The first complete genome of the extinct European wild ass (Equus hemionus hydruntinus).

We present palaeogenomes of three morphologically unidentified Anatolian equids dating to the first millennium BCE, sequenced to a coverage of 0.6-6.4×. Mitochondrial DNA haplotypes of the Anatolian individuals clustered with those of Equus hydruntinus (or Equus hemionus hydruntinus), the extinct European wild ass, secular name 'hydruntine'. Further, the Anatolian wild ass whole genome profiles fell outside the genomic diversity of other extant and past Asiatic wild ass (E. hemionus) lineages. These observations suggest that the three Anatolian wild asses represent hydruntines, making them the latest recorded survivors of this lineage, about a millennium later than the latest observations in the zooarchaeological record. Our mitogenomic and genomic analyses indicate that E. h. hydruntinus was a clade belonging to ancient and present-day E. hemionus lineages that radiated possibly between 0.6 and 0.8 Mya. We also find evidence consistent with recent gene flow between hydruntines and Middle Eastern wild asses. Analyses of genome-wide heterozygosity and runs of homozygosity suggest that the Anatolian wild ass population may have lost genetic diversity by the mid-first millennium BCE, a possible sign of its eventual demise.

Characterising HIV-1 transmission in Victoria, Australia: a molecular epidemiological study.

Background: In Australia the incidence of HIV has declined steadily, yet sustained reduction of HIV transmission in this setting requires improved public health responses. As enhanced public health responses and prioritisation of resources may be guided by molecular epidemiological data, here we aimed to assess the applicability of these approaches in Victoria, Australia. Methods: A comprehensive collection of HIV-1 pol sequences from individuals diagnosed with HIV in Victoria, Australia, between January 1st 2000 and December 31st 2020 were deidentified and used as the basis of our assessment. These sequences were subtyped and surveillance drug resistance mutations (SDRMs) identified, before definition of transmission groups was performed using HIV-TRACE (0.4.4). Phylodynamic methods were applied using BEAST (2.6.6), assessing effective reproductive numbers for large groups, and additional demographic data were integrated to provide a high resolution view of HIV transmission in Victoria on a decadal time scale. Findings: Based on standard settings for HIV-TRACE, 70% (2438/3507) of analysed HIV-1 pol sequences were readily assigned to a transmission group. Individuals in transmission groups were more commonly males (aOR 1.50), those born in Australia (aOR 2.13), those with probable place of acquisition as Victoria (aOR 6.73), and/or those reporting injectable drug use (aOR 2.13). SDRMs were identified in 375 patients (10.7%), with sustained transmission of these limited to a subset of smaller groups. Informative patterns of epidemic growth, stabilisation, and decline were observed; many transmission groups showed effective reproductive numbers (R e ) values reaching greater than 4.0, representing considerable epidemic growth, while others maintained low R e values. Interpretation: This study provides a high resolution view of HIV transmission in Victoria, Australia, and highlights the potential of molecular epidemiology to guide and enhance public health responses in this setting. This informs ongoing discussions with community groups on the acceptability and place of molecular epidemiological approaches in Australia. Funding: National Health and Medical Research Council, Australian Research Council.

Synthetic Alfalfa Infusion Odour Attracts Gravid Culex quinquefasciatus Under Laboratory Conditions.

Gravid culicine mosquitoes rely on olfactory cues for selecting breeding sites containing organic detritus. While this capacity of the mosquitoes is used for surveillance and control, the current methodology is unwieldy, unreliable and expensive in time and labour. This study evaluated the dose-dependent attraction and oviposition response of gravid Culex quinquefasciatus to alfalfa infusions. Through combined chemical and electrophysiological analyses, bioactive volatile organic compounds (VOCs) in the headspace of alfalfa infusions, eliciting attraction, were identified. While phenolic and indolic compounds were the most abundant bioactive VOCs, additional VOCs, including a monoterpene, were required to elicit a significant behavioural response to the synthetic odour blend of alfalfa infusions. Comparative analysis with the commercially available mosquito oviposition pheromone (MOP) was also conducted demonstrating that this standardised synthetic alfalfa infusion odour blend offers a promising lure for targeted surveillance and control of Culex mosquitoes, which may contribute to disease prevention and public health protection.

Admixture Mapping of Chronic Kidney Disease and Risk Factors in Hispanic/Latino Individuals From Central America Country of Origin.

BACKGROUND: Chronic kidney disease (CKD) is highly prevalent in Central America, and genetic factors may contribute to CKD risk. To understand the influences of genetic admixture on CKD susceptibility, we conducted an admixture mapping screening of CKD traits and risk factors in US Hispanic and Latino individuals from Central America country of origin. METHODS: We analyzed 1023 participants of HCHS/SOL (Hispanic Community Health Study/Study of Latinos) who reported 4 grandparents originating from the same Central America country. Ancestry admixture findings were validated on 8191 African Americans from WHI (Women's Health Initiative), 3141 American Indians from SHS (Strong Heart Study), and over 1.1 million European individuals from a multistudy meta-analysis. RESULTS: We identified 3 novel genomic regions for albuminuria (chromosome 14q24.2), CKD (chromosome 6q25.3), and type 2 diabetes (chromosome 3q22.2). The 14q24.2 locus driven by a Native American ancestry had a protective effect on albuminuria and consisted of 2 nearby regions spanning the RGS6 gene. Variants at this locus were validated in American Indians. The 6q25.3 African ancestry-derived locus, encompassing the ARID1B gene, was associated with increased risk for CKD and replicated in African Americans through admixture mapping. The European ancestry type 2 diabetes locus at 3q22.2, encompassing the EPHB1 and KY genes, was validated in European individuals through variant association. CONCLUSIONS: US Hispanic/Latino populations are culturally and genetically diverse. This study focusing on Central America grandparent country of origin provides new loci discovery and insights into the ancestry-of-origin influences on CKD and risk factors in US Hispanic and Latino individuals.

A deep-learning framework to predict cancer treatment response from histopathology images through imputed transcriptomics.

Advances in artificial intelligence have paved the way for leveraging hematoxylin and eosin-stained tumor slides for precision oncology. We present ENLIGHT-DeepPT, an indirect two-step approach consisting of (1) DeepPT, a deep-learning framework that predicts genome-wide tumor mRNA expression from slides, and (2) ENLIGHT, which predicts response to targeted and immune therapies from the inferred expression values. We show that DeepPT successfully predicts transcriptomics in all 16 The Cancer Genome Atlas cohorts tested and generalizes well to two independent datasets. ENLIGHT-DeepPT successfully predicts true responders in five independent patient cohorts involving four different treatments spanning six cancer types, with an overall odds ratio of 2.28 and a 39.5% increased response rate among predicted responders versus the baseline rate. Notably, its prediction accuracy, obtained without any training on the treatment data, is comparable to that achieved by directly predicting the response from the images, which requires specific training on the treatment evaluation cohorts.

HHV-8-associated diseases in transplantation: A case report and narrative review focused on diagnosis and prevention.

BACKGROUND: Human herpes virus 8 (HHV-8) or Kaposi sarcoma herpesvirus (KSHV) is an opportunistic oncovirus that causes multiple pathologic entities. METHODS: We present a case of fatal HHV-8-associated multisystem illness with disseminated Kaposi sarcoma and HHV8-associated lymphoproliferative disorder with systemic inflammation. We conducted a narrative review of the literature on HHV-8 in transplantation with a goal of illuminating the spectrum of HHV-8-associated diseases in this vulnerable population, modes of disease transmission, and the potential role for donor and recipient screening. RESULTS: HHV-8-associated KS, primary effusion lymphoma (PEL), multicentric Castleman disease (MCD), and KSHV inflammatory cytokine disorder (KICS) may affect transplant recipients; with the exception of KS, these conditions are rare but carry high morbidity and mortality. CONCLUSION: HHV-8-associated diseases have diverse and protean manifestations in transplant recipients, with potentially fatal outcomes. HHV-8 seroprevalence among organ donors and the magnitude of risk for donor-derived HHV-8 infection or clinically significant disease remain unknown and require further study.

Academic program enhancement supporting the success of undergraduate nursing students and graduates.

Nursing program administrators, faculty, academic success coaches, and remediation specialists have implemented many interventions in support of baccalaureate nursing students' retention and graduates' NCLEX-RN® first-time pass rates. A private university's undergraduate nursing program's team incorporated additional evidence-based interventions aimed improving students' achievement of benchmarks following a 3-year decline in NCLEX-RN pass rates. Interventions expanded the prelicensure academic program's activities using a continuous quality improvement approach. A simulation center was constructed and a director was hired. A consultant also facilitated faculty engagement in curricular revisions. A new position, coordinator tutor/remediation specialist, was filled and the academic success coach launched interventions that complemented an initial and subsequent strategies for success initiative. New interventions were trialed and evaluated and became integral to students' and graduates' success. The academic success coach's commitment to students' achievements promoted their engagement in interventions. Pass rates increased and were sustained. Examples of interventions, supported by evidence, are presented in tables for review. A logic model depicts components of the program plan and its interventions as augmented by prospective strategies and remediation interventions. Continuous quality improvement processes will continue. Students and graduates have commented positively on the benefits of the assorted, success-promoting interventions.

Adjunctive antimicrobial photodynamic therapy for treating periodontal and peri-implant diseases.

BACKGROUND: Periodontitis and peri-implant diseases are chronic inflammatory conditions occurring in the mouth. Left untreated, periodontitis progressively destroys the tooth-supporting apparatus. Peri-implant diseases occur in tissues around dental implants and are characterised by inflammation in the peri-implant mucosa and subsequent progressive loss of supporting bone. Treatment aims to clean the pockets around teeth or dental implants and prevent damage to surrounding soft tissue and bone, including improvement of oral hygiene, risk factor control (e.g. encouraging cessation of smoking) and surgical interventions. The key aspect of standard non-surgical treatment is the removal of the subgingival biofilm using subgingival instrumentation (SI) (also called scaling and root planing). Antimicrobial photodynamic therapy (aPDT) can be used an adjunctive treatment to SI. It uses light energy to kill micro-organisms that have been treated with a light-absorbing photosensitising agent immediately prior to aPDT. OBJECTIVES: To assess the effects of SI with adjunctive aPDT versus SI alone or with placebo aPDT for periodontitis and peri-implant diseases in adults. SEARCH METHODS: We searched the Cochrane Oral Health Trials Register, CENTRAL, MEDLINE, Embase, two other databases and two trials registers up to 14 February 2024. SELECTION CRITERIA: We included randomised controlled trials (RCTs) (both parallel-group and split-mouth design) in participants with a clinical diagnosis of periodontitis, peri-implantitis or peri-implant disease. We compared the adjunctive use of antimicrobial photodynamic therapy (aPDT), in which aPDT was given after subgingival or submucosal instrumentation (SI), versus SI alone or a combination of SI and a placebo aPDT given during the active or supportive phase of therapy. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures, and we used GRADE to assess the certainty of the evidence. We prioritised six outcomes and the measure of change from baseline to six months after treatment: probing pocket depth (PPD), bleeding on probing (BOP), clinical attachment level (CAL), gingival recession (REC), pocket closure and adverse effects related to aPDT. We were also interested in change in bone level (for participants with peri-implantitis), and participant satisfaction and quality of life. MAIN RESULTS: We included 50 RCTs with 1407 participants. Most studies used a split-mouth study design; only 18 studies used a parallel-group design. Studies were small, ranging from 10 participants to 88. Adjunctive aPDT was given in a single session in 39 studies, in multiple sessions (between two and four sessions) in 11 studies, and one study included both single and multiple sessions. SI was given using hand or power-driven instrumentation (or both), and was carried out prior to adjunctive aPDT. Five studies used placebo aPDT in the control group and we combined these in meta-analyses with studies in which SI alone was used. All studies included high or unclear risks of bias, such as selection bias or performance bias of personnel (when SI was carried out by an operator aware of group allocation). We downgraded the certainty of all the evidence owing to these risks of bias, as well as for unexplained statistical inconsistency in the pooled effect estimates or for imprecision when evidence was derived from very few participants and confidence intervals (CI) indicated possible benefit to both intervention and control groups. Adjunctive aPDT versus SI alone during active treatment of periodontitis (44 studies) We are very uncertain whether adjunctive aPDT during active treatment of periodontitis leads to improvement in any clinical outcomes at six months when compared to SI alone: PPD (mean difference (MD) 0.52 mm, 95% CI 0.31 to 0.74; 15 studies, 452 participants), BOP (MD 5.72%, 95% CI 1.62 to 9.81; 5 studies, 171 studies), CAL (MD 0.44 mm, 95% CI 0.24 to 0.64; 13 studies, 414 participants) and REC (MD 0.00, 95% CI -0.16 to 0.16; 4 studies, 95 participants); very low-certainty evidence. Any apparent differences between adjunctive aPDT and SI alone were not judged to be clinically important. Twenty-four studies (639 participants) observed no adverse effects related to aPDT (moderate-certainty evidence). No studies reported pocket closure at six months, participant satisfaction or quality of life. Adjunctive aPDT versus SI alone during supportive treatment of periodontitis (six studies) We were very uncertain whether adjunctive aPDT during active treatment of periodontitis leads to improvement in any clinical outcomes at six months when compared to SI alone: PPD (MD -0.04 mm, 95% CI -0.19 to 0.10; 3 studies, 125 participants), BOP (MD 4.98%, 95% CI -2.51 to 12.46; 3 studies, 127 participants), CAL (MD 0.07 mm, 95% CI -0.26 to 0.40; 2 studies, 85 participants) and REC (MD -0.20 mm, 95% CI -0.48 to 0.08; 1 study, 24 participants); very low-certainty evidence. These findings were all imprecise and included no clinically important benefits for aPDT. Three studies (134 participants) reported adverse effects: a single participant developed an abscess, though it is not evident whether this was related to aPDT, and two studies observed no adverse effects related to aPDT (moderate-certainty evidence). No studies reported pocket closure at six months, participant satisfaction or quality of life. AUTHORS' CONCLUSIONS: Because the certainty of the evidence is very low, we cannot be sure if adjunctive aPDT leads to improved clinical outcomes during the active or supportive treatment of periodontitis; moreover, results suggest that any improvements may be too small to be clinically important. The certainty of this evidence can only be increased by the inclusion of large, well-conducted RCTs that are appropriately analysed to account for change in outcome over time or within-participant split-mouth study designs (or both). We found no studies including people with peri-implantitis, and only one study including people with peri-implant mucositis, but this very small study reported no data at six months, warranting more evidence for adjunctive aPDT in this population group.

Oxidative Addition of (Hetero)aryl (Pseudo)halides at Palladium(0): Origin and Significance of Divergent Mechanisms.

Two limiting mechanisms are possible for oxidative addition of (hetero)aryl (pseudo)halides at Pd(0): a 3-centered concerted and a nucleophilic displacement mechanism. Until now, there has been little understanding about when each mechanism is relevant. Prior investigations to distinguish between these pathways were limited to a few specific combinations of the substrate and ligand. Here, we computationally evaluated over 180 transition structures for oxidative addition in order to determine mechanistic trends based on substrate, ligand(s), and coordination number. Natural abundance 13C kinetic isotope effects provide experimental results consistent with computational predictions. Key findings include that (1) differences in highest occupied molecular orbital (HOMO) symmetries dictate that, although 12e- PdL is strongly biased toward a 3-centered concerted mechanism, 14e- PdL2 often prefers a nucleophilic displacement mechanism; (2) ligand electronics and sterics, including ligand bite angle, influence the preferred mechanism of the reaction at PdL2; (3) phenyl triflate always reacts through a displacement mechanism regardless of the catalyst structure due to the stability of a triflate anion and the inability of oxygen to effectively donate electron density to Pd; and (4) the high reactivity of C-X bonds adjacent to nitrogen in pyridine substrates relates to stereoelectronic stabilization of a nucleophilic displacement transition state. This work has implications for controlling rate and selectivity in catalytic couplings, and we demonstrate application of the mechanistic insight toward chemodivergent cross-couplings of bromochloroheteroarenes.

Bringing optimised COVID-19 vaccine schedules to immunocompromised populations (BOOST-IC): study protocol for an adaptive randomised controlled clinical trial.

BACKGROUND: Immunocompromised hosts (ICH) experience more breakthrough infections and worse clinical outcomes following infection with COVID-19 than immunocompetent people. Prophylactic monoclonal antibody therapies can be challenging to access, and escape variants emerge rapidly. Immunity conferred through vaccination remains a central prevention strategy for COVID-19. COVID-19 vaccines do not elicit optimal immunity in ICH but boosting, through additional doses of vaccine improves humoral and cellular immune responses. This trial aims to assess the immunogenicity and safety of different COVID-19 vaccine booster strategies against SARS-CoV-2 for ICH in Australia. METHODS: Bringing optimised COVID-19 vaccine schedules to immunocompromised populations (BOOST-IC) is an adaptive randomised trial of one or two additional doses of COVID-19 vaccines 3 months apart in people living with HIV, solid organ transplant (SOT) recipients, or those who have haematological malignancies (chronic lymphocytic leukaemia, non-Hodgkin lymphoma or multiple myeloma). Key eligibility criteria include having received 3 to 7 doses of Australian Therapeutic Goods Administration (TGA)-approved COVID-19 vaccines at least 3 months earlier, and having not received SARS-CoV-2-specific monoclonal antibodies in the 3 months prior to receiving the study vaccine. The primary outcome is the geometric mean concentration of anti-spike SARS-CoV-2 immunoglobulin G (IgG) 28 days after the final dose of the study vaccine. Key secondary outcomes include anti-spike SARS-CoV-2 IgG titres and the proportion of people seroconverting 6 and 12 months after study vaccines, local and systemic reactions in the 7 days after vaccination, adverse events of special interest, COVID-19 infection, mortality and quality of life. DISCUSSION: This study will enhance the understanding of COVID-19 vaccine responses in ICH, and enable the development of safe, and optimised vaccine schedules in people with HIV, SOT, or haematological malignancy. TRIAL REGISTRATION: ClinicalTrials.gov NCT05556720. Registered on 23rd August 2022.

Urinary Metabolite Diagnostic and Prognostic Liquid Biopsy Biomarkers of Lung Cancer in Non-smokers and Tobacco Smokers.

PURPOSE: Non-smokers account for 10-13% of all lung cancer cases in the United States. Etiology is attributed to multiple risk factors including exposure to secondhand smoking, asbestos, environmental pollution, and radon, but these exposures are not within the current eligibility criteria for early lung cancer screening by low-dose computed tomography (LDCT). EXPERIMENTAL DESIGN: Urine samples were collected from two independent cohorts comprising 846 participants (exploratory cohort) and 505 participants (validation cohort). The cancer urinary biomarkers, creatine riboside (CR) and N-acetylneuraminic acid (NANA) were analyzed and quantified using liquid chromatography-mass spectrometry to determine if non-smoker cases can be distinguished from sex and age-matched controls in comparison to tobacco smoker cases and controls, potentially leading to more precise eligibility criteria for LDCT screening. RESULTS: Urinary levels of CR and NANA were significantly higher and comparable in non-smokers and tobacco smoker cases as compared to population controls in both cohorts. Receiver Operating Characteristics (ROC) analysis for combined CR and NANA levels in non-smokers of the exploratory cohort resulted in better predictive performance with the area under the curve (AUC) of 0.94, whereas the validation cohort non-smokers had an AUC of 0.80. Kaplan-Meier survival curves showed that high levels of CR and NANA were associated with increased cancer-specific death in non-smokers as well as tobacco smoker cases in both cohorts. CONCLUSIONS: Measuring CR and NANA in urine liquid biopsies could identify non-smokers at high risk for lung cancer as candidates for LDCT screening and warrant prospective studies of these biomarkers.

Global patterns in small-scale cannabis growers' distribution practices: Exploring the grower-distributor nexus.

BACKGROUND: While the supply of cannabis is commonly assumed to be dominated by criminal gangs, a sizable share of the domestic cannabis supply is provided by small-scale growers. This article examines the nature and scope of small-scale growers' distribution practices, with a particular focus on cross-country differences and variations between different types of grower-distributors, i.e., "non-suppliers", "exclusive social suppliers", "sharers and sellers" and "exclusive sellers". METHODS: Based on a large convenience web survey sample of predominantly small-scale cannabis growers from 18 countries, this article draws on data from two subsamples. The first subsample includes past-year growers in all 18 countries who answered questions regarding their market participation (n = 8,812). The second subsample includes past-year growers in 13 countries, who answered additional questions about their supply practices (n = 2,296). RESULTS: The majority of the cannabis growers engaged in distribution of surplus products, making them in effect "grower-distributors". Importantly, many did so as a secondary consequence of growing, and social supply (e.g., sharing and gifting) is much more common than selling. While growers who both shared and sold ("sharers and sellers"), and especially those who only sold ("exclusive sellers"), grew a higher number of plants and were most likely to grow due to a wish to sell for profits, the majority of these are best described as small-scale sellers. That is, the profit motive for growing was often secondary to non-financial motives and most sold to a limited number of persons in their close social network. CONCLUSION: We discuss the implications of the findings on the structural process of import-substitution in low-end cannabis markets, including a growing normalization of cannabis supply.

The Stigma and Infertility-Related Stress of Chinese Infertile Women: A Cross-Sectional Study.

OBJECTIVES: This study was conducted to investigate the stigma status of infertile women in China and to determine the influencing factors. METHODS: 366 infertile women from the gynecological and reproductive departments of two tertiary hospitals completed socio-demographic questionnaires, the Infertility Stigma Scale (ISS) and the Mandarin Fertility Problem Inventory (M-FPI). RESULTS: The scores of stigma and infertility-related stress in infertile women were (52.51 ± 17.74) and (150.03 ± 17.51), respectively. Multiple regression analysis found that location of residence, regarding children as the most important thing in life, talking to others about infertility and infertility-related stress were the main influencing factors of stigma in infertile women, which explained 17.3% of the total variance. CONCLUSIONS: In the current study, the level of stigma in women with infertility was at the middle range. Location of residence, regarding children as the most important thing in life, whether to talk with others about infertility and infertility-related stress were the four main influencing factors of stigma.

Nickel-Based Catalysts for the Selective Monoarylation of Dichloropyridines: Ligand Effects and Mechanistic Insights.

This report describes a detailed study of Ni phosphine catalysts for the Suzuki-Miyaura coupling of dichloropyridines with halogen-containing (hetero)aryl boronic acids. With most phosphine ligands these transformations afford mixtures of mono- and diarylated cross-coupling products as well as competing oligomerization of the boronic acid. However, a ligand screen revealed that PPh2Me and PPh3 afford high yield and selectivity for monoarylation over diarylation as well as minimal competing oligomerization of the boronic acid. Several key observations were made regarding the selectivity of these reactions, including: (1) phosphine ligands that afford high selectivity for monoarylation fall within a narrow range of Tolman cone angles (between 136° and 157°); (2) more electron-rich trialkylphosphines afford predominantly diarylated products, while less-electron rich di- and triarylphosphines favor monoarylation; (3) diarylation proceeds via intramolecular oxidative addition; and (4) the solvent (MeCN) plays a crucial role in achieving high monoarylation selectivity. Experimental and DFT studies suggest that all these data can be explained based on the reactivity of a key intermediate: a Ni0-π complex of the monoarylated product. With larger, more electron-rich trialkylphosphine ligands, this π complex undergoes intramolecular oxidative addition faster than ligand substitution by the MeCN solvent, leading to selective diarylation. In contrast, with relatively small di- and triarylphosphine ligands, associative ligand substitution by MeCN is competitive with oxidative addition, resulting in selective formation of monoarylated products. The generality of this method is demonstrated with a variety of dichloropyridines and chloro-substituted aryl boronic acids. Furthermore, the optimal ligand (PPh2Me) and solvent (MeCN) are leveraged to achieve the Ni-catalyzed monoarylation of a broader set of dichloroarene substrates.

Mechanistic Origin of Ligand Effects on Exhaustive Functionalization During Pd-Catalyzed Cross-Coupling of Dihaloarenes.

We describe a detailed investigation into why bulky ligands-those that enable catalysis at "12e -" Pd0-tend to promote overfunctionalization during Pd-catalyzed cross-couplings of dihalogenated substrates. After one cross-coupling event takes place, PdL initially remains coordinated to the π system of the nascent product. Selectivity for mono- vs. difunctionalization arises from the relative rates of π-decomplexation versus a second oxidative addition. Under the Suzuki coupling conditions in this work, direct dissociation of 12e - PdL from the π-complex cannot outcompete oxidative addition. Instead, Pd must be displaced from the π-complex as 14e - PdL(L') by a second incoming ligand L'. The incoming ligand is another molecule of dichloroarene if the reaction conditions do not include π-coordinating solvents or additives. More overfunctionalization tends to result when increased ligand or substrate sterics raises the energy of the bimolecular transition state for separating 14e - PdL(L') from the mono-cross-coupled product. This work has practical implications for optimizing selectivity in cross-couplings involving multiple halogens. For example, we demonstrate that small coordinating additives like DMSO can largely suppress overfunctionalization and that precatalyst structure can also impact selectivity.

Response to COVID-19 vaccination imaged by PD-L1 PET scanning.

BACKGROUND: During a phase 0 clinical trial of an investigational programmed cell death ligand-1 (PD-L1) PET tracer in patients with non-small cell lung cancer (NSCLC), three patients received booster doses of COVID-19 vaccines before PD-L1 imaging. METHODS: Five patients underwent whole-body PET/CT imaging with a novel PD-L1 tracer, constructed by attaching 89Zr to the anti PD-L1 antibody durvalumab. Intramuscular (deltoid) booster doses of mRNA BNT162b2 COVID-19 mRNA vaccine were coincidentally given to three patients in the month before PD-L1 tracer injection. RESULTS: Two recently-vaccinated patients, in remission of NSCLC and receiving non-immunosuppressive cancer therapies (immunotherapy and tyrosine kinase inhibitor respectively), showed increasing PD-L1 tracer uptake in ipsilateral axillary lymph nodes. No asymmetric nodal uptake was seen in a third recently-vaccinated patient who was receiving immunosuppressive chemotherapy, or in two patients not recently-vaccinated. CONCLUSION: Immune response to mRNA BNT162b2 vaccination may involve regulation by PD-L1 positive immune cells in local draining lymph nodes in immunocompetent patients. TRIAL REGISTRATION: This trial was registered with the Australian New Zealand Clinical Trials Registry. Registration number ACTRN12621000171819. Date of Trial Registration 8/2/2021. Date of enrolment of 1st patient 11/4/2021. URL of trial registry record: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12621000171819 .

Selective nitration of Hsp90 acts as a metabolic switch promoting tumor cell proliferation.

Tumors develop in an oxidative environment characterized by peroxynitrite production and downstream protein tyrosine (Y) nitration. We showed that tyrosine nitration supports schwannoma cell proliferation and regulates cell metabolism in the inheritable tumor disorder NF2-related Schwannomatosis (NF2-SWN). Here, we identified the chaperone Heat shock protein 90 (Hsp90) as the first nitrated protein that acts as a metabolic switch to promote schwannoma cell proliferation. Doubling the endogenous levels of nitrated Hsp90 in schwannoma cells or supplementing nitrated Hsp90 into normal Schwann cells increased their proliferation. Metabolically, nitration on either Y33 or Y56 conferred Hsp90 distinct functions; nitration at Y33 (Hsp90NY33) down-regulated mitochondrial oxidative phosphorylation, while nitration at Y56 (Hsp90NY56) increased glycolysis by activating the purinergic receptor P2X7 in both schwannoma and normal Schwann cells. Hsp90NY33 and Hsp90NY56 showed differential subcellular and spatial distribution corresponding with their metabolic and proliferative functions in schwannoma three-dimensional cell culture models. Collectively, these results underscore the role of tyrosine nitration as a post-translational modification regulating critical cellular processes. Nitrated proteins, particularly nitrated Hsp90, emerge as a novel category of tumor-directed therapeutic targets.

Prevalence and burden of difficult-to-treat and severe asthma in Australia: A national population survey.

BACKGROUND AND OBJECTIVE: Most evidence about difficult-to-treat and severe asthma (DTTA) comes from clinical trials and registries. We aimed to identify people with DTTA from a large nationally representative asthma population and describe their characteristics and healthcare utilization compared with people whose asthma was not 'difficult-to-treat'. METHODS: We conducted a cross-sectional survey of Australians aged ≥18 years with current asthma from large web-based survey panels. Enrolment was stratified by gender, age-group and state/territory based on national population data for people with asthma. Difficult-to-treat or severe asthma was defined by poor symptom control, exacerbations and/or oral corticosteroid/biologic use despite medium/high-dose inhaled therapy. Outcomes included exacerbations, healthcare utilization, multimorbidity, quality of life and coronavirus disease of 2019 (COVID-19)-related behaviour. Weighted data were analysed using SAS version 9.4. RESULTS: The survey was conducted in February-March 2021. The weighted sample comprised 6048 adults with current asthma (average age 47.3 ± SD 18.1 years, 59.9% female), with 1313 (21.7%) satisfying ≥1 DTTA criteria. Of these, 50.4% had very poorly controlled symptoms (Asthma Control Test ≤15), 36.2% were current smokers, and 85.4% had ≥1 additional chronic condition, most commonly anxiety/depression. More than twice as many participants with DTTA versus non-DTTA had ≥1 urgent general practitioner (GP) visit (61.4% vs. 27.5%, OR 4.8 [4.2-5.5, p < 0.0001]), or ≥1 emergency room visit (41.9% vs. 17.9%, OR 3.8 [3.3-4.4, p < 0.0001]) in the previous 12 months. CONCLUSION: Our findings emphasize the burden of uncontrolled symptoms, current smoking, multimorbidity and healthcare utilization in people with DTTA in the community, who may be under-represented in registries or clinical trials.

Simultaneous estimation of genotype error and uncalled deletion rates in whole genome sequence data.

Genotype data include errors that may influence conclusions reached by downstream statistical analyses. Previous studies have estimated genotype error rates from discrepancies in human pedigree data, such as Mendelian inconsistent genotypes or apparent phase violations. However, uncalled deletions, which generally have not been accounted for in these studies, can lead to biased error rate estimates. In this study, we propose a genotype error model that considers both genotype errors and uncalled deletions when calculating the likelihood of the observed genotypes in parent-offspring trios. Using simulations, we show that when there are uncalled deletions, our model produces genotype error rate estimates that are less biased than estimates from a model that does not account for these deletions. We applied our model to SNVs in 77 sequenced White British parent-offspring trios in the UK Biobank. We use the Akaike information criterion to show that our model fits the data better than a model that does not account for uncalled deletions. We estimate the genotype error rate at SNVs with minor allele frequency > 0.001 in these data to be [Formula: see text]. We estimate that 77% of the genotype errors at these markers are attributable to uncalled deletions [Formula: see text].