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This study explores vocal development as an early marker of autism, focusing on canonical babbling rate and onset, typically established by 7 months. Previous reports suggested delayed or reduced canonical babbling in infants later diagnosed with autism, but the story may be complicated. We present a prospective study on 44 infants later diagnosed with autism spectrum disorder compared with 127 infants later identified as typically developing who were followed longitudinally with day-long recordings from 0 to 13 months. Eight 5-min segments from each of their recordings were coded for canonical and noncanonical syllables. The results confirmed many reports that canonical babbling is a robust feature of human vocal development in the first year of life, with small overall mean differences in canonical babbling rates between the autism spectrum disorder and typically developing groups beginning around 9 months, primarily in males. Our findings highlight the importance of considering sex differences in vocal communication as part of the early detection and diagnosis of autism when determining the need for communication supports to maximize outcomes.

Abstract Background Bloodstream infection (BSI) is associated with poor outcomes especially when effective antimicrobial therapy and control of infection source are delayed. As the frequency of Enterobacterales producing metallo-β-lactamases (MBL) and/or OXA-48–like carbapenemases is increasing in some United States (US) medical centres, effective antimicrobials to treat the infections caused by these organisms are urgently needed. Aztreonam-avibactam is under clinical development for treatment of infections caused by Gram-negative bacteria, including MBL producers. Objectives To evaluate the antimicrobial susceptibility of Enterobacterales causing BSI in US medical centres and compare the activity of aztreonam-avibactam with ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol, and other antimicrobials used to treat BSI. Methods 4,802 Enterobacterales were consecutively collected (1/patient) from 72 US medical centres in 2020–2022 and susceptibility tested by broth microdilution. Aztreonam-avibactam was tested with avibactam at a fixed concentration of 4 mg/L. A pharmacokinetic/pharmacodynamic susceptible breakpoint of ≤ 8 mg/L was applied for aztreonam-avibactam for comparison. Carbapenem-resistant Enterobacterales (CRE) isolates were tested for β-lactamase–encoding genes using Next-generation sequencing. Results Aztreonam-avibactam was highly active against Enterobacterales; only 2 isolates showed aztreonam-avibactam MICs > 8 mg/L: 1 meropenem-susceptible E. coli and 1 K. aerogenes (CRE). All carbapenemase producers and 98.0% of CRE were inhibited at an aztreonam-avibactam MIC of ≤ 8 mg/L. CRE susceptibility rates were 81.6% for ceftazidime-avibactam, 65.3% for meropenem-vaborbactam, 61.2% for imipenem-relebactam, and 87.8% for cefiderocol. Aztreonam-avibactam retained activity (MIC, ≤ 8 mg/L) against all (100.0%) meropenem-vaborbactam nonsusceptible (n = 17), 99.5% of imipenem-relebactam nonsusceptible (n = 206), and 90.0% of ceftazidime-avibactam nonsusceptible (n = 10) isolates. The most common carbapenemases were KPC-2/3 (57.1% of CREs), OXA-48–like (16.3%), and NDM (14.3%). A carbapenemase gene was not observed in 12.3% of CREs. Ceftazidime-avibactam and meropenem-vaborbactam were active against 100.0% of KPC producers, but ceftazidime-avibactam showed limited activity against MBL producers and meropenem-vaborbactam showed limited activity against OXA-48–like and MBL producers. The most active non–β-lactam comparators against CRE were gentamicin (49.0% susceptible) and amikacin (44.9% susceptible). Conclusions Aztreonam-avibactam demonstrated potent activity against a large collection of Enterobacterales isolated from patients with BSI in US hospitals, including CRE, MBL producers, and isolates resistant to recently approved β-lactamase inhibitor combinations.

Public school students in the Black Belt of Alabama suffer from food insecurity disproportionately compared with national peers. Results of a recent mixed methods study indicated food insecurity levels that were three times the national average, with very low food security an alarming 11 times the national average. In the fight against hunger in our public schools, no professionals are more valuable than the Child Nutrition Programs (CNP) staff, headed by the local CNP director. The qualitative portion of the mixed methods study solicited input from CNP directors in 14 Black Belt counties in Alabama. The recommendations from structured interviews suggest an intentional,coordinated, and multifaceted approach to fight against food insecurity in our rural public schools.

ABSTRACT This study reports the activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp. isolates collected from the United States and Europe, including Israel and Turkey, from 2020 to 2021. Among Enterobacterales, 2.8% were carbapenem nonsusceptible (CNSE); cefiderocol inhibited 96.6%/85.1% [Clinical Laboratory Standards Institute (CLSI)/European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints] of these isolates. Imipenem-relebactam, meropenem-vaborbactam, and ceftazidime-avibactam displayed susceptibilities lower than cefiderocol against CNSE isolates (67.4–84.6% susceptible, CLSI). Cefiderocol was the only agent active against CNSE isolates carrying metallo-β-lactamase (MBL) carbapenemase or multiple carbapenemase genes (84.6%–92.3% susceptible, CLSI). Approximately 18% of carbapenem-susceptible Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis carried extended-spectrum-β-lactamases and/or plasmid-borne AmpC-encoding genes; cefiderocol inhibited 99.8%–100.0% (CLSI) of these genotypic groups. Multi-drug resistance (MDR) phenotypes were observed in 16.9% and 52.5% of P. aeruginosa and A. baumannii-calcoaceticus isolates, respectively. Carbapenemase genes were rare (4.9%) among cephalosporin and/or carbapenem nonsusceptible P. aeruginosa, compared to 87.6% carriage in A. baumannii-calcoaceticus, respectively. Against the MDR and carbapenemase-carrying P. aeruginosa and A. baumannii-calcoaceticus subsets, cefiderocol was active against 98.6%/98.7% and 97.1%/97.4% (CLSI), respectively. Only 69 isolates (0.3%) across all species groups were identified as cefiderocol nonsusceptible per CLSI criteria (>4 mg/L). Cefiderocol was the most active agent in vitro against Enterobacterales, P. aeruginosa, and Acinetobacter spp., with uniform activity against all phenotypic- and genotypic-resistant subsets. Coupled with the low incidence of nonsusceptibility observed across species groups, these results demonstrate cefiderocol as an important option for treating infections caused by pathogens with diverse mechanisms of resistance in US and European hospitals.IMPORTANCEThe worldwide spread of multi-drug-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacterales and Acinetobacter spp. poses a serious challenge in healthcare settings as infections caused by these organisms are commonly refractory to many frontline therapeutic agents. Multiple global health organizations highlighted these pathogens as critical priorities for new antibiotic development, thus necessitating continued surveillance of the activities of currently available antimicrobial agents and circulating mechanisms of resistance. To meet this need, this study phenotypically and genotypically characterized priority Gram-negative pathogens collected from patients in US and European hospitals to examine the activity of cefiderocol and other currently available treatment options, including carbapenems and β-lactam-β-lactamase inhibitor combinations. The results presented here provide a detailed perspective to healthcare practitioners of cefiderocol’s broad applicability, manifested in high activity and low nonsusceptibility rates, across phenotypic and genotypic organism groups relative to other agents and further support its use against the most intransigent infections.

Addiction is commonly characterized by escalation of drug intake, compulsive drug seeking, and continued use despite harmful consequences. However, the factors contributing to the transition from moderate drug use to these problematic patterns remain unclear, particularly regarding the role of sex. Many preclinical studies have been limited by small sample sizes, low genetic diversity, and restricted drug access, making it challenging to model significant levels of intoxication or dependence and translate findings to humans. To address these limitations, we characterized addiction-like behaviors in a large sample of >500 outbred heterogeneous stock (HS) rats using an extended cocaine self-administration paradigm (6 hr/daily). We analyzed individual differences in escalation of intake, progressive ratio (PR) responding, continued use despite adverse consequences (contingent foot shocks), and irritability-like behavior during withdrawal. Principal component analysis showed that escalation of intake, progressive ratio responding, and continued use despite adverse consequences loaded onto a single factor that was distinct from irritability-like behaviors. Categorizing rats into resilient, mild, moderate, and severe addiction-like phenotypes showed that females exhibited higher addiction-like behaviors, with a lower proportion of resilient individuals compared to males. These findings suggest that, in genetically diverse rats with extended drug access, escalation of intake, continued use despite adverse consequences, and PR responding are highly correlated measures of a shared underlying construct. Furthermore, our results highlight sex differences in resilience to addiction-like behaviors.

Chronic nicotine results in dependence with withdrawal symptoms on discontinuation of use, through desensitization of nicotinic acetylcholine receptors and altered cholinergic neurotransmission. Nicotine withdrawal is associated with increased whole-brain functional connectivity and decreased network modularity; however, the role of cholinergic neurons in those changes is unknown. To identify the contribution of nicotinic receptors and cholinergic regions to changes in the functional network, we analyzed the contribution of the main cholinergic regions to brain-wide activation of the immediate early-gene Fos during withdrawal in male mice and correlated these changes with the expression of nicotinic receptor mRNA throughout the brain. We show that the main functional connectivity modules included the main long-range cholinergic regions, which were highly synchronized with the rest of the brain. However, despite this hyperconnectivity, they were organized into two anticorrelated networks that were separated into basal forebrain-projecting and brainstem-thalamic-projecting cholinergic regions, validating a long-standing hypothesis of the organization of the brain cholinergic systems. Moreover, baseline (without nicotine) expression of Chrna2, Chrna3, Chrna10, and Chrnd mRNA of each brain region correlated with withdrawal-induced changes in Fos expression. Finally, by mining the Allen Brain mRNA expression database, we were able to identify 1755 gene candidates and three pathways (Sox2-Oct4-Nanog, JAK-STAT, and MeCP2-GABA) that may contribute to nicotine withdrawal-induced Fos expression. These results identify the dual contribution of the basal forebrain and brainstem-thalamic cholinergic systems to whole-brain functional connectivity during withdrawal; and identify nicotinic receptors and novel cellular pathways that may be critical for the transition to nicotine dependence.

A major limitation of the most widely used current animal models of alcohol dependence is that they use forced exposure to ethanol including ethanol-containing liquid diet and chronic intermittent ethanol (CIE) vapor to produce clinically relevant blood alcohol levels (BAL) and addiction-like behaviors. We recently developed a novel animal model of voluntary induction of alcohol dependence using ethanol vapor self-administration (EVSA). However, it is unknown whether EVSA leads to an escalation of alcohol drinking per se, and whether such escalation is associated with neuroadaptations in brain regions related to stress, reward, and habit. To address these issues, we compared the levels of alcohol drinking during withdrawal between rats passively exposed to alcohol (CIE) or voluntarily exposed to EVSA and measured the number of Fos+ neurons during acute withdrawal (16 h) in key brain regions important for stress, reward, and habit-related processes. CIE and EVSA rats exhibited similar BAL and similar escalation of alcohol drinking and motivation for alcohol during withdrawal. Acute withdrawal from EVSA and CIE recruited a similar number of Fos+ neurons in the Central Amygdala (CeA), however, acute withdrawal from EVSA recruited a higher number of Fos+ neurons in every other brain region analyzed compared to acute withdrawal from CIE. In summary, while the behavioral measures of alcohol dependence between the voluntary (EVSA) and passive (CIE) model were similar, the recruitment of neuronal ensembles during acute withdrawal was very different. The EVSA model may be particularly useful to unveil the neuronal networks and pharmacology responsible for the voluntary induction and maintenance of alcohol dependence and may improve translational studies by providing preclinical researchers with an animal model that highlights the volitional aspects of alcohol use disorder.

Introduction The rates of sudden unexpected infant death (SUID) are still high in the U.S. The longitudinal effects of SUID preventive education on infant safe sleep practices are less known. The current study evaluated the effects of a comprehensive hospital-based, SUID preventive intervention on safe infant sleep practices in the first six months of life and to identify factors associated with infant sleep practices. Methods Using a one-group pretest and multiple posttest design, the current quantitative study examined the impacts of the infant safe sleep intervention among 411 women recruited at a large, urban, university medical center. Participants were prospectively followed and completed four surveys from childbirth. Linear mixed models were used to evaluate the effects of the SUID prevention program on four sleep practice outcomes, including removing unsafe items from the sleeping environment, bed sharing, room sharing without bed sharing, and placing the infant in a supine sleep position. Results Compared to the baseline, participants were less likely to use unsafe items (e.g., soft bedding) in infants' sleeping areas over time. However, we found that participants reported more frequent bed sharing at 3-month and 6-month follow-ups, compared to the baseline. Conclusions Overall, maternal education and family income were positively related to healthy infant safe sleep practices. A hospital-based preventive intervention pairing an educational initiative with home-visiting services might improve safe sleep practices to remove accidental suffocation risks from the infant sleep environment., Author(s): Sunny H. Shin [sup.1] [sup.2] , Changyong Choi [sup.2] , Shu-Fang Shih [sup.3] , Camie A. Tomlinson [sup.2] , Tiffany Kimbrough [sup.4] Author Affiliations: (1) grid.224260.0, 0000 0004 0458 [...]

Palaeoclimate information on multiple climate variables at different spatiotemporal scales is becoming increasingly important to understand environmental and societal responses to climate change. A lack of high-quality reconstructions of past hydroclimate has recently been identified as a critical research gap. Speleothems, with their precise chronologies, widespread distribution, and ability to record changes in local to regional hydroclimate variability, are an ideal source of such information. Here, we present a new version of the Speleothem Isotopes Synthesis and AnaLysis database (SISALv3), which has been expanded to include trace element ratios and Sr isotopes as additional, hydroclimate-sensitive geochemical proxies. The oxygen and carbon isotope data included in previous versions of the database have been substantially expanded. SISALv3 contains speleothem data from 365 sites from across the globe, including 95 Mg/Ca, 85 Sr/Ca, 52 Ba/Ca, 25 U/Ca, 29 P/Ca, and 14 Sr-isotope records. The database also has increased spatiotemporal coverage for stable oxygen (892) and carbon (620) isotope records compared with SISALv2 (which consists of 673 and 430 stable oxygen and carbon records, respectively). Additional meta information has been added to improve the machine-readability and filtering of data. Standardized chronologies are included for all new entities along with the originally published chronologies. Thus, the SISALv3 database constitutes a unique resource of speleothem palaeoclimate information that allows regional to global palaeoclimate analyses based on multiple geochemical proxies, permitting more robust interpretations of past hydroclimate and comparisons with isotope-enabled climate models and other Earth system and hydrological models. The database can be accessed at https://doi.org/10.5287/ora-2nanwp4rk (Kaushal et al., 2024).

Abstract On 28 March 2005, the Indonesian islands of Nias and Simeulue experienced a powerful Mw 8.6 earthquake and coseismic uplift and subsidence. In areas of coastal uplift (up to ~ 2.8 m), fringing reef coral communities were killed by exposure, while deeper corals that survived were subjected to habitats with altered runoff, sediment and nutrient regimes. Here we present time-series (2000–2009) of Mn/Ca, Y/Ca and Ba/Ca variability in massive Porites corals from Nias to assess the environmental impact of a wide range of vertical displacement (+ 2.5 m to − 0.4 m). High-resolution LA-ICP-MS measurements show that skeletal Mn/Ca increased at uplifted sites, regardless of reef type, indicating a post-earthquake increase in suspended sediment delivery. Transient and/or long-term increases in skeletal Y/Ca at all uplift sites support the idea of increased sediment delivery. Coral Mn/Ca and Ba/Ca in lagoonal environments highlight the additional influences of reef bathymetry, wind-driven sediment resuspension, and phytoplankton blooms on coral geochemistry. Together, the results show that the Nias reefs adapted to fundamentally altered hydrographic conditions. We show how centuries of repeated subsidence and uplift during great-earthquake cycles along the Sunda megathrust may have shaped the modern-day predominance of massive scleractinian corals on the West Sumatran reefs.

IntroductionPneumococcal conjugate vaccines (PCVs), including higher valency vaccines such as PCV20, have the potential to reduce pediatric otitis media. We assessed serotype distribution, potential PCV coverage, and antimicrobial susceptibility of Streptococcus pneumoniae isolates cultured from middle ear fluid (MEF) of US children age ≤5 years.MethodsS. pneumoniae isolates identified from US hospitals participating in the SENTRY Antimicrobial Surveillance program from 2011 to 2021 were included. Serotypes were determined by in silico analysis based on Pneumococcal Capsular Typing methodology. The percentage of isolates belonging to serotypes included in PCV13 (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F), PCV15 (PCV13 plus 22F, 33F), and PCV20 (PCV13 plus, 8, 10A, 11A, 12F, 15B, 22F and 33F) was calculated. Antimicrobial susceptibility testing was performed by broth microdilution and interpreted using CLSI criteria. Nonsusceptibility was defined as isolates that were intermediate or resistant to a selected antimicrobial.ResultsAmong the 199 S. pneumoniae isolates that were identified, 56.8% were from children age

Background: While previous literature has shown that resident involvement increases operative time, the influence of resident involvement on operative time is generally not considered in current methods of case time predictions or operating room planning. Furthermore, evidence of prolonged case times based on the level of the assisting resident is yet scarce. We hypothesized that operative time would increase with the post-graduate year of assisting residents as they gain more autonomy in the operating room. Study design: This was an observational cohort study in which we retrospectively analyzed 802 laparoscopic cholecystectomy cases performed in a single academic institution between May 2014 and December 2020. Only cases in which a Post Graduate Year 1 to 5 (PGY) resident was assisting were included. Results: PGY1–4 residents had statistically significant positive time coefficient results in all linear regression models, except PGY2s in urgent cases. PGY-2 residents had the longest overall average case time of 98 min. Emergent cases were more likely to have prolonged case times. Conclusions: The increased average case time associated with PGY-2 residents is likely due to a new level of increased autonomy in the operating room (OR) during this year of training. The linear regression results indicated PGY1–4 residents were more likely to have longer laparoscopic cholecystectomy operative times than the PGY5 residents, except PGY2s in urgent cases. This may reflect the accumulation of surgical skills at the PGY5 level. Resident involvement should be considered in the prediction of operative time in an academic setting.

Marie M Plante,1 ErinMarie O Kimbrough,2 Amit K Agarwal,3 Liuyan Jiang,4 Kirk Bourgeois,4 Greta C Stamper,5 Michael W Stewart,6 Han W Tun2 1Department of Internal Medicine, Mayo Clinic, Jacksonville, FL, USA; 2Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA; 3Department of Radiology, Mayo Clinic, Jacksonville, FL, USA; 4Department of Pathology, Mayo Clinic, Jacksonville, FL, USA; 5Department of Otolaryngology and Audiology, Mayo Clinic, Jacksonville, FL, USA; 6Department of Ophthalmology, Mayo Clinic, Jacksonville, FL, USACorrespondence: Han W Tun, Division of Hematology and Oncology, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL, USA, Tel +1 904 953 7290, Fax +1 904 953 2315, Email Tun.Han@mayo.eduAbstract: Hyperviscosity syndrome (HVS) is an emergent complication of Waldenström macroglobulinemia (WM) characterized by visual, neurologic, and rarely auditory impairment. We report a 69-year-old female with MYD88 and CXCR4-mutant WM who developed HVS resulting in bilateral blindness and deafness associated with neurologic manifestations including confusion, severe generalized weakness, and imbalance. Ophthalmologic evaluation revealed bilateral central retinal vein occlusion (CRVO), diffuse retinal hemorrhages, macular edema, and serous macular detachments (SMD). Magnetic resonance imaging of the brain showed bleeding in the inner ears. Management was challenging as her WM was resistant to systemic therapies including bendamustine + rituximab (BR) and rituximab + bortezomib + dexamethasone (RVD). Bruton’s tyrosine kinase inhibitors could not be used initially due to ongoing lower gastrointestinal bleeding. She required five total sessions of plasma exchange and was finally initiated on zanubrutinib, achieving a partial response. She also received intravitreal bevacizumab with rapid resolution of the retinal hemorrhages but with little improvement of the SMD. She had partial restoration of her hearing in the right ear and only slight improvement in her bilateral visual deficits. The management of HVS in frail, elderly patients with therapy-resistant WM can be challenging. In these cases, plasma exchange is required until an effective systemic therapy can be safely instituted. Genomic profiling is important in the management of WM as it can predict treatment resistance and guide therapeutic decisions.Keywords: hyperviscosity syndrome, Waldenström macroglobulinemia, central retinal vein occlusion, exudative maculopathy, serous macular detachment, cochlear hemorrhage, plasma exchange, genomic sequencing, CXCR4

Abstract Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a FP-RMS mouse model driven by P3F expression and Cdkn2a loss in endothelial cells. Additionally, we show that P3F expression in TP53-null human iPSCs blocks endothelial-directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.

Background: Families with children with medical complexity endure high levels of chronic and toxic stress, impacting the overall health and wellbeing of all family members and the system as a whole. The purpose of this study was to examine the lived experiences of parents/caregivers with children with medical complexity. Methods: The lived experiences of 15 parents of children with complex medical needs were explored using focus group discussions. Focus group discussions were recorded, transcribed, and analyzed using van Manen’s 6-step process for hermeneutic phenomenology. Aligned with the research questions, the analysis draws on van Manen’s four lived existential analytical categories. Results: Themes include: (1) lived body, the psychological and physiological effect; (2) lived time and space, the immediate impact on the there, now, and then; (3) lived relationships, social life and family relational effect; (4) risk factors; and (5) protective factors. Conclusion: Caregivers of children with medical complexity have a unique experience of trauma and resilience. This study will inform interdisciplinary medical providers about the mental health and resiliency experiences of this population to support more effective healthcare practices.

Astrocytes extend endfeet that enwrap the vasculature, and disruptions to this association which may occur in disease coincide with breaches in blood-brain barrier (BBB) integrity. Here we investigate if focal ablation of astrocytes is sufficient to disrupt the BBB in mice. Targeted two-photon chemical apoptotic ablation of astrocytes induced a plasticity response whereby surrounding astrocytes extended processes to cover vascular vacancies. In young animals, replacement processes occur in advance of endfoot retraction, but this is delayed in aged animals. Stimulation of replacement astrocytes results in constriction of pre-capillary arterioles, suggesting that replacement astrocytes are functional. Pharmacological inhibition of pSTAT3, as well as astrocyte specific deletion of pSTAT3, reduces astrocyte replacement post-ablation, without perturbations to BBB integrity. Similar endfoot replacement occurs following astrocyte cell death due to reperfusion in a stroke model. Together, these studies uncover the ability of astrocytes to maintain cerebrovascular coverage via substitution from nearby cells.