity at GABAA receptors, prevented LTP inhibition by TLR2, TLR3 and TLR7. In vivo, both AlloP enantiomers prevented LPS-induced learning defects. These studies indicate that neurosteroids play complex roles in network effects of acute neuroinflammation and have potential importance for development of AlloP analogues as therapeutic agents.

Abstract As amniote vertebrates, lizards are the most closely related organisms to humans capable of appendage regeneration. Lizards can autotomize, or release their tails as a means of predator evasion, and subsequently regenerate a functional replacement. Green anoles (Anolis carolinensis) can regenerate their tails through a process that involves differential expression of hundreds of genes, which has previously been analyzed by transcriptomic and microRNA analysis. To investigate protein expression in regenerating tissue, we performed a whole proteomic analysis of regenerating tail tip and base. This is the first proteomic data set available for any anole lizard. We identified a total of 2646 proteins—976 proteins only in the regenerating tail base, 796 only in the tail tip, and 874 in both tip and base. For over 90% of these proteins in these tissues, we were able to assign a clear orthology to gene models in either the Ensembl or NCBI databases. For 13 proteins in the tail base, 9 proteins in the tail tip, and 10 proteins in both regions, the gene model in Ensembl and NCBI matched an uncharacterized protein, confirming that these predictions are present in the proteome. Ontology and pathways analysis of proteins expressed in the regenerating tail base identified categories, including actin filament‐based process, ncRNA metabolism, regulation of phosphatase activity, small GTPase‐mediated signal transduction, and cellular component organization or biogenesis. Analysis of proteins expressed in the tail tip identified categories, including regulation of organelle organization, regulation of protein localization, ubiquitin‐dependent protein catabolism, small GTPase‐mediated signal transduction, morphogenesis of epithelium, and regulation of biological quality. These proteomic findings confirm pathways and gene families activated in tail regeneration in the green anole as well as identify uncharacterized proteins whose role in regrowth remains to be revealed. This study demonstrates the insights that are possible from the integration of proteomic and transcriptomic data in tail regrowth in the green anole, with potentially broader application to studies in other regenerative models. KEY POINTS This research is highly interdisciplinary, combining our previous analyses with these most recent findings: Appendage regeneration is a conserved trait among vertebrates and has been characterized in animals ranging from teleost fish (zebrafish), urodele amphibians (axolotl), anuran amphibians (Xenopus frog), squamate reptiles (various species of lizards), and even crocodilians (American alligator). Comparative genomic and proteomic analysis of this process allows us to identify the genetic pathways and cellular processes under evolutionary selection for this regrowth capacity. Activating these conserved genetic pathways and cellular processes will be critical to developing regenerative medical therapies in humans. The identification of proteins expressed in regeneration extends analyses based only on predicted proteins from transcriptomic analysis, and permits integration with protein‐expression studies of regrowing nervous and musculoskeletal structures.

Abstract Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi‐state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non‐carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Abstract Background Genome-wide studies of gene–environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene–environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 × 10–5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability

In the preliminary design of aircraft lifting surfaces, accurate mass and inertia properties can be difficult to obtain. Typically, such methods as computer-aided design or statistical processes are used to determine these properties. These methods require significant time and effort to implement. The present paper presents an exact analytic method for calculating the volume, mass, center of gravity, and inertia properties of wing segments and rotors of constant density. The influence of taper, spanwise thickness distribution, airfoil geometry, and sweep are included. The utility of the method is presented, and the accuracy is evaluated with various test cases via percent difference with a corresponding computer-aided design model. These case studies demonstrate the present method to be accurate to within about 1% for typical wing geometries and within about 1.3% for typical propeller geometries.

Risk-stratified breast screening has been proposed as a strategy to overcome the limitations of age-based screening. A prospective cohort study was undertaken within the PERSPECTIVE I&I project, which will generate the first Canadian evidence on multifactorial breast cancer risk assessment in the population setting to inform the implementation of risk-stratified screening. Recruited females aged 40–69 unaffected by breast cancer, with a previous mammogram, underwent multifactorial breast cancer risk assessment. The adoption of multifactorial risk assessment, the effectiveness of methods for collecting risk factor information and the costs of risk assessment were examined. Associations between participant characteristics and study sites, as well as data collection methods, were assessed using logistic regression; all p-values are two-sided. Of the 4246 participants recruited, 88.4% completed a risk assessment, with 79.8%, 15.7% and 4.4% estimated at average, higher than average and high risk, respectively. The total per-participant cost for risk assessment was CAD 315. Participants who chose to provide risk factor information on paper/telephone (27.2%) vs. online were more likely to be older (p = 0.021), not born in Canada (p = 0.043), visible minorities (p = 0.01) and have a lower attained education (p < 0.0001) and perceived fair/poor health (p < 0.001). The 34.4% of participants requiring risk factor verification for missing/unusual values were more likely to be visible minorities (p = 0.009) and have a lower attained education (p ≤ 0.006). This study demonstrates the feasibility of risk assessment for risk-stratified screening at the population level. Implementation should incorporate an equity lens to ensure cancer-screening disparities are not widened.

Valley Fever (VF), caused by fungi in the genus Coccidioides, is a prevalent disease in southwestern and western parts of the United States that affects both humans and animals, such as dogs. Although the immune responses to infection with Coccidioides spp. are not fully characterized, antibody-detection assays are used in conjunction with clinical presentation and radiologic findings to aid in the diagnosis of VF. These assays often use Complement Fixation (CF) and Tube Precipitin (TP) antigens as the main targets of IgG and IgM reactivity, respectively. Our group previously reported evidence of over 800 genes expressed at the protein level in C. posadasii. However, antibody reactivity to the majority of these proteins has never been explored. Using a new, high-throughput screening technology, the Nucleic Acid Programmable Protein Array (NAPPA), we screened serum specimens from dogs against 708 of these previously identified proteins for IgG reactivity. Serum from three separate groups of dogs was analyzed and revealed a small panel of proteins to be further characterized for immuno-reactivity. In addition to CF/CTS1 antigen, sera from most infected dogs showed antibody reactivity to endo-1,3-betaglucanase, peroxisomal matrix protein, and another novel reactive protein, CPSG_05795. These antigens may provide additional targets to aid in antibody-based diagnostics.

Abstract Introduction Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. Patients and methods An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. Results In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04–1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66–0.84) and BRCA2 (HR 0.76, 95% CI 0.65–0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02–1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01–1.19, respectively). Conclusion Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.

Abstract The Y chromosome carries information about the demography of paternal lineages, and thus, can prove invaluable for retracing both the evolutionary trajectory of wild animals and the breeding history of domesticates. In horses, the Y chromosome shows a limited, but highly informative, sequence diversity, supporting the increasing breeding influence of Oriental lineages during the last 1500 years. Here, we augment the primary horse Y-phylogeny, which is currently mainly based on modern horse breeds of economic interest, with haplotypes (HT) segregating in remote horse populations around the world. We analyze target enriched sequencing data of 5 Mb of the Y chromosome from 76 domestic males, together with 89 whole genome sequenced domestic males and five Przewalski’s horses from previous studies. The resulting phylogeny comprises 153 HTs defined by 2966 variants and offers unprecedented resolution into the history of horse paternal lineages. It reveals the presence of a remarkable number of previously unknown haplogroups in Mongolian horses and insular populations. Phylogenetic placement of HTs retrieved from 163 archaeological specimens further indicates that most of the present-day Y-chromosomal variation evolved after the domestication process that started around 4200 years ago in the Western Eurasian steppes. Our comprehensive phylogeny significantly reduces ascertainment bias and constitutes a robust evolutionary framework for analyzing horse population dynamics and diversity.

Abstract We assessed the PREDICT v 2.2 for prognosis of breast cancer patients with pathogenic germline BRCA1 and BRCA2 variants, using follow-up data from 5453 BRCA1/2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC). PREDICT for estrogen receptor (ER)-negative breast cancer had modest discrimination for BRCA1 carrier patients overall (Gönen & Heller unbiased concordance 0.65 in CIMBA, 0.64 in BCAC), but it distinguished clearly the high-mortality group from lower risk categories. In an analysis of low to high risk categories by PREDICT score percentiles, the observed mortality was consistently lower than the expected mortality, but the confidence intervals always included the calibration slope. Altogether, our results encourage the use of the PREDICT ER-negative model in management of breast cancer patients with germline BRCA1 variants. For the PREDICT ER-positive model, the discrimination was slightly lower in BRCA2 variant carriers (concordance 0.60 in CIMBA, 0.65 in BCAC). Especially, inclusion of the tumor grade distorted the prognostic estimates. The breast cancer mortality of BRCA2 carriers was underestimated at the low end of the PREDICT score distribution, whereas at the high end, the mortality was overestimated. These data suggest that BRCA2 status should also be taken into consideration with tumor characteristics, when estimating the prognosis of ER-positive breast cancer patients.

The General Anxiety Disorder 7-Item (GAD-7) scale is commonly used in primary care as a self-report measure of general anxiety symptoms with adult populations. There is little psychometric research on this measure with adolescent populations, particularly those with persistent post-concussive symptoms (PPCS). This study examined the psychometrics properties of the GAD-7 among youth with PPCS. We used baseline data from a randomized controlled trial of collaborative care for treatment of PPCS among 200 sports-injured adolescents 11?18 years of age (Mage?=?14.7 years, standard deviation?=?1.7). Eligible adolescents had three or more PPCS that lasted for ?1 month and spoke English. Adolescents reported on their anxious (GAD-7 and Revised Child Anxiety and Depression Scale?Short Version [anxiety subscale]; RCADS) and depressive (Patient Health Questionnaire-9; PHQ-9) symptoms. Parents used the RCADS to report on their adolescents' anxious symptoms. The GAD-7 had good internal validity (Cronbach's alpha?=?0.87), and significant (p?0.001) correlations were detected between the GAD-7 and youth and parent report of anxiety on RCADS (r?=?0.73 and r?=?0.29) and PHQ-9 (r?=?0.77) scores. Confirmatory factor analysis suggested a one-factor solution. These results suggest that the GAD-7 is a valid measure of anxiety with good psychometric properties for youth experiencing PPCS. ClinicalTrials.gov identifier: NCT03034720

Glasses and glass-ceramics based on the Tb3+-doped SbPO4-GeO2-Al2O3 composition have been studied. Samples containing up to 0.4 mol % of Tb4O7 form glasses when obtained by melt-quenching while concentrations above that tends to form glass-containing single crystals. This work reports the thermal, structural, morphological, and optical studies of (96-x)(40SbPO4-60GeO2)-4Al2O3-xTb4O7 samples (where 0.2 ≤ x ≤ 0.7, in mol %) using Differential Scanning Calorimetry, X-ray Powder Diffraction, Scanning Electron Microscopy, Energy Dispersive Spectroscopy, UV–Vis absorption, Raman, and Photoluminescence spectroscopies. The diffraction pattern for the glass-ceramic containing 0.7 mol% of Tb4O7 shows diffraction peaks, which were assigned to the crystalline phase derived from terbium orthophosphate (TbPO4). In the same direction, the Raman spectra of the glass-ceramics containing 0.5, 0.6, and 0.7 mol% of Tb4O7 exhibited narrow bands in the region between 900 and 1300 cm-1, which are characteristic of the main vibrational modes of the PO4 tetrahedral units of TbPO4. The TbPO4 crystals exhibited an average size distribution ranging from 10 to 200 μm. The TbPO4 crystals exhibited an unusual morphology and design, resembling the shape of the letter ''H'' and is completely different from the crystals reported in the literature. Strong green emission from TbPO4 crystals was verified at 547 nm for all samples. The emission spectra showed not only bands assigned to 5D4→7FJ electronic transitions in the green-red range, but also those coming from 5D3→7FJ in blue region.

There are two major theories for setting up ecological communities, the Niche Theory and the Neutral Theory. Both seek to explain the main factors that form a community, which is a great challenge, since each community has its particularities and the environment has different ways to manifest. We devised a process-oriented study that sought to establish the role of environmental niche driven by coastal upwelling in the assembly of reef fish communities from exposed and sheltered environments a few kilometers apart, in the region of Arraial do Cabo (southwestern Atlantic). A multivariate hierarchical generalized linear mixed model fitted with Bayesian inference was applied to abundance and presence-absence data from visual census, together with environmental data from satellite and reanalysis. We found a stronger contribution of random effects to abundance variance with 24% for sites and 20.7% for sheltered vs. exposed locations, and weaker environmental effects with 7.1% for surface chlorophyll-a concentration (SCC) and 5.4% for sea surface temperature (SST). Environmental effects had a stronger contribution in the presence-absence model, with 20.1% for SCC and 14.6% for SST. The overall influence of the upwelling environment across all species was negative, e.g., Gymnothorax moringa and Canthigaster figueiredoi showing negative responses to SCC and Parablennius pilicornis and Malacoctenus delalandii to SST. The joint action of migration-niche mechanisms is inferred from the dominance of spatio-temporal structure, limited influence of life history traits and phylogeny, explaining around 95% of species niches in the abundance model. Our results bring new evidence for the importance of different filters for community assembly other than the environment, such as phylogenetic history and dispersal. We also discuss the balance between niche (environment) and neutral (stochasticity) processes for the assembly of reef fish communities in a tropical-subtropical transition zone.

Identifying of global or national biodiversity ‘hotspots’ has proven important for focusing and prioritizing conservation efforts worldwide. Canada has nearly 600 Important Bird and Biodiversity Areas (IBAs) identified by quantitative criteria to help guide avian conservation and management. Marine IBAs capture critical waterbird habitats such as nesting colonies, foraging sites, and staging areas. However, due to their remote locations, many lack recent population counts. Canada has begun transitioning IBAs into the global Key Biodiversity Areas (KBA) program; KBAs identify areas that are important for the persistence of biodiversity and encompass a wider scope of unique, rare, or vulnerable taxa. Assessing whether IBAs qualify as KBAs requires current data – as will future efforts to manage these biologically important sites. We conducted a pilot study in the Chain Islets and Great Chain Island IBA, in British Columbia, to assess the effectiveness of using drones to census surface-nesting seabirds in an IBA context. This IBA was originally designated for supporting a globally significant breeding colony of Glaucous-winged Gulls (Larus glaucescens). Total nest counts derived from orthomosaic imagery (1012 nesting pairs) show that this site now falls below the Global and National IBA designation criterion threshold, a finding consistent with regional declines in the species. Our trial successfully demonstrates a flexible and low cost approach to obtaining population data at an ecologically sensitive KBA site. We explore how drones will be a useful tool to assess and monitor species and habitats within remote, data-deficient IBAs, particularly during the transition to KBAs.

Abstract Background Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results In European ancestry samples, 14 genes were significantly associated (q

Neurosteroids are rapidly emerging as important new therapies in neuropsychiatry, with one such agent, brexanolone, already approved for treatment of postpartum depression, and others on the horizon. These steroids have unique properties, including neuroprotective effects that could benefit a wide range of brain illnesses including depression, anxiety, epilepsy, and neurodegeneration. Over the past 25 years, our group has developed ex vivo rodent models to examine factors contributing to several forms of neurodegeneration in the retina. In the course of this work, we have developed a model of acute closed angle glaucoma that involves incubation of ex vivo retinas under hyperbaric conditions and results in neuronal and axonal changes that mimic glaucoma. We have used this model to determine neuroprotective mechanisms that could have therapeutic implications. In particular, we have focused on the role of both endogenous and exogenous neurosteroids in modulating the effects of acute high pressure. Endogenous allopregnanolone, a major stress-activated neurosteroid in the brain and retina, helps to prevent severe pressure-induced retinal excitotoxicity but is unable to protect against degenerative changes in ganglion cells and their axons under hyperbaric conditions. However, exogenous allopregnanolone, at a pharmacological concentration, completely preserves retinal structure and does so by combined effects on gamma-aminobutyric acid type A receptors and stimulation of the cellular process of macroautophagy. Surprisingly, the enantiomer of allopregnanolone, which is inactive at gamma-aminobutyric acid type A receptors, is equally retinoprotective and acts primarily via autophagy. Both enantiomers are also equally effective in preserving retinal structure and function in an in vivo glaucoma model. These studies in the retina have important implications for the ongoing development of allopregnanolone and other neurosteroids as therapeutics for neuropsychiatric illnesses.

(1) Background: Lumbar spondylolisthesis affects ~20% of the US population and causes spine-related pain and disability. (2) Methods: This series reports on three patients (two females and one male) aged 68–71 years showing improvements in back pain, quality of life (QOL), and urinary dysfunction following correction of lumbar spondylolistheses using CBP® spinal rehabilitation. Pre-treatment radiographs showed lumbar hyperlordosis (−49.6°, ideal is −40°) and anterolisthesis (14.5 mm, ideal is 0 mm). Pre-treatment patient-reported outcome measures (PROMs) included a numeric rating scale (NRS) for back pain (7.3/10, ideal is 0), urinary urgency (8/10, ideal is 0), and SF-36 physical (PCS) and mental component score (MCS) (29.8 and 46.6, ideal is 46.8 and 52.8). Patients underwent 2–3 CBP® sessions per week to correct lumbar hyperlordosis and lumbar anterolistheses. (3) Results: Post-treatment radiographs showed improvements in lumbar curvature (−42.8°) and anterolisthesis (4.2 mm). Post-treatment PROMs showed improvements in NRS for back pain (1/10), urinary urgency (2.3/10), and SF-36 PCS and MCS (50.2 and 57.7). Long-term follow-up radiographs and PROMs showed maintained improvements. (4) Conclusions: This series documents the first-recorded long-term corrections of lumbar spondylolisthesis and concomitant improvements in back pain, urinary urgency, and QOL using CBP®. This series provides evidence for CBP® as a non-surgical approach to lumbar spinal rehabilitation and the possible impacts of spinal alignment on pain, urinary dysfunction, and QOL.

Introduction: It is estimated that around 5% of breast cancer cases carry pathogenic variants in established breast cancer susceptibility genes. However, the underlying prevalence and gene-specific population risk estimates in Cyprus are currently unknown.Methods: We performed sequencing on a population-based case-control study of 990 breast cancer cases and 1094 controls from Cyprus using the BRIDGES sequencing panel. Analyses were conducted separately for protein-truncating and rare missense variants.Results: Protein-truncating variants in established breast cancer susceptibility genes were detected in 3.54% of cases and 0.37% of controls. Protein-truncating variants in BRCA2 and ATM were associated with a high risk of breast cancer, whereas PTVs in BRCA1 and PALB2 were associated with a high risk of estrogen receptor (ER)-negative disease. Among participants with a family history of breast cancer, PTVs in ATM, BRCA2, BRCA1, PALB2 and RAD50 were associated with an increased risk of breast cancer. Furthermore, an additional 19.70% of cases and 17.18% of controls had at least one rare missense variant in established breast cancer susceptibility genes. For BRCA1 and PALB2, rare missense variants were associated with an increased risk of overall and triple-negative breast cancer, respectively. Rare missense variants in BRCA1, ATM, CHEK2 and PALB2 domains, were associated with increased risk of disease subtypes.Conclusion: This study provides population-based prevalence and gene-specific risk estimates for protein-truncating and rare missense variants. These results may have important clinical implications for women who undergo genetic testing and be pivotal for a substantial proportion of breast cancer patients in Cyprus.

Aim: To report improvements in post-concussion syndrome and concussion incidence following cervical spinal alignment correction. Case presentation: A 27-year-old professional rugby player with 20 documented concussions presented with abnormal cervical spinal alignment and post-concussion syndrome. After 30 sessions of cervical rehabilitation, health outcomes improved. Post-treatment radiographs showed improved cervical lordosis from -13.5° to -37.4° (ideal is -42°) and right head translation from -22.7 to -11.3 mm (ideal is 0 mm). 2-year follow-up radiographs and 6-year follow-up health outcomes showed post-treatment improvements were maintained. The patient reported two documented concussions in the 6 years following treatment while maintaining the same lifestyle and professional rugby career. Conclusion: Correction of abnormal cervical spinal alignment may help athletes with post-concussion syndrome and reduce risk of concussion.

The serine protease autotransporters of the Enterobacteriaceae (SPATEs) are a large family of virulence factors commonly found in enteric bacteria. These secreted virulence factors have diverse functions during bacterial infection, including adhesion, aggregation and cell toxicity. One such SPATE, the Pic mucinase (protein involved in colonisation) cleaves mucin, allowing enteric bacterial cells to utilise mucin as a carbon source and to penetrate the gut mucus lining, thereby increasing mucosal colonisation. The pic gene is widely distributed within the Enterobacteriaceae, being found in human pathogens, such as enteroaggregative Escherichia coli (EAEC), uropathogenic E. coli (UPEC) and Shigella flexneri 2a. As the pic promoter regions from EAEC strain 042 and UPEC strain CFT073 differ, we have investigated the regulation of each promoter. Here, using in vivo and in vitro techniques, we show that both promoters are activated by the global transcription factor, CRP (cyclic AMP receptor protein), but the architectures of the EAEC and the UPEC pic promoter differ. Expression from both pic promoters is repressed by the nucleoid-associated factor, Fis, and maximal promoter activity occurs when cells are grown in minimal medium. As CRP activates transcription in conditions of nutrient depletion, whilst Fis levels are maximal in nutrient-rich environments, the regulation of the EAEC and UPEC pic promoters is consistent with Pic’s nutritional role in scavenging mucin as a suitable carbon source during colonisation and infection.

Abstract Background: Emerging evidence suggests that access to chiropractic care may reduce the likelihood of initiating an opioid prescription for spinal pain; however, the impact of chiropractic care for patients already prescribed opioids is uncertain. We undertook a sequential explanatory mixed methods study to evaluate the association between initiating chiropractic care and continued opioid use among adult patients attending an Ontario community health centre (CHC) and receiving opioid therapy for chronic non-cancer spinal pain. Methods: We conducted a retrospective cohort study of 210 patient records between January 1, 2014 and December 31, 2020. We used generalized estimating equations, adjusted for patient demographics, co-morbidities, visit frequency, and calendar year, to evaluate the association between receipt versus non-receipt of chiropractic services and continued opioid use (e.g., unique opioid fills, number of refills, and dosages) up to one year following the index chiropractic visit. We also completed follow-up interviews with 14 patients and nine general practitioners from the CHC and integrated these data with our quantitative findings. Results: Over 12-month follow-up, there were lower rates of opioid fills (incidence rate ratio [IRR] = 0.66; 95% confidence interval [CI], 0.52–0.83) and refills (IRR = 0.27; 95% CI, 0.17–0.42) among chiropractic recipients (n = 49) versus non-recipients (n = 161). Although patients who did and did not receive chiropractic care began the study with the same dose of opioids, recipients were less likely to be prescribed higher-dose opioids (i.e., ≥ 50 mg morphine equivalents daily) compared to non-recipients at three months (odds ratio [OR] = 0.14; 95% CI, 0.04–0.47), six months (OR = 0.14; 95% CI, 0.05–0.40), nine months (OR = 0.19; 95% CI, 0.07–0.57), and 12 months (OR = 0.22; 95% CI, 0.08–0.62). Interviews suggested that patient self-efficacy, limited effectiveness of opioids for chronic pain, stigma regarding use of opioids, and access to chiropractic treatment were important influencing factors. Conclusion: We found that continued prescription opioid use among patients with chronic non-cancer spinal pain who received chiropractic care was lower than in patients who did not receive chiropractic care. Four themes emerged in our qualitative interviews to help provide a richer understanding of this association. Randomized controlled trials are needed to establish the effect of chiropractic care on opioid use for chronic spinal pain.

The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.

Abstract Background Prediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors. Methods We included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models. Results The discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56–0.74) versus 0.63 (95%PI 0.54–0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34–2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions Additional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging.

Lake, Roeder et al. measured neutralizing antibody responses after 2 and 3 doses of mRNA COVID vaccination. Recipients who did not generate strong neutralizing antibody responses after 2 vaccine doses were found to have high levels of neutralizing antibodies after a third vaccine dose.

Summary: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

Phosphorus (P) is a finite resource, and its environmental fate and transport is complex. With fertilizer prices expected to remain high for years and disruption to supply chains, there is a pressing need to recover and reuse P (primarily as fertilizer). Whether recovery is to occur from urban systems (e.g., human urine), agricultural soil (e.g., legacy P), or from contaminated surface waters, quantification of P in various forms is vital. Monitoring systems with embedded near real time decision support, so called cyber physical systems, are likely to play a major role in the management of P throughout agro-ecosystems. Data on P flow(s) connects the environmental, economic, and social pillars of the triple bottom line (TBL) sustainabilty framework. Emerging monitoring systems must account for complex interactions in the sample, and interface with a dynamic decision support system that considers adaptive dynamics to societal needs. It is known from decades of study that P is ubiquitous, yet without quantitative tools for studying the dynamic nature of P in the environment, the details may remain elusive. If new monitoring systems (including CPS and mobile sensors) are informed by sustainability frameworks, data-informed decision making may foster resource recovery and environmental stewardship from technology users to policymakers.

The following investigations describe the potential of handheld NIR spectroscopy and Raman imaging measurements for the identification and authentication of food products. On the one hand, during the last decade, handheld NIR spectroscopy has made the greatest progress among vibrational spectroscopic methods in terms of miniaturization and price/performance ratio, and on the other hand, the Raman spectroscopic imaging method can achieve the best lateral resolution when examining the heterogeneous composition of samples. The utilization of both methods is further enhanced via the combination with chemometric evaluation methods with respect to the detection, identification, and discrimination of illegal counterfeiting of food products. To demonstrate the solution to practical problems with these two spectroscopic techniques, the results of our recent investigations obtained for various industrial processes and customer-relevant product examples have been discussed in this article. Specifically, the monitoring of food extraction processes (e.g., ethanol extraction of clove and water extraction of wolfberry) and the identification of food quality (e.g., differentiation of cocoa nibs and cocoa beans) via handheld NIR spectroscopy, and the detection and quantification of adulterations in powdered dairy products via Raman imaging were outlined in some detail. Although the present work only demonstrates exemplary product and process examples, the applications provide a balanced overview of materials with different physical properties and manufacturing processes in order to be able to derive modified applications for other products or production processes.

Despite remarkable progress, a cure for HIV-1 infection remains elusive. Rebound competent latent and transcriptionally active reservoir cells persevere despite antiretroviral therapy and rekindle infection due to inefficient proviral silencing. We propose a novel “block-lock-stop” approach, entailing long term durable silencing of viral expression towards an irreversible transcriptionally inactive latent provirus to achieve long term antiretroviral free control of the virus. A graded transformation of remnant HIV-1 in PLWH from persistent into silent to permanently defective proviruses is proposed, emulating and accelerating the natural path that human endogenous retroviruses (HERVs) take over millions of years. This hypothesis was based on research into delineating the mechanisms of HIV-1 latency, lessons from latency reversing agents and advances of Tat inhibitors, as well as expertise in the biology of HERVs. Insights from elite controllers and the availability of advanced genome engineering technologies for the direct excision of remnant virus set the stage for a rapid path to an HIV-1 cure.

Purpose: Cranial radiation therapy remains an integral component of curative treatment for pediatric patients with brain tumors. Proton beam radiation therapy (PBT) can limit collateral radiation dose to surrounding normal tissue, thus reducing off-target exposure while maintaining appropriate tumor coverage. While PBT offers significant advantages over photon therapy for pediatric patients with intracranial malignancies, cases of brainstem necrosis after PBT have raised concerns that PBT may pose an increased risk of necrosis over photon therapy. We investigated the incidence of brainstem necrosis at our institution in children treated with PBT for intracranial malignancies. Patients and Methods: Patients with pediatric brain tumor treated with passively scattered PBT, using a gantry-mounted, synchrocyclotron single-vault system between 2013 and 2018, were retrospectively reviewed. Inclusion criteria included patients 21 years of age or younger who received a minimum 0.1 cm3 maximum brainstem dose of 50 Gray relative biological effectiveness (GyRBE). Patients were assessed for ‘‘central nervous system necrosis’’ in the brainstem per the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (US National Cancer Institute, Bethesda, Maryland) criteria. Results: Fifty-eight patients were included for analysis. The median age was 10.3 years. Twenty-one (36.2%) patients received craniospinal irradiation. Thirty-four (58.6%) patients received chemotherapy. The median prescription radiation dose was 54 GyRBE. Regarding published dosimetric constraints used at 3 separate proton centers, the goal brainstem D50%

Abstract Background Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47–2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. Conclusions These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.

Abstract Background Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. Methods We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. Results We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p

Abstract Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values

Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction. Methods: Genome-wide analysis of remission (nremit = 1852, nnonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism–based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA. Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism–based heritability was significantly different from zero for remission (h2 = 0.132, SE = 0.056) but not for percentage improvement (h2 = −0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response. Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

Background: Measurement of A1c using the Sebia Capillarys-2 capillary electrophoresis (A1c CE) involves relative quantitative measurements of peaks for hemoglobins A1c, A, A2. We examined correlation of A1c CE results with results of CE analysis for hemoglobins (Hb CE) for homozygous A and S-trait patients. We specifically examined whether abnormalities in A2 or the A/S ratio by A1c CE alone would reasonably be the basis for recommendation of red cell indices for evaluation of possible thalassemia. Methods: Selection of patients was from results for A1c CE, exhibiting either a normal pattern or a pattern consistent with S-trait. We then examined correlation of results of quantitation for A, S and A2 between A1c CE and Hb CE. Results: %A2 by A1c CE (y) had high correlation with %A2 by Hb CE (x): y = 0.88 x; r = 0.948. %A2 in S-trait patients was right-shifted in comparison to normals by 0.5%. For S-trait patients, the A/S ratio by A1c CE (y) had high correlation with the A/S ratio by Hb CE (x): y = 1.02 x; r = 0.995. Conclusions: Given high correlation of results between A1c CE and Hb CE, patent elevation of A2 by A1c CE for either normal or S-trait patients is a reasonable basis for recommendation of red cell indices for evaluation of possible beta thalassemia. For S-trait patients, patent abnormality in the A/S ratio by A1c CE is a reasonable basis for recommendation of red cell indices for evaluation of possible alpha or beta thalassemia.