Impact of nocturnal hypoxia on glycaemic control, appetite, gut microbiota and inflammation in adults with type 2 diabetes mellitus: A single-blind cross-over trial.

High altitude residents have a lower incidence of type 2 diabetes mellitus (T2DM). Therefore, we examined the effect of repeated overnight normobaric hypoxic exposure on glycaemic control, appetite, gut microbiota and inflammation in adults with T2DM. Thirteen adults with T2DM [glycated haemoglobin (HbA1c): 61.1 ± 14.1 mmol mol-1; aged 64.2 ± 9.4 years; four female] completed a single-blind, randomised, sham-controlled, cross-over study for 10 nights, sleeping when exposed to hypoxia (fractional inspired O2 [ F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ] = 0.155; ∼2500 m simulated altitude) or normoxic conditions ( F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$  = 0.209) in a randomised order. Outcome measures included: fasted plasma [glucose]; [hypoxia inducible factor-1α]; [interleukin-6]; [tumour necrosis factor-α]; [interleukin-10]; [heat shock protein 70]; [butyric acid]; peak plasma [glucose] and insulin sensitivity following a 2 h oral glucose tolerance test; body composition; appetite indices ([leptin], [acyl ghrelin], [peptide YY], [glucagon-like peptide-1]); and gut microbiota diversity and abundance [16S rRNA amplicon sequencing]. During intervention periods, accelerometers measured physical activity, sleep duration and efficiency, whereas continuous glucose monitors were used to assess estimated HbA1c and glucose management indicator and time in target range. Overnight hypoxia was not associated with changes in any outcome measure (P > 0.05 with small effect sizes) except fasting insulin sensitivity and gut microbiota alpha diversity, which exhibited trends (P = 0.10; P = 0.08 respectively) for a medium beneficial effect (d = 0.49; d = 0.59 respectively). Ten nights of overnight moderate hypoxic exposure did not significantly affect glycaemic control, gut microbiome, appetite, or inflammation in adults with T2DM. However, the intervention was well tolerated and a medium effect-size for improved insulin sensitivity and reduced alpha diversity warrants further investigation. KEY POINTS: Living at altitude lowers the incidence of type 2 diabetes mellitus (T2DM). Animal studies suggest that exposure to hypoxia may lead to weight loss and suppressed appetite. In a single-blind, randomised sham-controlled, cross-over trial, we assessed the effects of 10 nights of hypoxia (fractional inspired O2 ∼0.155) on glucose homeostasis, appetite, gut microbiota, inflammatory stress ([interleukin-6]; [tumour necrosis factor-α]; [interleukin-10]) and hypoxic stress ([hypoxia inducible factor 1α]; heat shock protein 70]) in 13 adults with T2DM. Appetite and inflammatory markers were unchanged following hypoxic exposure, but an increased insulin sensitivity and reduced gut microbiota alpha diversity were associated with a medium effect-size and statistical trends, which warrant further investigation using a definitive large randomised controlled trial. Hypoxic exposure may represent a viable therapeutic intervention in people with T2DM and particularly those unable or unwilling to exercise because barriers to uptake and adherence may be lower than for other lifestyle interventions (e.g. diet and exercise).

Massively parallel characterization of regulatory elements in the developing human cortex.

Nucleotide changes in gene regulatory elements are important determinants of neuronal development and diseases. Using massively parallel reporter assays in primary human cells from mid-gestation cortex and cerebral organoids, we interrogated the cis-regulatory activity of 102,767 open chromatin regions, including thousands of sequences with cell type-specific accessibility and variants associated with brain gene regulation. In primary cells, we identified 46,802 active enhancer sequences and 164 variants that alter enhancer activity. Activity was comparable in organoids and primary cells, suggesting that organoids provide an adequate model for the developing cortex. Using deep learning we decoded the sequence basis and upstream regulators of enhancer activity. This work establishes a comprehensive catalog of functional gene regulatory elements and variants in human neuronal development.

A Phase I Study of sequences of the CDK4/6 Inhibitor, Ribociclib Combined with Gemcitabine in Patients with Advanced Solid Tumors.

Background: Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine is synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Methods: In this single arm multicohort phase I trial, we evaluated the safety and efficacy of Ribociclib plus Gemcitabine in patients with advanced solid tumors. Patients received Gemcitabine intravenously on days 1 and 8 followed by Ribociclib days 8-14, with treatment repeated every 3 weeks. Results: The study enrolled 43 patients between October 2017 and September 2019. The escalation phase (19 patients) determined the MTD and recommended phase II dose (RP2D) to be ribociclib 800mg daily and gemcitabine 1000mg/m2 for the expansion phase (24 patients). One patient experienced Grade 4 thrombocytopenia. Eleven patients experienced Grade 3 adverse events (AE), the most common being neutropenia, thrombocytopenia, and anemia. No partial or complete responses were observed. 15/22 (68%) of efficacy evaluable patients who received the MTD achieved best response of stable disease. Conclusions: The addition of Ribociclib to Gemcitabine was tolerated well and yielded stability of tumors in both cohorts. Ribociclib and gemcitabine could have synergistic activity in certain tumor types, and our data provides support for the combination. Clinical Trial Registration: NCT03237390.

Kinase activities in pancreatic ductal adenocarcinoma with prognostic and therapeutic avenues.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a limited number of known driver mutations but considerable cancer cell heterogeneity. Phosphoproteomics provides a direct read-out of aberrant signaling and the resultant clinically relevant phenotype. Mass spectrometry (MS)-based proteomics and phosphoproteomics were applied to 42 PDAC tumors. Data encompassed over 19 936 phosphoserine or phosphothreonine (pS/T; in 5412 phosphoproteins) and 1208 phosphotyrosine (pY; in 501 phosphoproteins) sites and a total of 3756 proteins. Proteome data identified three distinct subtypes with tumor intrinsic and stromal features. Subsequently, three phospho-subtypes were apparent: two tumor intrinsic (Phos1/2) and one stromal (Phos3), resembling known PDAC molecular subtypes. Kinase activity was analyzed by the Integrative iNferred Kinase Activity (INKA) scoring. Phospho-subtypes displayed differential phosphorylation signals and kinase activity, such as FGR and GSK3 activation in Phos1, SRC kinase family and EPHA2 in Phos2, and EGFR, INSR, MET, ABL1, HIPK1, JAK, and PRKCD in Phos3. Kinase activity analysis of an external PDAC cohort supported our findings and underscored the importance of PI3K/AKT and ERK pathways, among others. Interestingly, unfavorable patient prognosis correlated with higher RTK, PAK2, STK10, and CDK7 activity and high proliferation, whereas long survival was associated with MYLK and PTK6 activity, which was previously unknown. Subtype-associated activity profiles can guide therapeutic combination approaches in tumor and stroma-enriched tissues, and emphasize the critical role of parallel signaling pathways. In addition, kinase activity profiling identifies potential disease markers with prognostic significance.

In vivo study of porous NiTi cryotweezers for bone tissue cryotherapy.

This study examined the effects of liquid nitrogen vapor on osteogenesis in the rabbit femur. Cryotweezers made of porous nickel titanium alloy (nitinol or NiTi) obtained by self-propagating high temperature synthesis were used in this experiment. The porous structure of the cryotweezers allows them to hold up to 10 g of liquid nitrogen after being immersed for 2 min, which completely evaporates after 160 s. To study the effects of liquid nitrogen evaporation on osteogenesis, a rabbit femur was perforated. The formed holes were subjected to cryotherapy with varying exposure times. It was found that a 3 s exposure time stimulates osteogenesis, which was manifested in a greater number of osteoblasts in the regenerate compared to the control sample without liquid nitrogen. It was observed that increasing the exposure to 6, 9 or 12 s had a destructive effect, to varying degrees. The most severe damage was exerted by a 12 s exposure, which resulted in the formation of osteonecrosis areas. In the samples exposed to 6 and 9 s of cryotherapy, destruction of the cytoplasm of osteocytes and osteoclasts was observed.

Long-term clinical outcomes of arthroscopic supraspinatus tendon repair using the single anchor tension band technique - Minimum 5-years follow-up.

Background: The primary aim of this study was to assess the long-term patient reported outcomes of arthroscopic rotator cuff tear (ARCR) using a single anchor tension band (TB) technique for small and medium supraspinatus tears at minimum 5-years follow-up. Methods: A retrospective cohort study of consecutive ARCRs of small and medium supraspinatus tears using a knotless single anchor TB technique with minimum 5-year follow-up was carried out. Outcomes of interest included: range of motion (ROM) on examination under anaesthesia (EUA), visual analogue scale (VAS), American Shoulder and Elbow Surgeons (ASES) scores, Oxford Shoulder Score (OSS) and Short-Form (SF-12). Results: From 243 consecutive ARCR procedures, 82 patients with a mean age of 55 ± 9.5 years met the inclusion criteria at 6.7 ± 1.5 years follow-up. There were significant improvements in VAS (5.5 ± 2.2 vs. 0.7 ± 1.5), ASES (47.6 ± 16.8 vs. 92.8 ± 13.0), OSS (31.3 ± 7.2 vs. 45.3 ± 3.5) and SF-12 (37.6 ± 7.6 vs. 50.3 ± 7.7) post-operatively (all p < 0.001). Conclusions: The single anchor TB ARCR technique has excellent patient reported outcomes at a minimum of 5 years and is suitable for supraspinatus tears smaller than 20 mm in the sagittal plane. Level of evidence: Level IV; Consecutive Case Series.

Prevalence, associated risk factors; and patient and economic impact of multiple sensory impairment in a multi-ethnic elderly population in Singapore: the PIONEER study.

BACKGROUND: To determine the prevalence, risk factors; and impact on patient health and economic outcomes across the laterality spectrum of multiple sensory impairment (MSI) in a multi-ethnic older Asian population. METHODS: In this population-based study of Singaporeans aged ≥ 60 years, MSI was defined as concomitant vision (visual acuity > 0.3 logMAR), hearing (pure-tone air conduction average > 25 dB), and olfactory (score < 12 on the Sniffin' Sticks test) impairments across the spectrum of laterality (any, unilateral, combination [of unilateral and bilateral], and bilateral). RESULTS: Among 2,057 participants (mean ± SD 72.2 ± 0.2 years; 53.1% female), the national census-adjusted prevalence rates of any, unilateral, combination, and bilateral MSI were 20.6%, 1.2%, 12.2%, and 7.2%, respectively. Older age, male gender, low socioeconomic status (SES), and smoking (all p < 0.05) were independently associated with higher likelihood of any MSI. Compared to those with no sensory loss, those with MSI had significantly decreased mobility (range 5.4%-9.2%), had poor functioning (OR range 3.25-3.45) and increased healthcare costs (range 4-6 folds) across the laterality spectrum. Additionally, bilateral MSI had a significant decrease in HRQoL (5.5%, p = 0.012). CONCLUSIONS: MSI is a highly prevalent medical condition, with 1 in 5; and almost 1 in 10 community-dwelling older Asians having any and bilateral MSI, respectively, with a higher likelihood in men, smokers, and those with low SES. Critically, MSI has a substantial negative impact on patient health and economic outcomes across the laterality spectrum. Sensory testing is critical to detect and refer individuals with MSI for management to improve their functional independence and QoL.

Preoperative Velopharyngeal Closure Predicts Hypernasality Outcomes of Secondary Furlow Double-Opposing Z-Plasty.

OBJECTIVE: To determine if preoperative velopharyngeal closure percentage (VCP) is predictive of successful Furlow double opposing Z-plasty (DOZP) and subsequently determine the optimal velopharyngeal closure cutoff for successful DOZP. DESIGN: Retrospective study. SETTING: Tertiary academic center. PATIENTS: 110 patients with repaired cleft lip and palate having hypernasality treated with DOZP. INTERVENTIONS: Speech videofluoroscopy images were used to obtain the preoperative VCP and other measurements. MAIN OUTCOME MEASURES: Changes in hypernasality scores using the Cleft Audit Protocol for Speech-Augmented-Americleft Modification (CAPS-A-AM) rating system were used as the primary outcome measure. A successful DOZP was defined as a postoperative hypernasality score of ≤ 1 or an improvement of 2 or more scores from baseline. A receiver operating characteristic (ROC) curve was calculated to determine preoperative VCP cutoff. RESULTS: There were 110 patients who underwent DOZP for treatment of velopharyngeal insufficiency. Of these patients, 94 (85%) had successful surgery as determined by their postoperative CAPS-A-AM hypernasality score. Preoperative VCP was a statistically significant predictor of successful DOZP (P < .0001). The ROC curve with Youden index (J) determined a cutoff (c*) of 55% preoperative VCP or greater to optimize surgical success rate. Grouping by preoperative VCP showed that surgical success increases directly with preoperative VCP, and patients with low VCP had above a 50% success rate in reducing hypernasality scores. CONCLUSIONS: Preoperative VCP was significantly associated with improved hypernasality ratings postoperatively. A preoperative VCP of ≥55% may be used to help predict success of Furlow palatoplasty treatment. Patients with lower VCP can still benefit from secondary DOZP.

A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors.

BACKGROUND: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. RESULTS: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56-62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1T1997M mutation. CONCLUSIONS: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations.

Advances in the Development of Biofertilizers and Biostimulants from Microalgae.

Microalgae have commercial potential in different sectors of the industry. Specifically in modern agriculture, they can be used because they have the ability to supply nutrients to the soil and produce plant growth hormones, polysaccharides, antimicrobial compounds, and other metabolites that improve agricultural productivity. Therefore, products formulated from microalgae as biofertilizers and biostimulants turn out to be beneficial for agriculture and are positioned as a novel and environmentally friendly strategy. However, these bioproducts present challenges in preparation that affect their shelf life due to the rapid degradation of bioformulated products. Therefore, this work aimed to provide a comprehensive review of biofertilizers and biostimulants from microalgae, for which a bibliometric analysis was carried out to establish trends using scientometric indicators, technological advances were identified in terms of formulation methods, and the global market for these bioproducts was analyzed.

Investigation of Rare Earth Element Binding to a Surface-Bound Affinity Peptide Derived from EF-Hand Loop I of Lanmodulin.

Bioinspired strategies have been given extensive attention for the recovery of rare earth elements (REEs) from waste streams because of their high selectivity, regeneration potential, and sustainability as well as low cost. Lanmodulin protein is an emerging biotechnology that is highly selective for REE binding. Mimicking lanmodulin with shorter peptides is advantageous because they are simpler and potentially easier to manipulate and optimize. Lanmodulin-derived peptides have been found to bind REEs, but their properties have not been explored when immobilized on solid substrates, which is required for many advanced separation technologies. Here, two peptides, LanM1 and scrambled LanM1, are designed from the EF-hand loop 1 of lanmodulin and investigated for their binding affinity toward different REEs when surface-bound. First, the ability of LanM1 to bind REEs was confirmed and characterized in solution using circular dichroism (CD), nuclear magnetic resonance (NMR), and molecular dynamics (MD) simulations for Ce(III) ions. Isothermal titration calorimetry (ITC) was used to further analyze the binding of the LanM1 to Ce(III), Nd(III), Eu(III), and Y(III) ions and in low-pH conditions. The performance of the immobilized peptides on a model gold surface was examined using a quartz crystal microbalance with dissipation (QCM-D). The studies show that the LanM1 peptide has a stronger REE binding affinity than that of scrambled LanM1 when in solution and when immobilized on a gold surface. QCM-D data were fit to the Langmuir adsorption model to estimate the surface-bound dissociation constant (Kd) of LanM1 with Ce(III) and Nd(III). The results indicate that LanM1 peptides maintain a high affinity for REEs when immobilized, and surface-bound LanM1 has no affinity for potential competitor calcium and copper ions. The utility of surface-bound LanM1 peptides was further demonstrated by immobilizing them to gold nanoparticles (GNPs) and capturing REEs from solution in experiments utilizing an Arsenazo III-based colorimetric dye displacement assay and ultraviolet-visible (UV-vis) spectrophotometry. The saturated adsorption capacity of GNPs was estimated to be around 3.5 µmol REE/g for Ce(III), Nd(III), Eu(III), and Y(III) ions, with no binding of non-REE Ca(II) ions observed.

Results of a phase I trial with Haploidentical mbIL-21 ex vivo expanded NK cells for patients with multiply relapsed and refractory AML.

Natural killer (NK)-cells have potent anti-tumor effects, yet it remains unclear if they are effective for patients with relapsed acute myeloid leukemia (AML). In a phase I clinical trial, we treated 12 patients (median age 60 years) with refractory AML (median 5 lines of prior therapy, median bone marrow blast count of 47%) with fludarabine/cytarabine followed by 6 infusions of NK-cells expanded from haploidentical donors using K562 feeder cells expressing membrane-bound IL21 and 4-1BBL. Patients received 106-107/kg/dose. No toxicity or graft-versus-host disease (GVHD) was observed and MTD was not reached. Seven patients (58.3%) responded and achieved a complete remission (CR) with/without count recovery. Median time to best response was 48 days. Five responding patients proceeded to a haploidentical transplant from the same donor. After a median follow-up of 52 months, 1-year overall survival (OS) for the entire group was 41.7%, better for patients who responded with CR/CRi (57.14%), and for patients who responded and underwent transplantation (60%). Persistence and expansion of donor-derived NK-cells were identified in patients' blood, and serum IFNγ levels rose concurrently with NK cell infusions. A higher count-functional inhibitory KIR was associated with higher likelihood of achieving CR/CRi. In conclusion, we observed a significant response to ex vivo expanded NK-cell administration in refractory AML patients without adverse effects.

Structurally divergent and recurrently mutated regions of primate genomes.

We sequenced and assembled using multiple long-read sequencing technologies the genomes of chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, owl monkey, and marmoset. We identified 1,338,997 lineage-specific fixed structural variants (SVs) disrupting 1,561 protein-coding genes and 136,932 regulatory elements, including the most complete set of human-specific fixed differences. We estimate that 819.47 Mbp or ∼27% of the genome has been affected by SVs across primate evolution. We identify 1,607 structurally divergent regions wherein recurrent structural variation contributes to creating SV hotspots where genes are recurrently lost (e.g., CARD, C4, and OLAH gene families) and additional lineage-specific genes are generated (e.g., CKAP2, VPS36, ACBD7, and NEK5 paralogs), becoming targets of rapid chromosomal diversification and positive selection (e.g., RGPD gene family). High-fidelity long-read sequencing has made these dynamic regions of the genome accessible for sequence-level analyses within and between primate species.

High yield clinical applications for photon counting CT in neurovascular imaging.

Photon-counting CT (PCCT) uses a novel X-ray detection mechanism that confers many advantages over that used in traditional energy integrating CT. As PCCT becomes more available, it is important to thoroughly understand its benefits and highest yield areas for improvements in diagnosis of various diseases. Based on our early experience, we have identified several areas of neurovascular imaging in which PCCT shows promise. Here, we describe the benefits in diagnosing arterial and venous diseases in the head, neck, and spine. Specifically, we focus on applications in head and neck CT angiography (CTA), spinal CT angiography, and CT myelography for detection of CSF-venous fistulas. Each of these applications highlights the technological advantages of PCCT in neurovascular imaging. Further understanding of these applications will not only benefit institutions incorporating PCCT into their practices but will also help guide future directions for implementation of PCCT for diagnosing other pathologies in neuroimaging.

fNIRS is capable of distinguishing laterality of lower body contractions.

The use of functional near-infrared spectroscopy (fNIRS) for brain imaging during human movement continues to increase. This technology measures brain activity non-invasively using near-infrared light, is highly portable, and robust to motion artifact. However, the spatial resolution of fNIRS is lower than that of other imaging modalities. It is unclear whether fNIRS has sufficient spatial resolution to differentiate nearby areas of the cortex, such as the leg areas of the motor cortex. Therefore, the purpose of this study was to determine fNIRS' ability to discern laterality of lower body contractions. Activity in the primary motor cortex was recorded in forty participants (mean = 23.4 years, SD = 4.5, female = 23, male = 17) while performing unilateral lower body contractions. Contractions were performed at 30% of maximal force against a handheld dynamometer. These contractions included knee extension, knee flexion, dorsiflexion, and plantar flexion of the left and right legs. fNIRS signals were recorded and stored for offline processing and analysis. Channels of fNIRS data were grouped into regions of interest, with five tolerance conditions ranging from strict to lenient. Four of five tolerance conditions resulted in significant differences in cortical activation between hemispheres. During right leg contractions, the left hemisphere was more active than the right hemisphere. Similarly, during left leg contractions, the right hemisphere was more active than the left hemisphere. These results suggest that fNIRS has sufficient spatial resolution to distinguish laterality of lower body contractions. This makes fNIRS an attractive technology in research and clinical applications in which laterality of brain activity is required during lower body activity.

Impact of Potential Case Misclassification by Administrative Diagnostic Codes on Outcome Assessment of Observational Study for People Who Inject Drugs.

Introduction: Initiation of medications for opioid use disorder (MOUD) within the hospital setting may improve outcomes for people who inject drugs (PWID) hospitalized because of an infection. Many studies used International Classification of Diseases (ICD) codes to identify PWID, although these may be misclassified and thus, inaccurate. We hypothesized that bias from misclassification of PWID using ICD codes may impact analyses of MOUD outcomes. Methods: We analyzed a cohort of 36 868 cases of patients diagnosed with Staphylococcus aureus bacteremia at 124 US Veterans Health Administration hospitals between 2003 and 2014. To identify PWID, we implemented an ICD code-based algorithm and a natural language processing (NLP) algorithm for classification of admission notes. We analyzed outcomes of prescribing MOUD as an inpatient using both approaches. Our primary outcome was 365-day all-cause mortality. We fit mixed-effects Cox regression models with receipt or not of MOUD during the index hospitalization as the primary predictor and 365-day mortality as the outcome. Results: NLP identified 2389 cases as PWID, whereas ICD codes identified 6804 cases as PWID. In the cohort identified by NLP, receipt of inpatient MOUD was associated with a protective effect on 365-day survival (adjusted hazard ratio, 0.48; 95% confidence interval, .29-.81; P < .01) compared with those not receiving MOUD. There was no significant effect of MOUD receipt in the cohort identified by ICD codes (adjusted hazard ratio, 1.00; 95% confidence interval, .77-1.30; P = .99). Conclusions: MOUD was protective of all-cause mortality when NLP was used to identify PWID, but not significant when ICD codes were used to identify the analytic subjects.

CO2 as an engine for neurofluid flow: Exploring the coupling between vascular reactivity, brain clearance, and changes in tissue properties.

The brain relies on an effective clearance mechanism to remove metabolic waste products for the maintenance of homeostasis. Recent studies have focused on elucidating the forces that drive the motion of cerebrospinal fluid (CSF), responsible for removal of these waste products. We demonstrate that vascular responses evoked using controlled manipulations of partial pressure of carbon dioxide (PaCO2 ) levels, serve as an endogenous driver of CSF clearance from the brain. To demonstrate this, we retrospectively surveyed our database, which consists of brain metastases patients from whom blood oxygen level-dependent (BOLD) images were acquired during targeted hypercapnic and hyperoxic respiratory challenges. We observed a correlation between CSF inflow signal around the fourth ventricle and CO2 -induced changes in cerebral blood volume. By contrast, no inflow signal was observed in response to the nonvasoactive hyperoxic stimulus, validating our measurements. Moreover, our results establish a link between the rate of the hemodynamic response (to elevated PaCO2 ) and peritumoral edema load, which we suspect may affect CSF flow, consequently having implications for brain clearance. Our expanded perspective on the factors involved in neurofluid flow underscores the importance of considering both cerebrovascular responses, as well as the brain mechanical properties, when evaluating CSF dynamics in the context of disease processes.

Thalamocortical organoids enable in vitro modeling of 22q11.2 microdeletion associated with neuropsychiatric disorders.

Thalamic dysfunction has been implicated in multiple psychiatric disorders. We sought to study the mechanisms by which abnormalities emerge in the context of the 22q11.2 microdeletion, which confers significant genetic risk for psychiatric disorders. We investigated early stages of human thalamus development using human pluripotent stem cell-derived organoids and show that the 22q11.2 microdeletion underlies widespread transcriptional dysregulation associated with psychiatric disorders in thalamic neurons and glia, including elevated expression of FOXP2. Using an organoid co-culture model, we demonstrate that the 22q11.2 microdeletion mediates an overgrowth of thalamic axons in a FOXP2-dependent manner. Finally, we identify ROBO2 as a candidate molecular mediator of the effects of FOXP2 overexpression on thalamic axon overgrowth. Together, our study suggests that early steps in thalamic development are dysregulated in a model of genetic risk for schizophrenia and contribute to neural phenotypes in 22q11.2 deletion syndrome.

Early prediction of end-stage kidney disease using electronic health record data: a machine learning approach with a 2-year horizon.

Objectives: In the United States, end-stage kidney disease (ESKD) is responsible for high mortality and significant healthcare costs, with the number of cases sharply increasing in the past 2 decades. In this study, we aimed to reduce these impacts by developing an ESKD model for predicting its occurrence in a 2-year period. Materials and Methods: We developed a machine learning (ML) pipeline to test different models for the prediction of ESKD. The electronic health record was used to capture several kidney disease-related variables. Various imputation methods, feature selection, and sampling approaches were tested. We compared the performance of multiple ML models using area under the ROC curve (AUCROC), area under the Precision-Recall curve (PR-AUC), and Brier scores for discrimination, precision, and calibration, respectively. Explainability methods were applied to the final model. Results: Our best model was a gradient-boosting machine with feature selection and imputation methods as additional components. The model exhibited an AUCROC of 0.97, a PR-AUC of 0.33, and a Brier score of 0.002 on a holdout test set. A chart review analysis by expert physicians indicated clinical utility. Discussion and Conclusion: An ESKD prediction model can identify individuals at risk for ESKD and has been successfully deployed within our health system.