Molecular and physiologic changes in the SpaceX Inspiration4 civilian crew.

Human spaceflight has historically been managed by government agencies, such as the NASA Twins Study1, but new commercial spaceflight opportunities have opened spaceflight to a broader population. In 2021, the SpaceX Inspiration4 mission launched the first-ever all civilian crew to low Earth orbit, which included the youngest American astronaut (age 29), novel in-flight experimental technologies (handheld ultrasound imaging, smartwatch wearables, and immune profiling), ocular alignment measurements, and new protocols for in-depth, multi-omic molecular and cellular profiling. Here we report the primary findings from the 3-day spaceflight mission, which induced a broad range of physiological and stress responses, neurovestibular changes indexed by ocular misalignment, and altered neurocognitive functioning, some of which match long-term spaceflight2, but almost all of which did not differ from baseline (pre-flight) after return to Earth. Overall, these preliminary civilian spaceflight data suggest that short-duration missions do not pose a significant health risk, and moreover present a rich opportunity to measure the earliest phases of adaptation to spaceflight in the human body at anatomical, cellular, physiologic, and cognitive levels. Finally, these methods and results lay the foundation for an open, rapidly expanding biomedical database for astronauts3, which can inform countermeasure development for both private and government-sponsored space missions.

A sustained high-temperature fusion plasma regime facilitated by fast ions.

Nuclear fusion is one of the most attractive alternatives to carbon-dependent energy sources1. Harnessing energy from nuclear fusion in a large reactor scale, however, still presents many scientific challenges despite the many years of research and steady advances in magnetic confinement approaches. State-of-the-art magnetic fusion devices cannot yet achieve a sustainable fusion performance, which requires a high temperature above 100 million kelvin and sufficient control of instabilities to ensure steady-state operation on the order of tens of seconds2,3. Here we report experiments at the Korea Superconducting Tokamak Advanced Research4 device producing a plasma fusion regime that satisfies most of the above requirements: thanks to abundant fast ions stabilizing the core plasma turbulence, we generate plasmas at a temperature of 100 million kelvin lasting up to 20 seconds without plasma edge instabilities or impurity accumulation. A low plasma density combined with a moderate input power for operation is key to establishing this regime by preserving a high fraction of fast ions. This regime is rarely subject to disruption and can be sustained reliably even without a sophisticated control, and thus represents a promising path towards commercial fusion reactors.

Nano-compositional imaging of the lanthanum silicide system at THz wavelengths.

Terahertz scattering-type scanning near-field optical microscopy (THz-sSNOM) provides a noninvasive way to probe the low frequency conductivity of materials and to characterize material compositions at the nanoscale. However, the potential capability of atomic compositional analysis with THz nanoscopy remains largely unexplored. Here, we perform THz near-field imaging and spectroscopy on a model rare-earth alloy of lanthanum silicide (La-Si) which is known to exhibit diverse compositional and structural phases. We identify subwavelength spatial variations in conductivity that is manifested as alloy microstructures down to much less than 1 µm in size and is remarkably distinct from the surface topography of the material. Signal contrasts from the near-field scattering responses enable mapping the local silicon/lanthanum content differences. These observations demonstrate that THz-sSNOM offers a new avenue to investigate the compositional heterogeneity of material phases and their related nanoscale electrical as well as optical properties.

Accuracy of artificial intelligence-assisted growth prediction in skeletal Class I preadolescent patients using serial lateral cephalograms for a 2-year growth interval.

OBJECTIVE: To investigate the accuracy of artificial intelligence-assisted growth prediction using a convolutional neural network (CNN) algorithm and longitudinal lateral cephalograms (Lat-cephs). MATERIALS AND METHODS: A total of 198 Japanese preadolescent children, who had skeletal Class I malocclusion and whose Lat-cephs were available at age 8 years (T0) and 10 years (T1), were allocated into the training, validation, and test phases (n = 161, n = 17, n = 20). Orthodontists and the CNN model identified 28 hard-tissue landmarks (HTL) and 19 soft-tissue landmarks (STL). The mean prediction error values were defined as 'excellent,' 'very good,' 'good,' 'acceptable,' and 'unsatisfactory' (criteria: 0.5 mm, 1.0 mm, 1.5 mm, and 2.0 mm, respectively). The degree of accurate prediction percentage (APP) was defined as 'very high,' 'high,' 'medium,' and 'low' (criteria: 90%, 70%, and 50%, respectively) according to the percentage of subjects that showed the error range within 1.5 mm. RESULTS: All HTLs showed acceptable-to-excellent mean PE values, while the STLs Pog', Gn', and Me' showed unsatisfactory values, and the rest showed good-to-acceptable values. Regarding the degree of APP, HTLs Ba, ramus posterior, Pm, Pog, B-point, Me, and mandibular first molar root apex exhibited low APPs. The STLs labrale superius, lower embrasure, lower lip, point of lower profile, B', Pog,' Gn' and Me' also exhibited low APPs. The remainder of HTLs and STLs showed medium-to-very high APPs. CONCLUSION: Despite the possibility of using the CNN model to predict growth, further studies are needed to improve the prediction accuracy in HTLs and STLs of the chin area.

Widening disparities in the national prevalence of diabetes mellitus for people with disabilities in South Korea.

OBJECTIVES: In Korea, diabetes mellitus has a high disease burden, based on disability-adjusted life years. However, the disease burden is disproportionately distributed, with people with disabilities (PWD) experiencing higher rates of health disparities. Our study investigated long-term trends in diabetes prevalence and risk according to disability status, grade, and type. STUDY DESIGN: Retrospective cohort study. METHODS: Approximately 10 million individuals aged ≥30 years were included yearly from the National Health Information Database (NHID) and national disability registration data in Korea between 2008 and 2017, corresponding to 40 % of those aged ≥30 years in Korea. In 2017, 12, 975, 757 individuals were included; 5.5 % had disabilities. We estimated annual diabetes age-standardized prevalence and used multiple logistic regression analyses to estimate the odds of having diabetes in 2017, according to disability status, severity, and type. RESULTS: Diabetes age-standardized prevalence consistently increased over 2008-2017 in PWD and people without disabilities. However, the prevalence increased more rapidly and was higher in all years among PWD, with widening disparities based on disability status. Additionally, diabetes prevalence was high in all years for specific subgroups, including women, individuals with intellectual or mental disabilities or autism, and individuals with severe disabilities, suggesting further disparities among PWD. CONCLUSIONS: Our findings reveal health disparities between those with and without disabilities and among PWD subgroups. In addition to timely prevention, diabetes screening and management among PWD is vital. Public investment in improving disparities in the root causes of diabetes is essential, including health behaviours, healthcare utilization, and self-care.

The Glasgow Microenvironment Score and risk and site of recurrence in TNM I-III colorectal cancer.

BACKGROUND: Glasgow Microenvironment Score (GMS) stratifies long-term survival into three groups based on tumour phenotype: peritumoural inflammation (Klintrup-Mäkinen (KM)) and tumour stroma percentage (TSP). However, it is not known if the location of disease recurrence is influenced by the GMS category. METHODS: Seven hundred and eighty-three TNM I-III colorectal cancers (CRC) were included. GMS (GMS0-high KM; GMS1-low KM, low TSP; GMS2-low KM, high TSP) and cancer-specific survival (CSS), overall survival (OS) and disease recurrence were assessed using Cox regression analysis. RESULTS: Of the 783 patients, 221 developed CRC recurrence; 65 developed local recurrence + systemic disease. GMS was independent for CSS (HR 1.50, 95% CI 1.17-1.92, p < 0.001) and OS (HR 1.23, 1.05-1.44, p = 0.01). Higher GMS category was associated with T-stage, N-stage, emergency presentation and venous invasion. GMS was independent for local+systemic recurrence (HR 11.53, 95% CI 1.45-91.85, p = 0.04) and distant-only recurrence (HR 3.01, 95% CI 1.59-5.71, p = 0.002). GMS 2 disease did not appear to have statistically better outcomes with adjuvant chemotherapy in high-risk disease. CONCLUSION: Although confounded by a higher rate of T4 and node-positive disease, GMS 1 and 2 are associated with an increased risk of local and distant recurrence. GMS is an independent poor prognostic indicator for recurrent colorectal cancer. Higher GMS patients may benefit from enhanced postoperative surveillance.

A phase I trial of LXS196, a protein kinase C (PKC) inhibitor, for metastatic uveal melanoma.

BACKGROUND: Up to 50% of patients with uveal melanoma develop metastases (MUM) with a poor prognosis and median overall survival of approximately 1 year. METHODS: This phase I study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of the oral protein kinase C inhibitor LXS196 in 68 patients with MUM (NCT02601378). Patients received LXS196 doses ranging from 100-1000 mg once daily (QD; n = 38) and 200-400 mg twice daily (BID; n = 30). RESULTS: First cycle dose-limiting toxicities (DLTs) were observed in 7/38 (18.4%) QD and 2/17 (11.8%) BID patients. Hypotension was the most common DLT, occurring at doses ≥500 mg/day, and manageable with LXS196 interruption and dose reduction. Median duration of exposure to LXS196 was 3.71 months (range: 1.81-15.28) for QD and 4.6 months (range: 0.33-58.32) for BID dosing. Clinical activity was observed in 6/66 (9.1%) evaluable patients achieving response (CR/PR), with a median duration of response of 10.15 months (range: 2.99-41.95); 45/66 had stable disease (SD) per RECIST v1.1. At 300 mg BID, the recommended dose for expansion, 2/18 (11.1%) evaluable patients achieved PR and 12/18 (66.7%) had SD. CONCLUSION: These results suggest manageable toxicity and encouraging clinical activity of single-agent LXS196 in patients with MUM.

Impact of changes in clinical practice guidelines for intra-articular injection treatments for knee osteoarthritis on public interest and social media.

OBJECTIVE: To summarize changes in recommendations for injection treatments for knee osteoarthritis (OA) in current clinical practice guidelines (CPGs) and to assess whether these changes have affected public interest according to Google data and content in YouTube videos. DESIGN: A literature search to identify CPGs revised since 2019 that provide recommendations regarding the five intra-articular injection treatments for knee OA (corticosteroid [CS], hyaluronic acid [HA], stem cell [SC], platelet-rich plasma [PRP], and botulinum toxin [BT]) was conducted to assess perspective changes for each treatment. Data from Google Trends were examined to identify changes in search volume from 2004 to 2021 using a join-point regression model. Relevant YouTube videos were divided into those uploaded before and after changes in CPGs and compared according to degrees of recommendation for each treatment to identify the effect of changes in CPGs on video production. RESULTS: All eight identified CPGs released after 2019 recommended HA and CS use. Most CPGs were the first to state a neutral or opposing stance concerning the use of SC, PRP, or BT. Interestingly, relative searches on Google for SC, PRP, and BT has increased greater than those for CS and HA. YouTube videos produced after CPGs changed continue to recommend SC, PRP, and BT as much as those produced before CPGs were revised. CONCLUSIONS: Although knee OA CPGs have changed, public interest and healthcare information providers on YouTube have not reacted to this shift. Improved methods to propagate updates to CPGs warrant consideration.

Hormonal stimulation reduces numbers and impairs function of human uterine natural killer cells during implantation.

STUDY QUESTION: How does an altered maternal hormonal environment, such as that seen during superovulation with gonadotropins in ART, impact human uterine immune cell distribution and function during the window of implantation? SUMMARY ANSWER: Hormonal stimulation with gonadotropins alters abundance of maternal immune cells including uterine natural killer (uNK) cells and reduces uNK cell ability to promote extravillous trophoblast (EVT) invasion. WHAT IS KNOWN ALREADY: An altered maternal hormonal environment, seen following ART, can lead to increased risk for adverse perinatal outcomes associated with disordered placentation. Maternal immune cells play an essential role in invasion of EVTs, a process required for proper establishment of the placenta, and adverse perinatal outcomes have been associated with altered immune cell populations. How ART impacts maternal immune cells and whether this can in turn affect implantation and placentation in humans remain unknown. STUDY DESIGN, SIZE, DURATION: A prospective cohort study was carried out between 2018 and 2021 on 51 subjects: 20 from natural cycles 8 days after LH surge; and 31 from stimulated IVF cycles 7 days after egg retrieval. PARTICIPANTS/MATERIALS, SETTING, METHODS: Endometrial biopsies and peripheral blood samples were collected during the window of implantation in subjects with regular menstrual cycles or undergoing superovulation. Serum estradiol and progesterone levels were measured by chemiluminescent competitive immunoassay. Immune cell populations in blood and endometrium were analyzed using flow cytometry. uNK cells were purified using fluorescence-activated cell sorting and were subjected to RNA sequencing (RNA-seq). Functional changes in uNK cells due to hormonal stimulation were evaluated using the implantation-on-a-chip (IOC) device, a novel bioengineered platform using human primary cells that mimics early processes that occur during pregnancy in a physiologically relevant manner. Unpaired t-tests, one-way ANOVA, and pairwise multiple comparison tests were used to statistically evaluate differences. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics were comparable for both groups. As expected, serum estradiol levels on the day of biopsy were significantly higher in stimulated (superovulated) patients (P = 0.0005). In the setting of superovulation, we found an endometrium-specific reduction in the density of bulk CD56+ uNK cells (P < 0.05), as well as in the uNK3 subpopulation (P = 0.025) specifically (CD103+ NK cells). In stimulated samples, we also found that the proportion of endometrial B cells was increased (P < 0.0001). Our findings were specific to the endometrium and not seen in peripheral blood. On the IOC device, uNK cells from naturally cycling secretory endometrium promote EVT invasion (P = 0.03). However, uNK cells from hormonally stimulated endometrium were unable to significantly promote EVT invasion, as measured by area of invasion, depth of invasion, and number of invaded EVTs by area. Bulk RNA-seq of sorted uNK cells from stimulated and unstimulated endometrium revealed changes in signaling pathways associated with immune cell trafficking/movement and inflammation. LIMITATIONS, REASONS FOR CAUTION: Patient numbers utilized for the study were low but were enough to identify significant overall population differences in select immune cell types. With additional power and deeper immune phenotyping, we may detect additional differences in immune cell composition of blood and endometrium in the setting of hormonal stimulation. Flow cytometry was performed on targeted immune cell populations that have shown involvement in early pregnancy. A more unbiased approach might identify changes in novel maternal immune cells not investigated in this study. We performed RNA-seq only on uNK cells, which demonstrated differences in gene expression. Ovarian stimulation may also impact gene expression and function of other subsets of immune cells, as well as other cell types within the endometrium. Finally, the IOC device, while a major improvement over existing in vitro methods to study early pregnancy, does not include all possible maternal cells present during early pregnancy, which could impact functional effects seen. Immune cells other than uNK cells may impact invasion of EVTs in vitro and in vivo, though these remain to be tested. WIDER IMPLICATIONS OF THE FINDINGS: These findings demonstrate that hormonal stimulation affects the distribution of uNK cells during the implantation window and reduces the proinvasive effects of uNK cells during early pregnancy. Our results provide a potential mechanism by which fresh IVF cycles may increase risk of disorders of placentation, previously linked to adverse perinatal outcomes. STUDY FUNDING/COMPETING INTEREST(S): Research reported in this publication was supported by the University of Pennsylvania University Research Funding (to M.M.), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD068157 to M.M., S.S., and S.M.), National Center for Advancing Translational Sciences of the National Institutes of Health (TL1TR001880 to J.K.), the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania, the Children's Hospital of Philadelphia Research Institute (to S.M.G.), and the National Institute of Allergy and Infectious Diseases (K08AI151265 to S.M.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Effect of pneumatic leg compression on post-induction hypotension in elderly patients undergoing robot-assisted laparoscopic prostatectomy: a double-blind randomised controlled trial.

Post-induction hypotension is common and associated with postoperative complications. We hypothesised that pneumatic leg compression reduces post-induction hypotension in elderly patients undergoing robot-assisted laparoscopic prostatectomy. In this double-blind randomised study, patients were allocated randomly to the pneumatic leg compression group (n = 50) or control (n = 50). In the intervention group, pneumatic leg compression was initiated before induction of anaesthesia. In the control group, pneumatic leg compression was initiated 20 min after anaesthesia induction. The primary outcome was the incidence of post-induction hypotension in these groups. Post-induction hypotension was defined as systolic blood pressure < 90 mmHg during the first 20 min after induction. Haemodynamic variables and area under the curve of post-induction systolic blood pressure over time were assessed. Complications associated with pneumatic leg compression were recorded, including: peripheral neuropathy; compartment syndrome; extensive bullae beneath the leg sleeves; and pulmonary thromboembolism. The incidence of post-induction hypotension decreased in the pneumatic leg compression group compared with that in the control group; 5 (10%) vs. 29 (58%), respectively, p < 0.001. In the pneumatic leg compression group, the lowest systolic, diastolic and mean blood pressures 20 min after induction of anaesthesia were significantly greater than the control group. Pneumatic leg compression resulted in an increased area under the curve of systolic blood pressure in the first 20 min after induction, p = 0.001. There were no pneumatic leg compression-related complications. Pneumatic leg compression reduced post-induction hypotension in elderly patients undergoing robot-assisted laparoscopic prostatectomy, suggesting that it is an effective and safe intervention to prevent post-induction hypotension among elderly patients undergoing general anaesthesia.

Upregulation of virulence genes promotes Vibrio cholerae biofilm hyperinfectivity.

Vibrio cholerae remains a major global health threat, disproportionately impacting parts of the world without adequate infrastructure and sanitation resources. In aquatic environments, V. cholerae exists both as planktonic cells and as biofilms, which are held together by an extracellular matrix. V. cholerae biofilms have been shown to be hyperinfective, but the mechanism of hyperinfectivity is unclear. Here we show that biofilm-grown cells, irrespective of the surfaces on which they are formed, are able to markedly outcompete planktonic-grown cells in the infant mouse. Using an imaging technique designed to render intestinal tissue optically transparent and preserve the spatial integrity of infected intestines, we reveal and compare three-dimensional V. cholerae colonization patterns of planktonic-grown and biofilm-grown cells. Quantitative image analyses show that V. cholerae colonizes mainly the medial portion of the small intestine and that both the abundance and localization patterns of biofilm-grown cells differ from that of planktonic-grown cells. In vitro biofilm-grown cells activate expression of the virulence cascade, including the toxin coregulated pilus (TCP), and are able to acquire the cholera toxin-carrying CTXФ phage. Overall, virulence factor gene expression is also higher in vivo when infected with biofilm-grown cells, and modulation of their regulation is sufficient to cause the biofilm hyperinfectivity phenotype. Together, these results indicate that the altered biogeography of biofilm-grown cells and their enhanced production of virulence factors in the intestine underpin the biofilm hyperinfectivity phenotype.

Nationwide prevalence and trends in cigarette smoking among adult men with and without disabilities in South Korea between 2009 and 2017.

OBJECTIVES: Current smoking rates for people with and without disabilities vary among countries. This study analyzed smoking behavior over 9 years in adult South Korean men with disabilities, according to disability severity and type, and in those without disabilities. STUDY DESIGN: This was a cross-sectional study. METHODS: This analysis was conducted using national disability registration data and national general health checkup data for 2009-2017. Age-standardized smoking behaviors were analyzed for each year according to the presence, severity, and type of disability. The odds of current smoking were determined by multivariate logistic regression after adjusting for sociodemographic and clinical variables. RESULTS: The age-standardized smoking rate and average number of cigarettes for men with mild disabilities in the younger age group were 1.16 (43.0 vs 36.8%) and 1.05 (16.1 vs 15.3 cigarettes) times higher than in non-disabled men as of 2017. The highest smoking rate was observed in men with physical disabilities in the younger age. In the older age group, the highest smoking rate was that of men with intellectual or psychological disabilities. CONCLUSION: Smoking behaviors remained poorest in men with disabilities, especially those with mild, physical, and intellectual/psychological disabilities. Public health policies should focus on people with disabilities to promote health, prevent secondary conditions, and reduce health disparities by implementing antismoking health policies.

Approximate extraction of late-time returns via morphological component analysis.

A fundamental challenge in acoustic data processing is to separate a measured time series into relevant phenomenological components. A given measurement is typically assumed to be an additive mixture of myriad signals plus noise whose separation forms an ill-posed inverse problem. In the setting of sensing elastic objects using active sonar, we wish to separate the early-time return from the object's geometry from late-time returns caused by elastic or compressional wave coupling. Under the framework of morphological component analysis (MCA), we compare two separation models using the short-duration and long-duration responses as a proxy for early-time and late-time returns. Results are computed for a broadside response using Stanton's elastic cylinder model as well as on experimental data taken from an in-air circular synthetic aperture sonar system, whose separated time series are formed into imagery. We find that MCA can be used to separate early and late-time responses in both the analytic and experimental cases without the use of time-gating. The separation process is demonstrated to be compatible with image reconstruction. The best separation results are obtained with a flexible, but computationally intensive, frame based signal model, while a faster Fourier transform based method is shown to have competitive performance.

Health and job-related factors associated with work ability in older working populations of Korea.

BACKGROUND: Knowledge about determinants of workability is crucial for designing interventions to increase the participation of older employees in the workforce and maintain or increase their productivity levels at work. AIMS: This study explored the impact of health conditions and job characteristics on poor work ability. METHODS: This study used data from the Korean Longitudinal Study of Aging (KLoSA) from 2014 to 2020, which is a nationally representative population-based panel study of Korean citizens aged ≥45 years. The KLoSA survey assessed subjective work ability using work ability score. The participants were asked if they had been diagnosed with any underlying diseases by a physician. The job characteristics were assessed in terms of working conditions and satisfaction. Generalized estimating equations were used to calculate the odds ratios (ORs) and 95% confidence intervals for workers' health-related variables and job characteristics associated with poor work ability. RESULTS: The results showed that workers' health-related factors were associated with poor work ability; poor vision (OR = 1.52) and bad hearing ability (OR = 2.37); low gripping strength (OR = 2.29); poor self-rated health (OR = 3.77) and various diseases such as hypertension, diabetes, cancer, chronic lung disease, liver disease, heart disease, cerebrovascular disease, mental illness, arthritis, prostate disease, gastrointestinal disease and disc disease. Additionally, high physical work demands (OR = 1.51) and low job satisfaction (OR = 4.23) were highly correlated with poor work ability. CONCLUSIONS: The findings addressing poor work abilities caused by individuals' health- and job-related factors can help prioritize worker health management and the development of more effective human capital investment strategies at the workplace.

Resection of the femoral neck: a new technique for the treatment of mallory type I intraoperative femoral fracture during total hip arthroplasty.

Intraoperative femoral fracture is a common complication during cementless total hip arthroplasty (THA). Cerclage wiring has been used for this type of fractures to attain intraoperative stability of the femoral stem. We designed a new technique to treat Mallory type 1 intraoperative femoral fractures. We excised fractured femoral neck fragment and without additional fixation and lightly tapped down the femoral stem to obtain a tight contact to the femoral cortex at the subtrochanteric level. In this case series, we described this technique and reported its outcomes. From January 2015 to December 2017, 600 cementless THAs (557 patients) were done with use of a proximally coated tapered stem design at our department. Among the 600 THAs, Mallory type 1 intraoperative femoral fracture occurred in 8 hips (8 patients), and all of them were treated with the excision of the fractured femoral neck. Mean age of the 8 patients was 58.1 years (range, 30.4 to 81.3 years) at the time of surgery. We report the results of this new technique at postoperative 2 to 5 years (mean, 3.4 years). All stems were placed in the neutral position. There was no revision and no stem showed any evidence of subsidence or loosening during the follow-up. The mean Harris hip score was 85.9 points at the latest follow-up. We recommend to use the femoral neck excision technique for the treatment of Mallory type 1 intraoperative femoral fractures.

Genomic Features and Classification of Homologous Recombination Deficient Pancreatic Ductal Adenocarcinoma.

BACKGROUND AND AIMS: Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline (g) alterations in BRCA1, BRCA2, and PALB2. METHODS: We interrogated whole genome sequencing (WGS) data on 391 patients, including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included (1) the genomic instability score (GIS) used by Myriad's MyChoice HRD assay; (2) substitution base signature 3 (SBS3); (3) HRDetect; and (4) structural variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status. RESULTS: Biallelic tumor inactivation of gBRCA or PALB2 was evident in 43 of 49 germline carriers identifying HRD-PDAC. HRDetect (score ≥0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumor classifiers suggested that 7% to 10% of PDACs that do not harbor gBRCA/PALB2 have features of HRD. Of the somatic HRDetecthi cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D, and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared with BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC; however in advanced disease the GIS (P = .02), SBS3 (P = .03), and HRDetect score (P = .005) were predictive of platinum response and superior survival. PVs in gATM (n = 6) or gCHEK2 (n = 2) did not result in HRD-PDAC by any of the classifiers. In 4 patients, BRCA2 reversion mutations associated with platinum resistance. CONCLUSIONS: Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7% to 10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.

Global Forum of Cancer Surgeons: Cancer Surgery During the COVID-19 Pandemic: Impact and Lessons Learned.

BACKGROUND: The purpose of this article is to summarize the opinions of the surgical oncology leaders from the Global Forum of Cancer Surgeons (GFCS) about the global impact of COVID-19 pandemic on cancer surgery. METHODS: A panel session (virtual) was held at the annual Society of Surgical Oncology 2021 International Conference on Surgical Cancer Care to address the impact of COVID-19 on cancer surgery globally. Following the virtual meeting, a questionnaire was sent to all the leaders to gather additional opinions. The input obtained from all the leaders was collated and analyzed to understand how cancer surgeons from across the world adapted in real-time to the impact of COVID-19 pandemic. RESULTS: The surgical oncology leaders noted that the COVID-19 pandemic led to severe disruptions in surgical cancer care across all domains of clinical care, education, and research. Several new changes/protocols associated with increased costs were implemented to deliver safe care. Leaders also noted that preexisting disparities in care were exacerbated, and the pandemic had a detrimental effect on well-being and financial status. CONCLUSIONS: The COVID-19 pandemic has led to severe disruptions in surgical cancer care globally. Leaders of the GFCS opined that new strategies need to be implemented to prepare for any future catastrophic events based on the lessons learned from the current events. The GFCS will embark on developing such a roadmap to ensure that surgical cancer care is preserved in the future regardless of any catastrophic global events.

Leveraging metabolic modeling to identify functional metabolic alterations associated with COVID-19 disease severity.

OBJECTIVE: Since the COVID-19 pandemic began in early 2020, SARS-CoV2 has claimed more than six million lives world-wide, with over 510 million cases to date. To reduce healthcare burden, we must investigate how to prevent non-acute disease from progressing to severe infection requiring hospitalization. METHODS: To achieve this goal, we investigated metabolic signatures of both non-acute (out-patient) and severe (requiring hospitalization) COVID-19 samples by profiling the associated plasma metabolomes of 84 COVID-19 positive University of Virginia hospital patients. We utilized supervised and unsupervised machine learning and metabolic modeling approaches to identify key metabolic drivers that are predictive of COVID-19 disease severity. Using metabolic pathway enrichment analysis, we explored potential metabolic mechanisms that link these markers to disease progression. RESULTS: Enriched metabolites associated with tryptophan in non-acute COVID-19 samples suggest mitigated innate immune system inflammatory response and immunopathology related lung damage prevention. Increased prevalence of histidine- and ketone-related metabolism in severe COVID-19 samples offers potential mechanistic insight to musculoskeletal degeneration-induced muscular weakness and host metabolism that has been hijacked by SARS-CoV2 infection to increase viral replication and invasion. CONCLUSIONS: Our findings highlight the metabolic transition from an innate immune response coupled with inflammatory pathway inhibition in non-acute infection to rampant inflammation and associated metabolic systemic dysfunction in severe COVID-19.

Resonance Excitations in

The anomaly in lithium abundance is a well-known unresolved problem in nuclear astrophysics. A recent revisit to the problem tried the avenue of resonance enhancement to account for the primordial ^{7}Li abundance in standard big-bang nucleosynthesis. Prior measurements of the ^{7}Be(d,p)^{8}Be^{*} reaction could not account for the individual contributions of the different excited states involved, particularly at higher energies close to the Q value of the reaction. We carried out an experiment at HIE-ISOLDE, CERN to study this reaction at E_{c.m.}=7.8 MeV, populating excitations up to 22 MeV in ^{8}Be for the first time. The angular distributions of the several excited states have been measured and the contributions of the higher excited states in the total cross section at the relevant big-bang energies were obtained by extrapolation to the Gamow window using the talys code. The results show that by including the contribution of the 16.63 MeV state, the maximum value of the total S factor inside the Gamow window comes out to be 167 MeV b as compared to earlier estimate of 100 MeV b. However, this still does not account for the lithium discrepancy.

Ichthyosis, psoriasiform dermatitis, and recurrent fungal infections in patients with biallelic mutations in PERP.

BACKGROUND: Germline autosomal dominant and autosomal recessive mutations in PERP, encoding p53 effector related to PMP-22 (PERP), a component of epidermal desmosomes, have been associated with a spectrum of keratodermas. Monoallelic nonsense mutations cause Olmsted syndrome with severe periorificial keratoderma and palmoplantar keratoderma (PPK). Biallelic recessive frameshift and missense mutations are associated with milder forms of the disease, including generalised erythrokeratoderma and PPK. OBJECTIVES: To add new insights into the genotype-phenotype correlations as a consequence of PERP mutations and to provide a comprehensive review of the literature. METHODS: Among 26 previously unresolved families within a cohort of 180 extended Iranian families with syndromic or non-syndromic ichthyosis, two families with shared clinical features were examined by whole-exome sequencing and genome-wide homozygosity mapping. Mycological and dermatopathological studies were performed to further characterise their atypical phenotypic presentations. RESULTS: In two unrelated multiplex consanguineous families affected by ichthyosis, two novel biallelic PERP variants, NM_022121.5, c.89T > C, p.Leu30Pro and c.466G > C, p.Gly156Arg, located inside of genomic homozygosity regions of the probands were detected. Interestingly, some patients had areas of scaly psoriasiform plaques on the background of generalised ichthyosis that appeared during active cutaneous fungal infections. Mycological examinations of these lesions revealed infections caused by Candida albicans, Epidermophyton floccosum, or Trichophyton rubrum. Histopathology of the psoriasiform lesions shared some features with psoriasis, which when combined with clinical presentation, led to incorrect diagnosis of guttate psoriasis or pustular psoriasis. CONCLUSIONS: PERP variants in ichthyosis patients can confer susceptibility to recalcitrant cutaneous fungal infections. Additionally, patients with episodic psoriasiform dermatitis in the setting of keratoderma should be considered for PERP genotyping and cutaneous fungal examinations.