Six reference-quality genomes reveal evolution of bat adaptations.

Bats possess extraordinary adaptations, including flight, echolocation, extreme longevity and unique immunity. High-quality genomes are crucial for understanding the molecular basis and evolution of these traits. Here we incorporated long-read sequencing and state-of-the-art scaffolding protocols1 to generate, to our knowledge, the first reference-quality genomes of six bat species (Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Pipistrellus kuhlii and Molossus molossus). We integrated gene projections from our 'Tool to infer Orthologs from Genome Alignments' (TOGA) software with de novo and homology gene predictions as well as short- and long-read transcriptomics to generate highly complete gene annotations. To resolve the phylogenetic position of bats within Laurasiatheria, we applied several phylogenetic methods to comprehensive sets of orthologous protein-coding and noncoding regions of the genome, and identified a basal origin for bats within Scrotifera. Our genome-wide screens revealed positive selection on hearing-related genes in the ancestral branch of bats, which is indicative of laryngeal echolocation being an ancestral trait in this clade. We found selection and loss of immunity-related genes (including pro-inflammatory NF-κB regulators) and expansions of anti-viral APOBEC3 genes, which highlights molecular mechanisms that may contribute to the exceptional immunity of bats. Genomic integrations of diverse viruses provide a genomic record of historical tolerance to viral infection in bats. Finally, we found and experimentally validated bat-specific variation in microRNAs, which may regulate bat-specific gene-expression programs. Our reference-quality bat genomes provide the resources required to uncover and validate the genomic basis of adaptations of bats, and stimulate new avenues of research that are directly relevant to human health and disease1.

Chiropterans Are a Hotspot for Horizontal Transfer of DNA Transposons in Mammalia.

Horizontal transfer of transposable elements (TEs) is an important mechanism contributing to genetic diversity and innovation. Bats (order Chiroptera) have repeatedly been shown to experience horizontal transfer of TEs at what appears to be a high rate compared with other mammals. We investigated the occurrence of horizontally transferred (HT) DNA transposons involving bats. We found over 200 putative HT elements within bats; 16 transposons were shared across distantly related mammalian clades, and 2 other elements were shared with a fish and two lizard species. Our results indicate that bats are a hotspot for horizontal transfer of DNA transposons. These events broadly coincide with the diversification of several bat clades, supporting the hypothesis that DNA transposon invasions have contributed to genetic diversification of bats.

Plasma proteins related to inflammatory diet predict future cognitive impairment.

Dysregulation of the immune system and dietary patterns that increase inflammation can increase the risk for cognitive decline, but the mechanisms by which inflammatory nutritional habits may affect the development of cognitive impairment in aging are not well understood. To determine whether plasma proteins linked to inflammatory diet predict future cognitive impairment, we applied high-throughput proteomic assays to plasma samples from a subset (n = 1528) of Women's Health Initiative Memory Study (WHIMS) participants (mean [SD] baseline age, 71.3 [SD 3.8] years). Results provide insights into how inflammatory nutritional patterns are associated with an immune-related proteome and identify a group of proteins (CXCL10, CCL3, HGF, OPG, CDCP1, NFATC3, ITGA11) related to future cognitive impairment over a 14-year follow-up period. Several of these inflammatory diet proteins were also associated with dementia risk across two external cohorts (ARIC, ESTHER), correlated with plasma biomarkers of Alzheimer's disease (AD) pathology (Aß42/40) and/or neurodegeneration (NfL), and related to an MRI-defined index of neurodegenerative brain atrophy in a separate cohort (BLSA). In addition to evaluating their biological relevance, assessing their potential role in AD, and characterizing their immune-tissue/cell-specific expression, we leveraged published RNA-seq results to examine how the in vitro regulation of genes encoding these candidate proteins might be altered in response to an immune challenge. Our findings indicate how dietary patterns with higher inflammatory potential relate to plasma levels of immunologically relevant proteins and highlight the molecular mediators which predict subsequent risk for age-related cognitive impairment.

Timing of Cognitive Test Score Decline Prior to Incident Dementia Diagnosis in Blacks and Whites: The Atherosclerosis Risk in Communities Neurocognitive Study.

INTRODUCTION: Commonly occurring dementias include those of Alzheimer's, vascular, and mixtures of these and other pathologies. They are believed to evolve over many years, but that time interval has been difficult to establish. Our objective was to determine how many years in advance of a dementia diagnosis cognitive scores begin to change. METHODS: 14,086 dementia-free ARIC participants underwent a cognitive exam at baseline visit 2 (1990-1992, mean age 57 ± 5.72), and 11,244 at visit 4 (1996-1998), 5,640 at visit 5 (2011-2013), and 3,574 at visit 6 (2016-2017) with surveillance for dementias of all-causes combined. Within 5-year intervals after each visit, we compared performance on the Delayed Word Recall Test (DWRT), the Digit Symbol Substitution Test (DSST), the Word Fluency Test (WFT), and the combined mean of three cognitive tests at baseline in participants who were diagnosed with dementia within each interval versus those who survived the interval without a dementia diagnosis. Z-scores were adjusted for demographics and education in separate regression models for each visit. We plotted adjusted z-score means by time interval following each visit. RESULTS: During follow-up 3,334, 2,821, 1,218, and 329 dementia cases were ascertained after visits 2, 4, 5, and 6, respectively. Adjusted DWRT z-scores were significantly lower 20-25 years before dementia than those who did not experience dementia within 25 years. DSST z-scores were significantly lower at 25-30 years and 3-test combination z-scores were significantly lower as early as 30-31 years before onset. The difference between dementia and non-dementia group in the visit 2 3-test combination z-score was -0.20 at 30-31 years prior to dementia diagnosis. As expected, differences between the dementia and non-dementia groups increased closer to the time of dementia occurrence, up to their widest point at 0-5 years prior to dementia diagnosis. The difference between dementia and non-dementia groups in the visit 2 3-test combination z-score at 0-5 years was -0.90. WFT z-score differences were smaller than for the DSST or DWRT and began later. Patterns were similar in Black and White participants. CONCLUSION: DWRT, DSST, and combined 3-test z-scores were significantly lower more than 20 years prior to diagnosis in the dementia group versus the non-dementia group. Findings contribute to our knowledge of the long prodromal period in Blacks and Whites.

Epstein Barr virus-directed T-cell therapy for refractory EBV-PTLD in a toddler post Orthotopic heart transplantation.

Epstein-Barr Virus (EBV) is a ubiquitous herpes type virus that is associated with post-transplant lymphoproliferative disorder (PTLD). Usual management includes reduction or cessation of immunosuppression and in some cases chemotherapy including rituximab. However, limited therapies are available if PTLD is refractory to rituximab. Several clinical trials have investigated the use of EBV-directed T cells in rituximab-refractory patients; however, data regarding response is scarce and inconclusive. Herein, we describe a patient with EBV-PTLD refractory to rituximab after orthotopic heart transplantation (OHT) requiring EBV-directed T-cell therapy. This article aims to highlight the unique and aggressive clinical presentation and progression of PTLD with utilization of EBV-directed T-cell therapy for management and associated pitfalls.

Serious bacterial infection risk in recently immunized febrile infants in the emergency department.

STUDY OBJECTIVES: Fever following immunizations is a common presenting chiefcomplaint among infants. The 2021 American Academy of Pediatrics (AAP) febrile infant clinical practice guidelines exclude recently immunized (RI) infants. This is a challenge for clinicians in the management of the febrile RI young infant. The objective of this study was to assess the prevalence of SBI in RI febrile young infants between 6 and 12 weeks of age. METHODS: This was a retrospective chart review of infants 6-12 weeks who presented with a fever ≥38 °C to two U.S. military academic Emergency Departments over a four-year period. Infants were considered recently immunized (RI) if they had received immunizations in the preceding 72 h prior to evaluation and not recently immunized (NRI) if they had not received immunizations during this time period. The primary outcome was prevalence of serious bacterial infection (SBI) further delineated into invasive-bacterial infection (IBI) and non-invasive bacterial infection (non-IBI) based on culture and/or radiograph reports. RESULTS: Of the 508 febrile infants identified, 114 had received recent immunizations in the preceding 72 h. The overall prevalence of SBI was 11.4% (95% CI = 8.9-14.6) in our study population. The prevalence of SBI in NRI infants was 13.7% (95% CI = 10.6-17.6) compared to 3.5% (95% CI = 1.1-9.3) in RI infants. The relative risk of SBI in the setting of recent immunizations was 0.3 (95% CI = 0.1-0.7). There were no cases of invasive-bacterial infections (IBI) in the RI group with all but one of the SBI being urinary tract infections (UTI). The single non-UTI was a case of pneumonia in an infant who presented with respiratory symptoms within 24 h of immunizations. CONCLUSION: The risk of IBI (meningitis or bacteremia) in RI infants aged 6 to 12 weeks is low. Non-IBI within the first 24 h following immunization was significantly lower than in febrile NRI infants. UTIs remain a risk in the RI population and investigation with urinalysis and urine culture should be encouraged. Shared decision making with families guide a less invasive approach to the care of these children. Future research utilizing a large prospective multi-center data registry would aid in further defining the risk of both IBI and non-IBI among RI infants.

A single-institutional experience with 36 children less than 5 kilograms supported with the Berlin Heart: Comparison of congenital versus acquired heart disease.

OBJECTIVES: We reviewed outcomes in all 36 consecutive children <5 kg supported with the Berlin Heart pulsatile ventricular assist device at the University of Florida, comparing those with acquired heart disease (n = 8) to those with congenital heart disease (CHD) (n = 28). METHODS: The primary outcome was mortality. The Kaplan-Meier method and log-rank tests were used to assess group differences in long-term survival after ventricular assist device insertion. T-tests using estimated survival proportions were used to compare groups at specific time points. RESULTS: Of 82 patients supported with the Berlin Heart at our institution, 49 (49/82 = 59.76%) weighed <10 kg and 36 (36/82 = 43.90%) weighed <5 kg. Of 36 patients <5 kg, 26 (26/36 = 72.22%) were successfully bridged to transplantation. (The duration of support with ventricular assist device for these 36 patients <5 kg was [days]: median = 109, range = 4-305.) Eight out of 36 patients <5 kg had acquired heart disease, and all eight [8/8 = 100%] were successfully bridged to transplantation. (The duration of support with ventricular assist device for these 8 patients <5 kg with acquired heart disease was [days]: median = 50, range = 9-130.) Twenty-eight of 36 patients <5 kg had congenital heart disease. Eighteen of these 28 [64.3%] were successfully bridged to transplantation. (The duration of support with ventricular assist device for these 28 patients <5 kg with congenital heart disease was [days]: median = 136, range = 4-305.) For all 36 patients who weighed <5 kg: 1-year survival estimate after ventricular assist device insertion = 62.7% (95% confidence interval = 48.5-81.2%) and 5-year survival estimate after ventricular assist device insertion = 58.5% (95% confidence interval = 43.8-78.3%). One-year survival after ventricular assist device insertion = 87.5% (95% confidence interval = 67.3-99.9%) in acquired heart disease and 55.6% (95% confidence interval = 39.5-78.2%) in CHD, P = 0.036. Five-year survival after ventricular assist device insertion = 87.5% (95% confidence interval = 67.3-99.9%) in acquired heart disease and 48.6% (95% confidence interval = 31.6-74.8%) in CHD, P = 0.014. CONCLUSION: Pulsatile ventricular assist device facilitates bridge to transplantation in neonates and infants weighing <5 kg; however, survival after ventricular assist device insertion in these small patients is less in those with CHD in comparison to those with acquired heart disease.

Patterns of cognitive domain abnormalities enhance discrimination of dementia risk prediction: The ARIC study.

INTRODUCTION: The contribution of neuropsychological assessments to risk assessment for incident dementia is underappreciated. METHODS: We analyzed neuropsychological testing results in dementia-free participants in the Atherosclerosis Risk in Communities (ARIC) study. We examined associations of index domain-specific neuropsychological test performance with incident dementia using cumulative incidence curves and Cox proportional hazards models. RESULTS: Among 5296 initially dementia-free participants (mean [standard deviation] age of 75.8 [5.1] years; 60.1% women, 22.2% Black) over a median follow-up of 7.9 years, the covariate-adjusted hazard ratio varied substantially depending on the pattern of domain-specific performance and age, in an orderly manner from single domain language abnormalities (lowest risk) to single domain executive or memory abnormalities, to multidomain abnormalities including memory (highest risk). DISCUSSION: By identifying normatively defined cognitive abnormalities by domains based on neuropsychological test performance, there is a conceptually orderly and age-sensitive spectrum of risk for incident dementia that provides valuable information about the likelihood of progression. HIGHLIGHTS: Domain-specific cognitive profiles carry enhanced prognostic value compared to mild cognitive impairment. Single-domain non-amnestic cognitive abnormalities have the most favorable prognosis. Multidomain amnestic abnormalities have the greatest risk for incident dementia. Patterns of domain-specific risks are similar by sex and race.

The CENP-T/-W complex is a binding partner of the histone chaperone FACT.

The CENP-T/-W histone fold complex, as an integral part of the inner kinetochore, is essential for building a proper kinetochore at the centromere in order to direct chromosome segregation during mitosis. Notably, CENP-T/-W is not inherited at centromeres, and new deposition is absolutely required at each cell cycle for kinetochore function. However, the mechanisms underlying this new deposition of CENP-T/-W at centromeres are unclear. Here, we found that CENP-T deposition at centromeres is uncoupled from DNA synthesis. We identified Spt16 and SSRP1, subunits of the H2A-H2B histone chaperone facilitates chromatin transcription (FACT), as CENP-W binding partners through a proteomic screen. We found that the C-terminal region of Spt16 binds specifically to the histone fold region of CENP-T/-W. Furthermore, depletion of Spt16 impairs CENP-T and CENP-W deposition at endogenous centromeres, and site-directed targeting of Spt16 alone is sufficient to ensure local de novo CENP-T accumulation. We propose a model in which the FACT chaperone stabilizes the soluble CENP-T/-W complex in the cell and promotes dynamics of exchange, enabling CENP-T/-W deposition at centromeres.

Tumor and Peritoneum-Associated Macrophage Gene Signature as a Novel Molecular Biomarker in Gastric Cancer.

A spectrum of immune states resulting from tumor resident macrophages and T-lymphocytes in the solid tumor microenvironment correlates with patient outcomes. We hypothesized that in gastric cancer (GC), macrophages in a polarized immunosuppressive transcriptional state would be prognostic of poor survival. We derived transcriptomic signatures for M2 (M2TS, MRC1; MS4A4A; CD36; CCL13; CCL18; CCL23; SLC38A6; FGL2; FN1; MAF) and M1 (M1TS, CCR7; IL2RA; CXCL11; CCL19; CXCL10; PLA1A; PTX3) macrophages, and cytolytic T-lymphocytes (CTLTS, GZMA; GZMB; GZMH; GZMM; PRF1). Primary GC in a TCGA stomach cancer dataset was evaluated for signature expressions, and a log-rank test determined overall survival (OS) and the disease-free interval (DFI). In 341 TCGA GC entries, high M2TS expression was associated with histological types and later stages. Low M2TS expression was associated with significantly better 5-year OS and DFI. We validated M2TS in prospectively collected peritoneal fluid of a GC patient cohort (n = 28). Single-cell RNA sequencing was used for signature expression in CD68+CD163+ cells and the log-rank test compared OS. GC patients with high M2TS in CD68+CD163+ cells in their peritoneal fluid had significantly worse OS than those with low expression. Multivariate analyses confirmed M2TS was significantly and independently associated with survival. As an independent predictor of poor survival, M2TS may be prognostic in primary tumors and peritoneal fluid of GC patients.

Blockade of interleukin 10 potentiates antitumour immune function in human colorectal cancer liver metastases.

OBJECTIVE: Programmed cell death protein 1 (PD-1) checkpoint inhibition and adoptive cellular therapy have had limited success in patients with microsatellite stable colorectal cancer liver metastases (CRLM). We sought to evaluate the effect of interleukin 10 (IL-10) blockade on endogenous T cell and chimeric antigen receptor T (CAR-T) cell antitumour function in CRLM slice cultures. DESIGN: We created organotypic slice cultures from human CRLM (n=38 patients' tumours) and tested the antitumour effects of a neutralising antibody against IL-10 (αIL-10) both alone as treatment and in combination with exogenously administered carcinoembryonic antigen (CEA)-specific CAR-T cells. We evaluated slice cultures with single and multiplex immunohistochemistry, in situ hybridisation, single-cell RNA sequencing, reverse-phase protein arrays and time-lapse fluorescent microscopy. RESULTS: αIL-10 generated a 1.8-fold increase in T cell-mediated carcinoma cell death in human CRLM slice cultures. αIL-10 significantly increased proportions of CD8+ T cells without exhaustion transcription changes, and increased human leukocyte antigen - DR isotype (HLA-DR) expression of macrophages. The antitumour effects of αIL-10 were reversed by major histocompatibility complex class I or II (MHC-I or MHC-II) blockade, confirming the essential role of antigen presenting cells. Interrupting IL-10 signalling also rescued murine CAR-T cell proliferation and cytotoxicity from myeloid cell-mediated immunosuppression. In human CRLM slices, αIL-10 increased CEA-specific CAR-T cell activation and CAR-T cell-mediated cytotoxicity, with nearly 70% carcinoma cell apoptosis across multiple human tumours. Pretreatment with an IL-10 receptor blocking antibody also potentiated CAR-T function. CONCLUSION: Neutralising the effects of IL-10 in human CRLM has therapeutic potential as a stand-alone treatment and to augment the function of adoptively transferred CAR-T cells.

Association of Lung Function With Cognitive Decline and Incident Dementia in the Atherosclerosis Risk in Communities Study.

We examined the associations between lung function and incident dementia and cognitive decline in 12,688 participants in the ARIC Study who provided lung function measurements in 1990-1992. Cognitive tests were administered up to 7 times, and dementia was ascertained through 2019. We used shared parameter models to jointly fit proportional hazard models and linear mixed-effect models to estimate lung-function-associated dementia rate and cognitive change, respectively. Higher forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were associated with reduced dementia (n = 2,452 persons developed dementia); hazard ratios per 1-L increase in FEV1 and FVC were 0.79 (95% confidence interval (CI): 0.71, 0.89) and 0.81 (95% CI: 0.74, 0.89), respectively. Each 1-L increase in FEV1 and FVC was associated with a 0.08-standard deviation (SD) (95% CI: 0.05, 0.12) and a 0.05-SD (95% CI: 0.02, 0.07) attenuation of 30-year cognitive decline, respectively. A 1% increase in FEV1/FVC ratio was associated with 0.008-SD (95% CI: 0.004, 0.012) less cognitive decline. We observed statistical interaction between FEV1 and FVC, suggesting that cognitive declines depended on values of specific FEV1 and FVC (as compared with FEV1, FVC, or FEV1/FVC ratio models that suggested linear incremental associations). Our findings may have important implications for reducing the burden of cognitive decline that is attributable to environmental exposures and associated lung function impairment.

Safety and Efficacy of Oxaliplatin Pressurized Intraperitoneal Aerosolized Chemotherapy (PIPAC) in Colorectal and Appendiceal Cancer with Peritoneal Metastases: Results of a Multicenter Phase I Trial in the USA.

BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a laparoscopic locoregional treatment for peritoneal metastases (PM) from colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery (CRS). While PIPAC has been studied in Europe and Asia, it has not been investigated in the USA. PATIENTS AND METHODS: We evaluated PIPAC with 90 mg/m2 oxaliplatin alone (cycle 1) and preceded by systemic chemotherapy with fluorouracil (5-FU) and leucovorin (LV) (cycle 2-3) as a multicenter prospective phase I clinical trial (NCT04329494). The primary endpoint was treatment-related adverse events (AEs). Secondary endpoints included survival and laparoscopic, histologic, and radiographic response. RESULTS: 12 patients were included: 8 with CRC and 4 with AC. Median prior chemotherapy cycles was 2 (interquartile range (IQR) 2-3). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median peritoneal carcinomatosis index (PCI) was 28 (IQR 19-32). Six (50%) of twelve patients completed three PIPAC cycles. No surgical complications or dose-limiting toxicities were observed. Two patients developed grade 3 treatment-related toxicities (one abdominal pain and one anemia). Median overall survival (OS) was 12.0 months, and median progression-free survival (PFS) was 2.9 months. OS was correlated with stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria but not with laparoscopic response by PCI or histologic response by peritoneal regression grading system (PRGS). CONCLUSIONS: This phase I trial in the USA demonstrated safety, feasibility, and early efficacy signal of PIPAC with oxaliplatin and chemotherapy in patients with PM from AC or CRC who are refractory to standard lines of systemic chemotherapy.

Support with Single Ventricle-Ventricular Assist Device (sVAD) in Patients with Functionally Univentricular Circulation Prior to Fontan Operation.

Some patients with functionally univentricular circulation develop cardiac failure refractory to maximal management and are supported with a ventricular assist device (VAD). The purpose of this manuscript is to summarize our previous publications related to single ventricle-ventricular assist device (sVAD) support in patients with functionally univentricular circulation and to describe our current institutional approach at University of Florida to sVAD support in neonates, infants, and children prior to Fontan. Our programmatic philosophy at University of Florida is to strive to identify the minority of neonates with functionally univentricular circulation who are extremely high-risk prior to initiating staged palliation and to stabilize these neonates with primary preemptive sVAD in preparation for cardiac transplantation; our rationale for this approach is related to the challenges associated with failed staged palliation and subsequent bail-out sVAD support and transplantation. A subset of extremely high-risk neonates and infants with functionally univentricular ductal-dependent circulation undergo primary preemptive sVAD insertion and subsequent cardiac transplantation. Support with VAD clearly facilitates survival on the waiting list during prolonged wait times and optimizes outcomes after Norwood (Stage 1) by providing an alternative pathway for extremely high-risk patients. Therefore, the selective utilization of sVAD in extremely high-risk neonates facilitates improved outcomes for all patients with functionally univentricular ductal-dependent circulation. At University of Florida, our programmatic approach to utilizing sVAD support as a bridge to transplantation in the minority of neonates with functionally univentricular circulation who are extremely high-risk for staged palliation is associated with Operative Mortality after Norwood (Stage 1) Operation of 2.9% (2/68) and a one-year survival of 91.1% (82/90) for all neonates presenting with hypoplastic left heart syndrome (HLHS) or HLHS-related malformation with functionally univentricular ductal-dependent systemic circulation. Meanwhile, at University of Florida, for all 82 consecutive neonates, infants, and children supported with pulsatile paracorporeal VAD: Kaplan-Meier survival estimated one year after VAD insertion = 73.3% (95% confidence interval [CI] = 64.1-83.8%), and Kaplan-Meier survival estimated five years after VAD insertion = 68.3% (95% CI = 58.4-79.8%). For all 48 consecutive neonates, infants, and children at University of Florida with biventricular circulation supported with pulsatile paracorporeal VAD: Kaplan-Meier survival estimated one year after VAD insertion = 82.7% (95% CI = 72.4-94.4%), and Kaplan-Meier survival estimated five years after VAD insertion = 79.7% (95% CI = 68.6-92.6%). For all 34 consecutive neonates, infants, and children at University of Florida with functionally univentricular circulation supported with pulsatile paracorporeal sVAD: Kaplan-Meier survival estimated one year after VAD insertion = 59.7% (95% CI = 44.9-79.5%), and Kaplan-Meier survival estimated five years after VAD insertion = 50.5% (95% CI = 35.0-73.0%). These Kaplan-Meier survival estimates for patients supported with pulsatile paracorporeal VAD are better in patients with biventricular circulation in comparison to patients with functionally univentricular circulation both one year after VAD insertion (P=0.026) and five years after VAD insertion (P=0.010). Although outcomes after VAD support in functionally univentricular patients are worse than in patients with biventricular circulation, sVAD provides a reasonable chance for survival. Ongoing research is necessary to improve the outcomes of these challenging patients, with the goal of developing strategies where outcomes after sVAD support in functionally univentricular patients are equivalent to the outcomes achieved after VAD support in patients with biventricular circulation.

Alectinib-induced hemolytic anemia.

INTRODUCTION: Alectinib is an oral anaplastic lymphoma kinase tyrosine kinase inhibitor with central nervous system activity. It is currently approved and a preferred first-line option for those with anaplastic lymphoma kinase-positive non-small cell lung cancer. Alectinib has been shown to cause anemia, usually mild. CASE REPORT: We report a case of alectinib-induced hemolytic anemia in a patient receiving alectinib as first-line treatment for anaplastic lymphoma kinase-positive non-small cell lung cancer. MANAGEMENT AND OUTCOME: The patient's dose was reduced from 600 mg twice daily to 450 mg twice daily and further down to 300 mg twice daily and eventually discontinued. At that point, the hemoglobin normalized. DISCUSSION: Our case demonstrates objective evidence for hemolytic anemia induced by alectinib.

Current Patterns of Probiotic Use in U.S. Neonatal Intensive Care Units: A Multi-Institution Survey.

OBJECTIVE: Probiotic supplementation is associated with health benefits in preterm infants. The 2021 American Academy of Pediatrics (AAP) statement on probiotic use advised caution, citing heterogeneity and absence of federal regulation. We assessed the impact of the AAP statement and current institution-wide patterns of probiotic use across neonatal intensive care units (NICU) across the United States. STUDY DESIGN: A cross-sectional web-based institutional survey using REDCap was emailed to 430 Children's Hospital Neonatal Consortium (CHNC) and Pediatrix Medical Group institutions. The survey captured data on probiotic formulations, supplementation, initiation and cessation criteria, reasons for discontinuation, interest in initiating, and AAP statement's impact. RESULTS: Ninety-five (22.1%) hospitals, including 42/46 (91%) CHNC and 53/384 (14%) Pediatrix institutions, completed the survey. Thirty-seven (39%) currently use probiotics. Fourteen different probiotic formulations were reported. The common criteria for initiation were birth weight <1,500 g and gestational age <32 weeks. Parental consent or assent was obtained at only 30% of institutions. Five hospitals (11%) with prior probiotic use discontinued solely due to the AAP statement. Overall, 23 (24%) of hospitals indicated that the AAP statement significantly influenced their decision regarding probiotic use. Nineteen of 51 nonusers (37%) are considering initiation. CONCLUSION: Probiotic use in preterm infants is likely increasing in NICUs across the United States, but significant variability exists. The 2021 AAP statement had variable impact on NICUs' decision regarding probiotic use. The growing interest in adopting probiotics and the significant interhospital variability highlight the need for better regulation and consensus guidelines to ensure standardized use. KEY POINTS: · Probiotic use in preterm infants is likely increasing in U.S. NICUs, but clinical variability exists.. · The AAP statement on probiotic use in preterm infants had a modest impact on current practices.. · There's a need for better product regulation and consensus guidelines to ensure standardized use..

IWATE criteria are associated with perioperative outcomes in robotic hepatectomy: a retrospective review of 225 resections.

BACKGROUND: Robotic hepatectomy (RH) is increasingly utilized for minor and major liver resections. The IWATE criteria were developed to classify minimally invasive liver resections by difficulty. The objective of this study was to apply the IWATE criteria in RH and to describe perioperative and oncologic outcomes of RH over the last decade at our institution. METHODS: Perioperative and oncologic outcomes of patients who underwent RH between 2011 and 2019 were retrospectively collected. The difficulty level of each operation was assessed using the IWATE criteria, and outcomes were compared at each level. Univariate linear regression was performed to characterize the relationship between IWATE criteria and perioperative outcomes (OR time, EBL, and LOS), and a multivariable model was also developed to address potential confounding by patient characteristics (age, sex, BMI, prior abdominal surgery, ASA class, and simultaneous non-hepatectomy operation). RESULTS: Two hundred and twenty-five RH were performed. Median IWATE criteria for RH were 6 (IQR 5-9), with low, intermediate, advanced, and expert resections accounting for 23% (n = 51), 34% (n = 77), 32% (n = 72), and 11% (n = 25) of resections, respectively. The majority of resections were parenchymal-sparing approaches, including anatomic segmentectomies and non-anatomic partial resections. 30-day complication rate was 14%, conversion to open surgery occurred in 9 patients (4%), and there were no deaths within 30 days postoperatively. In the univariate linear regression analysis, IWATE criteria were positively associated with OR time, EBL, and LOS. In the multivariable model, IWATE criteria were independently associated with greater OR time, EBL, and LOS. Two-year overall survival for hepatocellular carcinoma and intrahepatic cholangiocarcinoma was 94% and 50%, respectively. CONCLUSION: In conclusion, the IWATE criteria are associated with surgical outcomes after RH. This series highlights the utility of RH for difficult hepatic resections, particularly parenchymal-sparing resections in the posterosuperior sector, extending the indication of minimally invasive hepatectomy in experienced hands and potentially offering select patients an alternative to open hepatectomy or other less definitive liver-directed treatment options.

Warmed contrast media temperature loss in traditional manifold systems during angiographic procedures.

BACKGROUND: Extrinsic warming of contrast media (CM) to 37 °C before angiographic procedures is performed to improve bolus kinetics and avoid potential adverse effects. Extrinsically warmed CM readily loses temperature after removal from the warming cabinet, but the extent of its cooling has not been previously investigated. PURPOSE: To assess temperature loss of extrinsically warmed CM in tubing of traditional angiographic manifolds during simulated angiography. MATERIAL AND METHODS: In total, 35 scheduled diagnostic angiographic procedures were observed in a hospital setting. Relevant time points of CM use during the procedures were recorded. The shortest, median, and longest procedures were then simulated in the experimental laboratory to measure CM temperatures at specific times at three locations along the tubing system. RESULTS: The angiographic procedures lasted 7.0-26.6 min (median = 11.7 min), with the total duration dependent primarily on the time from contrast being removed from the warming cabinet to the commencement of imaging. During the simulated procedures, consistent patterns of temperature loss were observed. By the last simulated angiographic run, injected CM temperature decreased by 7.4-16.4 °C, depending on procedure length. Most of the heat loss occurred in the tubing between the CM bottle and coronary control syringe. CONCLUSION: During angiographic procedures, prewarmed CM loses its temperature rapidly with the duration of exposure to ambient room temperature. If no additional measures are employed to maintain its temperature outside of the warming cabinet, extrinsic warming has limited impact on injected CM temperature.

The association of motoric cognitive risk with incident dementia and neuroimaging characteristics: The Atherosclerosis Risk in Communities Study.

INTRODUCTION: Motoric cognitive risk (MCR), a clinical syndrome characterized by slow gait speed and subjective cognitive complaints, has been associated with dementia risk. The neuropathological features underlying MCR remain poorly understood. METHODS: The Atherosclerosis Risk in Communities (ARIC) community-based cohort study classified participants using standardized criteria as MCR+/- and mild cognitive impairment (MCI)+/- at study baseline (2011-2013). We examined the 5-year dementia risk and baseline brain structural/molecular abnormalities associated with MCR+ and MCI+ status. RESULTS: Of 5023 nondemented participants included, 204 were MCR+ and 1030 were MCI+. Both MCR+ and MCI+ participants demonstrated increased dementia risk. The pattern of structural brain abnormalities associated with MCR+ differed from that of MCI+. Whereas MCI+ was associated with comparatively smaller volumes in brain regions vulnerable to Alzheimer's disease pathology, MCR+ status was associated with smaller volumes in frontoparietal regions and greater white matter abnormalities. DISCUSSION: MCR may represent a predementia syndrome characterized by prominent white matter abnormalities and frontoparietal atrophy.

Association of Carotid Intima-Media Thickness with Brain MRI Markers in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS).

OBJECTIVE: Elevated carotid intima-media thickness (cIMT) and carotid plaque are markers of arterial injury and may be linked to structural brain injury. We hypothesized cIMT or presence of carotid plaque at midlife are associated with presence of infarcts and cerebral microbleeds, greater white matter hyperintensity (WMH) volume, and smaller regional brain volumes in late-life. METHODS: We included 1,795 Atherosclerosis Risk in Communities (ARIC) Study participants (aged 57±6 years, 57% female, 23% Black) with carotid ultrasounds in 1990-1992 and brain MRI scans in 2011-2013. Weighted linear regression was used for brain volume outcomes, while logistic regression was used for infarcts and cerebral microbleeds. RESULTS: After multivariable adjustments, the highest cIMT quintile was associated with smaller deep gray matter (ß [95% CI]: -0.11 [-0.22, -0.01]) and cortical volume in a temporal-parietal meta region of interest (ROI) (ß [95% CI]: -0.10 [-0.20, -0.01]) in late-life. Similarly, those with carotid plaque had smaller regional brain volumes than those without (ßs [95% CIs]: -0.05 [-0.12, 0.03] and -0.06 [-0.13, 0.01] for deep gray matter and temporal-parietal meta ROI). No significant relations were observed with WMH volume, infarcts, or cerebral microbleeds. CONCLUSION: Over a median follow-up of 21 years, greater midlife cIMT and presence of carotid plaque were associated with smaller deep gray matter volume and cortical volume in a meta ROI involving temporal and parietal lobe regions typically involved in neurodegeneration, including Alzheimer's disease, in later life. Contrary to our hypothesis, associations between measures of arterial injury and markers of vascular brain injury were null.