Experimental evolution reveals the synergistic genomic mechanisms of adaptation to ocean warming and acidification in a marine copepod.

Metazoan adaptation to global change relies on selection of standing genetic variation. Determining the extent to which this variation exists in natural populations, particularly for responses to simultaneous stressors, is essential to make accurate predictions for persistence in future conditions. Here, we identified the genetic variation enabling the copepod Acartia tonsa to adapt to experimental ocean warming, acidification, and combined ocean warming and acidification (OWA) over 25 generations of continual selection. Replicate populations showed a consistent polygenic response to each condition, targeting an array of adaptive mechanisms including cellular homeostasis, development, and stress response. We used a genome-wide covariance approach to partition the allelic changes into three categories: selection, drift and replicate-specific selection, and laboratory adaptation responses. The majority of allele frequency change in warming (57%) and OWA (63%) was driven by shared selection pressures across replicates, but this effect was weaker under acidification alone (20%). OWA and warming shared 37% of their response to selection but OWA and acidification shared just 1%, indicating that warming is the dominant driver of selection in OWA. Despite the dominance of warming, the interaction with acidification was still critical as the OWA selection response was highly synergistic with 47% of the allelic selection response unique from either individual treatment. These results disentangle how genomic targets of selection differ between single and multiple stressors and demonstrate the complexity that nonadditive multiple stressors will contribute to predictions of adaptation to complex environmental shifts caused by global change.

Pharmacological Characterization and Radiolabeling of VUF15485, a High-Affinity Small-Molecule Agonist for the Atypical Chemokine Receptor ACKR3.

Atypical chemokine receptor 3 (ACKR3), formerly referred to as CXCR7, is considered to be an interesting drug target. In this study, we report on the synthesis, pharmacological characterization and radiolabeling of VUF15485, a new ACKR3 small-molecule agonist, that will serve as an important new tool to study this ß-arrestin-biased chemokine receptor. VUF15485 binds with nanomolar affinity (pIC50 = 8.3) to human ACKR3, as measured in [125I]CXCL12 competition binding experiments. Moreover, in a bioluminescence resonance energy transfer-based ß-arrestin2 recruitment assay VUF15485 acts as a potent ACKR3 agonist (pEC50 = 7.6) and shows a similar extent of receptor activation compared with CXCL12 when using a newly developed, fluorescence resonance energy transfer-based ACKR3 conformational sensor. Moreover, the ACKR3 agonist VUF15485, tested against a (atypical) chemokine receptor panel (agonist and antagonist mode), proves to be selective for ACKR3. VUF15485 labeled with tritium at one of its methoxy groups ([3H]VUF15485), binds ACKR3 saturably and with high affinity (K d = 8.2 nM). Additionally, [3H]VUF15485 shows rapid binding kinetics and consequently a short residence time (<2 minutes) for binding to ACKR3. The selectivity of [3H]VUF15485 for ACKR3, was confirmed by binding studies, whereupon CXCR3, CXCR4, and ACKR3 small-molecule ligands were competed for binding against the radiolabeled agonist. Interestingly, the chemokine ligands CXCL11 and CXCL12 are not able to displace the binding of [3H]VUF15485 to ACKR3. The radiolabeled VUF15485 was subsequently used to evaluate its binding pocket. Site-directed mutagenesis and docking studies using a recently solved cryo-EM structure propose that VUF15485 binds in the major and the minor binding pocket of ACKR3. SIGNIFICANCE STATEMENT: The atypical chemokine receptor atypical chemokine receptor 3 (ACKR3) is considered an interesting drug target in relation to cancer and multiple sclerosis. The study reports on new chemical biology tools for ACKR3, i.e., a new agonist that can also be radiolabeled and a new ACKR3 conformational sensor, that both can be used to directly study the interaction of ACKR3 ligands with the G protein-coupled receptor.

Endovascular treatment versus no endovascular treatment after 6-24 h in patients with ischaemic stroke and collateral flow on CT angiography (MR CLEAN-LATE) in the Netherlands: a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial.

BACKGROUND: Endovascular treatment for anterior circulation ischaemic stroke is effective and safe within a 6 h window. MR CLEAN-LATE aimed to assess efficacy and safety of endovascular treatment for patients treated in the late window (6-24 h from symptom onset or last seen well) selected on the basis of the presence of collateral flow on CT angiography (CTA). METHODS: MR CLEAN-LATE was a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial done in 18 stroke intervention centres in the Netherlands. Patients aged 18 years or older with ischaemic stroke, presenting in the late window with an anterior circulation large-vessel occlusion and collateral flow on CTA, and a neurological deficit score of at least 2 on the National Institutes of Health Stroke Scale were included. Patients who were eligible for late-window endovascular treatment were treated according to national guidelines (based on clinical and perfusion imaging criteria derived from the DAWN and DEFUSE-3 trials) and excluded from MR CLEAN-LATE enrolment. Patients were randomly assigned (1:1) to receive endovascular treatment or no endovascular treatment (control), in addition to best medical treatment. Randomisation was web based, with block sizes ranging from eight to 20, and stratified by centre. The primary outcome was the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included all-cause mortality at 90 days after randomisation and symptomatic intracranial haemorrhage. All randomly assigned patients who provided deferred consent or died before consent could be obtained comprised the modified intention-to-treat population, in which the primary and safety outcomes were assessed. Analyses were adjusted for predefined confounders. Treatment effect was estimated with ordinal logistic regression and reported as an adjusted common odds ratio (OR) with a 95% CI. This trial was registered with the ISRCTN, ISRCTN19922220. FINDINGS: Between Feb 2, 2018, and Jan 27, 2022, 535 patients were randomly assigned, and 502 (94%) patients provided deferred consent or died before consent was obtained (255 in the endovascular treatment group and 247 in the control group; 261 [52%] females). The median mRS score at 90 days was lower in the endovascular treatment group than in the control group (3 [IQR 2-5] vs 4 [2-6]), and we observed a shift towards better outcomes on the mRS for the endovascular treatment group (adjusted common OR 1·67 [95% CI 1·20-2·32]). All-cause mortality did not differ significantly between groups (62 [24%] of 255 patients vs 74 [30%] of 247 patients; adjusted OR 0·72 [95% CI 0·44-1·18]). Symptomatic intracranial haemorrhage occurred more often in the endovascular treatment group than in the control group (17 [7%] vs four [2%]; adjusted OR 4·59 [95% CI 1·49-14·10]). INTERPRETATION: In this study, endovascular treatment was efficacious and safe for patients with ischaemic stroke caused by an anterior circulation large-vessel occlusion who presented 6-24 h from onset or last seen well, and who were selected on the basis of the presence of collateral flow on CTA. Selection of patients for endovascular treatment in the late window could be primarily based on the presence of collateral flow. FUNDING: Collaboration for New Treatments of Acute Stroke consortium, Dutch Heart Foundation, Stryker, Medtronic, Cerenovus, Top Sector Life Sciences & Health, and the Netherlands Brain Foundation.

Expert Consensus on Pediatric Urodynamics Reporting Using Modified Delphi Technique.

PURPOSE: Urodynamic testing (UDS) is an important tool in the management of pediatric lower urinary tract conditions. There have been notable efforts to standardize pediatric UDS nomenclature and technique, but no formal guidelines exist on essential elements to include in a clinical report. We sought to identify ideal structure and elements of a pediatric UDS assessment based on expert consensus. MATERIALS AND METHODS: Pediatric urologists regularly performing UDS were queried using a Delphi process. Participants were invited representing varied geographic, experience, and societal involvement. Participants underwent 3 rounds of questionnaires between November 2022 and August 2023 focusing on report organization, elements, definitions, and automated electronic health record clinical decision support. Professional billing requirements were also considered. Consensus was defined as 80% agreeing either in favor of or against a topic. Elements without consensus were discussed in subsequent rounds. RESULTS: A diverse sample of 30 providers, representing 27 institutions across 21 US states; Washington, District of Columbia; and Canada completed the study. Participants reported interpreting an average number of 5 UDS reports per week (range 1-22). The finalized consensus report identifies 93 elements that should be included in a pediatric UDS report based on applicable study conditions and findings. CONCLUSIONS: This consensus report details the key elements and structure agreed upon by an expert panel of pediatric urologists. Further standardization of documentation should aid collaboration and research for patients undergoing UDS. Based on this information, development of a standardized UDS report template using electronic health record implementation principles is underway, which will be openly available for pediatric urologists.

Antibiotic Overtreatment of Presumed Urinary Tract Infection Among Children with Spina Bifida.

OBJECTIVE: To identify factors associated with overtreatment of presumed urinary tract infection (UTI) among children with spina bifida using such criteria. STUDY DESIGN: A retrospective review of children with spina bifida (age <21 years) evaluated in the Emergency Department (ED) at a single institution was performed. Patients with a urinalysis (UA) performed who were reliant on assisted bladder emptying were included. The primary outcome was overtreatment, defined as receiving antibiotics for presumed UTI but ultimately not meeting spina bifida UTI criteria (≥2 urologic symptoms plus pyuria and urine culture growing >100k CFU/mL). The primary exposure was whether the components of the criteria available at the time of the ED visit (≥2 urologic symptoms plus pyuria) were met when antibiotics were initiated. RESULTS: Among 236 ED encounters, overtreatment occurred in 80% of cases in which antibiotics were initiated (47% of the entire cohort). Pyuria with <2 urologic symptoms was the most important factor associated with overtreatment (OR 9.6). Non-Hispanic White race was associated with decreased odds of overtreatment (OR 0.3). CONCLUSIONS: Overtreatment of presumed UTI among patients with spina bifida was common. Pyuria, which is not specific to UTI in this population, was the main driver of overtreatment. Symptoms are a cornerstone of UTI diagnosis among children with spina bifida, should be collected in a standardized manner, and considered in a decision to treat.

Long-Term Oncologic Outcome following Duodenum-Preserving Pancreatic Head Resection for Benign Tumors, Cystic Neoplasms, and Neuroendocrine Tumors: Systematic Review and Meta-analysis.

BACKGROUND: Pancreatoduodenectomy (PD) has a considerable surgical risk for complications and late metabolic morbidity. Parenchyma-sparing resection of benign tumors has the potential to cure patients associated with reduced procedure-related short- and long-term complications. MATERIALS AND METHODS: Pubmed, Embase, and Cochrane libraries were searched for studies reporting surgery-related complications following PD and duodenum-preserving total (DPPHRt) or partial (DPPHRp) pancreatic head resection for benign tumors. A total of 38 cohort studies that included data from 1262 patients were analyzed. In total, 729 patients underwent DPPHR and 533 PD. RESULTS: Concordance between preoperative diagnosis of benign tumors and final histopathology was 90.57% for DPPHR. Cystic and neuroendocrine neoplasms (PNETs) and periampullary tumors (PATs) were observed in 497, 89, and 31 patients, respectively. In total, 34 of 161 (21.1%) patients with intraepithelial papillar mucinous neoplasm exhibited severe dysplasia in the final histopathology. The meta-analysis, when comparing DPPHRt and PD, revealed in-hospital mortality of 1/362 (0.26%) and 8/547 (1.46%) patients, respectively [OR 0.48 (95% CI 0.15-1.58); p = 0.21], and frequency of reoperation of 3.26 % and 6.75%, respectively [OR 0.52 (95% CI 0.28-0.96); p = 0.04]. After a follow-up of 45.8 ± 26.6 months, 14/340 patients with intraductal papillary mucinous neoplasms/mucinous cystic neoplasms (IPMN/MCN, 4.11%) and 2/89 patients with PNET (2.24%) exhibited tumor recurrence. Local recurrence at the resection margin and reoccurrence of tumor growth in the remnant pancreas was comparable after DPPHR or PD [OR 0.94 (95% CI 0.178-5.34); p = 0.96]. CONCLUSIONS: DPPHR for benign, premalignant neoplasms provides a cure for patients with low risk of tumor recurrence and significantly fewer early surgery-related complications compared with PD. DPPHR has the potential to replace PD for benign, premalignant cystic and neuroendocrine neoplasms.

Prehabilitation for delirium prevention in elderly patients with chronic limb threatening ischemia.

OBJECTIVE: Elderly patients with Chronic Limb Threatening Ischemia (CLTI) undergoing revascularization are prone to delirium and prolonged hospitalization. Preoperative prehabilitation may prevent delirium and reduce the length of stay. This study investigates the effect of multimodal prehabilitation on delirium incidence in elderly CLTI patients undergoing revascularization. METHODS: A comparative observational cohort study conducted in a large teaching hospital (intervention cohort n=101, retrospective control cohort n=207) and a university hospital (prospective control cohort n=48) from 2020 to 2023. Patients aged ≥ 65 years undergoing revascularization were included, with acute treatment or severe cognitive impairment as exclusion criteria. The three-week prehabilitation program included screening of general health and presence of delirium risk factors by a vascular nurse practitioner, screening and provision of personalized, home-based exercises by a physiotherapist, provision of nutritional advice by a dietician, and if indicated comprehensive geriatric assessment by a geriatrician, assessment of self-reliance and home situation by a prearranged homecare nurse, guidance and support for smoking cessation by a quit smoking coach, and anaemia treatment. Primary outcome was 30-day delirium incidence, analysed using regression models adjusting for potential confounders (age, physical impairment, history of delirium, preoperative anaemia and revascularization type). Secondary outcomes were length of stay, postoperative complications, 30-day mortality, and patient experiences. RESULTS: Median age (IQR) was 76 years (71-82). Delirium incidence was lower in the prehabilitation cohort (n=2/101, 2%) compared to controls (n=23/255, 9%; OR=0.21, 95%CI 0.05-0.89, p=.04). Adjusted analysis showed a non-significant delirium reduction (OR=0.28, 95%CI 0.06-1.3, p=.097). The prehabilitation cohort had a significantly shorter length of stay (2 [1-5] vs 4 [2-9] days; p=<.001), and fewer minor complications (14% vs 26%, p=.01). No differences were present in major complications and 30-day mortality. Patients reported high compliance and satisfaction (median score 8/10, IQR 7-9). CONCLUSIONS: Prehabilitation among elderly CLTI patients is safe and has the potential to yield multiple beneficial effects on general outcomes following revascularization, while also achieving high levels of patient satisfaction. Further validation and considering implementation in surgical settings is recommended.

When the Going Gets Tough, the Females Get Going: Sex-Specific Physiological Responses to Simultaneous Exposure to Hypoxia and Marine Heatwave Events in a Ubiquitous Copepod.

The existence of sex-specific differences in phenotypic traits is widely recognized. Yet they are often ignored in studies looking at the impact of global changes on marine organisms, particularly within the context of combined drivers that are known to elicit complex interactions. We tested sex-specific physiological responses of the cosmopolitan and ecologically important marine copepod Acartia tonsa exposed to combined hypoxia and marine heatwave (MHW) conditions, both of which individually strongly affect marine ectotherms. Females and males were acutely exposed for 5 days to a combination of either control (18°C) or a high temperature mimicking a MHW (25°C), and normoxia (100% O2 sat.) or mild hypoxia (35% O2 sat.). Life-history traits, as well as sex-specific survival and physiological traits, were measured. Females had overall higher thermal tolerance levels and responded differently than males when exposed to the combined global change drivers investigated. Females also showed lower metabolic thermal sensitivity when compared to males. Additionally, the MHW exerted a dominant effect on the traits investigated, causing a lower survival and higher metabolic rate at 25°C. However, egg production rates appeared unaffected by hypoxia and MHW conditions. Our results showed that MHWs could strongly affect copepods' survival, that combined exposure to hypoxia and MHW exerted an interactive effect only on CTmax, and that sex-specific vulnerability to these global change drivers could have major implications for population dynamics. Our results highlight the importance of considering the differences in the responses of females and males to rapid environmental changes to improve the implementation of climate-smart conservation approaches.

Metabolic dysfunction-associated steatotic liver disease in older adults is associated with frailty and social disadvantage.

BACKGROUND & AIMS: The burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is growing rapidly, as is the number of older adults globally. However, relatively few studies have been performed evaluating the prevalence and risk factors for MASLD in older adults. As such, we aimed to identify the prevalence of MASLD in older adults, as well as sociodemographic, clinical, functional and biochemical associations. METHODS: The study population included older adults without a history of cardiovascular disease, dementia or independence-limiting functional impairment who had participated in the ASPirin in Reducing Events in the Elderly (ASPREE) randomised trial. MASLD was defined using the Fatty Liver Index (FLI). Associations were identified using Poisson regression with robust variance for FLI ≥ 60 vs FLI < 30. RESULTS: 9097 Australian participants aged ≥70 years had complete biochemical and anthropometric data to identify MASLD. The study population had a mean age of 75.1 ± 4.3 years and was 45.0% male. Almost one-third (33.0%) had prevalent MASLD, and the prevalence decreased with increasing age (adjusted RR [aRR] 0.96, 95% CI: 0.96-0.97). MASLD was also negatively associated with social advantage (aRR 0.94, 95% CI: 0.90-0.99) and exercise tolerance and was positively associated with diabetes mellitus (aRR: 1.22, 95% CI: 1.16-1.29), hypertension (aRR: 1.31, 95% CI: 1.22-1.41), male sex (aRR: 1.66, 95% CI: 1.57-1.74), pre-frailty (aRR: 1.99, 95% CI: 1.82-2.12) and frailty (aRR: 2.36, 95% CI: 2.16-2.56). MASLD and nonalcoholic fatty liver disease (NAFLD) results were 100% concordant. CONCLUSION: This study in a large cohort of relatively healthy community-dwelling older adults shows that MASLD is common, decreases with age and is associated with poorer metabolic health, social disadvantage and frailty.

Evaluation of revised UK-NEQAS CSF-xanthochromia method for subarachnoid hemorrhage: outcome data provide evidence for clinical value.

OBJECTIVES: Subarachnoid haemorrhage (SAH) has a high morbidity and mortality and requires prompt diagnosis. In patients with negative findings on computed-tomogram of the brain (CT-Brain) cerebrospinal fluid (CSF)-xanthochromia is considered the test of choice if performed 12 h or more after symptom onset. We audited the accuracy, usefulness and timing of CSF-xanthochromia testing and the interpretation of equivocal CSF-xanthochromia findings. We also investigated mortality outcomes for defined subsets of patients. METHODS: A retrospective audit of CSF-xanthochromia tests over 8 years was performed. The service uses the revised UK-NEQAS (United Kingdom National External Quality Assessment Service) method. RESULTS: We analysed 543 cases (F=299, median age 44yrs) with 19 cases (3.5 %) having SAH. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CSF-xanthochromia testing were 100 , 98.1, 65.9, 100 % respectively (equivocal results were counted as positives). 280 cases (F=153, median age 43yrs) had LP performed more than 24 h after the onset of headache (median time to LP=72 h). The sensitivity and specificity of the CSF-xanthochromia were 100 and 97.4 % in this group with NPV 100 % and PPV 66.6 %. 183 (65.4 %) CSF- xanthochromia negative cases in this subgroup had follow up data and survived without SAH occurring in the 12 months follow up. CONCLUSIONS: In this study, supported by follow up outcome data, we show that CSF-xanthochromia testing using the revised UK-NEQAS method is fit-for-purpose for the use as a second line test to exclude SAH in patients with negative CT-brain including delayed presentation more than 24 h after headache onset.

Establishing the TSH reference intervals for healthy adults aged over 70 years: the Australian ASPREE cohort study.

OBJECTIVES: As thyroid disorders are common amongst the elderly, this study aims to evaluate the reference interval (RI) for thyroid stimulating hormone (TSH) in healthy adults aged 70 years and over. METHODS: A proposed RI was determined from the Australian participants of the ASPirin in Reducing Events in the Elderly (ASPREE) randomised trial. Participants had no history of cardiovascular disease, thyroid cancer, dementia, or life-threatening illnesses. Participants prescribed with any thyroid-related medication at baseline were excluded. TSH levels were measured using a commercial chemiluminescence microparticle immunoassay. The RI was determined using the middle 95th percentile of the logarithmic transformed data of baseline TSH. Cox proportional hazard regression models were used to validate the RI by assessing disease incidence over time. RESULTS: A total of 10,995 participants had baseline TSH measures. Median (IQR) age was 73.9 (71.8-77.3) years. We propose a RI of 0.34-3.75 mU/L. TSH levels did not differ by age or sex. At baseline, there was no association between symptoms associated with thyroid disease and levels of TSH. Over the follow-up period of up to 11 years, no association was seen between baseline TSH levels and relevant disease outcomes for participants within the RI. CONCLUSIONS: From a group of initially healthy, community-dwelling adults aged >=70 years, we propose a RI of TSH to best represent euthyroidism. This concentration was not associated with an increased risk of thyroid related symptoms or outcomes, confirming its appropriateness for clinical use.

Tracheomalacia and surgical options: A case series perspective.

Tracheomalacia causes considerable morbidity in children, and the best treatment options remain debated. This paper presents a case series of seven Danish children who underwent surgical interventions, such as tracheopexy and aortopexy, demonstrating favourable clinical outcomes, notably with early intervention. We discuss the indications, timing and potential benefits of surgery for tracheomalacia in reducing respiratory symptoms caused by tracheal collapse. Our case series highlights the potential of surgical options in managing tracheomalacia, emphasising the need for standardised protocols, multidisciplinary and international collaboration, and further research to optimise treatment strategies and outcomes.

The discrete-time Kermack-McKendrick model: A versatile and computationally attractive framework for modeling epidemics.

The COVID-19 pandemic has led to numerous mathematical models for the spread of infection, the majority of which are large compartmental models that implicitly constrain the generation-time distribution. On the other hand, the continuous-time Kermack-McKendrick epidemic model of 1927 (KM27) allows an arbitrary generation-time distribution, but it suffers from the drawback that its numerical implementation is rather cumbersome. Here, we introduce a discrete-time version of KM27 that is as general and flexible, and yet is very easy to implement computationally. Thus, it promises to become a very powerful tool for exploring control scenarios for specific infectious diseases such as COVID-19. To demonstrate this potential, we investigate numerically how the incidence-peak size depends on model ingredients. We find that, with the same reproduction number and the same initial growth rate, compartmental models systematically predict lower peak sizes than models in which the latent and the infectious period have fixed duration.

Effect of Low-Dose Aspirin Versus Placebo on Incidence of Anemia in the Elderly : A Secondary Analysis of the Aspirin in Reducing Events in the Elderly Trial.

BACKGROUND: Daily low-dose aspirin increases major bleeding; however, few studies have investigated its effect on iron deficiency and anemia. OBJECTIVE: To investigate the effect of low-dose aspirin on incident anemia, hemoglobin, and serum ferritin concentrations. DESIGN: Post hoc analysis of the ASPREE (ASPirin in Reducing Events in the Elderly) randomized controlled trial. (ClinicalTrials.gov: NCT01038583). SETTING: Primary/community care in Australia and the United States. PARTICIPANTS: Community-dwelling persons aged 70 years or older (≥65 years for Black persons and Hispanic persons). INTERVENTION: 100 mg of aspirin daily or placebo. MEASUREMENTS: Hemoglobin concentration was measured annually in all participants. Ferritin was measured at baseline and 3 years after random assignment in a large subset. RESULTS: 19 114 persons were randomly assigned. Anemia incidence in the aspirin and placebo groups was 51.2 events and 42.9 events per 1000 person-years, respectively (hazard ratio, 1.20 [95% CI, 1.12 to 1.29]). Hemoglobin concentrations declined by 3.6 g/L per 5 years in the placebo group and the aspirin group experienced a steeper decline by 0.6 g/L per 5 years (CI, 0.3 to 1.0 g/L). In 7139 participants with ferritin measures at baseline and year 3, the aspirin group had greater prevalence than placebo of ferritin levels less than 45 µg/L at year 3 (465 [13%] vs. 350 [9.8%]) and greater overall decline in ferritin by 11.5% (CI, 9.3% to 13.7%) compared with placebo. A sensitivity analysis quantifying the effect of aspirin in the absence of major bleeding produced similar results. LIMITATIONS: Hemoglobin was measured annually. No data were available on causes of anemia. CONCLUSION: Low-dose aspirin increased incident anemia and decline in ferritin in otherwise healthy older adults, independent of major bleeding. Periodic monitoring of hemoglobin should be considered in older persons on aspirin. PRIMARY FUNDING SOURCE: National Institutes of Health and Australian National Health and Medical Research Council.

The effect of piston diameter in primary stapes surgery on surgical success.

PURPOSE: To evaluate the effect of piston diameter in patients undergoing primary stapes surgery on audiometric results and postoperative complications. METHODS: A retrospective single-center cohort study was performed. Adult patients who underwent primary stapes surgery between January 2013 and April 2022 and received a 0.4-mm-diameter piston or a 0.6-mm-diameter piston were included. The primary and secondary outcomes were pre- and postoperative pure-tone audiometry, pre- and postoperative speech audiometry, postoperative complications, intraoperative anatomical difficulties, and the need for revision stapes surgery. The pure-tone audiometry included air conduction, bone conduction, and air-bone gap averaged over 0.5, 1, 2 and 3 kHz. RESULTS: In total, 280 otosclerosis patients who underwent 321 primary stapes surgeries were included. The audiometric outcomes were significantly better in the 0.6 mm group compared to the 0.4 mm group in terms of gain in air conduction (median = 24 and 20 dB, respectively), postoperative air-bone gap (median = 7.5 and 9.4 dB, respectively), gain in air-bone gap (median = 20.0 and 18.1 dB, respectively), air-bone gap closure to 10 dB or less (75% and 59%, respectively) and 100% speech reception (median = 75 and 80 dB, respectively). We found no statistically significant difference in postoperative dizziness, postoperative complications and the need for revision stapes surgery between the 0.4 and 0.6 mm group. The incidence of anatomical difficulties was higher in the 0.4 mm group. CONCLUSION: The use of a 0.6-mm-diameter piston during stapes surgery seems to provide better audiometric results compared to a 0.4-mm-diameter piston, and should be the preferred piston size in otosclerosis surgery. We found no statistically significant difference in postoperative complications between the 0.4- and 0.6-mm-diameter piston. Based on the results, we recommend always using a 0.6-mm-diameter piston during primary stapes surgery unless anatomical difficulties do not allow it.

The cost evaluation of day-case compared to inpatient cochlear implantation in adults: subanalysis of a randomized controlled trial.

OBJECTIVE: To investigate the assumption that day-case cochlear implantation is associated with lower costs, compared to inpatient cochlear implantation, while maintaining equal quality of life (QoL) and hearing outcomes, for the Dutch healthcare setting. STUDY DESIGN: A single-center, non-blinded, randomized controlled trial in a tertiary referral center. METHODS: Thirty adult patients with post-lingual bilateral sensorineural hearing loss eligible for unilateral cochlear implantation surgery were randomly assigned to either the day-case or inpatient treatment group (i.e., one night admission). We performed an intention-to-treat evaluation of the difference of the total health care-related costs, hospital and out of hospital costs, between day-case and inpatient cochlear implantation, from a hospital and patient perspective over the course of one year. Audiometric outcomes, assessed using CVC scores, and QoL, assessed using the EQ-5D and HUI3 questionnaires, were taken into account. RESULTS: There were two drop-outs. The total health care-related costs were €41,828 in the inpatient group (n = 14) and €42,710 in the day-case group (n = 14). The mean postoperative hospital stay was 1.2 days (mean costs of €1,069) in the inpatient group and 0.7 days (mean costs of €701) for the day-case group. There were no statistically significant differences in postoperative hospital and out of hospital costs. The QoL at 2 months and 1 year postoperative, measured by the EQ-5D index value and HUI3 showed no statistically significant difference. The EQ-5D VAS score measured at 1 year postoperatively was statistically significantly higher in the inpatient group (84/100) than in the day-case group (65/100). There were no differences in postoperative complications, objective hearing outcomes, and number of postoperative hospital and out of hospital visits. CONCLUSION: A day-case approach to cochlear implant surgery does not result in a statistically significant reduction of health care-related costs compared to an inpatient approach and does not affect the surgical outcome (complications and objective hearing measurements), QoL, and postoperative course (number of postoperative hospital and out of hospital visits).

Quality of life, hearing results, patient satisfaction and postoperative complications of day-case versus inpatient unilateral cochlear implantation in adults: a randomized controlled, equivalence trial.

OBJECTIVE: To investigate the hypothesis that day-case cochlear implantation is associated with equal quality of life, hearing benefits and complications rates, compared to inpatient cochlear implantation. STUDY DESIGN: A single-center, non-blinded, randomized controlled, equivalence trial in a tertiary referral center. METHODS: Thirty adult patients with post-lingual bilateral sensorineural hearing loss eligible for unilateral cochlear implantation surgery were randomly assigned to either the day-case or inpatient treatment group. The effect on general quality of life, patient satisfaction, (subjective) hearing improvement, postoperative complications and causes of crossover and/or readmission were assessed using questionnaires, auditory evaluations and patients' charts over a follow-up period of 1 year. RESULTS: Overall quality of life measured by the HUI3 was equal between the day-case (n = 14) and inpatient group (n = 14). The overall patients' satisfaction showed a slight favor towards an inpatient approach. There was no significant difference in the subjective and objective hearing improvement between both treatment groups. During the 1-year follow-up period no major complications occurred. Minor complications occurred intraoperatively in three day-case patients resulting in three out of nine admissions of day-case patients. Other causes of admission of day-case patients were nausea and vomiting (n = 1), drowsiness (n = 1), late scheduled surgery (n = 2), social reasons (n = 1), or due to an unclear reason (n = 1). No patients required readmission. CONCLUSION: We found equal outcomes of QoL, patient satisfaction, objective, and subjective hearing outcomes between day-case and inpatient unilateral cochlear implantation. Nine out of 14 day-case patients were admitted for at least one night postoperatively (crossover). No major complications occurred in both groups. A day-case approach seems feasible when using specific patient selection, surgical planning and the preoperative provision of patient information into account. Besides this, the familiarity with a day-case approach of both patient and the surgical team can increase the feasibility of day-case surgery.

Redox-Triggered Debonding of Mussel-Inspired Pressure Sensitive Adhesives: Improving Efficiency Through Functional Design.

Debondable pressure-sensitive adhesives (PSAs) promise access to recyclability in microelectronics in the transition toward a circular economy. Two PSAs were synthesized from a tetravalent thiol star-polyester forming thiol-catechol-connectivities (TCC) with either the biorelated DiDopa-bisquinone (BY*Q) or the fossil-based bisquinone A (BQA). The PSAs enable debonding by oxidation of TCC-catechols to quinones. The extent of debonding efficiency depends on the interaction modes, which are determined by the chemical structure differences of both TCC-motifs. BY*Q-TCC-PSA debonds with exceptional loss of 99 % of its approx. 2 MPa shear strength in glass-on-glass junctions. For BQA-TCC-PSA, a debonding efficiency of only approx. 60 % was found, irrespective of its initial shear strength, which could be tuned up to approx. 7 MPa. The efficiency of debonding for BY*Q-TCC-PSA after TCC-oxidation is linked to the loss of synergistic interactions without strongly affecting the bulk glue properties, outperforming the purely catechol-based BQA-analogue.

Perioperative FLOT plus ramucirumab for resectable esophagogastric adenocarcinoma: A randomized phase II/III trial of the German AIO and Italian GOIM.

This multicenter, randomized phase II/III study evaluated the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab to FLOT as perioperative treatment for resectable esophagogastric adenocarcinoma. Patients received either FLOT alone (Arm A) or combined with ramucirumab followed by ramucirumab monotherapy (Arm B). The primary endpoint for the phase II portion was the pathological complete or subtotal response (pCR/pSR) rate. Baseline characteristics were comparable between both arms with a high rate of tumors signet-ring cell component (A:47% B:43%). No between-arm difference in pCR/pSR rate was seen (A:29% B:26%), therefore the transition to phase III was not pursued. Nevertheless, the combination was associated with a significantly increased R0-resection rate compared with FLOT alone (A:82% B:96%; P = .009). In addition, the median disease-free survival was numerically improved in Arm B (A:21 months B:32 months, HR 0.75, P = 0.218), while the median overall survival was similar in both treatment arms (A:45 months B:46 months, HR 0.94, P = 0.803). Patients with Siewert type I tumors receiving transthoracic esophagectomy with intrathoracic anastomosis showed an increased risk of serious postoperative complications after ramucirumab treatment, therefore recruitment of those patients was stopped after the first-third of the study. Overall, surgical morbidity and mortality was comparable, whereas more non-surgical grade ≥ 3 adverse events were observed with the combination, especially anorexia (A:1% B:11%), hypertension (A:4% B:13%) and infections (A:19% B:33%). The combination of ramucirumab and FLOT as perioperative treatment shows efficacy signals, particularly in terms of R0 resection rates, for a study population with a high proportion of prognostically poor histological subtypes, and further evaluation in this subgroup seems warranted.

Simultaneous warming and acidification limit population fitness and reveal phenotype costs for a marine copepod.

Phenotypic plasticity and evolutionary adaptation allow populations to cope with global change, but limits and costs to adaptation under multiple stressors are insufficiently understood. We reared a foundational copepod species, Acartia hudsonica, under ambient (AM), ocean warming (OW), ocean acidification (OA), and combined ocean warming and acidification (OWA) conditions for 11 generations (approx. 1 year) and measured population fitness (net reproductive rate) derived from six life-history traits (egg production, hatching success, survival, development time, body size and sex ratio). Copepods under OW and OWA exhibited an initial approximately 40% fitness decline relative to AM, but fully recovered within four generations, consistent with an adaptive response and demonstrating synergy between stressors. At generation 11, however, fitness was approximately 24% lower for OWA compared with the AM lineage, consistent with the cost of producing OWA-adapted phenotypes. Fitness of the OWA lineage was not affected by reversal to AM or low food environments, indicating sustained phenotypic plasticity. These results mimic those of a congener, Acartia tonsa, while additionally suggesting that synergistic effects of simultaneous stressors exert costs that limit fitness recovery but can sustain plasticity. Thus, even when closely related species experience similar stressors, species-specific costs shape their unique adaptive responses.