Clinical risk factors and blood protein biomarkers of 10-year pneumonia risk.

BACKGROUND: Chronic inflammation may increase susceptibility to pneumonia. RESEARCH QUESTION: To explore associations between clinical comorbidities, serum protein immunoassays, and long-term pneumonia risk. METHODS: Framingham Heart Study Offspring Cohort participants ≥65 years were linked to their Centers for Medicare Services claims data. Clinical data and 88 serum protein immunoassays were evaluated for associations with 10-year incident pneumonia risk using Fine-Gray models for competing risks of death and least absolute shrinkage and selection operators for covariate selection. RESULTS: We identified 1,370 participants with immunoassays and linkage to Medicare data. During 10 years of follow up, 428 (31%) participants had a pneumonia diagnosis. Chronic pulmonary disease [subdistribution hazard ratio (SHR) 1.87; 95% confidence interval (CI), 1.33-2.61], current smoking (SHR 1.79, CI 1.31-2.45), heart failure (SHR 1.74, CI 1.10-2.74), atrial fibrillation/flutter (SHR 1.43, CI 1.06-1.93), diabetes (SHR 1.36, CI 1.05-1.75), hospitalization within one year (SHR 1.34, CI 1.09-1.65), and age (SHR 1.06 per year, CI 1.04-1.08) were associated with pneumonia. Three baseline serum protein measurements were associated with pneumonia risk independent of measured clinical factors: growth differentiation factor 15 (SHR 1.32; CI 1.02-1.69), C-reactive protein (SHR 1.16, CI 1.06-1.27) and matrix metallopeptidase 8 (SHR 1.14, CI 1.01-1.30). Addition of C-reactive protein to the clinical model improved prediction (Akaike information criterion 4950 from 4960; C-statistic of 0.64 from 0.62). CONCLUSIONS: Clinical comorbidities and serum immunoassays were predictive of pneumonia risk. C-reactive protein, a routinely-available measure of inflammation, modestly improved pneumonia risk prediction over clinical factors. Our findings support the hypothesis that prior inflammation may increase the risk of pneumonia.

Defining Trajectories of Linguistic, Cognitive-Communicative, and Quality of Life Outcomes in Aphasia: Longitudinal Observational Study Protocol.

Objective: To describe the trajectories of linguistic, cognitive-communicative, and health-related quality of life (HRQOL) outcomes after stroke in persons with aphasia. Design: Longitudinal observational study from inpatient rehabilitation to 18 months after stroke. Setting: Four US mid-west inpatient rehabilitation facilities (IRFs). Participants: We plan to recruit 400 adult (older than 21 years) English speakers who meet the following inclusion criteria: (1) Diagnosis of aphasia after a left-hemisphere infarct confirmed by CT scan or magnetic resonance imaging (MRI); (2) first admission for inpatient rehabilitation due to a neurologic event; and (3) sufficient cognitive capacity to provide informed consent and participate in testing. Exclusion criteria include any neurologic condition other than stroke that could affect language, cognition or speech, such as Parkinson's disease, Alzheimer's disease, traumatic brain injury, or the presence of right-hemisphere lesions. Interventions: Not applicable. Main Outcome Measures: Subjects are administered a test battery of linguistic, cognitive-communicative, and HRQOL measures. Linguistic measures include the Western Aphasia Battery-Revised and the Apraxia of Speech Rating Scale. Cognitive-communicative measures include the Communication Participation Item Bank, Connor's Continuous Performance Test-3, the Communication Confidence Rating Scale for Aphasia, the Communication Effectiveness Index, the Neurological Quality of Life measurement system (Neuro-QoL) Communication short form, and the Neuro-QoL Cognitive Function short form. HRQOL measures include the 39-item Stroke & Aphasia Quality of Life Scale, Neuro-QoL Fatigue, Sleep Disturbance, Depression, Ability to Participate in Social Roles & Activities, and Satisfaction with Social Roles & Activities tests, and the Patient-Reported Outcome Measurement and Information System 10-item Global Health short form. The test battery is administered initially during inpatient rehabilitation, and at 3-, 6-, 12-, and 18-months post-IRF discharge. Biomarker samples are collected via saliva samples at admission and a subgroup of participants also undergo resting state fMRI scans. Results: Not applicable. Conclusions: This longitudinal observational study will develop trajectory models for recovery of clinically relevant linguistic, cognitive-communicative, and quality of life outcomes over 18 months after inpatient rehabilitation. Models will identify individual differences in the patterns of recovery based on variations in personal, genetic, imaging, and therapy characteristics. The resulting models will provide an unparalleled representation of recovery from aphasia resulting from stroke. This improved understanding of recovery will enable clinicians to better tailor and plan rehabilitation therapies to individual patient's needs.

Toll-like receptor 4 (TLR4) is the major pattern recognition receptor triggering the protective effect of a Candida albicans extracellular vesicle-based vaccine prototype in murine systemic candidiasis.

Systemic candidiasis remains a significant public health concern worldwide, with high mortality rates despite available antifungal drugs. Drug-resistant strains add to the urgency for alternative therapies. In this context, vaccination has reemerged as a prominent immune-based strategy. Extracellular vesicles (EVs), nanosized lipid bilayer particles, carry a diverse array of native fungal antigens, including proteins, nucleic acids, lipids, and glycans. Previous studies from our laboratory demonstrated that Candida albicans EVs triggered the innate immune response, activating bone marrow-derived dendritic cells (BMDCs) and potentially acting as a bridge between innate and adaptive immunity. Vaccination with C. albicans EVs induced the production of specific antibodies, modulated cytokine production, and provided protection in immunosuppressed mice infected with lethal C. albicans inoculum. To elucidate the mechanisms underlying EV-induced immune activation, our study investigated pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs) involved in EVs-phagocyte engagement. EVs from wild-type and mutant C. albicans strains with truncated mannoproteins were compared for their ability to stimulate BMDCs. Our findings revealed that EV decoration with O- and N-linked mannans and the presence of ß-1,3-glucans and chitin oligomers may modulate the activation of specific PRRs, in particular Toll-like receptor 4 (TLR4) and dectin-1. The protective effect of vaccination with wild-type EVs was found to be dependent on TLR4. These results suggest that fungal EVs can be harnessed in vaccine formulations to selectively activate PRRs in phagocytes, offering potential avenues for combating or preventing candidiasis.IMPORTANCESystemic candidiasis is a serious global health concern with high mortality rates and growing drug resistance. Vaccination offers a promising solution. A unique approach involves using tiny lipid-coated particles called extracellular vesicles (EVs), which carry various fungal components. Previous studies found that Candida albicans EVs activate the immune response and may bridge the gap between innate and adaptive immunity. To understand this better, we investigated how these EVs activate immune cells. We demonstrated that specific components on EV surfaces, such as mannans and glucans, interact with receptors on immune cells, including Toll-like receptor 4 (TLR4) and dectin-1. Moreover, vaccinating with these EVs led to strong immune responses and full protection in mice infected with Candida. This work shows how harnessing fungal EVs might lead to effective vaccines against candidiasis.

Opioid Administration Practice Patterns in Patients With Acute Respiratory Failure Who Undergo Invasive Mechanical Ventilation.

IMPORTANCE: The opioid crisis is impacting people across the country and deserves attention to be able to curb the rise in opioid-related deaths. OBJECTIVES: To evaluate practice patterns in opioid infusion administration and dosing for patients with acute respiratory failure receiving invasive mechanical ventilation. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Patients from 21 hospitals in Kaiser Permanente Northern California and 96 hospitals in Philips electronic ICU Research Institute. MAIN OUTCOMES AND MEASURES: We assessed whether patients received opioid infusion and the dose of said opioid infusion. RESULTS: We identified patients with a diagnosis of acute respiratory failure who were initiated on invasive mechanical ventilation. From each patient, we determined if opioid infusions were administered and, among those who received an opioid infusion, the median daily dose of fentanyl infusion. We used hierarchical regression models to quantify variation in opioid infusion use and the median daily dose of fentanyl equivalents across hospitals. We included 13,140 patients in the KPNC cohort and 52,033 patients in the eRI cohort. A total of 7,023 (53.4%) and 16,311 (31.1%) patients received an opioid infusion in the first 21 days of mechanical ventilation in the KPNC and eRI cohorts, respectively. After accounting for patient- and hospital-level fixed effects, the hospital that a patient was admitted to explained 7% (95% CI, 3-11%) and 39% (95% CI, 28-49%) of the variation in opioid infusion use in the KPNC and eRI cohorts, respectively. Among patients who received an opioid infusion, the median daily fentanyl equivalent dose was 692 µg (interquartile range [IQR], 129-1341 µg) in the KPNC cohort and 200 µg (IQR, 0-1050 µg) in the eRI cohort. Hospital explained 4% (95% CI, 1-7%) and 20% (95% CI, 15-26%) of the variation in median daily fentanyl equivalent dose in the KPNC and eRI cohorts, respectively. CONCLUSIONS AND RELEVANCE: In the context of efforts to limit healthcare-associated opioid exposure, our findings highlight the considerable opioid exposure that accompanies mechanical ventilation and suggest potential under and over-treatment with analgesia. Our results facilitate benchmarking of hospitals' analgesia practices against risk-adjusted averages and can be used to inform usual care control arms of analgesia and sedation clinical trials.

Intravenous Opioid Administration During Mechanical Ventilation and Use After Hospital Discharge.

Importance: Guidelines recommend an analgesia-first strategy for sedation during mechanical ventilation, but associations between opioids provided during mechanical ventilation and posthospitalization opioid-related outcomes are unclear. Objective: To evaluate associations between an intravenous opioid dose received during mechanical ventilation and postdischarge opioid-related outcomes in medical (nonsurgical) patients. Design, Setting, and Participants: This retrospective cohort study evaluated adults receiving mechanical ventilation lasting 24 hours or more for acute respiratory failure and surviving hospitalization. Participants from 21 Kaiser Permanente Northern California hospitals from January 1, 2012, to December 31, 2019, were included. Data were analyzed from October 1, 2020, to October 31, 2023. Exposures: Terciles of median daily intravenous fentanyl equivalents during mechanical ventilation. Main Outcomes and Measures: The primary outcome was the first filled opioid prescription in 1 year after discharge. Secondary outcomes included persistent opioid use and opioid-associated complications. Secondary analyses tested for interaction between opioid doses during mechanical ventilation, prior opioid use, and posthospitalization opioid use. Estimates were based on multivariable-adjusted time-to-event analyses, with death as a competing risk, and censored for hospice or palliative care referral, rehospitalization with receipt of opioid, or loss of Kaiser Permanente plan membership. Results: The study included 6746 patients across 21 hospitals (median age, 67 years [IQR, 57-76 years]; 53.0% male). Of the participants, 3114 (46.2%) filled an opioid prescription in the year prior to admission. The median daily fentanyl equivalent during mechanical ventilation was 200 µg (IQR, 40-1000 µg), with terciles of 0 to 67 µg, more than 67 to 700 µg, and more than 700 µg. Compared with patients who did not receive opioids during mechanical ventilation (n = 1013), a higher daily opioid dose was associated with opioid prescriptions in the year after discharge (n = 2942 outcomes; tercile 1: adjusted hazard ratio [AHR], 1.00 [95% CI, 0.85-1.17], tercile 2: AHR, 1.20 [95% CI, 1.03-1.40], and tercile 3: AHR, 1.25 [95% CI, 1.07-1.47]). Higher doses of opioids during mechanical ventilation were also associated with persistent opioid use after hospitalization (n = 1410 outcomes; tercile 3 vs no opioids: odds ratio, 1.44 [95% CI, 1.14-1.83]). No interaction was observed between opioid dose during mechanical ventilation, prior opioid use, and posthospitalization opioid use. Conclusions and Relevance: In this retrospective cohort study of patients receiving mechanical ventilation, opioids administered during mechanical ventilation were associated with opioid prescriptions following hospital discharge. Additional studies to evaluate risks and benefits of strategies using lower opioid doses are warranted.

SNAP: Supportive non-invasive ventilation for acute chest syndrome prevention for hospitalized children with sickle cell disease: Perspectives of patients, parents, and the healthcare team.

RATIONALE: Acute chest syndrome (ACS) often develops during hospitalizations for sickle cell disease (SCD) vaso-occlusive episodes and may be triggered by a combination of chest wall splinting, opioid use, hypoventilation, and atelectasis. In 2017, Boston Medical Center's general pediatric inpatient unit instituted the novel use of bi-level positive airway pressure (BiPAP) as "supportive non-invasive ventilation for ACS prevention" (SNAP) to prevent ACS and respiratory decompensation. OBJECTIVE: The goals of this qualitative study were to identify perceived benefits, harms, facilitators, and barriers to use of SNAP. METHODS: We conducted semi-structured key informant interviews at three sites with different levels of SNAP implementation (Site 1: extensive implementation; Site 2: limited implementation; Site 3: not yet implemented) regarding experiences with and/or perceptions of SNAP. Interviews and coding were guided by the Promoting Action on Research Implementation in Health Services (PARiHS) framework. RESULTS: Thirty-four participants (physicians, nurses, respiratory therapists, child life specialists, psychologists, youth with SCD, and parents) completed interviews. Major themes included: (i) participants perceive BiPAP as effective at preventing ACS, and for those with medically stable ACS, for preventing respiratory decompensation. (ii) BiPAP use is appropriate on the general pediatric inpatient unit for medically stable patients with SCD. (iii) Improving the patient experience is the most important factor to optimize acceptance of BiPAP by patients and families. CONCLUSION/FUTURE DIRECTIONS: SNAP is perceived as effective and appropriate for hospitalized pediatric patients with SCD. Improving the patient experience is the biggest challenge. These data will inform a future protocol for a multicenter hybrid effectiveness/implementation trial of SNAP.

Lawesson's Reagent: Providing a New Approach to the Forgotten 6-Thioverdazyl Radical.

A new method for the preparation of the underrepresented 1,5-dimethyl-6-thioverdazyl radicals has been developed employing Lawesson's reagent (LR). The synthetic route involves the direct thionation of the carbonyl group of the corresponding dialkylbishydrazone followed by cyclization to give the tetrazinanthione verdazyl precursor on a gram scale. Subsequent oxidation yields the 6-thioverdazyl radical. It was determined that thionation of substrates containing electron-withdrawing groups in the ortho- or para-positions was high yielding. In contrast, for the parent phenyl group or substrates bearing weakly electron-donating substituents, thionation efficiency was significantly reduced. This could be overcome by utilizing partial in situ cyclization, which occurs during work up, to generate the tetrazinanthione directly via a one-pot synthesis. Density functional theory suggests that the LR fragment interacts with the carbonyl prior to cycloaddition and subsequent to cycloreversion, leading to the thiocarbonyl. The electronic nature of the radical is characterized with electron paramagnetic resonance as well as the first report of 6-thioverdazyl redox properties.

Impact of maternal posture on fetal physiology in human pregnancy: a narrative review.

In numerous medical conditions, including pregnancy, gravity and posture interact to impact physiology and pathophysiology. Recent investigations, for example, pertaining to maternal sleeping posture during the third trimester and possible impact on fetal growth and stillbirth risk highlight the importance and potential clinical implications of the subject. In this review, we provide an extensive discussion of the impact of maternal posture on fetal physiology from conception to the postpartum period in human pregnancy. We conducted a systematic literature search of the MEDLINE database and identified 242 studies from 1991 through 2021, inclusive, that met our inclusion criteria. Herein, we provide a synthesis of the resulting literature. In the first section of the review, we group the results by the impact of maternal posture at rest on the cervix, uterus, placenta, umbilical cord, amniotic fluid, and fetus. In the second section of the review, we address the impact on fetal-related outcomes of maternal posture during various maternal activities (e.g., sleep, work, exercise), medical procedures (e.g., fertility, imaging, surgery), and labor and birth. We present the published literature, highlight gaps and discrepancies, and suggest future research opportunities and clinical practice changes. In sum, we anticipate that this review will shed light on the impact of maternal posture on fetal physiology in a manner that lends utility to researchers and clinicians who are working to improve maternal, fetal, and child health.

ALK Inhibition With Alectinib for Refractory Metastatic Renal Cell Carcinoma With ALK Rearrangement: A Rare Case Report and Literature Review.

ALK-rearranged RCC refractory to several lines of treatment has a durable response when treated with alectinib.

Peripapillary Hyperreflective Ovoid Mass-Like Structures in Stickler Syndrome.

PURPOSE: To report a previously undescribed finding of peripapillary hyperreflective ovoid mass-like structures (PHOMS) in Stickler syndrome. DESIGN: Noncomparative case series. SUBJECTS: Twenty-two eyes with anomalous optic disc from 11 Stickler syndrome patients were identified and imaged. METHODS: Peripapillary hyperreflective ovoid mass-like structures were graded using enhanced-depth imaging OCT (EDI-OCT) according to the consensus recommendations of the Optic Disc Drusen Studies Consortium. All EDI-OCT scans were obtained using the Heidelberg Spectralis (Heidelberg Engineering) with a dense horizontal raster (15 × 10°, 97 sections) centered on the optic nerve head and graded by 2 independent assessors. In case of disagreement, the image was graded by a third assessor. The presence of any coexisting optic disc drusen was also assessed using EDI-OCT and autofluorescence. MAIN OUTCOME MEASURES: The presence of PHOMS, clinical characteristics and genetic mutations. RESULTS: A pilot sample of 22 eyes with phenotypic optic disc abnormalities from 11 Stickler syndrome patients were identified and imaged. Eight patients were female and 3 were male. The mean age was 31 years (13-58 years). Peripapillary hyperreflective ovoid mass-like structures were present in 91% (n = 20) of imaged eyes. Seventy percent (n = 14) were type 1 Stickler syndrome and 30% (n = 6) were type 2 Stickler syndrome. All eyes were myopic and the degree of myopia did not seem to affect whether or not PHOMS was present in this cohort. One eye with PHOMS had retinal detachment, and 77.3% (n = 17) of eyes had undergone 360o prophylactic retinopexy. Thirty-two percent (n = 7) of eyes with PHOMS were present in patients with coexisting hearing loss and 22.7% (n = 5) had orofacial manifestation of Stickler syndrome in the form of a cleft palate. Seventy-seven percent (n = 15) of eyes with PHOMS were present in patients who reported joint laxity or symptoms of arthritis. No coexisting optic disc drusen were identified and raised intracranial pressure was also excluded after neurological investigation. CONCLUSIONS: These data suggest that PHOMS are a novel finding in Stickler syndrome patients and should be considered when evaluating the optic nerves of these patients. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Leishmania spp. amastigotes surrounding sensory nerve fibers in human painless skin ulcers: Evidence of pathogen-neuron proximity and absence of neuronal apoptosis.

In this present study, carried out between November 2020 and July 2023 at Londrina's University Hospital, patients with active lesions of cutaneous leishmaniasis (CL) were analyzed regarding pain perception and anatomopathological aspects of the ulcers. Pain was assessed using a numerical rating scale (NRS) to compare five patients diagnosed with CL with four control patients diagnosed with vascular skin ulcers. Histopathological evaluations were used to investigate the nociceptor neuron-Leishmania interface. Patients with CL ulcers reported less pain compared to patients with vascular ulcers (2.60 ± 2.30 and 7.25 ± 0.95, respectively, p = 0.0072). Histopathology evidenced Leishmania spp. amastigote forms nearby sensory nerve fibers in profound dermis. Schwann cells marker (S100 protein) was detected, and caspase-3 activation was not evidenced in the in the nerve fibers of CL patients' samples, suggesting absence of apoptotic activity in nerve endings. Additionally, samples taken from the active edge of the lesion were negative for bacilli acid-alcohol resistant (BAAR), which excludes concomitant leprosy, in which painless lesions are also observed. Thus, the present data unveil for the first time anatomopathological and microbiological details of painless ulcers in CL patients, which has important clinical implications for a better understanding on the intriguing painless clinical characteristic of CL.

A nuclear genome assembly of an extinct flightless bird, the little bush moa.

We present a draft genome of the little bush moa (Anomalopteryx didiformis)-one of approximately nine species of extinct flightless birds from Aotearoa, New Zealand-using ancient DNA recovered from a fossil bone from the South Island. We recover a complete mitochondrial genome at 249.9× depth of coverage and almost 900 megabases of a male moa nuclear genome at ~4 to 5× coverage, with sequence contiguity sufficient to identify more than 85% of avian universal single-copy orthologs. We describe a diverse landscape of transposable elements and satellite repeats, estimate a long-term effective population size of ~240,000, identify a diverse suite of olfactory receptor genes and an opsin repertoire with sensitivity in the ultraviolet range, show that the wingless moa phenotype is likely not attributable to gene loss or pseudogenization, and identify potential function-altering coding sequence variants in moa that could be synthesized for future functional assays. This genomic resource should support further studies of avian evolution and morphological divergence.

Mechanistic Basis of the Cu(OAc)2 Catalyzed Azide-Ynamine (3 + 2) Cycloaddition Reaction.

The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is used as a ligation tool throughout chemical and biological sciences. Despite the pervasiveness of CuAAC, there is a need to develop more efficient methods to form 1,4-triazole ligated products with low loadings of Cu. In this paper, we disclose a mechanistic model for the ynamine-azide (3 + 2) cycloadditions catalyzed by copper(II) acetate. Using multinuclear nuclear magnetic resonance spectroscopy, electron paramagnetic resonance spectroscopy, and high-performance liquid chromatography analyses, a dual catalytic cycle is identified. First, the formation of a diyne species via Glaser-Hay coupling of a terminal ynamine forms a Cu(I) species competent to catalyze an ynamine-azide (3 + 2) cycloaddition. Second, the benzimidazole unit of the ynamine structure has multiple roles: assisting C-H activation, Cu coordination, and the formation of a postreaction resting state Cu complex after completion of the (3 + 2) cycloaddition. Finally, reactivation of the Cu resting state complex is shown by the addition of isotopically labeled ynamine and azide substrates to form a labeled 1,4-triazole product. This work provides a mechanistic basis for the use of mixed valency binuclear catalytic Cu species in conjunction with Cu-coordinating alkynes to afford superior reactivity in CuAAC reactions. Additionally, these data show how the CuAAC reaction kinetics can be modulated by changes to the alkyne substrate, which then has a predictable effect on the reaction mechanism.

In-Hospital vs 30-Day Sepsis Mortality at US Safety-Net and Non-Safety-Net Hospitals.

Importance: In-hospital mortality of patients with sepsis is frequently measured for benchmarking, both by researchers and policymakers. Prior studies have reported higher in-hospital mortality among patients with sepsis at safety-net hospitals compared with non-safety-net hospitals; however, in critically ill patients, in-hospital mortality rates are known to be associated with hospital discharge practices, which may differ between safety-net hospitals and non-safety-net hospitals. Objective: To assess how admission to safety-net hospitals is associated with 2 metrics of short-term mortality (in-hospital mortality and 30-day mortality) and discharge practices among patients with sepsis. Design, Setting, and Participants: Retrospective, national cohort study of Medicare fee-for-service beneficiaries aged 66 years and older, admitted with sepsis to an intensive care unit from January 2011 to December 2019 based on information from the Medicare Provider Analysis and Review File. Data were analyzed from October 2022 to September 2023. Exposure: Admission to a safety-net hospital (hospitals with a Medicare disproportionate share index in the top quartile per US region). Main Outcomes and Measures: Coprimary outcomes: in-hospital mortality and 30-day mortality. Secondary outcomes: (1) in-hospital do-not-resuscitate orders, (2) in-hospital palliative care delivery, (3) discharge to a postacute facility (skilled nursing facility, inpatient rehabilitation facility, or long-term acute care hospital), and (4) discharge to hospice. Results: Between 2011 and 2019, 2 551 743 patients with sepsis (mean [SD] age, 78.8 [8.2] years; 1 324 109 [51.9%] female; 262 496 [10.3%] Black, 2 137 493 [83.8%] White, and 151 754 [5.9%] other) were admitted to 666 safety-net hospitals and 1924 non-safety-net hospitals. Admission to safety-net hospitals was associated with higher in-hospital mortality (odds ratio [OR], 1.09; 95% CI, 1.06-1.13) but not 30-day mortality (OR, 1.01; 95% CI, 0.99-1.04). Admission to safety-net hospitals was associated with lower do-not-resuscitate rates (OR, 0.86; 95% CI, 0.81-0.91), palliative care delivery rates (OR, 0.66; 95% CI, 0.60-0.73), and hospice discharge (OR, 0.82; 95% CI, 0.78-0.87) but not with discharge to postacute facilities (OR, 0.98; 95% CI, 0.95-1.01). Conclusions and Relevance: In this cohort study, among patients with sepsis, admission to safety-net hospitals was associated with higher in-hospital mortality but not with 30-day mortality. Differences in in-hospital mortality may partially be explained by greater use of hospice at non-safety-net hospitals, which shifts attribution of death from the index hospitalization to hospice. Future investigations and publicly reported quality measures should consider time-delimited rather than hospital-delimited measures of short-term mortality to avoid undue penalty to safety-net hospitals with similar short-term mortality.

Nerve-Targeted Surgical Treatments for Spasticity: A Narrative Review.

Spasticity is a potentially debilitating symptom of various acquired and congenital neurologic pathologies that, without adequate treatment, may lead to long-term disability, compromise functional independence, and negatively impact mental health. Several conservative as well as non-nerve targeted surgical strategies have been developed for the treatment of spasticity, but these may be associated with significant drawbacks, such as adverse side effects to medication, device dependence on intrathecal baclofen pumps, and inadequate relief with tendon-based procedures. In these circumstances, patients may benefit from nerve-targeted surgical interventions such as (i) selective dorsal rhizotomy, (ii) hyperselective neurectomy, and (iii) nerve transfer. When selecting the appropriate surgical approach, preoperative patient characteristics, as well as the risks and benefits of nerve-targeted surgical intervention, must be carefully evaluated. Here, we review the current evidence on the efficacy of these nerve-targeted surgical approaches for treating spasticity across various congenital and acquired neurologic pathologies.

Gfi1 controls the formation of effector CD8 T cells during chronic infection and cancer.

During chronic infections and tumor progression, CD8 T cells gradually lose their effector functions and become exhausted. These exhausted CD8 T cells are heterogeneous and comprised of different subsets, including self-renewing progenitors that give rise to Ly108 - CX3CR1 + effector-like cells. Generation of these effector-like cells is essential for the control of chronic infections and tumors, albeit limited. However, the precise cues and mechanisms directing the formation and maintenance of exhausted effector-like are incompletely understood. Using genetic mouse models challenged with LCMV Clone 13 or syngeneic tumors, we show that the expression of a transcriptional repressor, growth factor independent 1 (Gfi1) is dynamically regulated in exhausted CD8 T cells, which in turn regulates the formation of exhausted effector-like cells. Gfi1 deletion in T cells dysregulates the chromatin accessibility and transcriptomic programs associated with the differentiation of LCMV Clone 13-specific CD8 T cell exhaustion, preventing the formation of effector-like and terminally exhausted cells while maintaining progenitors and a newly identified Ly108 + CX3CR1 + state. These Ly108 + CX3CR1 + cells have a distinct chromatin profile and may represent an alternative target for therapeutic interventions to combat chronic infections and cancer. In sum, we show that Gfi1 is a critical regulator of the formation of exhausted effector-like cells.

Predicting stroke risk after sepsis hospitalization with new-onset atrial fibrillation.

BACKGROUND: New-onset atrial fibrillation (AF) during sepsis is common, but models designed to stratify stroke risk excluded patients with secondary AF. We assessed the predictive validity of CHA2DS2VASc scores among patients with new-onset AF during sepsis and developed a novel stroke prediction model incorporating presepsis and intrasepsis characteristics. METHODS: We included patients ≥40 years old who survived hospitalizations with sepsis and new-onset AF across 21 Kaiser Permanente Northern California hospitals from January 1, 2011 to September 30, 2017. We calculated the area under the receiver operating curve (AUC) for CHA2DS2VASc scores to predict stroke or transient ischemic attack (TIA) within 1 year after a hospitalization with new-onset AF during sepsis using Fine-Gray models with death as competing risk. We similarly derived and validated a novel model using presepsis and intrasepsis characteristics associated with 1-year stroke/TIA risk. RESULTS: Among 82,748 adults hospitalized with sepsis, 3992 with new-onset AF (median age: 80 years, median CHA2DS2VASc of 4) survived to discharge, among whom 70 (2.1%) experienced stroke or TIA outcome and 1393 (41.0%) died within 1 year of sepsis. The CHA2DS2VASc score was not predictive of stroke risk after sepsis (AUC: 0.50, 95% confidence interval [CI]: 0.48-0.52). A newly derived model among 2555 (64%) patients in the derivation set and 1437 (36%) in the validation set included 13 variables and produced an AUC of 0.61 (0.49-0.73) in derivation and 0.54 (0.43-0.65) in validation. CONCLUSION: Current models do not accurately stratify risk of stroke following new-onset AF secondary to sepsis. New tools are required to guide anticoagulation decisions following new-onset AF in sepsis.

Interpreting Change in Disorders of Consciousness Using the Coma Recovery Scale-Revised.

The purpose of this study was to differentiate clinically meaningful improvement or deterioration from normal fluctuations in patients with disorders of consciousness (DoC) following severe brain injury. We computed indices of responsiveness for the Coma Recovery Scale-Revised (CRS-R) using data from a clinical trial of 180 participants with DoC. We used CRS-R scores from baseline (enrollment in a clinical trial) and a 4-week follow-up assessment period for these calculations. To improve precision, we transformed ordinal CRS-R total scores (0-23 points) to equal-interval measures on a 0-100 unit scale using Rasch Measurement theory. Using the 0-100 unit total Rasch measures, we calculated distribution-based 0.5 standard deviation (SD) minimal clinically important difference, minimal detectable change using 95% confidence intervals, and conditional minimal detectable change using 95% confidence intervals. The distribution-based minimal clinically important difference evaluates group-level changes, whereas the minimal detectable change values evaluate individual-level changes. The minimal clinically important difference and minimal detectable change are derived using the overall variability across total measures at baseline and 4 weeks. The conditional minimal detectable change is generated for each possible pair of CRS-R Rasch person measures and accounts for variation in standard error across the scale. We applied these indices to determine the proportions of participants who made a change beyond measurement error within each of the two subgroups, based on treatment arm (amantadine hydrochloride or placebo) or categorization of baseline Rasch person measure to states of consciousness (i.e., unresponsive wakefulness syndrome and minimally conscious state). We compared the proportion of participants in each treatment arm who made a change according to the minimal detectable change and determined whether they also changed to another state of consciousness. CRS-R indices of responsiveness (using the 0-100 transformed scale) were as follows: 0.5SD minimal clinically important difference = 9 units, minimal detectable change = 11 units, and the conditional minimal detectable change ranged from 11 to 42 units. For the amantadine and placebo groups, 70% and 58% of participants showed change beyond measurement error using the minimal detectable change, respectively. For the unresponsive wakefulness syndrome and minimally conscious state groups, 54% and 69% of participants changed beyond measurement error using the minimal detectable change, respectively. Among 115 participants (64% of the total sample) who made a change beyond measurement error, 29 participants (25%) did not change state of consciousness. CRS-R indices of responsiveness can support clinicians and researchers in discerning when behavioral changes in patients with DoC exceed measurement error. Notably, the minimal detectable change can support the detection of patients who make a "true" change within or across states of consciousness. Our findings highlight that the continued use of ordinal scores may result in incorrect inferences about the degree and relevance of a change score.

Variation in Sedative and Analgesic Use During the COVID-19 Pandemic and Associated Outcomes.

BACKGROUND: Providing analgesia and sedation is an essential component of caring for many mechanically ventilated patients. The selection of analgesic and sedative medications during the COVID-19 pandemic, and the impact of these sedation practices on patient outcomes, remain incompletely characterized. RESEARCH QUESTION: What were the hospital patterns of analgesic and sedative use for patients with COVID-19 who received mechanical ventilation (MV), and what differences in clinical patient outcomes were observed across prevailing sedation practices? STUDY DESIGN AND METHODS: We conducted an observational cohort study of hospitalized adults who received MV for COVID-19 from February 2020 through April 2021 within the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) COVID-19 Registry. To describe common sedation practices, we used hierarchical clustering to group hospitals based on the percentage of patients who received various analgesic and sedative medications. We then used multivariable regression models to evaluate the association between hospital analgesia and sedation cluster and duration of MV (with a placement of death [POD] approach to account for competing risks). RESULTS: We identified 1,313 adults across 35 hospitals admitted with COVID-19 who received MV. Two clusters of analgesia and sedation practices were identified. Cluster 1 hospitals generally administered opioids and propofol with occasional use of additional sedatives (eg, benzodiazepines, alpha-agonists, and ketamine); cluster 2 hospitals predominantly used opioids and benzodiazepines without other sedatives. As compared with patients in cluster 2, patients admitted to cluster 1 hospitals underwent a shorter adjusted median duration of MV with POD (ß-estimate, -5.9; 95% CI, -11.2 to -0.6; P = .03). INTERPRETATION: Patients who received MV for COVID-19 in hospitals that prioritized opioids and propofol for analgesia and sedation experienced shorter adjusted median duration of MV with POD as compared with patients who received MV in hospitals that primarily used opioids and benzodiazepines.