A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation.

The isocortex and hippocampal formation (HPF) in the mammalian brain play critical roles in perception, cognition, emotion, and learning. We profiled ∼1.3 million cells covering the entire adult mouse isocortex and HPF and derived a transcriptomic cell-type taxonomy revealing a comprehensive repertoire of glutamatergic and GABAergic neuron types. Contrary to the traditional view of HPF as having a simpler cellular organization, we discover a complete set of glutamatergic types in HPF homologous to all major subclasses found in the six-layered isocortex, suggesting that HPF and the isocortex share a common circuit organization. We also identify large-scale continuous and graded variations of cell types along isocortical depth, across the isocortical sheet, and in multiple dimensions in hippocampus and subiculum. Overall, our study establishes a molecular architecture of the mammalian isocortex and hippocampal formation and begins to shed light on its underlying relationship with the development, evolution, connectivity, and function of these two brain structures.

A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain.

The mammalian brain consists of millions to billions of cells that are organized into many cell types with specific spatial distribution patterns and structural and functional properties1-3. Here we report a comprehensive and high-resolution transcriptomic and spatial cell-type atlas for the whole adult mouse brain. The cell-type atlas was created by combining a single-cell RNA-sequencing (scRNA-seq) dataset of around 7 million cells profiled (approximately 4.0 million cells passing quality control), and a spatial transcriptomic dataset of approximately 4.3 million cells using multiplexed error-robust fluorescence in situ hybridization (MERFISH). The atlas is hierarchically organized into 4 nested levels of classification: 34 classes, 338 subclasses, 1,201 supertypes and 5,322 clusters. We present an online platform, Allen Brain Cell Atlas, to visualize the mouse whole-brain cell-type atlas along with the single-cell RNA-sequencing and MERFISH datasets. We systematically analysed the neuronal and non-neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell-type organization in different brain regions-in particular, a dichotomy between the dorsal and ventral parts of the brain. The dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. Our study also uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types. Finally, we found that transcription factors are major determinants of cell-type classification and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole mouse brain transcriptomic and spatial cell-type atlas establishes a benchmark reference atlas and a foundational resource for integrative investigations of cellular and circuit function, development and evolution of the mammalian brain.

Prognostic implications of volume status assessed by blood volume analysis in ambulatory heart failure.

The prognostic implications of intravascular volume status assessed by blood volume analysis (BVA) in ambulatory heart failure (HF) remain uncertain. The incremental benefits of assessing volume status, beyond the well-established filling pressures, in predicting HF outcomes are unknown.

M-type potassium currents differentially affect activation of motoneuron subtypes and tune recruitment gain.

The size principle is a key mechanism governing the orderly recruitment of motor units and is believed to be dependent on passive properties of the constituent motoneurons. However, motoneurons are endowed with voltage-sensitive ion channels that create non-linearities in their input-output functions. Here we describe a role for the M-type potassium current, conducted by KCNQ channels, in the control of motoneuron recruitment in mice. Motoneurons were studied with whole-cell patch clamp electrophysiology in transverse spinal slices and identified based on delayed (fast) and immediate (slow) onsets of repetitive firing. M-currents were larger in delayed compared to immediate firing motoneurons, which was not reflected by variations in the presence of Kv7.2 or Kv7.3 subunits. Instead, a more depolarized spike threshold in delayed-firing motoneurons afforded a greater proportion of the total M-current to become activated within the subthreshold voltage range, which translated to a greater influence on their recruitment with little influence on their firing rates. Pharmacological activation of M-currents also influenced motoneuron recruitment at the population level, producing a rightward shift in the recruitment curve of monosynaptic reflexes within isolated mouse spinal cords. These results demonstrate a prominent role for M-type potassium currents in regulating the function of motor units, which occurs primarily through the differential control of motoneuron subtype recruitment. More generally, these findings highlight the importance of active properties mediated by voltage-sensitive ion channels in the differential control of motoneuron recruitment, which is a key mechanism for the gradation of muscle force. KEY POINTS: M-currents exert an inhibitory influence on spinal motor output. This inhibitory influence is exerted by controlling the recruitment, but not the firing rate, of high-threshold fast-like motoneurons, with limited influence on low-threshold slow-like motoneurons. Preferential control of fast motoneurons may be linked to a larger M-current that is activated within the subthreshold voltage range compared to slow motoneurons. Larger M-currents in fast compared to slow motoneurons are not accounted for by differences in Kv7.2 or Kv7.3 channel composition. The orderly recruitment of motoneuron subtypes is shaped by differences in the contribution of voltage-gated ion channels, including KCNQ channels. KCNQ channels may provide a target to dynamically modulate the recruitment gain across the motor pool and readily adjust movement vigour.

Agreements, Behaviour, and Change: Sex Outside the Relationship in Male HIV-negative Partners in HIV Serodiscordant Relationships in Australia, Brazil, and Thailand.

Male HIV serodiscordant couples have diverse relationship agreements regarding sex outside the relationship. We examined the relationship agreements as described by 343 male HIV-negative partners in HIV serodiscordant relationships in Australia, Brazil and Thailand participating in a multi-year cohort study. At baseline, 125 (34.1%) HIV-negative partners reported no agreement, 115 (33.5%) had a monogamous agreement, and 103 (37.9%) had an open agreement allowing sex outside the relationship. Relationship agreements were largely stable over time, with 76% of HIV-negative men reporting the same agreement across follow up, while changes were predominantly towards having an open agreement. Behaviour largely matched relationship agreements, and the predictors of breaking an agreement by having condomless anal intercourse (CLAI) with an outside partner were CLAI within the relationship (OR = 3.17, 95%CI: 1.64-6.14, p < 0.001) and PrEP use in the last three months (OR = 3.42, 95%CI: 1.48-7.92, p = 0.004). When considering HIV transmission risk for HIV-negative men in serodiscordant relationships, greater focus needs to be placed on sex that is occurring outside the relationship and the agreements that facilitate this.

Contaminant Exposure and Transport from Three Potential Reuse Waters within a Single Watershed.

Global demand for safe and sustainable water supplies necessitates a better understanding of contaminant exposures in potential reuse waters. In this study, we compared exposures and load contributions to surface water from the discharge of three reuse waters (wastewater effluent, urban stormwater, and agricultural runoff). Results document substantial and varying organic-chemical contribution to surface water from effluent discharges (e.g., disinfection byproducts [DBP], prescription pharmaceuticals, industrial/household chemicals), urban stormwater (e.g., polycyclic aromatic hydrocarbons, pesticides, nonprescription pharmaceuticals), and agricultural runoff (e.g., pesticides). Excluding DBPs, episodic storm-event organic concentrations and loads from urban stormwater were comparable to and often exceeded those of daily wastewater-effluent discharges. We also assessed if wastewater-effluent irrigation to corn resulted in measurable effects on organic-chemical concentrations in rain-induced agricultural runoff and harvested feedstock. Overall, the target-organic load of 491 g from wastewater-effluent irrigation to the study corn field during the 2019 growing season did not produce substantial dissolved organic-contaminant contributions in subsequent rain-induced runoff events. Out of the 140 detected organics in source wastewater-effluent irrigation, only imidacloprid and estrone had concentrations that resulted in observable differences between rain-induced agricultural runoff from the effluent-irrigated and nonirrigated corn fields. Analyses of pharmaceuticals and per-/polyfluoroalkyl substances in at-harvest corn-plant samples detected two prescription antibiotics, norfloxacin and ciprofloxacin, at concentrations of 36 and 70 ng/g, respectively, in effluent-irrigated corn-plant samples; no contaminants were detected in noneffluent irrigated corn-plant samples.

Commercial volumetric MRI reporting tools in multiple sclerosis: a systematic review of the evidence.

PURPOSE: MRI is integral to the diagnosis of multiple sclerosis (MS) and is important for clinical prognostication. Quantitative volumetric reporting tools (QReports) can improve the accuracy and objectivity of MRI-based assessments. Several QReports are commercially available; however, validation can be difficult to establish and does not currently follow a common pathway. To aid evidence-based clinical decision-making, we performed a systematic review of commercial QReports for use in MS including technical details and published reports of validation and in-use evaluation. METHODS: We categorized studies into three types of testing: technical validation, for example, comparison to manual segmentation, clinical validation by clinicians or interpretation of results alongside clinician-rated variables, and in-use evaluation, such as health economic assessment. RESULTS: We identified 10 companies, which provide MS lesion and brain segmentation and volume quantification, and 38 relevant publications. Tools received regulatory approval between 2006 and 2020, contextualize results to normative reference populations, ranging from 620 to 8000 subjects, and require T1- and T2-FLAIR-weighted input sequences for longitudinal assessment of whole-brain volume and lesions. In MS, six QReports provided evidence of technical validation, four companies have conducted clinical validation by correlating results with clinical variables, only one has tested their QReport by clinician end-users, and one has performed a simulated in-use socioeconomic evaluation. CONCLUSION: We conclude that there is limited evidence in the literature regarding clinical validation and in-use evaluation of commercial MS QReports with a particular lack of clinician end-user testing. Our systematic review provides clinicians and institutions with the available evidence when considering adopting a quantitative reporting tool for MS.

Inappropriate Shock Delivery Is Common During Pediatric In-Hospital Cardiac Arrest.

OBJECTIVES: To characterize inappropriate shock delivery during pediatric in-hospital cardiac arrest (IHCA). DESIGN: Retrospective cohort study. SETTING: An international pediatric cardiac arrest quality improvement collaborative Pediatric Resuscitation Quality [pediRES-Q]. PATIENTS: All IHCA events from 2015 to 2020 from the pediRES-Q Collaborative for which shock and electrocardiogram waveform data were available. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed 418 shocks delivered during 159 cardiac arrest events, with 381 shocks during 158 events at 28 sites remaining after excluding undecipherable rhythms. We classified shocks as: 1) appropriate (ventricular fibrillation [VF] or wide complex ≥ 150/min); 2) indeterminate (narrow complex ≥ 150/min or wide complex 100-149/min); or 3) inappropriate (asystole, sinus, narrow complex < 150/min, or wide complex < 100/min) based on the rhythm immediately preceding shock delivery. Of delivered shocks, 57% were delivered appropriately for VF or wide complex rhythms with a rate greater than or equal to 150/min. Thirteen percent were classified as indeterminate. Thirty percent were delivered inappropriately for asystole (6.8%), sinus (3.1%), narrow complex less than 150/min (11%), or wide complex less than 100/min (8.9%) rhythms. Eighty-eight percent of all shocks were delivered in ICUs or emergency departments, and 30% of those were delivered inappropriately. CONCLUSIONS: The rate of inappropriate shock delivery for pediatric IHCA in this international cohort is at least 30%, with 23% delivered to an organized electrical rhythm, identifying opportunity for improvement in rhythm identification training.

Quantitative Blood Volume Analysis and Hemodynamic Measures of Vascular Compliance in Patients With Worsening Heart Failure.

BACKGROUND: The role of blood volume (BV) expansion vs a change in vascular compliance in worsening heart failure (HF) remains under debate. We aimed to assess the relationship between BV and resting and stress hemodynamics in worsening HF and to further elucidate the significance of BV in cardiac decompensation. METHODS AND RESULTS: Patients with worsening HF underwent radiolabeled indicator-dilution BV analysis and cardiac catheterization. Intravascular volumes and resting/stress hemodynamics were recorded. Provocative stress maneuvers included change in systolic blood pressure (ΔSBP) from lying to standing and Valsalva and intracardiac pressure changes with leg raise. Correlation between BV and invasive hemodynamics were assessed by linear regression. Of 27 patients with worsening HF, patients' characteristics included mean age 61 ± 12 years, 70% male, 19% Black, and mean ejection fraction 29% ± 15%. Of the patients, 13 (48%) had hypervolemia as measured by total BV, which weakly correlated with ΔSBP by position (R2 = 0.009) and Valsalva (R2 = 0.003) and with right atrial (R2 = 0.049) and pulmonary capillary wedge (R2 = 0.047) pressure changes during leg raise. CONCLUSIONS: In patients with worsening HF, BV mildly correlated with intracardiac pressures at rest. Provocative maneuvers intended to test vascular compliance did not correlate with BV, indicating that compliance may serve as a stand-alone metric in HF.

Food, Beverage, and Feedstock Processing Facility Wastewater: a Unique and Underappreciated Source of Contaminants to U.S. Streams.

Process wastewaters from food, beverage, and feedstock facilities, although regulated, are an under-investigated environmental contaminant source. Food process wastewaters (FPWWs) from 23 facilities in 17 U.S. states were sampled and documented for a plethora of chemical and microbial contaminants. Of the 576 analyzed organics, 184 (32%) were detected at least once, with concentrations as large as 143 µg L-1 (6:2 fluorotelomer sulfonic acid), and as many as 47 were detected in a single FPWW sample. Cumulative per/polyfluoroalkyl substance concentrations up to 185 µg L-1 and large pesticide transformation product concentrations (e.g., methomyl oxime, 40 µg L-1; clothianidin TMG, 2.02 µg L-1) were observed. Despite 48% of FPWW undergoing disinfection treatment prior to discharge, bacteria resistant to third-generation antibiotics were found in each facility type, and multiple bacterial groups were detected in all samples, including total coliforms. The exposure-activity ratios and toxicity quotients exceeded 1.0 in 13 and 22% of samples, respectively, indicating potential biological effects and toxicity to vertebrates and invertebrates associated with the discharge of FPWW. Organic contaminant profiles of FPWW differed from previously reported contaminant profiles of municipal effluents and urban storm water, indicating that FPWW is another important source of chemical and microbial contaminant mixtures discharged into receiving surface waters.

Risk of malignancy following emergency department Bell's palsy diagnosis in children.

OBJECTIVE: To quantify the risk of malignancy following the emergency department (ED) diagnosis of Bell's Palsy (BP) using a large retrospective cohort. STUDY DESIGN: We performed a cohort study using the Pediatric Health Information System database. We included all children (6 months - 17 years) from 2011 to 2020 with an ED diagnosis of BP. We excluded children with previous neurologic chronic condition or malignancy diagnosed during or prior to the index visit. Our primary outcome was diagnosis of malignancy within 60 days following the index ED visit. We compared clinical characteristics between children with and without new-onset malignancy. RESULTS: Of 12,272 encounters for BP, 41 had a new oncologic diagnosis within 60 days (0.33%, 95% confidence interval [CI]: 0.25-0.45%). Median time to oncologic diagnosis was 22 days. Primary CNS malignancy (59%) and leukemia (17.1%) were the most common diagnoses. Younger children had a higher incidence of new oncologic diagnosis compared with older children. Incidences were 0.68% (95% CI 0.36-1.3%), 0.70% (95% CI 0.38-1.3%), 0.26% (95% CI 0.15-0.47%), and 0.21% (95% CI 0.12-0.37%) for children aged <2 years, 2-5 years, 6-11 years, and 12-17 years respectively. CONCLUSIONS: We found a small but potentially clinically significant rate of new-onset oncologic diagnosis within 60 days after BP diagnosis in the ED, especially in children younger than 5 years. Further studies of the diagnostic utility of laboratory testing or neuroimaging and the risk of empiric steroids in children with BP are needed.

Characteristics of Agreements to have Condomless Anal Intercourse in the Presence of an Undetectable Viral Load Among HIV Serodiscordant Male Couples in Australia, Brazil and Thailand.

The use of undetectable viral load (VL) to negotiate condomless anal intercourse (CLAI) in HIV serodiscordant male relationships has become more common as more data regarding the effectiveness of antiretroviral treatments for the prevention of HIV transmission has been described. We examined viral load agreements (VLAs) for condomless sex in the presence of an undetectable VL in 343 HIV serodiscordant male couples in Australia, Brazil and Thailand. Factors associated with having a VLA included having agreements for the HIV-positive partner to report his VL result (p < 0.001), agreeing that VL affects agreements about sexual practice (p < 0.001), the HIV-negative partner's perception of his partner's undetectable VL (p < 0.001), the couple's belief in the efficacy of undetectable VL in preventing HIV transmission (p < 0.001), and the couple engaging in CLAI with each other (p < 0.001). Over time, these agreements became more common although 49.3% of couples in the sample never had a viral load agreement. As these agreements become more common, further education is required to support male couples in using them safely.

Case Studies of Challenges in Emergency Care for Children With Autism Spectrum Disorder.

ABSTRACT: Autism spectrum disorder (ASD) affects more than 1% of children in the United States, with the rate of new diagnoses climbing significantly in the last 15 years. Emergent conditions and subsequent visits to the emergency department (ED) can be particularly challenging for children with ASD, most of whom also have comorbidities in addition to their deficits in social communication and interaction. In the emergency setting, these conditions can cause a range of behaviors that result in challenges for health care providers and may result in suboptimal experiences for children with ASD and their families. We present the ED course of 3 children with ASD to illustrate these challenges, emphasize successful strategies, and highlight opportunities for improvement.

Ondansetron Prescription for Home Use in a Pediatric Emergency Department.

OBJECTIVES: Ondansetron has been shown to decrease admission rate and the need for intravenous fluids among pediatric emergency department (ED) patients with acute gastroenteritis, but there is limited evidence regarding its use after ED discharge. This study describes prescribing patterns for ondansetron and assesses the effects of ondansetron home prescription on rate of return. METHODS: Data were gathered from the electronic health record on 2 separate but overlapping groups of patients seen in a pediatric ED from 2012 to 2014. The Gastroenteritis Group included all patients with a discharge diagnosis of gastroenteritis by International Classification of Diseases, Ninth Revision, code. The All Ondansetron Group included any child prescribed ondansetron at discharge. Patterns of ondansetron use and 3- and 7-day ED return rate were assessed for both groups. Discharge diagnosis was evaluated for the All Ondansetron Group. RESULTS: A total of 996 patients with acute gastroenteritis were identified during the study period. Of these, 76% received ondansetron in the ED, and 71% were discharged with prescriptions for ondansetron. Seven-day ED return rates were similar between groups (6% with prescription, 5% without, P = 0.66). A total of 2287 patients received home prescriptions for ondansetron. Fifty-four percent of these patients' discharge diagnoses were classed as gastrointestinal complaints, 14% other infectious conditions, 9% respiratory, and 4% injuries. Their return rate was 6%. There was wide variation in the number of doses prescribed. CONCLUSIONS: Home-use ondansetron is widely prescribed in this urban academic pediatric ED for a variety of indications, without effect on 3- or 7-day ED return. Further prospective studies are necessary to determine the efficacy of this practice.

Procedural sedation in children with autism spectrum disorders in the emergency department.

BACKGROUND AND OBJECTIVES: Children with autism spectrum disorder (ASD) present more frequently to the emergency department (ED) than children with normal development, and frequently have injuries requiring procedural sedation. Our objective was to describe sedation practice and outcomes in children with ASD in the ED. METHODS: We performed a retrospective chart review of children with ASD who underwent sedation at two tertiary care EDs between January 2009-December 2016. Data were collected on children 1-18 years of age with ASD who were sedated in the ED. RESULTS: There were 6020 ED visits by children with ASD, 126 (2.1%) of whom received sedation. The most frequent indications for sedation were laceration repair (24.6%), incision and drainage (17.5%), diagnostic imaging (14.3%), and physical examination (11.9%). The most common sedatives used were ketamine (50.8%) and midazolam (50.8%). Ketamine was most commonly given intravenously (71.9%), while midazolam was usually given intranasally (71.9%). Procedures could not be completed in 4 (3.2%) patients, and adverse events were noted in 23 (18.3%) patients. Only four (3.2%) patients required supplemental oxygenation, and one received positive pressure ventilation. CONCLUSIONS: Children with autism in the ED commonly received sedation; one in four of which were for non-painful diagnostic procedures or physical examination. Over one-third received sedation via a non-parenteral route for intended minimal sedation. Sedative medication dosing and observed adverse events were similar to those reported previously in children without ASD. Emergency providers must be prepared to meet the unique sedation needs of children with ASD.

Rapid HIV testing increases testing frequency among gay and bisexual men: a controlled before-after study.

Background Rapid HIV testing was introduced at 12 clinics in New South Wales (NSW) for routine testing and promoted with social marketing. The effect of the availability of rapid HIV testing on testing frequency among gay and bisexual men (GBM) was evaluated. METHODS: An observational design using patient data from 12 clinics was used. The primary outcome was the mean number of HIV tests in 12 months. The intervention group comprised GBM who had one or more rapid tests from October 2013 to September 2014 and this was compared with two control groups; a concurrent group (no rapid test in the same period) and a historical group (attended between July 2011 and June 2012). Independent sample t-tests were conducted to compare mean number of tests among men in the intervention, concurrent and historical groups. Multivariate logistic regression was used to assess the association between rapid HIV testing and testing frequency. RESULTS: Men in the intervention group (n = 3934) had a mean of 1.8 HIV tests in 12 months, compared with 1.4 in the concurrent group (n = 5063; P < 0.001) and 1.4 in the historical group (n = 5904; P < 0.001); testing frequency was higher among men at increased risk of HIV in the intervention group compared with the other two groups (mean 2.2, 1.6 and 1.5 respectively; P < 0.001). Membership of the intervention group was associated with increased odds of having two or more HIV tests in 12 months (AOR = 2.5, 95%CI 2.2-2.8; P < 0.001) compared with the concurrent group, after controlling for demographic and behavioural factors. CONCLUSION: Introducing and promoting rapid HIV testing in clinics in NSW was associated with increased HIV testing frequency among GBM.

Understanding the Targeting and Uptake of HIV Testing Among Gay and Bisexual Men Attending Sexual Health Clinics.

We assessed trends in HIV testing outcomes during a period of clinic-based initiatives introduced to increase HIV testing among gay and bisexual men (GBM) attending sexual health clinics (SHCs) in New South Wales (NSW). A cohort of 25,487 HIV-negative GBM attending 32 SHCs in NSW (2009-2015) was classified into six sub-groups each year based on client-type (new/existing), risk-status (low/high-risk), and any recent HIV testing. Poisson regression methods were used to assess HIV testing outcomes in sub-groups of GBM. HIV testing outcomes and the sub-groups with greatest statistically significant annual increases were: individuals attending (26% in high-risk existing clients with recent testing); testing uptake (4% in low-risk existing clients with no recent testing); testing frequency (6% in low-risk existing clients with no recent testing and 5% in high-risk existing clients with recent testing); and total tests (31% in high-risk existing clients with recent testing). High-risk existing clients with recent testing had a 13% annual increase in the proportional contribution to total tests. Our findings show improved targeting of testing to high-risk GBM at NSW SHCs. The clinic-based initiatives should be considered for translation to other similar settings.

Reconnaissance of Mixed Organic and Inorganic Chemicals in Private and Public Supply Tapwaters at Selected Residential and Workplace Sites in the United States.

Safe drinking water at the point-of-use (tapwater, TW) is a United States public health priority. Multiple lines of evidence were used to evaluate potential human health concerns of 482 organics and 19 inorganics in TW from 13 (7 public supply, 6 private well self-supply) home and 12 (public supply) workplace locations in 11 states. Only uranium (61.9 µg L-1, private well) exceeded a National Primary Drinking Water Regulation maximum contaminant level (MCL: 30 µg L-1). Lead was detected in 23 samples (MCL goal: zero). Seventy-five organics were detected at least once, with median detections of 5 and 17 compounds in self-supply and public supply samples, respectively (corresponding maxima: 12 and 29). Disinfection byproducts predominated in public supply samples, comprising 21% of all detected and 6 of the 10 most frequently detected. Chemicals designed to be bioactive (26 pesticides, 10 pharmaceuticals) comprised 48% of detected organics. Site-specific cumulative exposure-activity ratios (∑EAR) were calculated for the 36 detected organics with ToxCast data. Because these detections are fractional indicators of a largely uncharacterized contaminant space, ∑EAR in excess of 0.001 and 0.01 in 74 and 26% of public supply samples, respectively, provide an argument for prioritized assessment of cumulative effects to vulnerable populations from trace-level TW exposures.

Dynamic assessment of RBC-transfusion dependency improves the prognostic value of the revised-IPSS in MDS patients.

RBC-transfusion dependency (RBC-TD) is an independent prognostic factor for poor overall survival (OS) in the WHO classification-based prognostic scoring system (WPSS) for MDS patients. However, WPSS did not include cytopenia, whereas revised International Prognostic Scoring System (IPSS-R) did not include RBC-TD. Thus, neither of these prognostic scoring systems incorporates both cytopenia and RBC-TD. We aimed to test whether RBC-TD adds prognostic value to the IPSS-R. We analyzed MDS patients not treated with disease-modifying therapy, and enrolled in SA-MDS Registry (derivation cohort; n = 295) and Dusseldorf registry (Germany; validation cohort; n = 113) using time-dependent Cox proportional regression and serial landmark analyses. In the derivation cohort, RBC-TD patients had inferior OS compared to RBC transfusion-independent (RBC-TI) patients (P < 0.0001) at 6- (18 vs. 64 months), 12- (24 vs. 71 months), and 24-months (40 vs. 87 months). In a Cox proportional regression analysis, RBC-TD was an independent adverse prognostic marker in addition to age, sex, and IPSS-R variables (P < 0.0001). A prognostic index (PI) was derived using these Cox-proportional regression model variables. In the validation cohort, this PI classified patients into four prognostic groups with significantly different OS (P < 0.001) as in the derivation cohort. In conclusion, multivariate analysis by Cox proportional hazards regression and serial landmark analyses clearly demonstrates that development of RBC-TD at any time during the course of MDS is associated with poor OS, independent of IPSS-R. This study demonstrates that dynamic assessment of RBC-TD provides additional prognostic value to IPSS-R and should be included in treatment decision algorithms for MDS patients.

Factors Associated With Pediatric Ventilator-Associated Conditions in Six U.S. Hospitals: A Nested Case-Control Study.

OBJECTIVES: A newly proposed surveillance definition for ventilator-associated conditions among neonatal and pediatric patients has been associated with increased morbidity and mortality among ventilated patients in cardiac ICU, neonatal ICU, and PICU. This study aimed to identify potential risk factors associated with pediatric ventilator-associated conditions. DESIGN: Retrospective cohort. SETTING: Six U.S. hospitals PATIENTS:: Children less than or equal to 18 years old ventilated for greater than or equal to 1 day. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified children with pediatric ventilator-associated conditions and matched them to children without ventilator-associated conditions. Medical records were reviewed for comorbidities and acute care factors. We used bivariate and multivariate conditional logistic regression models to identify factors associated with ventilator-associated conditions. We studied 192 pairs of ventilator-associated conditions cases and matched controls (113 in the PICU and cardiac ICU combined; 79 in the neonatal ICU). In the PICU/cardiac ICU, potential risk factors for ventilator-associated conditions included neuromuscular blockade (odds ratio, 2.29; 95% CI, 1.08-4.87), positive fluid balance (highest quartile compared with the lowest, odds ratio, 7.76; 95% CI, 2.10-28.6), and blood product use (odds ratio, 1.52; 95% CI, 0.70-3.28). Weaning from sedation (i.e., decreasing sedation) or interruption of sedation may be protective (odds ratio, 0.44; 95% CI, 0.18-1.11). In the neonatal ICU, potential risk factors included blood product use (odds ratio, 2.99; 95% CI, 1.02-8.78), neuromuscular blockade use (odds ratio, 3.96; 95% CI, 0.93-16.9), and recent surgical procedures (odds ratio, 2.19; 95% CI, 0.77-6.28). Weaning or interrupting sedation was protective (odds ratio, 0.07; 95% CI, 0.01-0.79). CONCLUSIONS: In mechanically ventilated neonates and children, we identified several possible risk factors associated with ventilator-associated conditions. Next steps include studying propensity-matched cohorts and prospectively testing whether changes in sedation management, transfusion thresholds, and fluid management can decrease pediatric ventilator-associated conditions rates and improve patient outcomes.