Physical Activity and Progression of Coronary Artery Calcification in Men and Women.

Importance: Prior cross-sectional studies have suggested that very high levels of physical activity (PA) are associated with a higher prevalence of coronary artery calcium (CAC). However, less is known regarding the association between high-volume PA and progression of CAC over time. Objective: To explore the association between PA (measured at baseline and during follow-up) and the progression of CAC over time. Design, Setting, and Participants: This cohort study included data from 8771 apparently healthy men and women 40 years and older who had multiple preventive medicine visits at the Cooper Clinic (Dallas, Texas), with a mean (SD) follow-up time of 7.8 (4.7) years between the first and last clinic visit. Participants with reported PA and CAC measurements at each visit during 1998 to 2019 were included in the study. Data were analyzed from March 2023 to February 2024. Exposures: PA reported at baseline and follow-up, examined continuously per 500 metabolic equivalent of task minutes per week (MET-min/wk) and categorically: less than 1500, 1500 to 2999, 3000 or more MET-min/wk. Main Outcomes and Measures: Negative binomial regression was used to estimate the rate of mean CAC progression between visits, with potential modification by PA volume, calculated as the mean of PA at baseline and follow-up. In addition, proportional hazards regression was used to estimate hazard ratios for baseline PA as a predictor of CAC progression to 100 or more Agatston units (AU). Results: Among 8771 participants, the mean (SD) age at baseline was 50.2 (7.3) years for men and 51.1 (7.3) years for women. The rate of mean CAC progression per year from baseline was 28.5% in men and 32.1% in women, independent of mean PA during the same time period. That is, the difference in the rate of CAC progression per year was 0.0% per 500 MET-min/wk for men and women (men: 95% CI, -0.1% to 0.1%; women: 95% CI, -0.4% to 0.5%). Moreover, baseline PA was not associated with CAC progression to a clinically meaningful threshold of 100 AU or more over the follow-up period. The hazard ratio for a baseline PA value of 3000 or more MET-min/wk vs less than 1500 MET-min/wk to cross this threshold was 0.84 (95% CI, 0.66 to 1.08) in men and 1.16 (95% CI, 0.57 to 2.35) in women. Conclusions and Relevance: This study found that PA volume was not associated with progression of CAC in a large cohort of healthy men and women who were initially free of overt cardiovascular disease.

Structural and Dynamic Features of Acinetobacter baumannii OXA-66 ß-Lactamase Explain Its Stability and Evolution of Novel Variants.

OXA-66 is a member of the OXA-51 subfamily of class D ß-lactamases native to the Acinetobacter genus that includes Acinetobacter baumannii, one of the ESKAPE pathogens and a major cause of drug-resistant nosocomial infections. Although both wild type OXA-66 and OXA-51 have low catalytic activity, they are ubiquitous in the Acinetobacter genomes. OXA-51 is also remarkably thermostable. In addition, newly emerging, single and double amino acid variants show increased activity against carbapenems, indicating that the OXA-51 subfamily is growing and gaining clinical significance. In this study, we used molecular dynamics simulations, X-ray crystallography, and thermal denaturation data to examine and compare the dynamics of OXA-66 wt and its gain-of-function variants: I129L (OXA-83), L167V (OXA-82), P130Q (OXA-109), P130A, and W222L (OXA-234). Our data indicate that OXA-66 wt also has a high melting temperature, and its remarkable stability is due to an extensive and rigid hydrophobic bridge formed by a number of residues around the active site and harbored by the three loops, P, Ω, and ß5-ß6. Compared to the WT enzyme, the mutants exhibit higher flexibility only in the loop regions, and are more stable than other robust carbapenemases, such as OXA-23 and OXA-24/40. All the mutants show increased rotational flexibility of residues I129 and W222, which allows carbapenems to bind. Overall, our data support the hypothesis that structural features in OXA-51 and OXA-66 promote evolution of multiple highly stable variants with increased clinical relevance in A. baumannii.

Coronary Artery Calcification and High-Volume Physical Activity: Role of Lower Intensity versus Longer Duration of Exercise.

AIM: While high-volume physical activity (PA) has been linked to elevated coronary artery calcification (CAC), the role of intensity versus duration of PA has not been investigated. The purpose of the study was to examine the role of intensity versus duration of PA in relation to CAC. METHODS: Data are from 23,383 apparently healthy men who completed a PA questionnaire and underwent CAC scanning as part of a preventive exam. Self-reported PA was categorized into 4 groups of average intensity and weekly duration of PA and (average intensity: 1, 3-5.9, 6-8.9, and 9-12 metabolic equivalents of task [METs]; weekly duration: 0, > 0-<2, 2-<5, and ≥5 hours/week). Mean CAC and CAC ≥ 100 Agatston Units (AU) were regressed separately on continuous or categorical average intensity and weekly duration of PA. RESULTS: The mean and standard deviation (SD) age was 51.7 (8.3) years, and mean CAC was 174.8 (543.6) AU with 23.5% of men presenting with CAC ≥ 100 AU. Higher average intensity of PA was related to lower mean CAC (-3.1%/MET, 95% confidence interval [CI]: -4.6, -1.6%/MET) and lower relative risk (RR) of CAC ≥ 100 AU (RR: 0.99, 95% CI: 0.98, 1.00/MET). Opposite trend was observed for the duration component wherein higher weekly duration of PA was significantly associated with greater mean CAC and RR of CAC ≥ 100 AU. CONCLUSIONS: Elevated CAC was associated with lower average intensity and longer duration of PA in men, providing new insight into the complex relationship between leisure-time PA behaviors and risk of CAC.

Does greater extent of coronary artery calcification observed at high volumes of leisure time physical activity relate more to the intensity or the duration of the activity? Higher average intensity of activity is associated with less coronary artery calcification at any age and weekly duration of activity.Higher weekly duration of activity is associated with more coronary artery calcification at any age and average intensity of activity.

The Nuances of Hand Transplantation After Sepsis.

Vascularized composite allotransplantation (VCA) of the upper extremity is an established restorative procedure for selected patients with acquired upper limb loss. The majority of upper limb VCAs performed worldwide have been for victims of various forms of trauma. However, in the developed world, amputation following severe sepsis seems to be an increasingly common indication for referral to hand transplant programs. Unlike trauma patients with isolated limb injuries, patients with amputations as a complication of sepsis have survived through a state of global tissue hypoperfusion and multisystem organ failure with severe, enduring effects on the entire body's physiology. This article reviews the unique considerations for VCA candidacy in postsepsis patients with upper limb amputation. These insights may also be relevant to postsepsis patients undergoing other forms of transplantation or to VCA patients requiring additional future solid organ transplants.

Independent and joint associations of cardiorespiratory fitness and BMI with dementia risk: the Cooper Center Longitudinal Study.

OBJECTIVE: This study aimed to examine the association of midlife fitness and body mass index (BMI) with incident dementia later in life. DESIGN AND PARTICIPANTS: A cohort study of 6428 individuals (mean age 50.9±7.6 years) from the Cooper Center Longitudinal Study. MEASURES: Cardiorespiratory fitness and BMI were assessed twice (1970-1999) during visits to the Cooper Clinic, a preventive medicine clinic in Dallas, Texas. These measures were examined as continuous and categorical variables. As continuous variables, fitness and BMI were examined at baseline (averaged of two examinations) and as absolute change between exams (mean time 2.1±1.8 years). Variables were categorised: unfit versus fit and normal versus overweight/obese. Medicare claims data were used to obtain all-cause dementia incidence (1999-2009). Mean follow-up between midlife examinations and Medicare surveillance was 15.7 ((SD=6.2) years. Multivariable models were used to assess the associations between fitness, BMI and dementia. RESULTS: During 40 773 person years of Medicare surveillance, 632 cases of dementia were identified. After controlling for BMI and covariates, each 1-metabolic equivalent increment in fitness was associated with 5% lower (HR 0.95; 95% CI 0.90 to 0.99) dementia risk. In comparison, after controlling for fitness and covariates, each 1 kg/m2 increment in BMI was associated with a 3.0% (HR 1.03; 95% CI 1.00 to 1.07) higher risk for dementia, yet without significance (p=0.051). Similar findings were observed when the exposures were categorised. Changes in fitness and BMI between examinations were not related to dementia. Jointly, participants who were unfit and overweight/obese had the highest (HR 2.28 95% CI 1.57 to 3.32) dementia risk compared with their fit and normal weight counterparts. CONCLUSION: Lower midlife fitness is a risk marker for dementia irrespective of weight status. Being unfit coupled with overweight/obese status might increase one's risk for dementia even further.

Association between baseline levels of muscular strength and risk of stroke in later life: The Cooper Center Longitudinal Study.

PURPOSE: Muscular strength is an important component of physical fitness. We evaluated the relationship between baseline muscular strength and risk of stroke among adults who were aged ≥65 years during follow-up. METHODS: We included 7627 healthy adults (mean age = 43.9 years, 86.0% male) underwent a baseline physical examination between 1980 and 1989. Muscular strength was determined by 1-repetition maximum measures for bench press and leg press and categorized into age- and sex-specific tertiles for each measure. Cardiorespiratory fitness (CRF) was assessed via a maximal treadmill exercise test. Those enrolled in fee-for-service Medicare from 1999 to 2019 were included in the analyses. Associations between baseline strength and stroke outcomes were estimated using a modified Cox proportional hazards model. In a secondary analysis, we examined stroke risk by categories of CRF where Quintile 1 = low, Quintiles 2-3 = moderate, and Quintiles 4-5 = high CRF based on age and sex. RESULTS: After 70,072 person-years of Medicare follow-up, there were 1211 earliest indications of incident stroke. In multivariable analyses, the hazard ratio (95% confidence interval (95%CI)) for stroke across bench press categories were 1.0 (referent), 0.96 (0.83-1.11), and 0.89 (0.77-1.04), respectively (p trend = 0.14). The trend across categories of leg press was also non-significant (p trend = 0.79). Adjusted hazard ratio (95%CI) for stroke across ordered CRF categories were 1.0 (referent), 0.90 (0.71-1.13), and 0.72 (0.57-0.92) (p trend < 0.01). CONCLUSION: While meeting public health guidelines for muscular strengthening activities is likely to improve muscular strength as well as many health outcomes in older adults, performing such activities may not be helpful in preventing stroke. Conversely, meeting guidelines for aerobic activity is likely to improve CRF and lower stroke risk.

Automated production of gene-modified chimeric antigen receptor T cells using the Cocoon Platform.

Autologous cell-based therapeutics have gained increasing attention in recent years because of their efficacy at treating diseases with limited therapeutic options. Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical success in hematologic oncology indications, providing critically ill patients with a potentially curative therapy. Although engineered cell therapies such as CAR T cells provide new options for patients with unmet needs, the high cost and complexity of manufacturing may hinder clinical and commercial translation. The Cocoon Platform (Lonza, Basel, Switzerland) addresses many challenges, such as high labor demand, process consistency, contamination risks and scalability, by enabling efficient, functionally closed and automated production, whether at clinical or commercial scale. This platform is customizable and easy to use and requires minimal operator interaction, thereby decreasing process variability. We present two processes that demonstrate the Cocoon Platform's capabilities. We employed different T-cell activation methods-OKT3 and CD3/CD28 Dynabeads (Thermo Fisher Scientific, Waltham, MA, USA)-to generate final cellular products that meet the critical quality attributes of a clinical autologous CAR T-cell product. This study demonstrates a manufacturing solution for addressing challenges with manual methods of production and facilitating the scale-up of autologous cell therapy.

Omega-3 index, cardiorespiratory fitness, and cognitive function in mid-age and older adults.

Higher levels of omega-3 fatty acids in red blood cell membranes (omega-3 index or O3I) and cardiorespiratory fitness (CRF) are each associated with reduced cognitive impairment, but little research has examined the relationship between O3I and cognitive function while accounting for CRF. We analyzed cross-sectional data from 5,464 healthy men and women aged 55-85 years who had preventive medical examinations between 2009 and 2023. Primary exposures included O3I (<4.0%, 4.0-7.9%, or ≥ 8.0%) and age- and sex-based CRF quintile (1 = low, 2-3 = moderate, 4-5 = high). Cognitive impairment was defined as a Montreal Cognitive Assessment score of ≤ 25. We used Poisson regression to estimate relative risks (RR) of cognitive impairment, controlling for covariates. O3I < 4% was associated with increased cognitive impairment relative to ≥ 8.0% (RR, 1.21; 95% CI, 1.01-1.44) in a partially adjusted model. This association did not remain statistically significant in the fully adjusted model which included CRF. Low versus high CRF was associated with cognitive impairment (RR, 1.28; 95% CI, 1.07-1.53), independent of O3I and clinical biomarkers. The interaction between CRF and O3I was not significant (P = 0.8). In joint association analysis, risk of cognitive impairment was elevated with lower omega-3 index or CRF or both. Additional research is needed to fully understand the association between O3I and cognitive function at varying CRF levels.

Sulfonamidoboronic Acids as "Cross-Class" Inhibitors of an Expanded-Spectrum Class C Cephalosporinase, ADC-33, and a Class D Carbapenemase, OXA-24/40: Strategic Compound Design to Combat Resistance in Acinetobacter baumannii.

Acinetobacter baumannii is a Gram-negative organism listed as an urgent threat pathogen by the World Health Organization (WHO). Carbapenem-resistant A. baumannii (CRAB), especially, present therapeutic challenges due to complex mechanisms of resistance to ß-lactams. One of the most important mechanisms is the production of ß-lactamase enzymes capable of hydrolyzing ß-lactam antibiotics. Co-expression of multiple classes of ß-lactamases is present in CRAB; therefore, the design and synthesis of "cross-class" inhibitors is an important strategy to preserve the efficacy of currently available antibiotics. To identify new, nonclassical ß-lactamase inhibitors, we previously identified a sulfonamidomethaneboronic acid CR167 active against Acinetobacter-derived class C ß-lactamases (ADC-7). The compound demonstrated affinity for ADC-7 with a Ki = 160 nM and proved to be able to decrease MIC values of ceftazidime and cefotaxime in different bacterial strains. Herein, we describe the activity of CR167 against other ß-lactamases in A. baumannii: the cefepime-hydrolysing class C extended-spectrum ß-lactamase (ESAC) ADC-33 and the carbapenem-hydrolyzing OXA-24/40 (class D). These investigations demonstrate CR167 as a valuable cross-class (C and D) inhibitor, and the paper describes our attempts to further improve its activity. Five chiral analogues of CR167 were rationally designed and synthesized. The structures of OXA-24/40 and ADC-33 in complex with CR167 and select chiral analogues were obtained. The structure activity relationships (SARs) are highlighted, offering insights into the main determinants for cross-class C/D inhibitors and impetus for novel drug design.

Cardiorespiratory Fitness and All-Cause Mortality in Women with Metabolic Syndrome.

Purpose: To examine the association between cardiorespiratory fitness (fitness) and all-cause mortality in women with metabolic syndrome (MetSyn). Methods: The sample included 1798 women with MetSyn (mean age 50.2 years) who received a comprehensive preventive baseline examination between 1978 and 2016, with mortality follow-up through December 31, 2017. MetSyn was identified using Adult Treatment Panel-III Guidelines. Fitness was determined by duration of a maximal treadmill exercise test and grouped as fit or unfit on the basis of the upper 80% and lower 20% of the age-standardized fitness distribution. Age- and smoking-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated in a proportional hazards regression model. Results: During a mean follow-up of 16.6 ± 8.7 years, 204 deaths occurred. Crude all-cause mortality rates were 6.8 and 6.9 deaths per 10,000 woman-years in fit and unfit groups, respectively. The adjusted HR (95% CI) for all-cause mortality in unfit versus fit women (referent) with MetSyn was 1.36 (95% CI 1.01-1.83). Conclusions: Higher levels of fitness significantly attenuate the risk of all-cause mortality in women with MetSyn. In accordance with the American Heart Association scientific statement, to more accurately determine mortality risk in this population, health care professionals should measure or estimate fitness and should strongly encourage women to meet current public health guidelines for physical activity with the goal of reaching higher fitness levels.

Associations among cardiorespiratory fitness, C-reactive protein, and all-cause mortality in men and women.

We examined individual and joint associations among high-sensitivity C-reactive protein (CRP), cardiorespiratory fitness (fitness), and mortality in healthy men and women. Between January 1, 2000 and December 31, 2016, 30,077 adults (31.3% women) received a comprehensive physical examination. Fitness was determined from maximal treadmill exercise test duration. Participants were categorized as unfit (Quintile 1) and fit (Quintiles 2-5), and by normal (<2 mg/L) and elevated (≥2 mg/L) CRP categories. Adjusted hazard ratios (HRs) with 95% confidence interval (CI) for all-cause mortality were computed with Cox regression. During an average of 10.1 years of follow-up, 576 deaths occurred. Following adjustment for age, smoking status, sex, exam year, body mass index, systolic blood pressure, total cholesterol, triglyceride:high-density lipoprotein ratio, and fasting glucose, HR (95% CI) for all-cause mortality were 1.0 (referent) and 1.52 (1.14-2.02) for fit and unfit categories, respectively. Corresponding values for normal and elevated CRP categories were 1.0 and 1.50 (1.20-1.89), respectively. When grouped by fitness and CRP category, there was significantly greater mortality risk in the unfit than the fit category within the elevated CRP category (HR = 1.77 (1.14-2.75)), but not in the normal CRP category (HR = 1.38 (0.96-1.98)). Each 1 metabolic equivalent increment in fitness and 1 mg/L increment in CRP were associated with 10.0% (95% CI: 5.1-14.8%) decreased and 7.3% (95% CI: 2.0%-12.9%) increased mortality hazard, respectively. Compared to the unfit, fit individuals have an attenuated mortality risk within each CRP category. Thus, higher fitness appears to provide some protection against all-cause mortality, particularly among those with elevated levels of inflammation.

Hand transplantation: can we balance the risks and benefits?

Asking 'can we balance the risks and benefits?' implies that a quantification of both risk and benefit in hand transplantation (here the terms hand transplant and hand transplantation refer to allotransplantation of the human hand or hand and part or all of the upper limb or limbs) is possible. Despite all we have learned in recent years about hand transplantation, much remains unknown. Even if reliable methods for quantification of risk and benefit were available, fundamental issues relating to effective communication across the gulf of lived experience between the (presumably) handed surgeon and the handless patient remain. Inherent complexities mean some consider hand transplantation an unsolved problem, but we believe the medical and technical considerations fall within the ambit of a competent multidisciplinary team, and that psychosocial and ethical challenges are open to management through robust frameworks for assessment and decision making, underpinned by an extended period of assessment and dialogue, with candid acknowledgement where uncertainty remains. This respects the patient's autonomy while addressing the need for a prolonged period of informing consent.Level of evidence: V.

Pandemic-Related Life Events and Physical Inactivity During COVID-19 Among Israeli Adults: The Smoking and Lifestyles in Israel Study.

BACKGROUND: Public health measures to contain the COVID-19 pandemic have led to disruptions in daily life, such as job loss and changes in activity. The present study examines the relationship between pandemic-related life events and disuse (prolonged sitting coupled with inactivity) among adults. METHODS: A cross-sectional study of 4084 adults in Israel (September 2020). The primary independent variables were pandemic-related life events, such as job loss. The primary dependent variable was disuse as measured by the Rapid Assessment Disuse Index (RADI). The RADI was examined continuously and dichotomously as a low RADI score (<26: yes/no). RESULTS: Linear regression indicated that experiencing a major life event during the pandemic was associated with lower RADI scores (-1.04; 95% confidence interval, -1.48 to -0.61). Similarly, logistic regression revealed that those experiencing a major life event had 1.18 (95% confidence interval, 1.03 to 1.34) times greater odds for low RADI scores in comparison to those not experiencing an event. CONCLUSIONS: Experiencing pandemic-related major life events was linked to less sitting time and increased activity levels among Israeli adults. Future research should examine underlying mechanisms explaining this relationship to facilitate the design and implementation of targeted interventions.

Cardiorespiratory fitness and depression symptoms among adults during the COVID-19 Pandemic: Cooper Center Longitudinal Study.

This study examined the relation between cardiorespiratory fitness (fitness) and depression symptoms prior to and during COVID-19 among adults seeking preventive medical care. Participants consisted of 967 patients attending the Cooper Clinic (Dallas, TX) pre-pandemic (March 2018-December 2019) and during the pandemic (March-December 2020). The outcome, depression symptoms, was based on the Center for Epidemiological Studies-Depression (CES-D). Maximal metabolic equivalents task (MET) levels for fitness were determined from the final treadmill speed and grade. Multiple linear regression models were computed by sex. Analysis revealed that mean fitness decreased from 11.4 METs (SD = 2.1) prior to the pandemic to 10.9 METs (SD = 2.3) during the pandemic (p-value < 0.001). The mean CES-D score increased from 2.8 (SD = 3.1) before to pandemic to 3.1 (SD = 3.2) during the pandemic (p-value = 0.003). Results from multiple linear regression indicate that increased fitness was associated with a statistically significant decrease in depression scores in men (-0.17 per MET; 95% CI -0.33, -0.02) but not women. This modest decrease may have been tempered by high fitness levels and low depression scores at baseline in this well-educated sample.

Examining the Gradient of All-Cause Mortality Risk in Women across the Cardiorespiratory Fitness Continuum.

PURPOSE: Although cardiorespiratory fitness (CRF) is inversely associated with all-cause mortality in women, less is known regarding the gradient of mortality risk in women, particularly at the lower end of the CRF continuum. METHODS: A total of 17,901 healthy women (mean age, 45.9 yr) completed a baseline clinical examination, including a maximal treadmill exercise test at the Cooper Clinic in Dallas, TX, between 1971 and 2016. Participants were placed into CRF quintiles based on age and treadmill time. RESULTS: After a mean follow-up period of 17.9 yr, 1198 all-cause deaths occurred. More favorable cardiometabolic risk factors, smoking status, and physical activity levels were observed across ordered CRF quintiles ( P < 0.001 for all). Adjusted all-cause mortality hazard ratios with 95% confidence intervals were 1.71 (1.40-2.09), 1.55 (1.29-1.87), 1.25 (1.03-1.51), 1.16 (0.97-1.38), and 1.0 (referent), respectively, across CRF quintiles ( P trend ≤ 0.001). When utilizing CRF as a continuous variable in a spline analysis and using 4.5 METs as the referent, we estimate a 10% reduction in mortality risk per 1-MET increment in CRF ( P < 0.001) until a threshold of approximately 11 METs. Mortality risk was approximately 50% lower at the 11-MET threshold when compared with the referent. No further significant reduction in mortality risk was observed beyond the 11-MET threshold. In addition, age-adjusted hemodynamic variables including resting and maximal double product, heart rate reserve, double-product reserve, and 1-min recovery heart rate were more favorable across CRF quintiles ( P < 0.001 for all). CONCLUSIONS: Beginning at a referent value of 4.5 METs, a significant decreasing gradient of all-cause mortality exists across the CRF continuum, until a threshold of approximately 11 METs is reached. Although all women should be encouraged to work toward meeting public health guidelines for physical activity, it is especially important to target those at the low end of the CRF continuum.

Long-term Cardiovascular Risk in Astronauts: Comparing NASA Mission Astronauts With a Healthy Cohort From the Cooper Center Longitudinal Study.

OBJECTIVE: To determine the long-term cardiovascular disease risk of astronauts with spaceflight exposure compared with a well-matched cohort. METHODS: National Aeronautics and Space Administration (NASA) astronauts are selected into their profession based upon education, unique skills, and health and are exposed to cardiovascular disease risk factors during spaceflight. The Cooper Center Longitudinal Study (CCLS) is a generally healthy cohort from a preventive medicine clinic in Dallas, Texas. Using a matched cohort design, astronauts who were selected beginning April 1, 1959, (and each subsequent selection class through 2009) and exposed to spaceflight were matched to CCLS participants who met astronaut selection criteria; 1514 CCLS participants matched to 303 astronauts in a 5-to-1 ratio on sex, date of birth, and age. The outcome of cardiovascular mortality through December 31, 2016, was determined by death certificate or National Death Index. RESULTS: There were 11 deaths caused by cardiovascular disease (CVD) among astronauts and 46 among CCLS participants. There was no evidence of increased mortality risk in astronauts (hazard ratio [HR]=1.10; 95% confidence interval [CI], 0.50 to 2.45) with adjustment for baseline cardiovascular covariates. However, the secondary outcome of CVD events showed an increased adjusted risk in astronauts (HR=2.41; 95% CI, 1.26 to 4.63). CONCLUSION: No increased risk of CVD mortality was observed in astronauts with spaceflight exposure compared with a well-matched cohort, but there was evidence of increased total CVD events. Given that the duration of spaceflight will increase, particularly on missions to Mars, continued surveillance and mitigation of CVD risk is needed to ensure the safety of those who venture into space.

Conformational flexibility in carbapenem hydrolysis drives substrate specificity of the class D carbapenemase OXA-24/40.

The evolution of multidrug resistance in Acinetobacter spp. increases the risk of our best antibiotics losing their efficacy. From a clinical perspective, the carbapenem-hydrolyzing class D ß-lactamase subfamily present in Acinetobacter spp. is particularly concerning because of its ability to confer resistance to carbapenems. The kinetic profiles of class D ß-lactamases exhibit variability in carbapenem hydrolysis, suggesting functional differences. To better understand the structure-function relationship between the carbapenem-hydrolyzing class D ß-lactamase OXA-24/40 found in Acinetobacter baumannii and carbapenem substrates, we analyzed steady-state kinetics with the carbapenem antibiotics meropenem and ertapenem and determined the structures of complexes of OXA-24/40 bound to imipenem, meropenem, doripenem, and ertapenem, as well as the expanded-spectrum cephalosporin cefotaxime, using X-ray crystallography. We show that OXA-24/40 exhibits a preference for ertapenem compared with meropenem, imipenem, and doripenem, with an increase in catalytic efficiency of up to fourfold. We suggest that superposition of the nine OXA-24/40 complexes will better inform future inhibitor design efforts by providing insight into the complicated and varying ways in which carbapenems are selected and bound by class D ß-lactamases.

Frontal Balloon Sinuplasty in Complicated Acute Pediatric Rhinosinusitis (ARS).

Utilization of frontal balloon sinuplasty in pediatric complicated acute rhinosinusitis (ARS) is demonstrated to be a safe and expedient alternative to other procedures such as trephination or functional endoscopic sinus surgery (FESS) in this case series. We performed a retrospective review of six pediatric cases of frontal balloon sinuplasty for ARS with intracranial complications at a tertiary academic center. Patients underwent unilateral (n = 5) or bilateral dilation (n = 1) in addition to functional endoscopic sinus surgery (FESS) including anterior ethmoidectomy (n = 5) and maxillary antrostomy (n = 6). This technique effectively addressed frontal sinus obstruction and served as an alternative to procedures such as trephination or functional endoscopic sinus surgery. No immediate or short-term complications of balloon dilation were observed in these cases. A larger cohort and extended follow-up are necessary to determine the use and long-term impact of this technique.