Adaptive Pressure Control-Continuous Mandatory Ventilation Versus Volume Control-Continuous Mandatory Ventilation: Factors Associated With Initiation, Maintenance, and Adjustment.

BACKGROUND: Adaptive pressure control-continuous mandatory ventilation (APC-CMV) is a frequently utilized ventilator mode in ICU settings. This analysis compared APC-CMV and traditional volume control-continuous mandatory ventilation (VC-CMV) mode, describing factors associated with initiation, maintenance, and changes in settings of each mode. METHODS: We analyzed ventilator data from a retrospective electronic health record data set collected as part of a quality improvement project in a single academic ICU. The majority ventilator mode was defined as the mode comprising the highest proportion of mechanical ventilation time. Multivariable logistic regression was used to identify variables associated with initial and majority APC-CMV or VC-CMV modes. Wilcoxon rank-sum tests were used to compare ventilator setting changes/d and sedation as a function of APC-CMV and VC-CMV majority modes. RESULTS: Among 1,213 subjects initiated on mechanical ventilation from January 2013-March 2017, 68% and 24% were initiated on APC-CMV and VC-CMV, respectively, which composed 62% and 21% of the majority ventilator modes. Age, sex, race, and ethnicity were not associated with the initial or majority APC-CMV or VC-CMV modes. Subjects initiated on APC-CMV spent 88% of the mechanical ventilation time on APC-CMV mode. Compared to VC-CMV, subjects with APC-CMV majority mode experienced more ventilator setting changes/d (1.1 vs 0.8, P < .001). There were no significant differences in sedative medications when comparing subjects receiving APC-CMV versus VC-CMV majority modes. CONCLUSIONS: APC-CMV was highly utilized in the medical ICU. Subjects on APC-CMV had more ventilator setting changes/d than those on VC-CMV. APC-CMV offered no advantage of reduced setting adjustments or less sedation compared to VC-CMV.

Chimpanzee gestural exchanges share temporal structure with human language.

Humans regularly engage in efficient communicative conversations, which serve to socially align individuals1. In conversations, we take fast-paced turns using a human-universal structure of deploying and receiving signals which shows consistent timing across cultures2. We report here that chimpanzees also engage in rapid signal-to-signal turn-taking during face-to-face gestural exchanges with a similar average latency between turns to that of human conversation. This correspondence between human and chimpanzee face-to-face communication points to shared underlying rules in communication. These structures could be derived from shared ancestral mechanisms or convergent strategies that enhance coordinated interactions or manage competition for communicative 'space'.

Spin-coated and vacuum-processed hole-extracting self-assembled multilayers with H-aggregation for high-performance inverted perovskite solar cells.

We report a highly crystalline self-assembled multilayer (SAMUL) that is fundamentally different from the conventional monolayer or disordered bilayer used for hole-extraction in inverted perovskite solar cells (PSCs). The SAMUL can be easily formed on ITO substrate to form better surface coverage for enhancing the performance and stability of PSCs. A detailed structure-property-performance relationship of molecules used for SAMUL is established through a systematic study of their crystallinity, molecular packing, and hole-transporting properties. These SAMULs are rationally optimized by varying their molecular structures and deposition through thermal evaporation or spin-coating for fabricating PSCs. The CbzNaphPPA-based SAMUL was chosen for fabricating inverted PSCs due to its highest crystallinity and hole mobility derived from the ordered H-aggregation, which resulted in a remarkably high fill factor of 86.45%. This enables a very impressive power conversion efficiency (PCE) of 26.07% to be achieved along with excellent device stability (94% of its initial PCE retained after continuous operation for 1200 h under 1-sun irradiation at maximum power point at 65°C). Additionally, a record-high PCE of 23.50% could be achieved by adopting a thermally evaporated SAMUL. This greatly simplifies and broadens the scope for SAM to be used for large-area devices on diverse substrates.

Analysis of the microsurgery fellowship match: 2019-2022 update.

BACKGROUND: A recent analysis of microsurgery fellowship match data published in 2019 demonstrated increased competition for available positions. With growing opportunities in the field, the authors hypothesize that the landscape for both applicants and programs has become more competitive. The aim of this study is to compare two periods of match data to inform residents and programs in microsurgery. METHODS: Microsurgery fellowship match data was obtained from the San Francisco Match with approval by the American Society for Reconstructive Microsurgery for the years 2014-2022. Data were stratified into the categories of 2016-2018 and 2019-2022. Parameters assessed included: program and position fill rates, match rates, and in-service examination percentiles. Data were analyzed using Pearson's Chi-square tests and unpaired t-tests. RESULTS: The median number of participating programs and positions increased to 29 and 47 in 2019-2022, compared with 23 and 40 in 2016-2018. This coincided with a decrease in the number of applicants per position (1.3 [52-40] vs. 1.1 [50-47], p = .45). There was a significant increase in the match rate between groups (67.8% vs. 80.2%, p = .007). Recently, 2022 saw the lowest position fill rate on record, at 75.4% (40 of 53 positions filled), down from 85.3% (35 of 41) in 2018 (p = .35) and 95.6% (43 of 45) in 2019 (p = .006). Mean in-service examination percentiles for successfully matched applicants did not differ between (2016-2018) and (2019-2022) applicants. CONCLUSION: Recent years have seen a rise in the number of microsurgery fellowship training programs with a decline in the number of applicants. Accordingly, there has been an increased match rate for prospective applicants. Despite this, a pool of unmatched applicants and unfilled positions with training opportunities still remain. The reasons for which are likely multifactorial.

Sex differences in positional behavior of chimpanzees (Pan troglodytes schweinfurthii) living in the dry and open habitat of Issa Valley, Tanzania.

OBJECTIVES: Many early fossil hominins are associated with savanna-mosaic paleohabitats, and high sexual dimorphism that may reflect differences in positional behavior between sexes. However, reconstructions of hominin behavior and the selective pressures they faced in an open habitat are limited by a lack of studies of extant apes living in contemporary, analogous habitats. Here, we describe adult chimpanzee positional behavior in the savanna-mosaic habitat of the Issa Valley, Tanzania, to test whether Issa chimpanzees show larger sex-differences in positional behavior than their forest-dwelling counterparts. MATERIALS AND METHODS: We quantified and compared adult locomotor and postural behavior across sexes (6 females, 7 males) in the riparian forest (closed) and miombo woodland (open) vegetation types at Issa Valley (13,743 focal observations). We then compared our results to published data of chimpanzee communities living in more forested habitats. RESULTS: Issa females and males both spent less time arboreally in open vegetation and showed similar locomotor and postural behavior on the same substrates, notably using a high level of suspensory locomotion when arboreal. Females were, however, more arboreal than males during locomotor behavior, as well as compared with females from other communities. Issa males behaved similarly to males from other communities. CONCLUSION: Results suggest that open habitats do not elicit less arboreal behaviors in either sex, and may even select for suspensory locomotion to effectively navigate an open canopy. An open habitat may, however, increase sex differences in positional behavior by driving female arboreality. We suggest this is because of higher energetic demands and predator pressures associated with open vegetation, which are likely exaggerated for reproducing females. These results have implications for the interpretation of how sexual dimorphism may influence reconstructions of hominin positional behavior.

Prostate-Specific Antigen Stratification for Predicting Advanced Prostate Cancer Events in Men Approaching Age Limits for Recommended Screening.

PURPOSE: Our goal was to quantify the ability of various PSA values in predicting the likelihood of developing metastatic or fatal prostate cancer in older men. MATERIALS AND METHODS: We used a random sample of patients in the US Veterans Health Administration to identify 80,706 men who had received PSA testing between ages 70 to 75. Our primary end point was time to development of either metastatic prostate cancer or death from prostate cancer. We used cumulative/dynamic modeling to account for competing events (death from non-prostate cancer causes) in studying both the discriminative ability of PSA as well as for positive predictive value and negative predictive value at 3 time points. RESULTS: PSA demonstrated time-dependent predictive discrimination, with receiver operating characteristic AUC at 5, 10, and 14 years decreasing from 0.83 to 0.77 to 0.73, respectively, but without statistically significant difference when stratified by race. At PSA thresholds between 1 and 8 ng/mL, the positive predictive value of developing advanced prostate cancer was significantly greater in Black than White patients. For instance, at a PSA > 3, at 5, 10, and 14 years, White patients had 2.4%, 2.9%, and 3.7% risk of an event, whereas Black patients had 4.3%, 6.5%, and 8.3% risk. CONCLUSIONS: In men aged 70 to 75 deciding whether to cease PSA testing with borderline-elevated PSA values, the risk of developing metastatic or fatal prostate cancer is quantifiable and relatively low. Risk assessment in this setting must account for the higher incidence of prostate cancer in Black men.

Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer.

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.

Quantifying the Risk of Technology-Driven Health Disparities in Radiation Oncology.

PURPOSE: New technologies are continuously emerging in radiation oncology. Inherent technological limitations can result in health care disparities in vulnerable patient populations. These limitations must be considered for existing and new technologies in the clinic to provide equitable care. MATERIALS AND METHODS: We created a health disparity risk assessment metric inspired by failure mode and effects analysis. We provide sample patient populations and their potential associated disparities, guidelines for clinics and vendors, and example applications of the methodology. RESULTS: A disparity risk priority number can be calculated from the product of 3 quantifiable metrics: the percentage of patients impacted, the severity of the impact of dosimetric uncertainty or quality of the radiation plan, and the clinical dependence on the evaluated technology. The disparity risk priority number can be used to rank the risk of suboptimal care due to technical limitations when comparing technologies and to plan interventions when technology is shown to have inequitable performance in the patient population of a clinic. CONCLUSIONS: The proposed methodology may simplify the evaluation of how new technology impacts vulnerable populations, help clinics quantify the limitations of their technological resources, and plan appropriate interventions to improve equity in radiation treatments.

Distinct olfactory mucosal macrophage populations mediate neuronal maintenance and pathogen defense.

The olfactory mucosa is important for both the sense of smell and as a mucosal immune barrier to the upper airway and brain. However, little is known about how the immune system mediates the conflicting goals of neuronal maintenance and inflammation in this tissue. A number of immune cell populations reside within the olfactory mucosa and yet we have little understanding of how these resident olfactory immune cells functionally interact with the chemosensory environment. Identifying these interactions will allow therapeutic manipulations that treat disorders such as post-viral olfactory dysfunction. Macrophages are the most prevalent immune cell type in the uninflamed olfactory mucosa and here, we identify two distinct tissue macrophage populations in murine olfactory mucosa. P2ry12hi macrophages are transcriptionally specialized for neuron interactions, closely associated with olfactory neuron cell bodies, long-term tissue residents, and functionally specialized to phagocytose cells and debris, including olfactory neurons. Conversely, MHC Class IIhi macrophages are transcriptionally dedicated to cytokine production and antigen presentation, localized primarily within the olfactory lamina propria, more rapidly replaced by blood monocytes, and rapidly produce chemokines in response to viral infection. We further show that these macrophage signatures are present in human olfactory biopsies, and P2ry12-like olfactory macrophages are reduced in patients with long-term smell loss following COVID-19. Together, these data show that two olfactory macrophage populations regulate neurons and initiate the immune response, contributing to our understanding of both olfactory immunity and tissue-resident macrophage biology.

Radiofrequency ablation compared to surgery for thyroid nodules: A case for office based treatment.

Objective: We aim to evaluate the safety and effectiveness of radiofrequency ablation (RFA) for benign thyroid nodules by ENT surgeons and to compare it to conventional hemithyroidectomy in the public healthcare, operating theater contained setting. Methods: 50 patients who underwent a single session of RFA for symptomatic benign thyroid nodules in Prince of Wales Hospital and Tseung Kwan O Hospital in Hong Kong from 2020 to 2022 were evaluated. Objective outcomes including nodule volume, volume reduction rate (VRR) and complications were recorded. Subjective response in the form of a 0-10 point scale for patient symptoms including obstructive, cosmetic, pain and satisfaction scores were collected. Results: Significant reduction in mean VRR was found at 3, 6 and 12 months post treatment, accompanied by a significant reduction in the mean obstructive and cosmetic symptom scores. Comparing with conventional hemithyroidectomy, the RFA group had a significantly shorter mean procedure time and lower rate of complications. Estimated cost to patient for RFA was found to be less than half of that of hemithyroidectomy. Conclusion: RFA is a safe and effective treatment modality for benign thyroid nodules by ENT surgeons with advantages of being a scarless local anesthetic procedure with shorter procedure time, lower complication rate and lower cost to patient compared to hemithyroidectomy. In Hong Kong, where most of the population is treated in the public sector, there are limited resources, often with high caseload burden and long operation waiting times. Therefore, RFA is an office-based treatment that serves as a valuable alternative to hemithyroidectomy for benign nodules, especially in lower resource settings. Level of evidence: 3.

Single-cell and spatiotemporal profile of ovulation in the mouse ovary.

Ovulation is a spatiotemporally coordinated process that involves several tightly controlled events, including oocyte meiotic maturation, cumulus expansion, follicle wall rupture and repair, and ovarian stroma remodeling. To date, no studies have detailed the precise window of ovulation at single-cell resolution. Here, we performed parallel single-cell RNA-seq and spatial transcriptomics on paired mouse ovaries across an ovulation time course to map the spatiotemporal profile of ovarian cell types. We show that major ovarian cell types exhibit time-dependent transcriptional states enriched for distinct functions and have specific localization profiles within the ovary. We also identified gene markers for ovulation-dependent cell states and validated these using orthogonal methods. Finally, we performed cell-cell interaction analyses to identify ligand-receptor pairs that may drive ovulation, revealing previously unappreciated interactions. Taken together, our data provides a rich and comprehensive resource of murine ovulation that can be mined for discovery by the scientific community.

Patient reported and functional outcome measures after surgical salvage procedures for posttraumatic radiocarpal osteoarthritis - a systematic review.

BACKGROUND: Posttraumatic wrist osteoarthritis is an irreversible and often progressive condition. Many surgical treatments, used in (daily) practice, aim to relieve symptoms like pain and restore function. The aim of this systematic review is to assess the patient reported and functional outcomes of the most common surgical interventions in patients with posttraumatic wrist osteoarthritis. This overview can help clinicians select the best treatment and manage patient's expectations. METHODS: A literature search was performed in Pubmed, Embase and Cochrane for articles published between 1990 and November 2022 according to the PRISMA guidelines. The study protocol has been registered in the PROSPERO database (CRD42017080427). Studies that describe patient reported outcomes (pain and Disability of Arm, Shoulder and Hand (DASH) -score) and functional outcomes (range of motion (ROM) and grip strength) after surgical intervention with a minimal follow-up of 1 year were included. The identified surgical procedures included denervation, proximal row carpectomy, interpositional- and total arthroplasty, and midcarpal-, radiocarpal- and total arthrodesis. The pre-and postoperative outcomes were pooled and presented per salvage procedure. RESULTS: Data from 50 studies was included. Pain score improved after all surgeries except denervation. Flexion/extension decreased after radiocarpal arthrodesis, did not show significant changes after proximal row carpectomy, and improved for all other surgeries. DASH score improved after arthroplasty, proximal row carpectomy and midcarpal arthrodesis. Grip strength improved after interposition arthroplasty and partial arthrodesis. CONCLUSION: Evidence from this review did not support the indication for denervation in this particular patient population. In patients with SLAC/SNAC II, proximal row carpectomy might be favourable to a midcarpal arthrodesis solely based on better FE ROM of the radiocarpal joint after proximal row carpectomy. In terms of radiocarpal mobility, total wrist arthroplasty might be preferred to radiocarpal arthrodesis in patients with osteoarthritis after a distal radius fracture. More uniform measurements of outcomes would improve the understanding of the effect of surgical treatments of the posttraumatic osteoarthritic wrist.

B cell activation gene signature in blood and liver of HBeAg+ immune active chronic hepatitis B patients.

BACKGROUND: Immunological studies on chronic hepatitis B virus (HBV) infection have convincingly shown immune dysfunction involving multiple cell types. The focus of the majority of studies has been on the role of T cells and showed an impaired functional T cell response to HBV. B cells have been evaluated more recently, but in contrast to T cells, more pronounced activation of circulating B cells has been reported. To gain more insight into the activation status of B cells, we investigated the activation gene profile of B cells in the blood and liver of chronic HBV patients. METHODS: RNA-seq and flow cytometric analysis was performed on peripheral blood B cells of immune active chronic HBV patients, comparing them with samples from healthy controls. In addition, gene expression profiles of B cells in the liver were analyzed by bulk and single-cell RNA-seq. RESULTS AND CONCLUSIONS: Our data show a distinctive B cell activation gene signature in the blood of immune active chronic HBV patients, characterized by a significant upregulation of immune-related genes, including IRF1, STAT1, STAT3, TAP1, and TAPBP. This peripheral activation profile was also observed in B cells from the liver by single cell RNA-seq showing upregulation of IRF1, CD83 and significantly higher CD69 expression, with naive and memory B cell subsets being the primary carriers of the signature. Our findings suggest that B cell gene profiles reflect responsiveness to HBV infection, these findings are relevant for clinical studies evaluating immunomodulatory treatment strategies for HBV.

Mutation and cell state compatibility is required and targetable in Ph+ acute lymphoblastic leukemia minimal residual disease.

Efforts to cure BCR::ABL1 B cell acute lymphoblastic leukemia (Ph+ ALL) solely through inhibition of ABL1 kinase activity have thus far been insufficient despite the availability of tyrosine kinase inhibitors (TKIs) with broad activity against resistance mutants. The mechanisms that drive persistence within minimal residual disease (MRD) remain poorly understood and therefore untargeted. Utilizing 13 patient-derived xenograft (PDX) models and clinical trial specimens of Ph+ ALL, we examined how genetic and transcriptional features co-evolve to drive progression during prolonged TKI response. Our work reveals a landscape of cooperative mutational and transcriptional escape mechanisms that differ from those causing resistance to first generation TKIs. By analyzing MRD during remission, we show that the same resistance mutation can either increase or decrease cellular fitness depending on transcriptional state. We further demonstrate that directly targeting transcriptional state-associated vulnerabilities at MRD can overcome BCR::ABL1 independence, suggesting a new paradigm for rationally eradicating MRD prior to relapse. Finally, we illustrate how cell mass measurements of leukemia cells can be used to rapidly monitor dominant transcriptional features of Ph+ ALL to help rationally guide therapeutic selection from low-input samples.

Impact of lung cancer screening on stage migration and mortality among the national Veterans Health Administration population with lung cancer.

BACKGROUND: Despite randomized trials demonstrating a mortality benefit to low-dose computed tomography screening to detect lung cancer, uptake of lung cancer screening (LCS) has been slow, and the benefits of screening remain unclear in clinical practice. METHODS: This study aimed to assess the impact of screening among patients in the Veterans Health Administration (VA) health care system diagnosed with lung cancer between 2011 and 2018. Lung cancer stage at diagnosis, lung cancer-specific survival, and overall survival between patients with cancer who did and did not receive screening before diagnosis were evaluated. We used Cox regression modeling and inverse propensity weighting analyses with lead time bias adjustment to correlate LCS exposure with patient outcomes. RESULTS: Of 57,919 individuals diagnosed with lung cancer in the VA system between 2011 and 2018, 2167 (3.9%) underwent screening before diagnosis. Patients with screening had higher rates of stage I diagnoses (52% vs. 27%; p ≤ .0001) compared to those who had no screening. Screened patients had improved 5-year overall survival rates (50.2% vs. 27.9%) and 5-year lung cancer-specific survival (59.0% vs. 29.7%) compared to unscreened patients. Among screening-eligible patients who underwent National Comprehensive Cancer Network guideline-concordant treatment, screening resulted in substantial reductions in all-cause mortality (adjusted hazard ratio [aHR], 0.79; 95% confidence interval [CI], 0.67-0.92; p = .003) and lung-specific mortality (aHR, 0.61; 95% CI, 0.50-0.74; p < .001). CONCLUSIONS: While LCS uptake remains limited, screening was associated with earlier stage diagnoses and improved survival. This large national study corroborates the value of LCS in clinical practice; efforts to widely adopt this vital intervention are needed.

Physicochemical properties of edible cricket oils: Implications for use in pharmaceutical and food industries.

The prevailing global market demands locally produced, sustainable oils for biomedical applications. This study focused on evaluating the quality of cricket-derived oils and meals from Scapsipedus icipe Hugel, Tanga, and Gryllus bimaculatus De Geer common delicacy in Africa, following standard methods for physicochemical properties, fatty acid composition, and phytochemicals (oxalates, phytates, tannins, and polyphenols). The cricket oils physicochemical properties aligned with Codex Alimentarius standards for edible oils, including low solidification temperature (< 2 °C), a high refractive index (1.46), and a specific gravity of 0.88. Notably, peroxide values (1.9 to 2.5 mg mEq O2/kg), acid values (1.1 to 2.2 mg KOH/g), and saponification values (234-246 mg KOH/g) all are indicative of lightness and unsaturated fatty acids. Nutritionally, cricket powder was rich in protein (56.8-56.9% -) and fat (31.7-33.5% -of dry matter), with significant amounts of essential omega-3 and omega-6 fatty acids. Predominant saturated and monounsaturated fatty acids were palmitic (23.9-31.2 mg/100 g-) and oleic acids (10.9-11.4 mg/100 g- of oil), respectively. Antioxidant values (48.0 to 65.0 mg/100 g), inferred from total polyphenols, suggests a stable oil with long shelf-life. These results highlight the promising and sustainable potential of cricket-derived oils for applications in the food and pharmaceutical industries.

Artificial intelligence to unlock real-world evidence in clinical oncology: A primer on recent advances.

PURPOSE: Real world evidence is crucial to understanding the diffusion of new oncologic therapies, monitoring cancer outcomes, and detecting unexpected toxicities. In practice, real world evidence is challenging to collect rapidly and comprehensively, often requiring expensive and time-consuming manual case-finding and annotation of clinical text. In this Review, we summarise recent developments in the use of artificial intelligence to collect and analyze real world evidence in oncology. METHODS: We performed a narrative review of the major current trends and recent literature in artificial intelligence applications in oncology. RESULTS: Artificial intelligence (AI) approaches are increasingly used to efficiently phenotype patients and tumors at large scale. These tools also may provide novel biological insights and improve risk prediction through multimodal integration of radiographic, pathological, and genomic datasets. Custom language processing pipelines and large language models hold great promise for clinical prediction and phenotyping. CONCLUSIONS: Despite rapid advances, continued progress in computation, generalizability, interpretability, and reliability as well as prospective validation are needed to integrate AI approaches into routine clinical care and real-time monitoring of novel therapies.

B cell heterogeneity in human tuberculosis highlights compartment-specific phenotype and functional roles.

B cells are important in tuberculosis (TB) immunity, but their role in the human lung is understudied. Here, we characterize B cells from lung tissue and matched blood of patients with TB and found they are decreased in the blood and increased in the lungs, consistent with recruitment to infected tissue, where they are located in granuloma associated lymphoid tissue. Flow cytometry and transcriptomics identify multiple B cell populations in the lung, including those associated with tissue resident memory, germinal centers, antibody secretion, proinflammatory atypical B cells, and regulatory B cells, some of which are expanded in TB disease. Additionally, TB lungs contain high levels of Mtb-reactive antibodies, specifically IgM, which promotes Mtb phagocytosis. Overall, these data reveal the presence of functionally diverse B cell subsets in the lungs of patients with TB and suggest several potential localized roles that may represent a target for interventions to promote immunity or mitigate immunopathology.