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Background: Frailty is a prevalent state associated with several aging-related traits and conditions. The relationship between frailty and stroke remains understudied. Here we aim to investigate whether the hospital frailty risk score (HFRS) is associated with the risk of stroke and determine whether a significant association between genetically determined frailty and stroke exists. Design: Observational study using data from All of Us research program and Mendelian Randomization analyses. Methods: Participants from All of Us with available electronic health records were selected for analysis. All of Us began national enrollment in 2018 and is expected to continue for at least 10 years. All of Us is recruiting members of groups that have traditionally been underrepresented in research. All participants provided informed consent at the time of enrollment, and the date of consent was recorded for each participant. Incident stroke was defined as stroke event happening on or after the date of consent to the All of Us study HFRS was measured with a 3-year look-back period before the date of consent for stroke risk. The HFRS was stratified into 4 categories: no-frailty (HFRS=0), low (HFRS ≥1 and Results: Two hundred fifty-three thousand two hundred twenty-six participants were at risk of stroke. In multivariable analyses, frailty status was significantly associated with risk of any (ischemic or hemorrhagic) stroke following a dose-response way: not-frail versus low HFRS (HR, 4.9 [CI, 3.5–6.8]; P P P P value for all comparisons P =0.002). Conclusions: Frailty, based on the HFRS was associated with higher risk of any stroke. Mendelian Randomization analyses confirmed this association providing evidence to support a causal relationship.

Background Comorbidities among cancer survivors remain a serious healthcare burden and require appropriate management. Using two widely used frailty indicators, this study aimed to evaluate whether frailty was associated with the incidence risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) among long-term cancer survivors. Methods We included 13,388 long-term cancer survivors (diagnosed with cancer over 5 years before enrolment) free of CVD and 6101 long-term cancer survivors free of T2DM, at the time of recruitment (aged 40–69 years), from the UK Biobank. Frailty was assessed by the frailty phenotype (FP_Frailty, range: 0–5) and the frailty index (FI_Frailty, range: 0–1) at baseline. The incident CVD and T2DM were ascertained through linked hospital data and primary care data, respectively. The associations were examined using Cox proportional hazards regression models. Results Compared with non-frail participants, those with pre-frailty (FP_Frailty [met 1–2 of the components]: hazard ratio [HR]=1.18, 95% confidence interval [CI]: 1.05, 1.32; FI_Frailty [0.10< FI ≤0.21]: HR=1.51, 95% CI: 1.32, 1.74) and frailty (FP_Frailty [met ≥3 of the components]: HR=2.12, 95% CI: 1.73, 2.60; FI_Frailty [FI >0.21]: HR=2.19, 95% CI: 1.85, 2.59) had a significantly higher risk of CVD in the multivariable-adjusted model. A similar association of FI_Frailty with the risk of incident T2DM was observed. We failed to find such an association for FP_Frailty. Notably, the very early stage of frailty (1 for FP_Frailty and 0.1-0.2 for FI_Frailty) was also positively associated with the risk of CVD and T2DM (FI_Frailty only). A series of sensitivity analyses confirmed the robustness of the findings. Conclusions Frailty, even in the very early stage, was positively associated with the incidence risk of CVD and T2DM among long-term cancer survivors, although discrepancies existed between frailty indicators. While the validation of these findings is required, they suggest that routine monitoring, prevention, and interventive programs of frailty among cancer survivors may help to prevent late comorbidities and, eventually, improve their quality of life. Especially, interventions are recommended to target those at an early stage of frailty when healthcare resources are limited.

Objective Evaluate the in vivo efficacy and resistance prevention of cefiderocol in combination with ceftazidime/avibactam, ampicillin/sulbactam and meropenem using human-simulated regimens (HSR) in the murine infection model. Methods In total, 15 clinical A. baumannii were assessed: cefiderocol MICs, 2 mg/L (previously developed resistance on therapy), n = 3; 8 mg/L, n = 2; ≥32 mg/L, n = 10 (including VEB and PER-harbouring isolates). Mice received inactive control, cefiderocol, cefiderocol + ceftazidime/avibactam (C-CZA), cefiderocol + ampicillin/sulbactam (C-SAM) or cefiderocol + meropenem (C-MEM) HSRs. The mean change in log10 cfu/thigh compared with starting inoculum was assessed. Resistance development on treatment was a >4-fold increase in MIC relative control animals. In vitro activities of combinations were assessed by disc stacking. Results Against cefiderocol-non-susceptible isolates, combinations produced significant kill with C-CZA −3.75 ± 0.37 reduction in log10 cfu/thigh, C-SAM produced −3.55 ± 0.50 and C-MEM produced −2.18 ± 1.75 relative to baseline. Elevated MICs in cefiderocol treated animals occurred in three out of three isolates with MICs of 2 mg/L. Of these isolates, one developed elevated MICs with C-MEM compared with none treated with C-CZA or C-SAM. Disc stacking with C-CZA or C-SAM returned all isolates to at least the CLSI intermediate breakpoint, which may correlate with in vivo efficacy. Conclusions Against cefiderocol-non-susceptible isolates, cefiderocol + ceftazidime/avibactam or ampicillin/sulbactam HSR produced in vivo kill against all 12 cefiderocol-non-susceptible isolates. Cefiderocol with ceftazidime/avibactam or ampicillin/sulbactam prevented the development of resistance during treatment against cefiderocol-high-end-susceptible isolates with a propensity for resistance on therapy. These data support the clinical evaluation of cefiderocol with ceftazidime/avibactam or ampicillin/sulbactam against A. baumannii, including multi-drug-resistant isolates.

Background Early detection of mobility decline is critical to prevent subsequent reductions in quality of life, disability, and mortality. However, traditional approaches to mobility assessment are limited in their ability to capture daily fluctuations that align with sporadic health events. We aim to describe findings from a pilot study of our Real-time Online Assessment and Mobility Monitor (ROAMM) smartwatch application, which uniquely captures multiple streams of data in real time in ecological settings. Methods Data come from a sample of 31 participants (Mage = 74.7, 51.6% female) who used ROAMM for approximately 2 weeks. We describe the usability and feasibility of ROAMM, summarize prompt data using descriptive metrics, and compare prompt data with traditional survey-based questionnaires or other established measures. Results Participants were satisfied with ROAMM’s function (87.1%) and ranked the usability as “above average.” Most were highly engaged (average adjusted compliance = 70.7%) and the majority reported being “likely” to enroll in a 2-year study (77.4%). Some smartwatch features were correlated with their respective traditional measurements (eg, certain GPS-derived life-space mobility features (r = 0.50–0.51, p < .05) and ecologically measured pain (r = 0.72, p = .01), but others were not (eg, ecologically measured fatigue). Conclusions ROAMM was usable, acceptable, and effective at measuring mobility and risk factors for mobility decline in our pilot sample. Additional work with a larger and more diverse sample is necessary to confirm associations between smartwatch-measured features and traditional measures. By monitoring multiple data streams simultaneously in ecological settings, this technology could uniquely contribute to the evolution of mobility measurement and risk factors for mobility loss.

BackgroundTwo of the three recently approved β-lactam agent (BL)/β-lactamase inhibitor (BLI) combinations have higher CLSI susceptibility breakpoints (ceftazidime/avibactam 8 mg/L; meropenem/vaborbactam 4 mg/L) compared with the BL alone (ceftazidime 4 mg/L; meropenem 1 mg/L). This can lead to a therapeutic grey area on susceptibility reports depending on resistance mechanism. For instance, a meropenem-resistant OXA-48 isolate (MIC 4 mg/L) may appear as meropenem/vaborbactam-susceptible (MIC 4 mg/L) despite vaborbactam’s lack of OXA-48 inhibitory activity.MethodsOXA-48-positive (n = 51) and OXA-48-negative (KPC, n = 5; Klebsiella pneumoniae wild-type, n = 1) Enterobacterales were utilized. Susceptibility tests (broth microdilution) were conducted with ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam, as well as their respective BL partner. Antimicrobial activity of all six agents was evaluated in the murine neutropenic thigh model using clinically relevant exposures. Efficacy was assessed as the change in bacterial growth at 24 h, compared with 0 h controls.ResultsOn average, the three BL/BLI agents resulted in robust bacteria killing among OXA-48-negative isolates. Among OXA-48-positive isolates, poor in vivo activity with imipenem/relebactam was concordant with its resistant phenotypic profile. Variable meropenem/vaborbactam activity was observed among isolates with a ‘susceptible’ MIC of 4 mg/L. Only 30% (7/23) of isolates at meropenem/vaborbactam MICs of 2 and 4 mg/L met the ≥1-log bacterial reduction threshold predictive of clinical efficacy in serious infections. In contrast, ceftazidime/avibactam resulted in marked bacterial density reduction across the range of MICs, and 96% (49/51) of isolates exceeded the ≥1-log bacterial reduction threshold.ConclusionsData demonstrate that current imipenem/relebactam and ceftazidime/avibactam CLSI breakpoints are appropriate. Data also suggest that higher meropenem/vaborbactam breakpoints relative to meropenem can translate to potentially poor clinical outcomes in patients infected with OXA-48-harbouring isolates.

Insomnia or poor sleep quality with objective short sleep duration (hereafter referred to as ISSD) has been identified as a high-risk phenotype among middle-aged persons. We evaluated the prevalence and clinical correlates of ISSD among community-living older persons.In 3053 men from the Osteoporotic Fractures in Men Sleep Study (MrOS; average age 76.4 ± 5.5 years) and 3044 women from the Study of Osteoporotic Fractures (SOF; average age 83.6 ± 3.8 years), we evaluated the prevalence of ISSD (trouble getting to sleep within 30 minutes, waking up in the middle of the night or early morning, and/or taking a medication to help with sleep ≥3 times per week and actigraphy-estimated sleep duration6 h). Using separate logistic regression models in men and women, we evaluated the cross-sectional associations between predisposing, precipitating, and perpetuating factors for ISSD, as compared with normal sleep (no insomnia and actigraphy-estimated sleep duration of 6-9 h).Overall, 20.6% of older men and 12.8% of older women had insomnia with short sleep duration. Multiple predisposing, precipitating, and perpetuating factors were cross-sectionally associated with ISSD in both men and women. In multivariable models that adjusted for predisposing factors (demographics, multimorbidity, obesity), precipitating (depression, anxiety, central nervous system-active medication use, restless legs syndrome) and perpetuating (napping, falls) factors were significantly associated with ISSD in men and women (adjusted odds ratios ranging 1.63-4.57).In this cross-sectional study of community-living older men and women, ISSD was common and associated with multiple predisposing, precipitating, and perpetuating factors, akin to a multifactorial geriatric health condition. Future work should examine causal pathways and determine whether the identified correlates represent modifiable risk factors.

Meningiomas are common intracranial tumors with variable prognoses not entirely captured by commonly used classification schemes. We sought to determine the relationship between meningioma mutations and oncologic outcomes using a targeted next-generation sequencing panel.We identified 184 grade I and II meningiomas with both90 days of post-surgical follow-up and linked targeted next-generation sequencing. For mutated genes in greater than 5% of the sample, we computed progression-free survival Cox-regression models stratified by gene. We then built a multi-gene model by including all gene predictors with aMutations in ATM and CREBBP were associated with accelerated meningioma recurrence, and mutations in POLE were protective of recurrence. Each mutation has potential implications for treatment. The effect of these mutations on oncologic outcomes and as potential targets for intervention warrants future study.

Objectives To evaluate the genotypic and ceftazidime/avibactam-susceptibility profiles amongst ceftolozane/tazobactam-non-susceptible (NS), MBL-negative Pseudomonas aeruginosa in a global surveillance programme. Methods Isolates were collected as part of the ERACE-PA Global Surveillance programme. Carbapenem-resistant P. aeruginosa deemed clinically relevant by the submitting laboratories were included. Broth microdilution MICs were conducted per CLSI standards to ceftolozane/tazobactam, ceftazidime/avibactam, ceftazidime and cefepime. Genotypic carbapenemases were detected using CarbaR and CarbaR NxG (research use only). Isolates negative for carbapenemases by PCR were assessed via WGS. Isolates were included in the analysis if they were ceftolozane/tazobactam-NS and lacked detection of known MBLs. Results Of the 807 isolates collected in the ERACE-PA programme, 126 (16%) were ceftolozane/tazobactam-NS and lacked MBLs. Cross-resistance to ceftazidime and cefepime was common, with only 5% and 16% testing susceptible, respectively. Ceftazidime/avibactam retained in vitro activity, with 65% of isolates testing susceptible. GES was the most common enzymology, detected in 57 (45%) isolates, and 89% remained susceptible to ceftazidime/avibactam. Seven isolates harboured KPC and all tested susceptible to ceftazidime/avibactam. In the remaining 62 isolates, WGS revealed various ESBLs or OXA β-lactamases. While 39% remained susceptible to ceftazidime/avibactam, marked variability was observed among the diverse resistance mechanisms. Conclusions Ceftazidime/avibactam remained active in vitro against the majority of ceftolozane/tazobactam-NS, MBL-negative P. aeruginosa. Ceftazidime/avibactam was highly active against isolates harbouring GES and KPC β-lactamases. These data highlight the potential clinical utility of genotypic profiling as well as the need to test multiple novel agents when carbapenem-resistant P. aeruginosa are encountered.

Critical illness often leads to persistent functional impairment among older Intensive Care Unit (ICU) survivors. Identification of high-risk survivors prior to discharge from their ICU hospitalization can facilitate targeting for restorative interventions after discharge, potentially improving the likelihood of functional recovery. Our objective was to develop and validate a prediction model for persistent functional impairment among older adults in the year after an ICU hospitalization.The analytic sample included community-living participants enrolled in the National Health and Aging Trends Study 2011 cohort who survived an ICU hospitalization through December 2017 and had a follow-up interview within 1 year. Persistent functional impairment was defined as failure to recover to the pre-ICU level of function within 12 months of discharge from an ICU hospitalization. We used Bayesian model averaging to identify the final predictors from a comprehensive set of 17 factors. Discrimination and calibration were assessed using area-under-the-curve (AUC) and calibration plots.The development cohort included 456 ICU admissions (2,654,685 survey-weighted admissions) and the validation cohort included 227 ICU admissions (1,350,082 survey-weighted admissions). In the development cohort, the median age was 81.0 years (interquartile range [IQR] 76.0, 86.0) and 231 (50.7%) participants were women; demographic characteristics were comparable in the validation cohort. The rates of persistent functional impairment were 49.3% (development) and 50.2% (validation). The final model included age, pre-ICU disability, probable dementia, frailty, prior hospitalizations, vision impairment, depressive symptoms, and hospital length of stay. The model demonstrated good discrimination (AUC 71%, 95% confidence interval [CI] 0.66-0.76) and good calibration. When applied to the validation cohort, the model demonstrated comparable discrimination (AUC 72%, 95% CI 0.66-0.78) and good calibration.Application of the model prior to discharge from an ICU hospitalization may identify older adults at the highest risk of persistent functional impairment in the subsequent year, thereby facilitating targeted interventions and follow-up.

Older (older than 50 years) persons living with HIV (PWH) are at elevated risk for falls. We explored how well our algorithm for predicting falls in a general population of middle-aged Veterans (age 45-65 years) worked among older PWH who use antiretroviral therapy (ART) and whether model fit improved with inclusion of specific ART classes.This analysis included 304,951 six-month person-intervals over a 15-year period (2001-2015) contributed by 26,373 older PWH from the Veterans Aging Cohort Study who were taking ART. Serious falls (those falls warranting a visit to a health care provider) were identified by external cause of injury codes and a machine-learning algorithm applied to radiology reports. Potential predictors included a fall within the past 12 months, demographics, body mass index, Veterans Aging Cohort Study Index 2.0 score, substance use, and measures of multimorbidity and polypharmacy. We assessed discrimination and calibration from application of the original coefficients (model derived from middle-aged Veterans) to older PWH and then reassessed by refitting the model using multivariable logistic regression with generalized estimating equations. We also explored whether model performance improved with indicators of ART classes.With application of the original coefficients, discrimination was good (C-statistic 0.725; 95% CI: 0.719 to 0.730) but calibration was poor. After refitting the model, both discrimination (C-statistic 0.732; 95% CI: 0.727 to 0.734) and calibration were good. Including ART classes did not improve model performance.After refitting their coefficients, the same variables predicted risk of serious falls among older PWH nearly and they had among middle-aged Veterans.

With increasing use of rituximab and other B-cell depleting monoclonal antibodies for multiple indications, infectious complications are being recognized. We summarize clinical findings of patients on rituximab with arboviral diseases identified through literature review or consultation with the Centers for Disease Control and Prevention. We identified 21 patients on recent rituximab therapy who were diagnosed with an arboviral disease caused by West Nile, tick-borne encephalitis, eastern equine encephalitis, Cache Valley, Jamestown Canyon, and Powassan viruses. All reported patients had neuroinvasive disease. The diagnosis of arboviral infection required molecular testing in 20 (95%) patients. Median illness duration was 36 days (range, 12 days to 1 year), and 15/19 (79%) patients died from their illness. Patients on rituximab with arboviral disease can have a severe or prolonged course with an absence of serologic response. Patients should be counseled about mosquito and tick bite prevention when receiving rituximab and other B-cell depleting therapies.

Research has found gun violence is a social contagion that spreads from one individual to another. To understand the social networks of violence, previous research has used social network analysis, a tool that explores the relationships between social actors. Most of the prior research uses coarrest data and incident reports to produce social networks. The current study incorporates the use of an underused data source, ballistic evidence, to better understand gun violence. The aim was to identify drivers of gun violence and to examine network concentration. Specifically, National Integrated Ballistic Information Network (NIBIN) leads and associated criminal incidents in combination with all incident reports were collected from a large urban county in the Pacific Northwest between 2015 and 2017. Social network analysis was conducted to produce a NIBIN network to demonstrate the connections between incidents where the same firearm was used. Social network analysis was also conducted to identify individuals who were the most involved in gun violence. Results reveal gun violence is very interconnected as many of the same firearms were discharged in multiple different incidents with several other individuals involved, indicating a connection between these individuals. This demonstrates the utility of using ballistic evidence beyond using only incident and coarrest data because it provides more information that directly relates to gun violence and the transfer of guns. Additionally, this can be very useful for law enforcement agencies to identify who is integral in the gun violence networks that can be helpful for prevention and intervention strategies.

The evidence linking chronic kidney disease (CKD) to spontaneous intracerebral hemorrhage (ICH) is inconclusive owing to possible confounding by comorbidities that frequently coexist in patients with these 2 diseases.To determine whether there is an association between CKD and ICH risk.A 3-stage study that combined observational and genetic analyses was conducted. First, the association between CKD and ICH risk was tested in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, a multicenter case-control study in the US. All participants with available data on CKD from ERICH were included. Second, this analysis was replicated in the UK Biobank (UKB), an ongoing population study in the UK. All participants in the UKB were included in this study. Third, mendelian randomization analyses were implemented in the UKB using 27 CKD-related genetic variants to test for genetic associations. ERICH was conducted from August 1, 2010, to August 1, 2017, and observed participants for 1 year. The UKB enrolled participants between 2006 and 2010 and will continue to observe them for 30 years. Data analysis was performed from November 11, 2019, to May 10, 2022.CKD stages 1 to 5.The outcome of interest was ICH, ascertained in ERICH via expert review of neuroimages and in the UKB via a combination of self-reported data and International Statistical Classification of Diseases, Tenth Revision, codes.In the ERICH study, a total of 2914 participants with ICH and 2954 controls who had available data on CKD were evaluated (mean [SD] age, 61.6 [14.0] years; 2433 female participants [41.5%]; 3435 male participants [58.5%]); CKD was found to be independently associated with higher risk of ICH (odds ratio [OR], 1.95; 95% CI, 1.35-2.89; P .001). This association was not modified by race and ethnicity. Replication in the UKB with 1341 participants with ICH and 501 195 controls (mean [SD] age, 56.5 [8.1] years; 273 402 female participants [54.4%]; 229 134 male participants [45.6%]) confirmed this association (OR, 1.28; 95% CI, 1.01-1.62; P = .04). Mendelian randomization analyses indicated that genetically determined CKD was associated with ICH risk (OR, 1.56; 95% CI, 1.13-2.16; P = .007).In this 3-stage study that combined observational and genetic analyses among study participants enrolled in 2 large observational studies with different characteristics and study designs, CKD was consistently associated with higher risk of ICH. Mendelian randomization analyses suggest that this association was causal. Further studies are needed to identify the specific biological pathways that mediate this association.

Looking out over the Pacific Ocean or the Grand Canyon can lead to a sense of vastness. As a perceptual phenomenon, vastness poses a unique challenge because traditional measures of distance are not capable of explaining such large spatial extents. Vastness, however, may lead to a sense of awe, and awe, in turn, can dilate one's experience of time. Time, then, may be a meaningful proxy measure of vastness. Whether vastness is related to the perception of time and if the emotional experience of awe plays a role in that relation was explored herein. Across three experiments, we examined the relation between vastness, awe, and perceived time. In Experiment 1, participants reproduced the perceived duration of images varying in vastness and rated them in terms of the awe experienced as if they were in the spaces. Greater vastness led to higher awe scores and longer duration estimates, with awe mediating the relation between vastness and time. Experiment 2 assessed if the average brightness of images, absent of scene structure, explained changes in perceived duration. Brightness did not explain variance in perceived duration; thus, the scene structure of vast scenes may play a role in altering perceived time. Experiment 3 examined if scene semantics could explain changes in perceived duration. Whereas the relation between vastness and perceived duration vanished, a weak, mediated effect still occurred. Ultimately, time may not be a proxy measure of vastness, but we find evidence that emotion can link the relation between spatial and temporal perception.

Evidence-based multifactorial fall prevention interventions in clinical practice have been less effective than expected. One plausible reason is that older adults' engagement in fall prevention care is suboptimal. This was a post-hoc analysis of 2403 older adults' engagement in a multifactorial fall prevention intervention in the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) pragmatic trial. Based on the direct clinical care level of the Patient and Family Continuum of Engagement (CE) framework, three indicators of progressively interactive engagement were assessed: (1) Consultation (receiving information), (2) Involvement (prioritizing risks), and (3) Partnership (identifying prevention actions). Drop off at each step was determined as well as predictors of engagement. The participants' engagement waned with increasingly interactive CE domains. Although all participants received information about their positive fall risk factors (consultation) and most (51%-96%) prioritized them (involvement), fewer participants (33%-55%) identified fall prevention actions (partnership) for most of their risk factors, except for strength gait or balance problems (95%). More participants (70%) identified home exercises than other actions. Finally, fall prevention actions were identified more commonly among participants who received two visits compared to one (OR=2.33 [95% CI, 2.06-2.64]), were ≥80 years old (OR=1.83 [95% CI, 1.51-2.23]), and had fewer fall risk factors (OR=0.90 [95% CI, 0.83-0.99]). The drop-off in participants' engagement based on the level of their interaction with clinicians suggests that future multifactorial fall prevention interventions need to be more focused on interactive patient-clinician partnerships that help older adults increase and maintain fall prevention actions. Our analyses suggest that more frequent contact with clinicians and more monitoring of the implementation and outcomes of Fall Prevention Care Plans could potentially improve engagement and help older adults maintain fall prevention actions.

Objectives To evaluate the in vivo killing profile of human-simulated exposures of ceftazidime, ceftazidime/avibactam and meropenem against GES-harbouring Pseudomonas aeruginosa in the murine thigh infection model. Methods Five P. aeruginosa isolates [three isogenic (GES-1, GES-5 and GES-15) and two clinical (GES-5 and GES-15)] were evaluated. MICs were determined using broth microdilution. Human-simulated regimens (HSRs) of ceftazidime 2 g IV q8h as a 2 h infusion, ceftazidime/avibactam 2.5 g IV q8h as a 2 h infusion and meropenem 2 g IV q8h as a 3 h infusion were administered. Change in bacterial burden relative to baseline was assessed. Results Modal MICs ranged from 8 to >64 mg/L for ceftazidime, from 1 to 16 mg/L for ceftazidime/avibactam and from 1 to >64 mg/L for meropenem. In vivo, for the isogenic strains, avibactam augmented ceftazidime activity against the GES-1- and GES-15-harbouring isolates. Both ceftazidime and ceftazidime/avibactam resulted in significant kill against the GES-5 isogenic isolate. The meropenem HSR produced >1 log10 kill against each isogenic isolate (MICs of 1–4 mg/L). Against the GES-5 clinical isolate, ceftazidime and ceftazidime/avibactam resulted in >1 log10 kill compared with bacterial growth with the meropenem HSR. In the clinical isolate harbouring GES-15, the elevated MICs of ceftazidime and ceftazidime/avibactam reduced the effectiveness of both compounds, while the observed reduction in meropenem MIC translated into in vivo efficacy of the HSR regimen, predictive of clinical efficacy. Conclusions In GES-harbouring P. aeruginosa, quantitative reductions in bacterial density observed with the translational murine model suggest that the phenotypic profile of ceftazidime, ceftazidime/avibactam and meropenem is predictive of clinical efficacy when using the evaluated dosing regimens.

Background Compared with adults with normal glucose metabolism, those with prediabetes tend to be frail. However, it remains poorly understood whether frailty could identify adults who are most at risk of adverse outcomes related to prediabetes. Objective We aimed to systematically evaluate the associations between frailty, a simple health indicator, and risks of multiple adverse outcomes including incident type 2 diabetes mellitus (T2DM), diabetes-related microvascular disease, cardiovascular disease (CVD), chronic kidney disease (CKD), eye disease, dementia, depression, and all-cause mortality in late life among middle-aged adults with prediabetes. Methods We evaluated 38,950 adults aged 40 years to 64 years with prediabetes using the baseline survey from the UK Biobank. Frailty was assessed using the frailty phenotype (FP; range 0-5), and participants were grouped into nonfrail (FP=0), prefrail (1≤FP≤2), and frail (FP≥3). Multiple adverse outcomes (ie, T2DM, diabetes-related microvascular disease, CVD, CKD, eye disease, dementia, depression, and all-cause mortality) were ascertained during a median follow-up of 12 years. Cox proportional hazards regression models were used to estimate the associations. Several sensitivity analyses were performed to test the robustness of the results. Results At baseline, 49.1% (19,122/38,950) and 5.9% (2289/38,950) of adults with prediabetes were identified as prefrail and frail, respectively. Both prefrailty and frailty were associated with higher risks of multiple adverse outcomes in adults with prediabetes (P for trend Conclusions In UK Biobank participants with prediabetes, both prefrailty and frailty are significantly associated with higher risks of multiple adverse outcomes, including T2DM, diabetes-related diseases, and all-cause mortality. Our findings suggest that frailty assessment should be incorporated into routine care for middle-aged adults with prediabetes, to improve the allocation of health care resources and reduce diabetes-related burden.