Comparing deposition characteristics of various embolic particles using an in vitro prostate microvasculature model.

PURPOSE: To compare spatial distributions of radiopaque glass (RG) microspheres, trisacryl gelatin (TAG) microspheres, and polyvinyl alcohol (PVA) foam particles within a planar in vitro microvascular model of the hyperplastic hemiprostate. MATERIALS AND METHODS: A microvascular model simulating hyperplastic hemiprostate was perfused with a water-glycerin mixture. A microcatheter was positioned distal to the model's prostatic artery origin and embolic particles (RG: 50 µm, 100 µm, and 150 µm; TAG: 100-300 µm and 300-500 µm; and PVA: 90-180 µm and 180-300 µm) were administered using a syringe pump. Microscopic imaging and subsequent semantic segmentation were performed to quantify particle distributions within the models. Distal penetrations were quantified statistically via modal analysis of the particle distributions. RESULTS: Maximum distal penetration was observed for RG 50, followed by RG 100 and then TAG 100-300 and RG 150. TAG 300-500, PVA 90-180, and PVA 180-300 particles exhibited the lowest distal penetrations. The distal penetration metrics between groups were significantly different (p < 0.05) except between TAG 100-300 and RG 150 and between PVA 90-180 and PVA 180-300. CONCLUSIONS: Comparing the spatial distributions of embolic particles in an in vitro microvascular model simulating the hyperplastic hemiprostate revealed that noncompressible particles and those with narrower size calibrations and smaller relative diameters exhibited higher degrees of distal packing. The embolization front was less distinct for particles with wider size calibrations, which resulted in smaller, more distal emboli along with larger, more proximal emboli. PVA and TAG 300-500 particles both exhibited relatively low overall distal penetration.

Effect of Preoperative Motor Weakness on Postoperative Clinical Outcomes in Patients Undergoing Cervical Disk Replacement.

STUDY DESIGN: This is a retrospective review. OBJECTIVE: To examine the effect of preoperative motor weakness on clinical outcomes in patients undergoing cervical disk replacement (CDR). SUMMARY OF BACKGROUND DATA: Studies examining the effect of preoperative motor weakness on postoperative clinical outcomes in CDR are limited. METHODS: Patient cohorts were based on documented upper-extremity motor weakness on physical exam versus no motor weakness. Demographics, perioperative characteristics, and preoperative patient-reported outcome measures (PROMs) were compared using univariate inferential statistics. PROMs consisted of Visual Analog Pain Scale-Neck (VAS-N), Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS-PF), VAS-Arm (VAS-A), 12-Item Short Form (SF-12) Physical Component Score (PCS), Oswestry Neck Disability Index (NDI), and SF-12 Mental Component Score (MCS). Postoperative PROMs were collected at the 6-week, 12-week, 6-month, and final follow-up up to 1-yeartime points, and intercohort minimum clinically important difference (MCID) achievement was compared through multivariable linear logistic regression adjusting for significant differences in preoperative characteristics. RESULTS: A total of 118 patients formed cohorts based on documented upper-extremity weakness (n=73) versus no weakness (n=45). The average time to postoperative follow-up was 9.7±7.0 mo. The differences in insurance type between the 2 cohorts were significant (P<0.042). Perioperative diagnosis of foraminal stenosis was significantly more common in the motor weakness cohort (P<0.013). There were no differences in reported PROMs between cohorts. Patients with motor weakness reported significant MCID achievement for PROMIS-PF at 6-/12-weeks (P<0.012, P<0.041 respectively), SF-12 PCS at 6-months (P<0.042), VAS-N at final follow-up (P<0.021), and NDI at final follow-up (P<0.013). CONCLUSIONS: CDR patients with preoperative muscle weakness achieved MCID across several PROMs compared with patients without muscle weakness. Patients with motor weakness reported greater improvement in mental health, pain, and disability as early as 6 weeks and up to 1 year after CDR. This information serves to inform physicians that motor weakness may not indicate a negative overall outcome.

Construct length analysis of type B and C cervical and thoracolumbar fractures.

Objectives: The purpose of this study is to identify if construct length affects the rate of surgical complications and instrumentation revision following surgical fixation of subaxial and thoracolumbar Type B and C fractures. This study evaluates the effect of ankylosing spondylitis/diffuse idiopathic skeletal hyperostosis (AS/DISH) within this population on outcomes. Methods: Retrospective review of 91 cervical and 89 thoracolumbar Type B and C fractures. Groups were divided by construct length for analysis: short-segment (constructs spanning two or less segments adjacent to the fracture) and long-segment (constructs spanning more than two segments adjacent to the vertebral fracture). Results: For cervical fractures, construct length did not impact surgical complications (P = 0.641), surgical hardware revision (P = 0.167), or kyphotic change (P = 0.994). For thoracolumbar fractures, construct length did not impact surgical complications (P = 0.508), surgical hardware revision (P = 0.224), and kyphotic change (P = 0.278). Cervical Type B fractures were nonsignificantly more likely to have worsened kyphosis (P = 0.058) than Type C fractures. Assessing all regions of the spine, a diagnosis of AS/DISH was associated with an increase in kyphosis (P = 0.030) and a diagnosis of osteoporosis was associated with surgical hardware failure (P = 0.006). Conclusion: Patients with short-segment instrumentation have similar surgical outcomes and changes in kyphosis compared to those with long-segment instrumentation. A diagnosis of AS/DISH or osteoporosis was associated with worse surgical outcomes.

Human plasma cells engineered to secrete bispecifics drive effective in vivo leukemia killing.

Bispecific antibodies are an important tool for the management and treatment of acute leukemias. As a next step toward clinical translation of engineered plasma cells, we describe approaches for secretion of bispecific antibodies by human plasma cells. We show that human plasma cells expressing either fragment crystallizable domain-deficient anti-CD19 × anti-CD3 (blinatumomab) or anti-CD33 × anti-CD3 bispecific antibodies mediate T cell activation and direct T cell killing of B acute lymphoblastic leukemia or acute myeloid leukemia cell lines in vitro. We demonstrate that knockout of the self-expressed antigen, CD19, boosts anti-CD19-bispecific secretion by plasma cells and prevents self-targeting. Plasma cells secreting anti-CD19-bispecific antibodies elicited in vivo control of acute lymphoblastic leukemia patient-derived xenografts in immunodeficient mice co-engrafted with autologous T cells. In these studies, we found that leukemic control elicited by engineered plasma cells was similar to CD19-targeted chimeric antigen receptor-expressing T cells. Finally, the steady-state concentration of anti-CD19 bispecifics in serum 1 month after cell delivery and tumor eradication was comparable with that observed in patients treated with a steady-state infusion of blinatumomab. These findings support further development of ePCs for use as a durable delivery system for the treatment of acute leukemias, and potentially other cancers.

Relationship between patient activation and utilisation of health care and harm reduction services among people who inject drugs in Baltimore, Maryland.

INTRODUCTION: Given structural barriers, access to services is key for preventing drug-related harms and managing chronic disease among people who inject drugs (PWID). The Patient Activation Measure (PAM), a validated scale to assess self-efficacy in navigating one's own health care, was operationalised to improve service utilisation and outcomes but has not been assessed among PWID. We characterised PAM and its association with healthcare and harm reduction utilisation among PWID in the AIDS Linked to IntraVenous Experience cohort in Baltimore. METHODS: From 2019 to 2020, participants completed surveys on PAM, service utilisation and drug use. We used log-binomial regression to identify correlates of "Lower" PAM and modelled the association between lower PAM and service utilisation, stratified by recent IDU. RESULTS: Participants (n = 351) were primarily male (67%), Black (85%) and 24% reported recent IDU. Lower PAM was significantly more common in those reporting IDU (aPR 1.45; 95% CI 1.03, 2.04), heavy alcohol (aPR 1.77; 95% CI 1.24, 2.51) and marijuana (aPR: 1.70; 95% CI 1.23, 2.36) but less common among women (aPR 0.57; 95% CI 0.38, 0.84) and those living with HIV (APR 0.52; 95% CI 0.35, 0.78). In modelling service utilisation, lower PAM was associated with a lower prevalence of methadone utilisation (aPR 0.27; 95% CI 0.09, 0.84) among those reporting IDU, but a higher prevalence of methadone utilisation (aPR 2.72; 95% CI 1.46, 5.08) among those not reporting IDU, after controlling for correlates of PAM. DISCUSSION AND CONCLUSION: PAM-tailored interventions targeting methadone utilisation warrant consideration but should account for socio-structural barriers to utilisation and correlates of PAM among PWID.

Chirped Laser Pulse Control of Vibronic Wavepackets and Energy Transfer in Phycocyanin 645.

Photosynthetic organisms use light-harvesting complexes to increase the spectrum of light that they absorb from solar photons. Recent ultrafast spectroscopic studies have revealed that efficient (sub-ps) energy transfer is mediated by vibronic coherence in the phycobiliprotein phycocyanin 645 (PC645). Here, we report studies that employ broadband pump-probe spectroscopy with linearly chirped excitation pulses to further investigate the relationship between vibronic state preparation and energy transfer dynamics in PC645. Negatively chirped pulse excitation is found to enhance wavepackets of a high-frequency mode (1580 cm-1) and increase the rate of downhill energy transfer, while on the other hand, positively chirped pulses suppress these oscillatory features and decrease this rate. Model calculations incorporating the influence of the chirped pump pulse are used to understand its effect on initial state preparation. These results provide mechanistic insight into how the overall nonequilibrium rate of energy transfer is influenced by initial state preparation.

A novel controlled metabolic accelerator for the treatment of obesity-related heart failure with preserved ejection fraction: Rationale and design of the Phase 2a HuMAIN trial.

AIMS: Compared with those without obesity, patients with obesity-related heart failure with preserved ejection fraction (HFpEF) have worse symptoms, haemodynamics, and outcomes. Current weight loss strategies (diet, drug, and surgical) work through decreased energy intake rather than increased expenditure and cause significant loss of skeletal muscle mass in addition to adipose tissue. This may have adverse implications for patients with HFpEF, who already have reduced skeletal muscle mass and function and high rates of physical frailty. Mitochondrial uncoupling agents may have unique beneficial effects by producing weight loss via increased catabolism rather than reduced caloric intake, thereby causing loss of adipose tissue while sparing skeletal muscle. HU6 is a controlled metabolic accelerator that is metabolized to the mitochondrial uncoupling agent 2,4-dinotrophenol. HU6 selectively increases carbon oxidation from fat and glucose while also decreasing toxic reactive oxygen species (ROS) production. In addition to sparing skeletal muscle loss, HU6 may have other benefits relevant to obesity-related HFpEF, including reduced specific tissue depots contributing to HFpEF; improved glucose utilization; and reduction in systemic inflammation via both decreased ROS production from mitochondria and decreased cytokine elaboration from excess, dysfunctional adipose. METHODS: We describe the rationale and design of HuMAIN-HFpEF, a Phase 2a randomized, double-blind, placebo-controlled, dose-titration, parallel-group trial in patients with obesity-related HFpEF to evaluate the effects of HU6 on weight loss, body composition, exercise capacity, cardiac structure and function, metabolism, and inflammation, and identify optimal dosage for future Phase 3 trials. CONCLUSIONS: HuMAIN will test a promising novel agent for obesity-related HFpEF.

Strain-Dependent Assessment of Powassan Virus Transmission to Ixodes scapularis Ticks.

Powassan virus (POWV) is an emerging tick-borne encephalitic virus in Lyme disease-endemic sites in North America. Due to range expansion and local intensification of blacklegged tick vector (Ixodes scapularis) populations in the northeastern and upper midwestern U.S., human encephalitis cases are increasingly being reported. A better understanding of the transmission cycle between POWV and ticks is required in order to better predict and understand their public health burden. Recent phylogeographic analyses of POWV have identified geographical structuring, with well-defined northeastern and midwestern clades of the lineage II subtype. The extent that geographic and genetically defined sublineages differ in their ability to infect and be transmitted by blacklegged ticks is unclear. Accordingly, we determined whether there are strain-dependent differences in the transmission of POWV to ticks at multiple life stages. Five recent, low-passage POWV isolates were used to measure aspects of vector competence, using viremic and artificial infection methods. Infection rates in experimental ticks remained consistent between all five isolates tested, resulting in a 12-20% infection rate and some differences in viral load. We confirm that these differences are likely not due to differences in host viremia. Our results demonstrate that blacklegged ticks are susceptible to, and capable of transmitting, all tested strains and suggest that the tick-virus association is stable across diverse viral genotypes.

Pyridopyrimidinones as a new chemotype of calcium dependent protein kinase 1 (CDPK1) inhibitors for Cryptosporidium.

The protozoan protein kinase calcium-dependent protein kinase 1 (CDPK1) has emerged as a potential therapeutic target for the treatment of cryptosporidiosis. A focused screen of known kinase inhibitors identified a pyridopyrimidinone as a new chemotype of Cryptosporidium parvum (Cp) CDPK1 inhibitors. Structural comparison of CpCDPK1 to two representative human kinases, RIPK2 and Src, revealed differences in the positioning of the αC-helix that was used in the design of a potent pyridopyrimidinone-based CpCDPK1 inhibitor 7 (a.k.a. UH15-16, IC50 = 10 nM), which blocked the growth of three C. parvum strains (EC50 = 12-40 nM) as well as C. hominis (EC50 = 85 nM) in HCT-8 host cells. Pharmacokinetic and tissue distribution analyses indicated that 7 had low systemic exposure after oral administration, but high gastrointestinal concentration, as well as good Caco-2 cell permeability. Finally, 7 demonstrated partial efficacy in an IL-12 knock-out mouse model of acute cryptosporidiosis.

Worse Preoperative 12-Item Veterans Rand Physical Component Scores Prognosticate Inferior Outcomes Following Outpatient Lumbar Decompression.

STUDY DESIGN: Retrospective Review. OBJECTIVE: Evaluate the influence of the 12-Item veterans Rand (VR-12) physical component score (PCS) on patient-reported outcome measures (PROMs) in an outpatient lumbar decompression (LD) cohort. SUMMARY OF BACKGROUND DATA: The influence of baseline VR-12 PCS on postoperative clinical outcomes has not been evaluated in patients undergoing outpatient LD. METHODS: Patients undergoing primary, elective, 1/2-level outpatient LD with baseline VR-12 PCS scores were retrospectively identified from a prospectively maintained single-surgeon database. Cohorts were preoperative VR-12 PCS<30 and VR-12 PCS≥30. Patient/perioperative characteristics and preoperative/postoperative 6-week/final follow-up (FF) PROMs were collected. Physical health PROMs included the VR-12 PCS, 12-Item Short Form (SF-12) PCS, patient-reported outcome measure information system-physical function (PROMIS-PF), visual analog scale (VAS)-back/leg, and Oswestry disability index (ODI). Mental health PROMs included the VR-12/SF-12 mental component score (MCS) and the patient-health questionnaire-9 (PHQ-9). Average FF was 13.8±8.9 months postoperatively. PROM improvements at 6 weeks/FF and minimal clinically important difference (MCID) achievement rates were determined. χ2 analysis and the Student's t tests compared demographics, perioperative data, and preoperative PROMs. Multivariate linear/logistic regression compared postoperative PROMs, PROM improvements, and MCID achievement rates. RESULTS: Six weeks postoperatively, VR-12 PCS<30 reported worse baseline PROMs (P≤0.042, all) and worse scores except VR-12/SF-12 MCS (P≤0.043, all). Compared with VR-12 PCS≥30, VR-12 PCS<30 had worse FF VR-12 PCS, SF-12 PCS/MCS, PROMIS-PF, PHQ-9, and VAS-Back (P≤0.033, all). VR-12 PCS<30 experienced greater 6-week improvements in VR-12/SF-12 PCS, PHQ-9, VAS-Back, and ODI (P≤0.039, all). VR-12 PCS<30 had greater FF improvements in VR-12/SF-12 PCS, PHQ-9, and ODI (P≤0.001, all) and greater overall MCID achievement in VR-12 PCS/MCS, SF-12 PCS, PHQ-9, and ODI (P≤0.033, all). CONCLUSIONS: VR-12 PCS<30 patients-reported worse baseline/postoperative mental/physical health scores. However, they reported greater improvements in physical function, depressive burden, back pain, and disability by 6 weeks and FF and experienced greater MCID achievement for physical functioning, mental health, and disability scores.

Worse Pain and Disability at Presentation Predicts Greater Improvement in Pain, Disability, and Mental Health in Patients Undergoing Minimally Invasive Transforaminal Lumbar Interbody Fusion for Degenerative Spondylolisthesis.

STUDY DESIGN: Retrospective Review. OBJECTIVE: To assess the impact of preoperative pain and disability on patient-reported outcome measures (PROMs) following minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) for degenerative spondylolisthesis. SUMMARY OF BACKGROUND DATA: Varying preoperative symptom severity in lumbar fusion patients alters perceptions of surgical success. METHODS: Degenerative spondylolisthesis patients undergoing elective, primary, single-level MI-TLIF were stratified by preoperative symptom severity: Mild (VAS-B<7/ODI<50), Moderate (VAS-B≥7/ODI<50 or VAS-B<7/ODI≥50), and Severe (VAS-B≥7/ODI≥50). PROMs, Patient-reported Outcomes Measurement Information System-Physical Function (PROMIS-PF), ODI, VAS-B, VAS-Leg (VAS-L), and 9-item Patient Health Questionnaire (PHQ-9) were compared at baseline, 6 weeks, and final follow-up (µ=16.3±8.8 mo). Postoperative PROMs, magnitudes of improvement, and minimal clinically important difference (MCID) achievement rates were compared between cohorts through multivariable regression. RESULTS: A total of 177 patients were included. Acute postoperative pain and narcotic consumption were highest in the severe cohort (P≤0.003). All preoperative PROMs worsened from mild to severe cohorts (P<0.001). All PROMs continued to be significantly different between cohorts at 6 weeks and final follow-up, with the worst scores in the Severe cohort (P≤0.003). At 6 weeks, all cohorts improved in ODI, VAS-B, VAS-L, and PHQ-9 (P≤0.003), with the Moderate cohort also improving in PROMIS-PF (P=0.017). All Cohorts improved across PROMs at the final follow-up (P≤0.044). Magnitudes of improvement in ODI, VAS-B, and PHQ-9 increased with worsening preoperative symptom severity (P≤0.042). The Moderate and Severe cohorts demonstrated higher MCID achievement in ODI, VAS-B, and PHQ-9 rates than the Mild cohort. CONCLUSIONS: Despite preoperative pain and disability severity, patients undergoing MI-TLIF for degenerative spondylolisthesis report significant improvement in physical function, pain, disability, and mental health postoperatively. Patients with increasing symptom severity continued to report worse severity postoperatively compared with those with milder symptoms preoperatively but were more likely to report larger improvements and achieve clinically meaningful improvement in disability, pain, and mental health.

The Impact of Outpatient Physical Therapy on Patient-Reported Outcomes after Lumbar Fusion: Perspective from A Bundled Care Dataset.

OBJECTIVE/BACKGROUND: As value-based care grows in popularity across the United States, more payers have turned toward bundled payment models for surgical procedures. Though episode costs in spine are highly variable, physical therapy (PT) has been identified as a driver of 90-day cost. The goal of this study is to assess the impact of postoperative PT on patient-reported outcomes and cost after lumbar fusion surgery using bundled insurance data. METHODS: Bundled payment information of lumbar fusion episodes-of-care (EOC) from 2019 to 2021 was reviewed at a single, urban, tertiary care center. EOC comprised a 210-day period surrounding the date of the procedure, beginning 30 days preoperatively and ending 180 days postoperatively. Patients were grouped into physical therapy (PT) and no physical therapy (no PT) groups based on the presence of physical therapy claims. RESULTS: Bivariate analysis of surgical outcomes revealed similar overall complication rates (p=0.413), 30-day readmissions (p=0.366) and 90-day readmissions (p=0.774). Patients that did not participate in postoperative PT had significantly better preoperative PCS (p=0.003), six-month postoperative PCS (p=0.001), and six-month ΔPCS (p=0.026) compared to patients who participated in postoperative PT. At one-year follow-up, patients who did not participate in PT had less leg pain (p=0.041) than those who did participate in PT. CONCLUSIONS: Our study finds that PT after lumbar fusion is not associated with significant improvement in ODI, PCS, MCS, or VAS pain scores. Additionally, the number of PT sessions a patient attends has no correlation with improvement in these outcomes.

Primary human papillomavirus testing by clinician- versus self-collection: Awareness and acceptance among cervical cancer screening-eligible women.

OBJECTIVES: Primary human papillomavirus (HPV) testing by clinician-collection is endorsed by U.S. guideline organizations for cervical cancer screening, but uptake remains low and insights into patients' understanding are limited. This study aims to primarily address patient awareness of primary HPV screening by clinician-collection and acceptance of primary HPV screening by clinician- and self-collection, and secondarily assess factors associated with awareness and acceptance. SETTING: Primary care practices affiliated with an academic medical center. METHODS: A cross-sectional survey study of screening-eligible women aged 30-65 years was conducted to assess awareness and acceptability of primary HPV screening. We analyzed bivariate associations of respondent characteristics with awareness of primary HPV screening by clinician-collection, willingness to have clinician- or self-collected primary HPV testing, and reasons for self-collection preference. RESULTS: Respondents (n = 351; response rate = 23.4%) reported cervical cancer screening adherence of 82.8% but awareness of clinician-collected primary HPV as an option was low (18.9%) and only associated with HPV testing with recent screening (p = 0.003). After reviewing a description of primary HPV screening, willingness for clinician-collected (81.8%) or home self-collected (76.1%) HPV testing was high, if recommended by a provider. Acceptability of clinician-collected HPV testing was associated with higher income (p = 0.009) and for self-collection was associated with higher income (p = 0.002) and higher education (p = 0.02). Higher education was associated with reporting self-collection as easier than clinic-collection (p = 0.02). Women expected self-collection to be more convenient (94%), less embarrassing (85%), easier (85%), and less painful (81%) than clinician-collection. CONCLUSIONS: Educational interventions are needed to address low awareness about the current clinician-collected primary HPV screening option and to prepare for anticipated federal licensure of self-collection kits. Informing women about self-collection allows them to recognize benefits which could address screening barriers.

Diazoxide for Severe or Recurrent Neonatal Hypoglycemia: A Randomized Clinical Trial.

Importance: Neonatal hypoglycemia is an important preventable cause of neurodevelopmental impairment, but there is a paucity of evidence to guide treatment. Objective: To evaluate whether early, low-dose oral diazoxide for severe or recurrent neonatal hypoglycemia reduces time to resolution of hypoglycemia. Design, Setting, and Participants: This 2-arm, placebo-controlled randomized clinical trial was conducted from May 2020 to February 2023 in tertiary neonatal units at 2 New Zealand hospitals. Participants were neonates born at 35 or more weeks' gestation and less than 1 week of age with severe hypoglycemia (blood glucose concentration <22 mg/dL or <36 mg/dL despite 2 doses of dextrose gel) or recurrent hypoglycemia (≥3 episodes of a blood glucose concentration <47 mg/dL within 48 hours). Interventions: Newborns were randomized 1:1 to receive diazoxide suspension (loading dose, 5 mg/kg; maintenance, 1.5 mg/kg every 12 hours) or placebo, titrated per protocol. Main Outcome and Measures: The primary outcome was time to resolution of hypoglycemia, defined as enteral bolus feeding without intravenous fluids and normoglycemia (blood glucose concentration of 47-98 mg/dL) for at least 24 hours, compared between groups using adjusted Cox proportional hazards regression. Hazard ratios adjusted for stratification variables and gestation length are reported. Prespecified secondary outcomes, including number of blood glucose tests and episodes of hypoglycemia, duration of hypoglycemia, and time to enteral bolus feeding and weaning from intravenous fluids, were compared by generalized linear models. Newborns were followed up for at least 2 weeks. Results: Of 154 newborns screened, 75 were randomized and 74 with evaluable data were included in the analysis (mean [SD] gestational age for the full cohort, 37.6 [1.6] weeks), 36 in the diazoxide group and 38 in the placebo group. Baseline characteristics were similar: in the diazoxide group, mean (SD) gestational age was 37.9 (1.6) weeks and 26 (72%) were male; in the placebo group, mean (SD) gestational age was 37.4 (1.5) weeks and 27 (71%) were male. There was no significant difference in time to resolution of hypoglycemia (adjusted hazard ratio [AHR], 1.39; 95% CI, 0.84-2.23), possibly due to increased episodes of elevated blood glucose concentration and longer time to normoglycemia in the diazoxide group. Resolution of hypoglycemia, when redefined post hoc as enteral bolus feeding without intravenous fluids for at least 24 hours with no further hypoglycemia, was reached by more newborns in the diazoxide group (AHR, 2.60; 95% CI, 1.53-4.46). Newborns in the diazoxide group had fewer blood glucose tests (adjusted count ratio [ACR], 0.63; 95% CI, 0.56-0.71) and episodes of hypoglycemia (ACR, 0.32; 95% CI, 0.17-0.63), reduced duration of hypoglycemia (adjusted ratio of geometric means [ARGM], 0.18; 95% CI, 0.06-0.53), and reduced time to enteral bolus feeding (ARGM, 0.74; 95% CI, 0.58-0.95) and weaning from intravenous fluids (ARGM, 0.72; 95% CI, 0.60-0.87). Only 2 newborns (6%) treated with diazoxide had hypoglycemia after the loading dose compared with 20 (53%) with placebo. Conclusions and Relevance: In this randomized clinical trial, early treatment of severe or recurrent neonatal hypoglycemia with low-dose oral diazoxide did not reduce time to resolution of hypoglycemia but reduced time to enteral bolus feeding and weaning from intravenous fluids, duration of hypoglycemia, and frequency of blood glucose testing compared with placebo. Trial Registration: ANZCTR.org.au Identifier: ACTRN12620000129987.

Impact of Early Depressive Burden on Patient-Reported Outcomes Following Minimally Invasive Transforaminal Lumbar Interbody Fusion.

STUDY DESIGN: Retrospective review. OBJECTIVE: To evaluate mental health influence on minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) patients. SUMMARY OF BACKGROUND DATA: Poor mental health has been postulated to indicate inferior patient perceptions of surgical outcomes in spine literature. Few studies have assessed mental health as a dynamic metric throughout the perioperative period. METHODS: A single-surgeon database was retrospectively searched for patients who underwent primary, elective MIS-TLIF for degenerative or isthmic spondylolisthesis. Summative depressive burden (SDB) was defined by the sum of preoperative and 6-week postoperative 9-item Patient Health Questionnaire (PHQ-9), with Lesser Burden (LB, SDB<10) and Greater Burden (GB, SDB≥10) cohorts. Patient-reported outcomes measures (PROMs) were compared preoperatively, at 6 weeks, and at final postoperative follow-up (11.4±10.9 mo), using Patient-Reported Outcomes Measurement Information System-Physical Function (PROMIS-PF), Oswestry disability index (ODI), visual analog scale-back (VAS-B), VAS-leg (VAS-L), and PHQ-9. Improvements at 6-week (∆PROM-6W), final follow-up (∆PROM-FF), and minimum clinically important difference (MCID) achievement were compared. RESULTS: The GB cohort consisted of 44 of 105 patients. Demographic variations included older age, higher Charlson comorbidity index, increased hypertension prevalence, and private insurance in the LB cohort (P≤0.018). The LB cohort demonstrated better baseline and 6-week PROMIS-PF/ODI/VAS-L (P≤0.032) and better final PROMIS-PF/ODI/VAS-L/PHQ-9 (P≤0.031). Both cohorts improved in all PROMs at 6 weeks and final follow-up (P≤0.029), except for PROMIS-PF at 6 weeks in the GB cohort. ∆PROM-6W, ∆PROM-FF, and MCID achievement rate for PHQ-9 were greater in the GB cohort (P≤0.001). CONCLUSION: On average, patients undergoing MIS-TLIF for degenerative or isthmic spondylolisthesis improved in all PROMs by final follow-up. Patients with GB suffered inferior perceptions of physical function, disability, and leg pain. MCID rates in mental health were higher for GB cohort. Surgeons are encouraged to adopt a compassionate understanding of depressive burden and educate the patient on possible consequential postoperative outcomes.

Automated quantitative assessment of bone contusions and overlying articular cartilage following anterior cruciate ligament injury.

Quantitative methods to characterize bone contusions and associated cartilage injury remain limited. We combined standardized voxelwise normalization and 3D mapping to automate bone contusion segmentation post-anterior cruciate ligament (ACL) injury and evaluate anomalies in articular cartilage overlying bone contusions. Forty-five patients (54% female, 26.4 ± 11.8 days post-injury) with an ACL tear underwent 3T magnetic resonance imaging of their involved and uninvolved knees. A novel method for voxelwise normalization and 3D anatomical mapping was used to automate segmentation, labeling, and localization of bone contusions in the involved knee. The same mapping system was used to identify the associated articular cartilage overlying bone lesions. Mean regional T1ρ was extracted from articular cartilage regions in both the involved and uninvolved knees for quantitative paired analysis against ipsilateral cartilage within the same compartment outside of the localized bone contusion. At least one bone contusion lesion was detected in the involved knee within the femur and/or tibia following ACL injury in 42 participants. Elevated T1ρ (p = 0.033) signal were documented within the articular cartilage overlying the bone contusions resulting from ACL injury. In contrast, the same cartilaginous regions deprojected onto the uninvolved knees showed no ipsilateral differences (p = 0.795). Automated bone contusion segmentation using standardized voxelwise normalization and 3D mapping deprojection identified altered cartilage overlying bone contusions in the setting of knee ACL injury.

Comparison of Length of Stay and Discharge Disposition after Short-Segment Lumbar Fusion Surgery at Tertiary Care and Non-Tertiary Care Hospitals: A Propensity Score Matched Analysis.

STUDY DESIGN: A retrospective study. OBJECTIVE: To compare the perioperative and postoperative outcomes among lumbar fusion patients treated at an orthopaedic specialty hospital (OSH), a hybrid community hospital (HCH), and a conventional community hospital in comparison to a tertiary care hospital (TCH). SUMMARY OF BACKGROUND DATA: In spine surgery, strategies to reduce length of stay (LOS) include a myriad of pre-, intra-, and postoperative strategies that require a multidisciplinary infrastructure. The sum of these efforts has led to the creation of orthopedic specialty hospitals and protocols that have been adopted by community hospitals as well. There is a notable lack of information regarding the results of these efforts across different healthcare institution models. METHODS: This was a retrospective study of patients undergoing elective one or two-level lumbar fusion between 2017 and 2022 at a large urban TCH, an OSH, a HCH, and a conventional CH. Data was collected on patient characteristics, demographics, comorbidities, BMI, smoking status, surgical type, surgical levels, surgery duration, hospital length of stay, readmissions, reoperations, and discharge status within a year. Patients across the four surgical settings were matched based on age, BMI, CCI, type of procedure, and number of levels fused. RESULTS: A total of 1435 patients met the inclusion criteria. Length of hospital stay was significantly longer at TCH compared to OSH, HCH, and CH by an average of 1-2 days (P<0.001). 90-day readmissions were higher at TCH compared to OSH (P=0.001). TCH patients also were less likely to be discharged home than OSH and HCH patients (P=0.001 and P=0.016, respectively). No significant differences were noted in 1-year reoperation rates across all hospital models. CONCLUSION: Shorter lengths of stays and more home discharges at the orthopaedic specialty hospital and community hospital settings did not compromise surgical quality or postoperative outcomes.

Proteomic analysis of cardiorespiratory fitness for prediction of mortality and multisystem disease risks.

Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.50 (95% confidence interval 0.48-0.52) per 1 s.d. increase). The proteomic CRF score was also associated with multisystem disease risk and provided risk reclassification and discrimination beyond clinical risk factors, as well as modulating high polygenic risk of certain diseases. Finally, we observed dynamicity of the proteomic CRF score in individuals who undertook a 20-week exercise training program and an association of the score with the degree of the effect of training on CRF, suggesting potential use of the score for personalization of exercise recommendations. These results indicate that population-based proteomics provides biologically relevant molecular readouts of CRF that are additive to genetic risk, potentially modifiable and clinically translatable.

Sources of variability in Luminex bead-based cytokine assays: Evidence from twelve years of multi-site proficiency testing.

Bead array assays, such as those sold by Luminex, BD Biosciences, Sartorius, Abcam and other companies, are a well-established platform for multiplexed quantification of cytokines and other biomarkers in both clinical and discovery research environments. In 2011, the National Institute of Allergy and Infectious Diseases (NIAID)-funded External Quality Assurance Program Oversight Laboratory (EQAPOL) established a proficiency assessment program to monitor participating laboratories performing multiplex cytokine measurements using Luminex bead array technology. During every assessment cycle, each site was sent an assay kit, a protocol, and blinded samples of human sera spiked with recombinant cytokines. Site results were then evaluated for performance relative to peer laboratories. After over a decade of biannual assessments, the cumulative dataset contained over 15,500 bead array observations collected at more than forty laboratories in twelve countries. These data were evaluated alongside post-assessment survey results to empirically test factors that may contribute to variability and accuracy in Luminex bead-based cytokine assays. Bead material, individual technical ability, analyte, analyte concentration, and assay kit vendor were identified as significant contributors to assay performance. In contrast, the bead reader instrument model and the use of automated plate washers were found not to contribute to variability or accuracy, and sample results were found to be highly-consistent between assay kit-manufacturing lots and over time. In addition to these statistical analyses, subjective evaluations identified technical ability, instrument failure, protocol adherence, and data transcription errors as the most common causes of poor performance in the proficiency program. The findings from the EQAPOL multiplex program were then used to develop recommended best practices for bead array monitoring of human cytokines. These included collecting samples to assay as a single batch, centralizing analysis, participating in a quality assurance program, and testing samples using paramagnetic-bead kits from a single manufacturer using a standardized protocol.