Patient-Reported Outcomes Following Periprosthetic Joint Infection of the Hip and Knee: A Longitudinal, Prospective Observational Study.

BACKGROUND: The role of patient-reported outcome measures (PROMs) as tools for monitoring the impact and outcomes of periprosthetic joint infection (PJI) is not well described. This study analyzed the Oxford Hip Score (OHS) or Oxford Knee Score (OKS) in a prospective observational cohort of patients with hip or knee PJI. METHODS: The PIANO (Prosthetic joint Infection in Australia and New Zealand, Observational study) cohort prospectively enrolled patients with newly diagnosed PJI from multiple centers. The OHS and OKS were evaluated at PJI diagnosis (baseline) and at 3, 12, and 24 months. Scores and score changes were examined according to PJI type, patient characteristics, and management. A successful functional outcome at 12 months was defined as an OHS of >38 or OHS of >36 and/or an improvement from baseline of >12 or >9, respectively. RESULTS: Of the 741 participants, PROMs were available at 12 months for 233 with hip and 342 with knee PJI. Significant improvements (p < 0.0001) were seen at 12 months for both the OHS (24.5 to 36) and OKS (25 to 34), with no further improvement at 24 months. Patients with late-acute PJI had a higher median baseline OHS (35; interquartile range [22 to 46]) and OKS (30 [18 to 41]) than those with early PJI (OHS: 19 [15 to 29]; OKS: 22 [16 to 29.5]) or chronic PJI (OHS: 23 [14 to 34]; OKS 22 [14 to 28]). Logistic regression showed that a clinical cure (adjusted odds ratio [aOR] = 1.88, 95% confidence interval [CI] = 1.28 to 2.76, p = 0.001) and early PJI (aOR = 2.56, 95% CI = 1.64 to 4.07, p < 0.0001) independently predicted a successful functional outcome. Chronic renal impairment (aOR = 0.31, 95% CI = 0.13 to 0.71, p = 0.007), congestive cardiac failure (aOR = 0.41, 95% CI = 0.17 to 0.95, p = 0.04), and clinical signs of inflammation (aOR = 0.53, 95% CI = 0.33 to 0.85, p = 0.009) at diagnosis independently predicted failure to achieve a successful functional outcome. CONCLUSIONS: The OHS and OKS varied significantly at baseline and 12 months according to PJI type, emphasizing the need to consider the PJI type when evaluating treatment success. This study highlights superior functional outcomes associated with early PJI and with achievement of a clinical cure. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Effect of Quorum Sensing Molecules on the Quality of Bacterial Nanocellulose Materials.

Bacterial nanocellulose (BNC) biofilms, produced by various bacterial species, such as Gluconacetobacter xylinus, represent a highly promising multifunctional material characterized by distinctive physiochemical properties. These biofilms have demonstrated remarkable versatility as nano biomaterials, finding extensive applications across medical, defense, electronics, optics, and food industries. In contrast to plant cellulose, BNC biofilms exhibit numerous advantages, including elevated purity and crystallinity, expansive surface area, robustness, and excellent biocompatibility, making them exceptional multifunctional materials. However, their production with consistent morphological properties and their transformation into practical forms present challenges. This difficulty often arises from the heterogeneity in cell density, which is influenced by the presence of N-acyl-homoserine lactones (AHLs) serving as quorum sensing signaling molecules during the biosynthesis of BNC biofilms. In this study, we employed surface characterization methodologies including scanning electron microscopy, energy-dispersive spectroscopy, diffuse reflectance infrared Fourier transform spectroscopy, and atomic force microscopy to characterize BNC biofilms derived from growth media supplemented with varying concentrations of distinct N-acyl-homoserine lactone signaling molecules. The data obtained through these analytical techniques elucidated that the morphological properties of the BNC biofilms were influenced by the specific AHLs, signaling molecules, introduced into the growth media. These findings lay the groundwork for future exploration of leveraging synthetic biology and biomimetic methods for tailoring BNC with predetermined morphological properties.

Phase I Trial of SPECT-Guided Liver-Directed Radiotherapy for Patients with Low Functional Liver Volume.

BACKGROUND: Traditional constraints specify that 700 cc of liver should be spared a hepatotoxic dose when delivering liver-directed radiotherapy to reduce the risk of inducing liver failure. We investigated the role of single photon emission computed tomography (SPECT) to identify and preferentially avoid functional liver during liver-directed radiation treatment planning in patients with preserved liver function but limited functional liver volume after receiving prior hepatotoxic chemotherapy or surgical resection. METHODS: This phase I trial with a 3 + 3 design evaluated the safety of liver-directed radiotherapy using escalating functional liver radiation dose constraints in patients with liver metastases. Dose limiting toxicities (DLTs) were assessed 6-8 weeks and 6 months after completing radiotherapy. RESULTS: All twelve patients had colorectal liver metastases and received prior hepatotoxic chemotherapy. Eight patients underwent prior liver resection. Median computed tomography (CT) anatomical non-tumor liver volume was 1,584 cc (range 764-2,699 cc). Median SPECT functional liver volume was 1,117 cc (range 570-1,928cc). Median non-target CT and SPECT liver volumes below the volumetric dose constraint were 997 cc (range 544-1,576 cc) and 684 cc (range 429-1,244 cc), respectively. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. No DLTs were observed during follow-up. One-year in-field control was 57%. One-year overall survival was 73%. CONCLUSION: Liver-directed radiotherapy can be safely delivered to high doses when incorporating functional SPECT into the radiation treatment planning process which may enable sparing of lower volumes of liver than traditionally accepted in patients with preserved liver function. TRIAL REGISTRATION: NCT02626312.

Secondary analysis of Staphylococcus aureus whole genomes reveals diverse antimicrobial resistance profiles.

Antimicrobial resistance (AMR) in microorganisms is an ongoing threat to human health across the globe. To better characterize the AMR profiles of six strains of Staphylococcus aureus , we performed a secondary analysis that consisted of the following steps: 1) download fastq files from the Sequence Read Archive, 2) perform a de novo genome assembly from the sequencing reads, 3) annotate the assembled contigs, 4) predict the presence of antimicrobial resistance genes. We predicted the presence of 75 unique genes that conferred resistance against 22 unique antimicrobial compounds.

Differences in Reimbursements, Procedural Volumes, and Patient Characteristics Based on Surgeon Gender in Total Hip Arthroplasty.

BACKGROUND: Prior studies have suggested there may be differences in reimbursement and practice patterns by gender. The purpose of this study was to comprehensively evaluate differences in reimbursement, procedural volume, and patient characteristics in total hip arthroplasty (THA) between men and women surgeons from 2013 to 2021. METHODS: The Medicare Physician and Other Practitioners database from 2013 to 2021 was queried. Inflation-adjusted reimbursement, procedural volume, surgeon information, and patient demographics were extracted for surgeons performing over 10 primary THAs each year. Wilcoxon, t-tests, and multivariate linear regressions were utilized to compare men and women surgeons. RESULTS: Only 1.4% of THAs billed to Medicare between 2013 and 2021 were billed by women surgeons. Men surgeons earned significantly greater reimbursement nationally in 2021 compared to women surgeons per THA ($1018.56 versus $954.17, P = 0.03), but no difference was found when assessing each region separately. Reimbursement declined at similar rates for both men and women surgeons (-18.3 versus -19.8%, P = 0.38). An increase in the proportion of women surgeons performing THA between 2013 and 2021 was seen in all regions except the South. In 2021, the proportion of all THAs performed by women surgeons was highest in the West (3.5%) and lowest in the South (1.0%). Women surgeons had comparable patient populations in terms of age, race, comorbidity status, and Medicaid eligibility to their men counterparts, but performed significantly fewer services per beneficiary (5.6 versus 8.1, P < 0.001) and fewer unique services (51.1 versus 69.6, P < 0.001). CONCLUSIONS: Average reimbursement per THA has declined at a similar rate for men and women physicians between 2013 and 2021. Women's representation in THA surgery nationwide has nearly doubled between 2013 and 2021, with the greatest increase in the West. However, there are notable differences in billing practices between genders.

An Analysis of Intrapitch Variation in Joint and Segment Velocities With Throwing Arm Kinetics in High School and Professional Baseball Pitchers.

BACKGROUND: Improper sequencing order of maximal joint and segment velocities has been identified as an important predictor for both throwing arm kinetics and ball velocity. PURPOSE: To investigate the intrapitcher variation of maximal segment velocities and the relationship to throwing arm kinetics and ball velocity in high school (HS) and professional (PRO) pitchers. STUDY DESIGN: Descriptive laboratory study. METHODS: HS (n = 59) and PRO (n = 338) pitchers, instructed to throw 8 to 12 fastball pitches, were evaluated with 3-dimensional motion capture (480 Hz). Maximal joint and segment velocities were calculated for each pitch, and the standard deviation of the maxima was calculated per pitcher. These standard deviations were used to classify pitchers as "low variance" or "high variance" for each segmental velocity subgroup, "overall low variance" or "overall high variance" based on cumulative segment velocity variation, or "population," with any pitcher eligible to be included in multiple subcategories. Maximal velocities and throwing arm kinetics were compared among the various subgroups. RESULTS: The HS low-variance shoulder internal rotation velocity subgroup (4949 ± 642 deg/s) had significantly lower maximal shoulder internal rotation velocity compared with HS population (5774 ± 1057 deg/s) (P < .001); similar findings were observed for PROs (5269 ± 835 vs 5824 ± 1076 deg/s; P < .001), as well as lower shoulder superior force compared with the PRO population (14.8% ± 8.8% vs 17.8% ± 8.8% body weight; P = .001). The PRO low-variance lead knee extension velocity subgroup had significantly lower maximal lead knee extension velocity (216 ± 135 vs 258 ± 125 deg/s; P = .001) and shoulder distractive force (111.5% ± 14.4% vs 115.6% ± 15.9% body weight; P = .003) compared with the PRO population. The PRO overall low-variance subgroup had significantly lower shoulder distractive force (111.8% ± 14.1% vs 119.6% ± 15.5% body weight; P = .008) and elbow anterior force (40.6% ± 5.0% vs 43.6% ± 6.2% body weight; P = .008) compared with the PRO overall high-variance subgroup. CONCLUSION: HS and PRO pitchers with low variance for joint and segment velocities achieved significantly lower maximal velocities in the subgroup of interest, while preserving ball velocity. PRO pitchers with overall low variance among multiple maximal joint and segment velocities demonstrated decreased shoulder distractive and elbow anterior force. CLINICAL RELEVANCE: PRO pitchers with low intrapitch variation in maximal joint and segment velocities may be viewed as kinetically conservative throwers. These pitchers with similarly maintained mechanics between pitches may have an increasingly regimented form that preserves kinetic forces about the throwing arm. The opposite may be true for PRO pitchers with increased variability in segmental velocities during their pitching motion, as they showed increased throwing arm kinetics including shoulder distractive and elbow anterior force compared with the overall low-variance group, theoretically increasing their risk of injury.

Risk Versus Reward - Hospitals Incentivized More than Surgeons to Care for Riskier Arthroplasty Patients.

PURPOSE: The purpose of this study was to assess the relationship between risk and reimbursement for both surgeons and hospitals among Medicare patients undergoing primary total joint arthroplasty (TJA). METHODS: The "2021-Medicare-Physician-and-Other-Provider" and "2021-Medicare-Inpatient-Hospitals" files were utilized. Patient comorbidity profiles were collected, including the mean patient-hierarchal-condition-category (HCC) risk score, which is a standardized metric accounting for comorbidities. Surgeon data included all primary TJA procedures (inpatient and outpatient) billed to Medicare in 2021, while hospital data included all inpatient episodes of primary TJA billed to Medicare in 2021. Surgeon and hospital reimbursements were collected. All episodes were split into a "sicker-cohort" with an HCC risk score of 1.5 or greater and a "healthier-cohort" with HCC risk scores less than 1.5. Variables were compared across cohorts. RESULTS: In 2021, 386,355 primary total hip and knee arthroplasty procedures were billed to Medicare and were included. The mean surgeon reimbursement among the sicker cohort was $1,021.91, which was less than for the healthier cohort of $1,060.13 (P < 0.001). Meanwhile, for the hospital analysis, 112,012 Medicare patients were admitted as inpatients for primary TJA in 2021 and included. The mean reimbursement to hospitals was significantly greater for the sicker cohort at $13,950.66, compared to the healthier cohort of $8,430.46. For both the surgeon and hospital analyses, the sicker patient cohorts had a significantly higher rate of all comorbidities assessed (P < 0.001). CONCLUSION: This study demonstrates that mean surgeon reimbursement was lower for primary TJA among sicker patients in comparison to their healthier counterparts, while hospital reimbursement was higher for sicker patients. This represents a discrepancy in the incentivization of care for complex patients, as hospitals receive increased remuneration for taking on extra risk, while surgeons get paid less on average for performing TJA on sicker patients. Such data should inform future policy to assure continued access to arthroplasty care among complex patients.

Estimating heterogeneity of treatment effect in psychiatric clinical trials.

Currently, placebo-controlled clinical trials report mean change and effect sizes, which masks information about heterogeneity of treatment effects (HTE). Here, we present a method to estimate HTE and evaluate the null hypothesis (H0) that a drug has equal benefit for all participants (HTE=0). We developed measure termed 'estimated heterogeneity of treatment effect' or eHTE, which estimates variability in drug response by comparing distributions between study arms. This approach was tested across numerous large placebo-controlled clinical trials. In contrast with variance-based methods which have not identified heterogeneity in psychiatric trials, reproducible instances of treatment heterogeneity were found. For example, heterogeneous response was found in a trial of venlafaxine for depression (peHTE=0.034), and two trials of dasotraline for binge eating disorder (Phase 2, peHTE=0.002; Phase 3, 4mg peHTE=0.011; Phase 3, 6mg peHTE=0.003). Significant response heterogeneity was detected in other datasets as well, often despite no difference in variance between placebo and drug arms. The implications of eHTE as a clinical trial outcomes independent from central tendency of the group is considered and the important of the eHTE method and results for drug developers, providers, and patients is discussed.

Wiring between close nodes in molecular networks evolves more quickly than between distant nodes.

As species diverge, a wide range of evolutionary processes lead to changes in protein-protein interaction networks and metabolic networks. The rate at which molecular networks evolve is an important question in evolutionary biology. Previous empirical work has focused on interactomes from model organisms to calculate rewiring rates, but this is limited by the relatively small number of species and sparse nature of network data across species. We present a proxy for variation in network topology: variation in drug-drug interactions (DDIs), obtained by studying drug combinations (DCs) across taxa. Here, we propose the rate at which DDIs change across species as an estimate of the rate at which the underlying molecular network changes as species diverge. We computed the evolutionary rates of DDIs using previously published data from a high throughput study in gram-negative bacteria. Using phylogenetic comparative methods, we found that DDIs diverge rapidly over short evolutionary time periods, but that divergence saturates over longer time periods. In parallel, we mapped drugs with known targets in protein-protein interaction and co-functional networks. We found that the targets of synergistic DDIs are closer in these networks than other types of DCs and that synergistic interactions have a higher evolutionary rate, meaning that nodes that are closer evolve at a faster rate. Future studies of network evolution may use DC data to gain larger-scale perspectives on the details of network evolution within and between species.

Lower Income and Nonheterosexual Orientation Are Associated With Poor Access to Care in Patients With Knee Osteoarthritis.

Background: Social determinants of health are implicated in the experience of knee osteoarthritis, a key component of which is access to care and healthcare utilization. The objective of this study was to describe difficulties in access to care and healthcare utilization in the United States knee osteoarthritis population. Methods: The publicly available All of Us Database was utilized to conduct a retrospective cohort study. Patients with a diagnosis of knee osteoarthritis were included and matched to a control group who did not have knee osteoarthritis. The association of knee osteoarthritis and patient-specific demographic features with self-reported domains of access to care was analyzed. Results: Among 15,718 patients with knee osteoarthritis, 27.6% reported delayed care (n = 4343), 25.6% reported inability to afford care (n = 4015), 12.8% reported skipped medications (n = 2011), and 1.6% reported not seeing a healthcare provider in over 1 year (n = 247). Patients with knee osteoarthritis were more likely to be unable to afford care (odds ratio 1.21, P < .001) or skip medications (odds ratio 1.12, P = .004) in comparison to matched patients without knee osteoarthritis. Among the knee osteoarthritis cohort, low income and nonheterosexual orientation were both associated with increased rates of delayed care and an inability to afford care. Conclusions: Patients with knee osteoarthritis report significant challenges with delayed care, affordability of care, and medication adherence. Among patients with knee osteoarthritis, patients who are younger age, female sex, low-income, low-education, nonheterosexual orientation, or have poor physical and mental health are at increased risk of having decreased access to treatment.

Determinants of mosaic chromosomal alteration fitness.

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Structural Changes in Brain White Matter Tracts Associated With Overactive Bladder Revealed by Diffusion Tensor Magnetic Resonance Imaging: Findings From a Symptoms of Lower Urinary Tract Dysfunction Research Network Cross-Sectional Case-Control Study.

PURPOSE: Our objective was to investigate structural changes in brain white matter tracts using diffusion tensor imaging (DTI) in patients with overactive bladder (OAB). MATERIALS AND METHODS: Treatment-seeking OAB patients and matched controls enrolled in the cross-sectional case-control LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) Neuroimaging Study received a brain DTI scan. Microstructural integrity of brain white matter was assessed using fractional anisotropy (FA) and mean diffusivity. OAB and urgency urinary incontinence (UUI) symptoms were assessed using the OAB Questionnaire Short-Form and International Consultation on Incontinence Questionnaire-Urinary Incontinence. The Lower Urinary Tract Symptoms Tool UUI questions and responses were correlated with FA values. RESULTS: Among 221 participants with evaluable DTI data, 146 had OAB (66 urinary urgency-only without UUI, 80 with UUI); 75 were controls. Compared with controls, participants with OAB showed decreased FA and increased mean diffusivity, representing greater microstructural abnormalities of brain white matter tracts among OAB participants. These abnormalities occurred in the corpus callosum, bilateral anterior thalamic radiation and superior longitudinal fasciculus tracts, and bilateral insula and parahippocampal region. Among participants with OAB, higher OAB Questionnaire Short-Form scores were associated with decreased FA in the left inferior fronto-occipital fasciculus, P < .0001. DTI differences between OAB and controls were driven by the urinary urgency-only (OAB-dry) but not the UUI (OAB-wet) subgroup. CONCLUSIONS: Abnormalities in microstructural integrity in specific brain white matter tracts were more frequent in OAB patients. More severe OAB symptoms were correlated with greater degree of microstructural abnormalities in brain white matter tracts in patients with OAB.

Food Insecurity and Family Dynamics: A Systematic Review.

BACKGROUND: Undernutrition is related to numerous childhood outcomes. However, little research has investigated the relationship between food insecurity and family dynamics. This systematic review seeks to validate the evidence for a relationship between these 2 factors. METHODS: A systematic literature review was conducted in Embase, PubMed, and Scopus. Inclusion criteria include peer-reviewed research articles published during or after 1996 in English, using standardized measures of family function and food insecurity. Exclusion criteria include measurement of parent or child characteristics without assessing household or family characteristics or demographics. Two reviewers independently voted using Covidence, and Alpha agreement was determined at each phase. RESULTS: A total of 15 studies were included for data extraction after the initial search being completed in April 2022. All included studies were found to be appropriate in numerous categories for quality assessment. Primary findings from these studies show a potential relationship exists between food insecurity and family dynamics. DISCUSSION: The findings in this review suggest that effects of food insecurity expand to various aspects of healthy family functioning. Unhealthy family dynamics in childhood can also expose children to trauma and lead to increased physical and mental health disorders in the future.

Genome-informed trophic classification and functional characterization of virulence proteins from the maize tar spot pathogen Phyllachora maydis.

Phyllachora maydis is an ascomycete foliar fungal pathogen and the causal agent of tar spot in maize. Though P. maydis is considered an economically important foliar pathogens of maize, our general knowledge of the trophic lifestyle and functional role of effector proteins from this fungal pathogen remains limited. Here, we utilized a genome-informed approach to predict the trophic lifestyle of P. maydis and functionally characterized a subset of candidate effectors from this fungal pathogen. Leveraging the most recent P. maydis genome annotation and the CATAStrophy pipeline, we show this fungal pathogen encodes a predicted Carbohydrate-active enzymes (CAZymes) repertoire consistent with that of biotrophs. To investigate fungal pathogenicity, we selected 18 candidate effector proteins that were previously shown to be expressed during primary disease development. We assessed whether these putative effectors share predicted structural similarity with other characterized fungal effectors and determined whether any suppress plant immune responses. Using AlphaFold2 and Foldseek, we showed one candidate effector, PM02_g1115, adopts a predicted protein structure similar to that of an effector from Verticillium dahlia. Furthermore, transient expression of candidate effector-fluorescent protein fusions in Nicotiana benthamiana revealed two putative effectors, PM02_g378 and PM02_g2610, accumulated predominantly in the cytosol, and three candidate effectors, PM02_g1115, PM02_g7882, and PM02_g8240 consistently attenuated chitin-mediated reactive oxygen species production. Collectively, these results presented herein provide insights into the predicted trophic lifestyle and putative functions of effectors from P. maydis and will likely stimulate continued research to elucidate the molecular mechanisms used by P. maydis to induce tar spot.

Reversibility of Cognitive Deficits and Functional Connectivity With Transfusion in Children With Sickle Cell Disease.

BACKGROUND AND OBJECTIVES: People with sickle cell disease (SCD) are at risk of cognitive dysfunction independent of stroke. Diminished functional connectivity in select large-scale networks and white matter integrity reflect the neurologic consequences of SCD. Because chronic transfusion therapy is neuroprotective in preventing stroke and strengthening executive function abilities in people with SCD, we hypothesized that red blood cell (RBC) transfusion facilitates the acute reversal of disruptions in functional connectivity while white matter integrity remains unaffected. METHODS: Children with SCD receiving chronic transfusion therapy underwent a brain MRI measuring white matter integrity with diffusion tensor imaging and resting-state functional connectivity within 3 days before and after transfusion of RBCs. Cognitive assessments with the NIH Toolbox were acquired after transfusion and then immediately before the following transfusion cycle. RESULTS: Sixteen children with a median age of 12.5 years were included. Global assessments of functional connectivity using homotopy (p = 0.234) or modularity (p = 0.796) did not differ with transfusion. Functional connectivity within the frontoparietal network significantly strengthened after transfusion (median intranetwork Z-score 0.21 [0.17-0.30] before transfusion, 0.29 [0.20-0.36] after transfusion, p < 0.001), while there was not a significant change seen within the sensory motor, visual, auditory, default mode, dorsal attention, or cingulo-opercular networks. Corresponding to the change within the frontoparietal network, there was a significant improvement in executive function abilities after transfusion (median executive function composite score 87.7 [81.3-90.7] before transfusion, 90.3 [84.3-93.7] after transfusion, p = 0.021). Participants with stronger connectivity in the frontoparietal network before transfusion had a significantly greater improvement in the executive function composite score with transfusion (r = 0.565, 95% CI 0.020-0.851, p = 0.044). While functional connectivity and executive abilities strengthened with transfusion, there was not a significant change in white matter integrity as assessed by fractional anisotropy and mean diffusivity within 16 white matter tracts or globally with tract-based spatial statistics. DISCUSSION: Strengthening of functional connectivity with concomitant improvement in executive function abilities with transfusion suggests that functional connectivity MRI could be used as a biomarker for acutely reversible neurocognitive injury as novel therapeutics are developed for people with SCD.

Garadacimab for hereditary angioedema attack prevention: long-term efficacy, quality of life, and safety data from a phase 2, randomised, open-label extension study.

BACKGROUND: Garadacimab is a fully human immunoglobulin G4 monoclonal antibody targeting activated factor XII. This study evaluated long-term efficacy, health-related quality of life (HRQoL), and safety data for garadacimab in adults with hereditary angioedema. METHODS: This global phase 2 study comprised a treatment period 1 (TP1: 12 weeks, double-blind, placebo-controlled) and a treatment period 2 (TP2: ≥44-week open-label extension). Patients aged 18-65 years with clinically confirmed hereditary angioedema were eligible. In TP1, 32 patients were randomly assigned (1:1:1:1) to receive subcutaneous garadacimab (75 mg, 200 mg, or 600 mg) or placebo every 4 weeks (once monthly). Randomisation was done using interactive response technology via block randomisation (block sizes 1-4). Subsequently, six additional patients in TP1 were assigned to open-label garadacimab 400 mg every 2 weeks. At the start of TP2, patients were re-randomised (if receiving placebo, garadacimab 75 mg, or garadacimab 400 mg) or continued to receive garadacimab 200 mg or garadacimab 600 mg once monthly. After a protocol amendment on March 20, 2020, patients originally assigned to the 600 mg dose were down-titrated to 200 mg at their next visit. The primary endpoint (published previously) was monthly attack rate for patients receiving 200 mg or 600 mg garadacimab in TP1 in the intention-to-treat population. Here, we assessed the impact of garadacimab on patient-reported and investigator-reported outcomes and HRQoL as well as long-term efficacy and safety. This trial is registered with ClinicalTrials.gov, NCT03712228, and is completed. FINDINGS: Of 54 patients screened between Oct 29, 2018, and Aug 28, 2019, 32 randomised and six open-label patients completed TP1 and entered TP2 (20 in the garadacimab 200 mg group; 18 in the garadacimab 600 mg group; total 38 patients). Median age was 39·0 years (IQR 27·0-53·0), and 21 patients (55%) were female and 17 (45%) were male. In TP2, the median garadacimab exposure was 87·9 weeks (IQR 50·0-106·6) in the garadacimab 200 mg group and 44·1 weeks (24·1-56·1) in the garadacimab 600 mg group. Median monthly attack rates were 0·0 (IQR 0·0-0·1) in the garadacimab 200 mg group and 0·1 (0·0-0·4) in the garadacimb 600 mg group. Median reduction in monthly attack rate versus run-in was 100% (IQR 98-100) with garadacimab 200 mg. HRQoL improvements observed during TP1 with garadacimab were sustained throughout TP2. TP2 safety signals were consistent with TP1. Two patients experienced serious adverse events of diverticular perforation and asthma (not garadacimab-related). Treatment-emergent adverse events were mostly mild or moderate in severity. The most common adverse events were headache (nine of 38, 24%) and abdominal pain (seven of 38, 18%). There were no treatment-related deaths. INTERPRETATION: Once-monthly garadacimab for more than 2 years in patients with hereditary angioedema was well tolerated and efficacious in reducing monthly attack rate and improving HRQoL. These results reveal the potential of long-term prophylactic treatment with 200 mg once-monthly garadacimab towards complete disease control of patients with hereditary angioedema. FUNDING: CSL Behring.

Removal and Reoccurrence of LLZTO Surface Contaminants under Glovebox Conditions.

The reactivity of Li6.4La3Zr1.4Ta0.6O12 (LLZTO) solid electrolytes to form lithio-phobic species such as Li2CO3 on their surface when exposed to trace amounts of H2O and CO2 limits the progress of LLZTO-based solid-state batteries. Various treatments, such as annealing LLZTO within a glovebox or acid etching, aim at removing the surface contaminants, but a comprehensive understanding of the evolving LLZTO surface chemistry during and after these treatments is lacking. Here, glovebox-like H2O and CO2 conditions were recreated in a near ambient pressure X-ray photoelectron spectroscopy chamber to analyze the LLZTO surface under realistic conditions. We find that annealing LLZTO at 600 °C in this atmosphere effectively removes the surface contaminants, but a significant level of contamination reappears upon cooling down. In contrast, HCl(aq) acid etching demonstrates superior Li2CO3 removal and stable surface chemistry post treatment. To avoid air exposure during the acid treatment, an anhydrous HCl solution in diethyl ether was used directly within the glovebox. This novel acid etching strategy delivers the lowest lithium/LLZTO interfacial resistance and the highest critical current density.

Combination of Antistaphylococcal ß-Lactam With Standard Therapy Compared to Standard Therapy Alone for the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia: A Post Hoc Analysis of the CAMERA2 Trial Using a Desirability of Outcome Ranking Approach.

Background: Desirability of outcome ranking (DOOR) is an emerging approach to clinical trial outcome measurement using an ordinal scale to incorporate efficacy and safety endpoints. Methods: We applied a previously validated DOOR endpoint to a cohort of CAMERA2 trial participants with methicillin-resistant Staphylococcus aureus bacteremia (MRSAB). Participants were randomly assigned to standard therapy, or to standard therapy plus an antistaphylococcal ß-lactam (combination therapy). Each participant was assigned a DOOR category, within which they were further ranked according to their hospital length of stay (LOS) and duration of intravenous antibiotic treatment. We calculated the probability and the generalized odds ratio of participants receiving combination therapy having worse outcomes than those receiving standard therapy. Results: Participants assigned combination therapy had a 54.5% (95% confidence interval [CI], 48.9%-60.1%; P = .11) probability and a 1.2-fold odds (95% CI, .95-1.50; P = .12) of having a worse outcome than participants on standard therapy. When further ranked according to LOS and duration of antibiotic treatment, participants in the combination group had a 55.6% (95% CI, 49.5%-61.7%) and 55.3% (95% CI, 49.2%-61.4%) probability of having a worse outcome than participants in the standard treatment group, respectively. Conclusions: When considering both efficacy and safety, treatment of MRSAB with a combination of standard therapy and a ß-lactam likely results in a worse clinical outcome than standard therapy. However, a small benefit of combination therapy cannot be excluded. Most likely the toxicity of combination therapy outweighed any benefit from faster clearance of bacteremia.

Spatial, temporal, and biological factors influencing plant responses to deicing salt in roadside bioinfiltration basins.

Plants are arguably the most visible components of stormwater bioretention basins and play key roles in stabilizing soils and removing water through transpiration. In regions with cold winters, bioretention basins along roadways can receive considerable quantities of deicing salt, much of which migrates out of the systems prior to the onset of plant growth but the rest remains in the soil. The resulting effects on plants presumably vary with time (due to annual weather patterns), space (because stormwater exposure is location-dependent), and biology (because plant taxa differ in their salt tolerance). The goal of this study was to investigate the magnitude of deicing salt's effects on bioretention plants and how it varies with spatial, temporal, and biological factors. The study took place in a set of five bioretention basins in Philadelphia, USA that receive runoff from a major highway. Over a five-year period, the electrical conductivity (EC) of influent stormwater frequently exceeded 1 mS cm-1 in winter, and occasionally surpassed that of seawater (∼50 mS cm-1). In both of the years when soil EC was measured as well, it remained elevated through all spring months, especially near basin inlets and centers. Mortality of nine plant taxa ranged widely after three years (0-90%), with rankings largely corresponding to salt tolerances. Moreover, leaf areas and/or crown volumes were strongly reduced in proportion to stormwater exposure in seven of these taxa. In the three taxa evaluated for tissue concentrations of 14 potentially toxic elements (Hemerocallis 'Happy Returns', Iris 'Caesar's Brother', and Cornus sericea 'Cardinal'), only sodium consistently exceeded the toxicity limit for salt intolerant plants (500 mg kg-1). However, exceedance of the sodium toxicity limit was associated with plants' topographic positions, with median concentrations greatest in the bottom of basins and least on basin rims. This study demonstrates that deicing salts can have detrimental effects on plants in bioretention basins, with the strongest effects likely to occur in years with the greatest snowfall (and therefore deicing salt use), in portions of basins with greatest stormwater exposure (typically around inlets and centers), and in plants with minimal salinity tolerance. Our results therefore underscore the value of installing salt-tolerant taxa in basins likely to experience any frequency of deicing salt exposure.