The Streptococcus pyogenes stand-alone regulator RofA exhibits characteristics of a PRD-containing virulence regulator.

Streptococcus pyogenes [group A streptococcus (GAS)] is a human pathogen capable of infecting diverse tissues. To successfully infect these sites, GAS must detect available nutrients and adapt accordingly. The phosphoenolpyruvate transferase system (PTS) mediates carbohydrate uptake and metabolic gene regulation to adapt to the nutritional environment. Regulation by the PTS can occur through phosphorylation of transcriptional regulators at conserved PTS-regulatory domains (PRDs). GAS has several PRD-containing stand-alone regulators with regulons encoding both metabolic genes and virulence factors [PRD-containing virulence regulators (PCVRs)]. One is RofA, which regulates the expression of virulence genes in multiple GAS serotypes. It was hypothesized that RofA is phosphorylated by the PTS in response to carbohydrate levels to coordinate virulence gene expression. In this study, the RofA regulon of M1T1 strain 5448 was determined using RNA sequencing. Two operons were consistently differentially expressed across growth in the absence of RofA; the pilus operon was downregulated, and the capsule operon was upregulated. This correlated with increased capsule production and decreased adherence to keratinocytes. Purified RofA-His was phosphorylated in vitro by PTS proteins EI and HPr, and phosphorylated RofA-FLAG was detected in vivo when GAS was grown in low-glucose C medium. Phosphorylated RofA was not observed when C medium was supplemented 10-fold with glucose. Mutations of select histidine residues within the putative PRDs contributed to the in vivo phosphorylation of RofA, although phosphorylation of RofA was still observed, suggesting other phosphorylation sites exist in the protein. Together, these findings support the hypothesis that RofA is a PCVR that may couple sugar metabolism with virulence regulation.

Neotropical mammal responses to megafires in the Brazilian Pantanal.

The increasing frequency and severity of human-caused fires likely have deleterious effects on species distribution and persistence. In 2020, megafires in the Brazilian Pantanal burned 43% of the biome's unburned area and resulted in mass mortality of wildlife. We investigated changes in habitat use or occupancy for an assemblage of eight mammal species in Serra do Amolar, Brazil, following the 2020 fires using a pre- and post-fire camera trap dataset. Additionally, we estimated the density for two naturally marked species, jaguars Panthera onca and ocelots Leopardus pardalis. Of the eight species, six (ocelots, collared peccaries Dicotyles tajacu, giant armadillos Priodontes maximus, Azara's agouti Dasyprocta azarae, red brocket deer Mazama americana, and tapirs Tapirus terrestris) had declining occupancy following fires, and one had stable habitat use (pumas Puma concolor). Giant armadillo experienced the most precipitous decline in occupancy from 0.431 ± 0.171 to 0.077 ± 0.044 after the fires. Jaguars were the only species with increasing habitat use, from 0.393 ± 0.127 to 0.753 ± 0.085. Jaguar density remained stable across years (2.8 ± 1.3, 3.7 ± 1.3, 2.6 ± 0.85/100 km2), while ocelot density increased from 13.9 ± 3.2 to 16.1 ± 5.2/100 km2. However, the low number of both jaguars and ocelots recaptured after the fire period suggests that immigration may have sustained the population. Our results indicate that the megafires will have significant consequences for species occupancy and fitness in fire-affected areas. The scale of megafires may inhibit successful recolonization, thus wider studies are needed to investigate population trends.

A crescente frequência e gravidade dos incêndios causados pelo homem provavelmente terão efeitos deletérios na distribuição e persistência das espécies. Em 2020, mega incêndios no Pantanal brasileiro queimaram 43% do bioma e resultaram na mortalidade em massa da vida selvagem. Nós investigamos mudanças no uso ou ocupação do habitat para uma comunidade de oito espécies de mamíferos na Serra do Amolar, Brasil, após os incêndios de 2020, usando um conjunto de dados de armadilhas fotográficas instaladas no período pré e pós­fogo. Além disso, estimamos a densidade de duas espécies naturalmente marcadas, a onça­pintada Panthera onca e a jaguatirica Leopardus pardalis. Das oito espécies, seis (a jaguatirica, o cateto Dicotyles tajacu, o tatu­canastra Priodontes maximus, a cutia Dasyprocta azarae, o veado mateiro Mazama americana e a anta Tapirus terrestris) tiveram ocupação reduzida após os incêndios, e uma teve uso de habitat estável (a onça­parda, Puma concolor). O tatu­canastra apresentou o declínio mais acentuado na ocupação após os incêndios de 0,431 ± 0,171 para 0,077 ± 0,044. A onça­pintada foi a única espécie com uso crescente de habitat, de 0,393 ± 0,127 para 0,753 ± 0,085. A densidade da onça­pintada permaneceu estável ao longo dos anos (2,8 ± 1,3, 3,7 ± 1,3, 2,6 ± 0,85/100 km2), enquanto a densidade da jaguatirica aumentou de 13,9 ± 3,2 para 16,1 ± 5,2/100 km2. No entanto, o baixo número de onças­pintadas e jaguatiricas recapturadas após o período do fogo sugere que a imigração pode ter sustentado as populações. Nossos resultados indicam que os mega incêndios terão consequências significativas para a ocupação e resiliência das espécies nas áreas afetadas pelo fogo. A escala dos mega incêndios pode inibir uma recolonização bem­sucedida, pelo que são necessários estudos mais amplos para investigar as tendências populacionais.

Trends of Total Applied Pesticide Toxicity in German Agriculture.

Expressing temporal changes in the use of pesticides, based not only on amounts (masses) but also on their toxicity for different species groups, was proposed as a sensible approach for evaluating potential environmental risks. Here, we calculated the total applied toxicity (TAT) between 1995 and 2019 for Germany, mapped it, and compared it to the US TAT and other risk indicators. Results show that the German TAT for terrestrial vertebrates decreased over time by about 20%. The TAT increased by a factor of three for fishes, largely due to insecticides, by a factor of two for soil organisms, largely due to fungicides and insecticides, and, to a lower extent, for terrestrial plants, solely due to herbicides. Other species groups showed no trends in TAT, which for pollinators likely results from neonicotinoid use restrictions. Many TAT trends from Germany and the US differ, partly due to different insecticide and fungicide uses. TAT, SYNOPS risk indicators, and the EU Harmonized Risk Indicators, currently being used to assess the German National Action Plan's goal to reduce risks by 30% by 2023, lead to clearly different risk perceptions. Validated approaches are needed for evaluation of risk quantifications at the national scale.

Building Fucoidan/Agarose-Based Hydrogels as a Platform for the Development of Therapeutic Approaches against Diabetes.

Current management for diabetes has stimulated the development of versatile 3D-based hydrogels as in vitro platforms for insulin release and as support for the encapsulation of pancreatic cells and islets of Langerhans. This work aimed to create agarose/fucoidan hydrogels to encapsulate pancreatic cells as a potential biomaterial for diabetes therapeutics. The hydrogels were produced by combining fucoidan (Fu) and agarose (Aga), marine polysaccharides derived from the cell wall of brown and red seaweeds, respectively, and a thermal gelation process. The agarose/fucoidan (AgaFu) blended hydrogels were obtained by dissolving Aga in 3 or 5 wt % Fu aqueous solutions to obtain different proportions (4:10; 5:10, and 7:10 wt). The rheological tests on hydrogels revealed a non-Newtonian and viscoelastic behavior, while the characterization confirmed the presence of the two polymers in the structure of the hydrogels. In addition, the mechanical behavior showed that increasing Aga concentrations resulted in hydrogels with higher Young's modulus. Further, the ability of the developed materials to sustain the viability of human pancreatic cells was assessed by encapsulation of the 1.1B4HP cell line for up to 7 days. The biological assessment of the hydrogels revealed that cultured pancreatic beta cells tended to self-organize and form pseudo-islets during the period studied.

Psychomotor and neurofunctional aspects after COVID-19.

OBJECTIVE: The pandemic caused by the coronavirus disease 2019 (COVID-19, SARS-CoV-2 virus) has infected more than 646 million people and caused more than 6.6 million deaths worldwide (December/2022). It is surprising that a virus that affects airways can trigger neurological manifestations. The aim of this study was to create and apply specific questionnaires/evaluations for post-COVID-19 patients to profile any neurofunctional sequelae. METHODS: Epidemiological and psychomotor aspects as well as the intensity of cognitive, memory, attention, and concentration impairment were assessed. A total of 184 subjects post-COVID-19 and a control group (n = 30) were evaluated. RESULTS: The most prevalent blood types in the COVID-19 group were the same as those from control group and in Brazilian population (no influence). Loss of smell/taste and headache were the most common reported symptoms. Talking about psychomotor and neurofunctional aspects, COVID-19 induced marked impairments in the tests: fine motor development (diadochokinesis, puppets, fan, and knead paper); balance (immobility, static balance, feet in line, and persistence); episodic memory after distractors; verbal fluency; and clock, compared to the control group data. There was also marked increase of synkinesis. Therefore, COVID-19 induced impairments in psychomotor assessments and in different cognitive aspects of the Mini-Mental State Examination. These results are more surprising considering that most participants did not report pre-existing disease and did not require hospitalisation. CONCLUSION: COVID-19 induced psychomotor, neurofunctional, and memory impairments, including in young and healthy subjects. The present study revealed neurological impairments, which should be considered in the development of rehabilitation protocols for patients affected by COVID-19.

A Regional Analysis of Hospital Readmissions Following Total Hip and Knee Arthroplasty and the Impact of Medicaid Expansion.

The Hospital Readmissions Reduction Program (HRRP) works to temper nationally rising readmission rates. Total knee arthroplasty (TKA) and total hip arthroplasty (THA) have a 30-day readmission cost burden of $889,300 and $689,400, respectively. No research has compared TKA and THA readmission rates by region and Medicaid expansion status. This study compares THA and TKA readmission rates in the United States by region, Medicaid status, and performance. One-way ANOVAs were conducted to determine the regions with the highest and lowest mean excess readmission ratios (ERRs). An independent t-test compared Medicaid versus non-Medicaid expansion states. Southern hospitals have the highest mean ERR, followed by northeastern, midwestern, and then western hospitals. Although Medicaid expansion states have significantly lower ERRs compared to non-expansion states, Medicaid status alone does not account for regional differences in ERRs after THA and TKA. Regional factors likely confound Medicaid status's effect on readmission rates. (Journal of Surgical Orthopaedic Advances 32(1):005-008, 2023).

Pesticide Mixtures in Surface Waters of Two Protected Areas in Southwestern Germany.

Pesticides enter non-target surface waters as a result of agricultural activities and may reach water bodies in protected areas. We measured in southwestern Germany pesticide concentrations after heavy rainfalls in streams of a drinking water protection area near Hausen (Freiburg) and in the catchment of the Queich (Landau), which originates from the biosphere reserve Palatinate Forest. On average, 32 (n = 21) and 21 (n = 10) pesticides were detected per sample and event in the area of Hausen (n = 56) and in the Queich catchment (n = 17), respectively. The majority of pesticides detected in > 50% of all samples were fungicides, with fluopyram being detected throughout all samples. Aquatic invertebrates exhibited highest risks with 16.1% of samples exceeding mixture toxicity thresholds, whereas risks were lower for aquatic plants (12.9%) and fish (6.5%). Mixture toxicity threshold exceedances indicate adverse ecological effects to occur at half of sites (50%). This study illustrates the presence of pesticide mixtures and highlights ecological risks for aquatic organisms in surface waters of protected areas in Germany.

Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis.

BACKGROUND: Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test. METHODS: In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review. RESULTS: We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment. CONCLUSIONS: Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.).

Interaction of curcumin with a winter flounder alpha-helical antifreeze protein.

The winter flounder, Pseudopleuronectes americanus, synthesizes a variety of alpha-helical antifreeze proteins (AFPs) that adhere to ice and inhibit its growth. The best studied of these is AFP6, which is a 37-residue protein abundant in the flounder blood plasma during winter. Curcumin from the turmeric plant (Curcuma longa) was found to interact with AFP6 in aqueous solutions, resulting in measurable changes in the curcumin, but not in the protein. Specifically, the secondary structure and unfolding of synthetic AFP6, shown by circular dichroism, appeared to be unaffected by curcumin. In contrast, the peak absorbance of curcumin shifted and increased in the presence of AFP6, and the maximum fluorescence emission was greater and blue shifted. These results also suggested the possibility of AFP6 detection by curcumin fluorescence. Synthetic AFP6 did not interact with Coomassie blue, silver or a commercial fluorescent stain following electrophoresis; however, the change in curcumin fluorescence upon binding to electrophoresed AFP6 resulted in a fluorescent signal, which was also detected upon interaction with purified natural AFP and flounder blood plasma containing the protein. Thus, aqueous curcumin can be used for the direct detection of AFP6 and curcumin binding could provide new avenues for the study of this protein.

Goal-directed haemodynamic therapy during general anaesthesia for noncardiac surgery: a systematic review and meta-analysis.

BACKGROUND: During general anaesthesia for noncardiac surgery, there remain knowledge gaps regarding the effect of goal-directed haemodynamic therapy on patient-centred outcomes. METHODS: Included clinical trials investigated goal-directed haemodynamic therapy during general anaesthesia in adults undergoing noncardiac surgery and reported at least one patient-centred postoperative outcome. PubMed and Embase were searched for relevant articles on March 8, 2021. Two investigators performed abstract screening, full-text review, data extraction, and bias assessment. The primary outcomes were mortality and hospital length of stay, whereas 15 postoperative complications were included based on availability. From a main pool of comparable trials, meta-analyses were performed on trials with homogenous outcome definitions. Certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). RESULTS: The main pool consisted of 76 trials with intermediate risk of bias for most outcomes. Overall, goal-directed haemodynamic therapy might reduce mortality (odds ratio=0.84; 95% confidence interval [CI], 0.64 to 1.09) and shorten length of stay (mean difference=-0.72 days; 95% CI, -1.10 to -0.35) but with low certainty in the evidence. For both outcomes, larger effects favouring goal-directed haemodynamic therapy were seen in abdominal surgery, very high-risk surgery, and using targets based on preload variation by the respiratory cycle. However, formal tests for subgroup differences were not statistically significant. Goal-directed haemodynamic therapy decreased risk of several postoperative outcomes, but only infectious outcomes and anastomotic leakage reached moderate certainty of evidence. CONCLUSIONS: Goal-directed haemodynamic therapy during general anaesthesia might decrease mortality, hospital length of stay, and several postoperative complications. Only infectious postoperative complications and anastomotic leakage reached moderate certainty in the evidence.

Ventilation Strategies During General Anesthesia for Noncardiac Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: The optimal ventilation strategy during general anesthesia is unclear. This systematic review investigated the relationship between ventilation targets or strategies (eg, positive end-expiratory pressure [PEEP], tidal volume, and recruitment maneuvers) and postoperative outcomes. METHODS: PubMed and Embase were searched on March 8, 2021, for randomized trials investigating the effect of different respiratory targets or strategies on adults undergoing noncardiac surgery. Two investigators reviewed trials for relevance, extracted data, and assessed risk of bias. Meta-analyses were performed for relevant outcomes, and several subgroup analyses were conducted. The certainty of evidence was evaluated using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: This review included 63 trials with 65 comparisons. Risk of bias was intermediate for all trials. In the meta-analyses, lung-protective ventilation (ie, low tidal volume with PEEP) reduced the risk of combined pulmonary complications (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.28-0.49; 9 trials; 1106 patients), atelectasis (OR, 0.39; 95% CI, 0.25-0.60; 8 trials; 895 patients), and need for postoperative mechanical ventilation (OR, 0.36; 95% CI, 0.13-1.00; 5 trials; 636 patients). Recruitment maneuvers reduced the risk of atelectasis (OR, 0.44; 95% CI, 0.21-0.92; 5 trials; 328 patients). We found no clear effect of tidal volume, higher versus lower PEEP, or recruitment maneuvers on postoperative pulmonary complications when evaluated individually. For all comparisons across targets, no effect was found on mortality or hospital length of stay. No effect measure modifiers were found in subgroup analyses. The certainty of evidence was rated as very low, low, or moderate depending on the intervention and outcome. CONCLUSIONS: Although lung-protective ventilation results in a decrease in pulmonary complications, randomized clinical trials provide only limited evidence to guide specific ventilation strategies during general anesthesia for adults undergoing noncardiac surgery.

Fraction of inspired oxygen during general anesthesia for non-cardiac surgery: Systematic review and meta-analysis.

BACKGROUND: Controversy exists regarding the effects of a high versus a low intraoperative fraction of inspired oxygen (FiO2 ) in adults undergoing general anesthesia. This systematic review and meta-analysis investigated the effect of a high versus a low FiO2 on postoperative outcomes. METHODS: PubMed and Embase were searched on March 22, 2022 for randomized clinical trials investigating the effect of different FiO2 levels in adults undergoing general anesthesia for non-cardiac surgery. Two investigators independently reviewed studies for relevance, extracted data, and assessed risk of bias. Meta-analyses were performed for relevant outcomes, and potential effect measure modification was assessed in subgroup analyses and meta-regression. The evidence certainty was evaluated using GRADE. RESULTS: This review included 25 original trials investigating the effect of a high (mostly 80%) versus a low (mostly 30%) FiO2 . Risk of bias was intermediate for all trials. A high FiO2 did not result in a significant reduction in surgical site infections (OR: 0.91, 95% CI 0.81-1.02 [p = .10]). No effect was found for all other included outcomes, including mortality (OR = 1.27, 95% CI: 0.90-1.79 [p = .18]) and hospital length of stay (mean difference = 0.03 days, 95% CI -0.25 to 0.30 [p = .84). Results from subgroup analyses and meta-regression did not identify any clear effect modifiers across outcomes. The certainty of evidence (GRADE) was rated as low for most outcomes. CONCLUSIONS: In adults undergoing general anesthesia for non-cardiac surgery, a high FiO2 did not improve outcomes including surgical site infections, length of stay, or mortality. However, the certainty of the evidence was assessed as low.

A temporospatial histomorphometric analysis of bone density adjacent to acid-etched self-tapping dental implants with an external hexagon connection in the female baboon.

OBJECTIVE: To characterize osseointegration as the percent of bone-implant contact (%BIC) along the surface (0.0 mm) as well as at surface profiles 0.5 mm and 1.0 mm lateral to the implant, determining any differences between early occlusally loaded and non-loaded implants. MATERIAL AND METHODS: In ten adult female baboons, 120 dental implants were randomly placed in opposing mandibular and maxillary locations. Eighty sites had two groups of healing (no load) of either 1 (n = 40) or 2 (n = 40) months leading to 3 months of functional loading. These sites received full acid-etched surface implants. The 40 control implants represented healing only periods (no load) for 1 (n = 10), 2 (n = 10), 4 (n = 10), and 5 (n = 10) months. These implants were of a vertically split surface texture design (acid-etched and machined). Block sections and photomicrographs were obtained. Blinded histometric analyses determined the %BIC via a superimposed template. RESULTS: The unloaded groups (1, 2, and 4 months) had higher %BIC compared to the 5-month group (p < 0.0001). The loaded groups exhibited mean bone densities of 59.2% and 55.5% (1-month healing at 0.5 mm and 1.0 mm, respectively) and 61.0% and 57.1% (2-month healing at 0.5 mm and 1.0 mm, respectively) with no significant difference between healing time (p = 0.4118). CONCLUSION: There was a lateral increase in %BIC in the loaded compared to unloaded groups. CLINICAL RELEVANCE: The decrease in bone densities at the 5-month unloaded group suggests that there is a critical earlier time period when dental implants should be placed into functional load.

Spinal Fusion in Pediatric Patients With Low Bone Density: Defining the Value of DXA.

BACKGROUND: Children with medical complexity are at increased risk of low bone mineral density (BMD) and complications after spinal fusion compared with idiopathic scoliosis patients. Our aim was to compare treatments and outcomes of children with medical complexity undergoing spinal fusion in those who had dual-energy x-ray absorptiometry (DXA) scans versus those who did not in an effort to standardize the workup of these patients before undergoing spinal surgery. METHODS: We conducted a retrospective review of patients with low BMD who underwent spinal fusion at a tertiary care pediatric hospital between 2004 and 2016. We consulted with a pediatric endocrinologist to create standard definitions for low BMD to classify each subject. Regardless of DXA status, all patients were given a clinical diagnosis of osteoporosis [at least 2 long bone or 1 vertebral pathologic fracture(s)], osteopenia (stated on radiograph or by the physician), or clinically low bone density belonging to neither category. The last classification was used for patients whose clinicians had documented low bone density not meeting the criteria for osteoporosis or osteopenia. Fifty-nine patients met the criteria, and 314 were excluded for insufficient follow-up and/or not meeting a diagnosis definition. BMD Z -scores compare bone density ascertained by DXA to an age-matched and sex-matched average. Patients who had a DXA scan were also given a DXA diagnosis of low bone density (≤-2 SD), slightly low bone density (-1.0 to -1.9 SD), or neither (>-1.0 SD) based on the lowest BMD Z -score recorded. RESULTS: Fifty-nine patients were analyzed. Fifty-four percent had at least 1 DXA scan preoperatively. Eighty-one percent of DXA patients received some form of treatment compared with 52% of non-DXA patients ( P =0.03). CONCLUSIONS: Patients referred for DXA scans were more likely to be treated for low BMD, although there is no standardized system in place to determine which patients should get scans. Our research highlights the need to implement clinical protocols to optimize bone health preoperatively. LEVEL OF EVIDENCE: Level II-retrospective prognostic study.

Breaking Down Barriers: Easter Island's First Telestroke Thrombolysis Experience and Case Report.

Easter Island (Rapa Nui), Chile, is remote, located in the Polynesian Triangle in Oceania. The closest continental point is Chile, 3,512 km east. It has a population of 7,750 inhabitants, who are Chilean citizens, and receives more than 60,000 tourists a year. For this entire population, there is a medium complexity hospital without a neurology specialist. In 2019, local professionals were trained in a Telestroke program with remote clinical support conducted by neurologists located on mainland Chile. We present a 50-year-old native male, with unknown medical history, who suddenly presented right-half-body weakness and aphasia. He was evaluated via Telestroke consultation, and thrombolysis with tenecteplase was indicated. The patient improved rapidly and 45 min later the NIHSS score was 0 points. To our knowledge, this is the first reported case of Telestroke treatment in such a remote area, highlighting the importance of telemedicine to overcome geographical and technological stroke care barriers and to improve patients' outcome, no matter where they live.

Analyzing the Orthopaedic Surgery Personal Statement: Do Residency Applicants See Value in Its Use?

Orthopaedic surgery is one of the most competitive specialties in the residency match. The personal statement (PS) is one component of the application. The significance of the PS to orthopaedic surgery residency applicants is unknown. This study evaluates applicant perceptions of the PS. Applicants to two separate United States orthopaedic residency programs for the 2019-2020 cycle were invited to participate. Survey was distributed via email. Twenty-one percent (204/978) of applicants completed the survey. Most were men (157/204, 77%), and most (125/204, 61%) spent up to 15 hours writing their PS. Many [79.4% (162/204)] believed the PS should continue to be included in the application. Women always edited their PS, while 7.0% (11/ 157) of men did not use any editors. Applicants believe the PS is valuable. The PS is time consuming but allows applicants to communicate details that otherwise may not be included in their application. (Journal of Surgical Orthopaedic Advances 31(1):034-041, 2022).

Program Directors' Perception of the Role of Personal Statements in the Orthopaedic Surgery Residency Selection Process.

The purpose of this study was (1) to determine how much emphasis is placed on the Personal Statement (PS) by program directors (PDs) and (2) to gain a better understanding of what factors within the PS are considered most important to PDs. An anonymous survey was distributed to PDs at allopathic orthopaedic residency programs in the United States using Survey Monkey (San Mateo, CA). Survey responses were received from 51 of 152 (34%) PDs. Forty-five (88.2%) identified as male, five (9.8%) identified as female, and one (1.9%) chose not to disclose. PDs reported the PS was of average importance, with an average score of 2.82 (range,1-4). Although the PS is still given consideration as part of the overall orthopaedic surgery residency application process, it does not play a major role in determining which applicants will be invited for an interview or how they will be ranked. (Journal of Surgical Orthopaedic Advances 31(2):090-095, 2022).

Prophylactic Radiotherapy for Prevention of Heterotopic Ossification After Periacetabular Fractures: A Review of Efficacy and Associated Conditions.

Prophylactic radiotherapy (XRT) is a commonly used treatment to decrease heterotopic ossification (HO) in patients with traumatic hip injuries. We conducted a retrospective review of patients at risk for HO who underwent XRT. Of the patients reviewed, 27.3% developed radiographic HO, 11.2% developed symptoms, and 2.0% required resection surgery. Patients were divided into primary (n = 71) and secondary prophylaxis (n = 27) cohorts. In the primary group, 25.0% developed radiographic HO, 5.6% developed symptoms, and 0 required surgery. In the secondary cohort, 33.3% of patients developed new radiographic HO, and 25.9% were symptomatic: four had a Brooker score of 3, and three had a score of 4 (p = 0.03), and 7.4% required surgical resection. (Journal of Surgical Orthopaedic Advances 31(2):113-118, 2022).

Inflammasome Genetic Variants, Macrophage Function, and Clinical Outcomes in Cystic Fibrosis.

Cystic fibrosis (CF) is characterized by chronic airway infection, inflammation, and tissue damage that lead to progressive respiratory failure. NLRP3 and NLRC4 are cytoplasmic pattern recognition receptors that activate the inflammasome, initiating a caspase-1-mediated response. We hypothesized that gain-of-function inflammasome responses are associated with worse outcomes in children with CF. We genotyped nonsynonymous variants in NLRP3 and the NLRC4 pathway from individuals in the EPIC (Early Pseudomonas Infection Control) Observational Study cohort and tested for association with CF outcomes. We generated knockouts of NLRP3 and NLRC4 in human macrophage-like cells and rescued knockouts with wild-type or variant forms of NLRP3 and NLRC4. We identified a SNP in NLRP3, p.(Q705K), that was associated with a higher rate of P. aeruginosa colonization (N = 609; P = 0.01; hazard ratio, 2.3 [Cox model]) and worsened lung function over time as measured by forced expiratory volume in 1 second (N = 445; P = 0.001 [generalized estimating equation]). We identified a SNP in NLRC4, p.(A929S), that was associated with a lower rate of P. aeruginosa colonization as part of a composite of rare variants (N = 405; P = 0.045; hazard ratio, 0.68 [Cox model]) and that was individually associated with protection from lung function decline (P < 0.001 [generalized estimating equation]). Rescue of the NLRP3 knockout with the p.(Q705K) variant produced significantly more IL-1ß in response to NLRP3 stimulation than rescue with the wild type (P = 0.020 [Student's t test]). We identified a subset of children with CF at higher risk of early lung disease progression. Knowledge of these genetic modifiers could guide therapies targeting inflammasome pathways.

Treatment of adults with intracranial hemorrhage on apixaban or rivaroxaban with prothrombin complex concentrate products.

To analyze the efficacy and safety of activated prothrombin complex concentrates (aPCC) and four-factor prothrombin complex concentrates (4F-PCC) to prevent hematoma expansion in patients taking apixaban or rivaroxaban with intracranial hemorrhage (ICH). In this multicenter, retrospective study, sixty-seven ICH patients who received aPCC or 4F-PCC for known use of apixaban or rivaroxaban between February 2014 and September 2018 were included. The primary outcome was the percentage of patients who achieved excellent/good or poor hemostasis after administration of aPCC or 4F-PCC. Secondary outcomes included hospital mortality, thromboembolic events during admission, and transfusion requirements. Excellent/good hemostasis was achieved in 87% of aPCC patients, 89% of low-dose 4F-PCC [< 30 units per kilogram (kg)], and 89% of high-dose 4F-PCC (≥ 30 units per kg). There were no significant differences in excellent/good or poor hemostatic efficacy (p = 0.362). No differences were identified in transfusions 6 h prior (p = 0.087) or 12 h after (p = 0.178) the reversal agent. Mortality occurred in five patients, with no differences among the groups (p = 0.838). There were no inpatient thromboembolic events. Both aPCC and 4F-PCC appear safe and equally associated with hematoma stability in patients taking apixaban or rivaroxaban who present with ICH. Prospective studies are needed to identify a superior reversal agent when comparing andexanet alfa to hospital standard of care (4F-PCC or aPCC) and to further explore the optimal dosing strategy for patients with ICH associated with apixaban or rivaroxaban use.