In out-of-hospital cardiac arrest (OHCA) without ST-elevation, predictive markers that can identify those with a high risk of acute coronary syndrome are lacking.
In this post hoc analysis of the ...Coronary Angiography after Cardiac Arrest (COACT) trial, the baseline, median, peak, and time-concentration curves of troponin-T (cTnT) (T-AUC) in OHCA patients without ST-elevation were studied. cTnT values were obtained at predefined time points at 0, 3, 6, 12, 24, 36, 28, and 72 hours after admission. All patients who died within the measurement period were not included. The primary outcome was the association between cTnT and 90-day survival. Secondary outcomes included the association of cTnT and acute thrombotic occlusions, acute unstable lesions, and left ventricular function.
In total, 352 patients were included in the analysis. The mean age was 64 ± 13 years (80.4% men). All cTnT measures were independent prognostic factors for mortality after adjustment for potential confounders age, sex, history of coronary artery disease, witnessed arrest, time to BLS, and time to return of spontaneous circulation (eg, for T-AUC: hazard ratio, 1.44; 95% CI, 1.06-1.94; P = .02; P value for all variables ≤.02). Median cTnT (odds ratio OR, 1.58; 95% CI, 1.18-2.12; P = .002) and T-AUC (OR, 2.03; 95% CI, 1.25-3.29; P = .004) were independent predictors for acute unstable lesions. Median cTnT (OR, 1.62; 95% CI, 1.17-2.23; P = .003) and T-AUC (OR, 2.16; 95% CI, 1.27-3.68; P = .004) were independent predictors for acute thrombotic occlusions. CTnT values were not associated with the left ventricular function (eg, for T-AUC: OR, 2.01; 95% CI, 0.65-6.19; P = .22; P value for all variables ≥.14)
In OHCA patients without ST-segment elevation, cTnT release during the first 72 hours after return of spontaneous circulation was associated with clinical outcomes.
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•Troponin-T release in the first days after return of spontaneous circulation was associated with survival.•Patients with significant coronary artery disease had higher troponin T values.•The performance of troponin T values in predicting survival was poor.•The performance in predicting acute coronary syndrome, troponin T had a fair discrimination ability.
When out-of-hospital cardiac arrest (OHCA) becomes refractory, extracorporeal cardiopulmonary resuscitation (ECPR) is a potential option to restore circulation and improve the patient's outcome. ...However, ECPR requires specific materials and highly skilled personnel, and it is unclear whether increased survival and health-related quality of life (HRQOL) justify these costs.
This cost-effectiveness study was part of the INCEPTION study, a multicenter, pragmatic randomized trial comparing hospital-based ECPR to conventional CPR (CCPR) in patients with refractory OHCA in 10 cardiosurgical centers in the Netherlands. We analyzed healthcare costs in the first year and measured HRQOL using the EQ-5D-5L at 1, 3, 6, and 12 months. Incremental cost-effectiveness ratio's (ICER), cost-effectiveness planes, and acceptability curves were calculated. Sensitivity analyses were performed for per-protocol and as-treated subgroups as well as imputed productivity loss in deceased patients.
In total 132 patients were enrolled: 62 in the CCPR and 70 in the ECPR group. The difference in mean costs after one year was €5,109 (95%CI -7,264-15,764). Mean QALY after one year was 0.15 in the ECPR group and 0.11 in the CCPR group, resulting in an ICER of €121,643 per additional QALY gained. The acceptability curve shows that at a willingness-to-pay threshold of €80.000, the probability of ECPR being cost-effective compared to CCPR is 36%. Sensitivity analysis showed increasing ICER in the per-protocol and as-treated groups and lower probabilities of acceptance.
Hospital-based ECPR in refractory OHCA has a low probability of being cost-effective in a trial-based economic evaluation.
A particular class of small noncoding RNAs are transcribed from DNA and then processed by enzymes to generate short oligonucleotides that then control gene expression. This study underscores their ...relevance to human health and fitness.
Immune checkpoint inhibitors (ICI) can achieve remarkable responses in urothelial cancer (UC), which may depend on tumor microenvironment (TME) characteristics. However, the relationship between the ...TME, usually characterized by immune cell density, and response to ICI is unclear. Here, we quantify the TME immune cell densities and spatial relationships (SRs) of 24 baseline UC samples, obtained before pre-operative combination ICI treatment, using multiplex immunofluorescence. We describe SRs by approximating the first nearest-neighbor distance distribution with a Weibull distribution and evaluate the association between TME metrics and ipilimumab+nivolumab response. Immune cell density does not discriminate between response groups. However, the Weibull SR metrics of CD8
T cells or macrophages to their closest cancer cell positively associate with response. CD8
T cells close to B cells are characteristic of non-response. We validate our SR response associations in a combination ICI cohort of head and neck tumors. Our data confirm that SRs, in contrast to density metrics, are strong biomarkers of response to pre-operative combination ICIs.
The efficacy of cancer therapeutic antibodies varies considerably among patients. Anti‐cancer antibodies act through different mechanisms, including antibody‐dependent cellular cytotoxicity (ADCC) ...triggered via Fcγ receptors (FcγR). This phagocyte ADCC can be promoted by interference with CD47‐SIRPα interactions, but the magnitude of this enhancement also varies among individuals. Both FcγR and SIRPα display considerable genetic variation, and we investigated whether this explains some of the variability in ADCC. Because of linkage disequilibrium between FcγR variants the interpretation of previous reports suggesting a potential link between FcγR polymorphisms and ADCC has been troublesome. We performed an integrated genetic analysis that enables stratification. ADCC by activated human neutrophils towards Trastuzumab‐coated breast cancer cells was predominantly dependent on FcγRIIa. Neutrophils from individuals with the FcγRIIa‐131H polymorphic variant displayed significantly higher killing capacity relative to those with FcγRIIa‐131R. Furthermore, ADCC was consistently enhanced by targeting CD47‐SIRPα interactions, and there were no significant functional differences between the two most prevalent SIRPα polymorphic variants. Thus, neutrophil ADCC capacity is directly related to the FcγRIIa polymorphism, and targeting CD47‐SIRPα interactions enhances ADCC independently of FcγR and SIRPα genotype, thereby further suggesting that CD47‐SIRPα interference might be a generic strategy for potentiating the efficacy of antibody therapy in cancer.
ADCC of activated human neutrophils towards Trastuzumab‐opsonized breast cancer cells was strictly FcγRIIa dependent with the FcγRIIa‐131H polymorphic variant showing increased cytotoxicity over FcγRIIa‐131R. There was no functional difference between the two principal polymorphisms in the inhibitory immunoreceptor SIRPα, further supporting the idea that CD47‐SIRPα checkpoint blockade can provide a generic approach to potentiate antibody therapy against cancer.
The function of the low-affinity IgG-receptor FcγRIIIb (CD16b), which is uniquely and abundantly expressed on human granulocytes, is not clear. Unlike the other Fcγ receptors (FcγR), it is a ...glycophosphatidyl inositol (GPI) -anchored molecule and does not have intracellular signaling motifs. Nevertheless, FcγRIIIb can cooperate with other FcγR to promote phagocytosis of antibody-opsonized microbes by human neutrophils. Here we have investigated the role of FcγRIIIb during antibody-dependent cellular cytotoxicity (ADCC) by neutrophils toward solid cancer cells coated with either trastuzumab (anti-HER2) or cetuximab (anti-EGFR). Inhibiting FcγRIIIb using CD16-F(ab')
blocking antibodies resulted in substantially enhanced ADCC. ADCC was completely dependent on FcγRIIa (CD32a) and the enhanced ADCC seen after FcγRIIIb blockade therefore suggested that FcγRIIIb was competing with FcγRIIa for IgG on the opsonized target cells. Interestingly, the function of neutrophil FcγRIIIb as a decoy receptor was further supported by using neutrophils from individuals with different gene copy numbers of
causing different levels of surface FcγRIIIb expression. Individuals with one copy of
showed higher levels of ADCC compared to those with two or more copies. Finally, we show that therapeutic antibodies intended to improve FcγRIIIa (CD16a)-dependent natural killer (NK) cell ADCC due to the lack of fucosylation on the N-linked glycan at position N297 of the IgG
heavy chain Fc-region, show decreased ADCC as compared to regularly fucosylated antibodies. Together, these data confirm FcγRIIIb as a negative regulator of neutrophil ADCC toward tumor cells and a potential target for enhancing tumor cell destruction by neutrophils.
Male infertility affects ∼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, ...only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity.
Background: Previously published research describes short-term outcomes after proximal interphalangeal (PIP) joint arthroplasty, however, long-term outcomes are scarce. Therefore, we evaluated ...patient-reported outcomes and complications after a follow-up of at least five years following PIP joint arthroplasty. Methods: We used prospectively gathered data from patients undergoing PIP joint arthroplasty with silicone or surface replacement implants. Time points included preoperative, one year, and at least five years postoperatively. We were able to include 74 patients. Primarily, we focussed on patient satisfaction with the treatment outcome, measured using a validated 5-point Likert scale. Secondary outcomes included the question whether patients would undergo the same surgery again, the assessment of factors associated with (dis)satisfaction, the Michigan Hand outcomes Questionnaire (MHQ), and the number of reoperations. Results: The mean follow-up was seven years (SD 1.2, range 5-11 years). Patient satisfaction was excellent in 14 (19%), good in 17 (23%), reasonable in 18 (24%), moderate in 10 (14%), and poor in 15 (20%) patients. Seventy-three percent of patients (n=54) would undergo the same procedure again. We found no factors associated with (dis)satisfaction. All MHQ scores improved significantly in the first year after surgery and did not deteriorate afterward. Sixteen (16%) fingers required a reoperation, of whom 3 (4%) needed a prosthesis replacement. Conclusion: Patient satisfaction with treatment outcomes seven years post-PIP implant surgery ranges from moderate to good for many patients, with a notable proportion expressing dissatisfaction. Patient-reported outcomes improve primarily within the first year and remain stable at five years or more. Level of evidence: II
To compare pyrocarbon disc interposition arthroplasty (PDI) with trapeziectomy plus ligament reconstruction tendon interposition (LRTI), the authors assessed whether PDI resulted in a higher pinch ...strength, and compared grip strength, range of motion (ROM), patient-reported outcomes, satisfaction, and complications between the approaches.BACKGROUNDTo compare pyrocarbon disc interposition arthroplasty (PDI) with trapeziectomy plus ligament reconstruction tendon interposition (LRTI), the authors assessed whether PDI resulted in a higher pinch strength, and compared grip strength, range of motion (ROM), patient-reported outcomes, satisfaction, and complications between the approaches.Because of scarcity of preoperative hand measurements, the authors performed a descriptional cross-sectional cohort study of patients operated on between 2006 and 2014, with a minimum of 5 years of follow-up. Patients were treated with PDI or LRTI. The authors determined key pinch strength as the primary outcome, followed by tip and tripod pinch, grip strength, palmar abduction and opposition, Michigan Hand Outcomes Questionnaire (MHQ) and Patient-Reported Hand and Wrist Evaluation (PRWHE) scores, satisfaction level, and complications. Propensity score matching was used to match the study groups on demographic variables. A ratio of 2:1 was used, resulting in inclusion of 62 (of 154) PDI and 31 (of 31) LRTI thumbs.METHODSBecause of scarcity of preoperative hand measurements, the authors performed a descriptional cross-sectional cohort study of patients operated on between 2006 and 2014, with a minimum of 5 years of follow-up. Patients were treated with PDI or LRTI. The authors determined key pinch strength as the primary outcome, followed by tip and tripod pinch, grip strength, palmar abduction and opposition, Michigan Hand Outcomes Questionnaire (MHQ) and Patient-Reported Hand and Wrist Evaluation (PRWHE) scores, satisfaction level, and complications. Propensity score matching was used to match the study groups on demographic variables. A ratio of 2:1 was used, resulting in inclusion of 62 (of 154) PDI and 31 (of 31) LRTI thumbs.Patients in the PDI group showed stronger key and tip pinch strength than did patients in the LRTI group ( P = 0.027 and P = 0.036, respectively). Tripod pinch, grip strength, and ROM were equal between the groups. MHQ and PRWHE were comparable, with higher satisfaction levels in the PDI group. Eight patients with PDI were converted to LRTI because of pain.RESULTSPatients in the PDI group showed stronger key and tip pinch strength than did patients in the LRTI group ( P = 0.027 and P = 0.036, respectively). Tripod pinch, grip strength, and ROM were equal between the groups. MHQ and PRWHE were comparable, with higher satisfaction levels in the PDI group. Eight patients with PDI were converted to LRTI because of pain.This study confirmed the hypothesis that key and tip pinch strength is stronger after PDI compared with LRTI for first carpometacarpal joint osteoarthritis. Both techniques have comparable outcomes considering patient-reported outcome (MHQ and PRWHE), ROM, and complications.CONCLUSIONSThis study confirmed the hypothesis that key and tip pinch strength is stronger after PDI compared with LRTI for first carpometacarpal joint osteoarthritis. Both techniques have comparable outcomes considering patient-reported outcome (MHQ and PRWHE), ROM, and complications.Therapeutic, III.CLINICAL QUESTION/LEVEL OF EVIDENCETherapeutic, III.
Antenatal betamethasone and dexamethasone are prescribed to women who are at high risk of premature birth to prevent neonatal respiratory distress syndrome (RDS). The current treatment regimens, ...effective to prevent neonatal RDS, may be suboptimal. Recently, concerns have been raised regarding possible adverse long-term neurological outcomes due to high fetal drug exposures. Data from nonhuman primates and sheep suggest maintaining a fetal plasma concentration above 1 ng/mL for 48 hours to retain efficacy, while avoiding undesirable high fetal plasma levels.
We aimed to re-evaluate the current betamethasone and dexamethasone dosing strategies to assess estimated fetal exposure and provide new dosing proposals that meet the efficacy target but avoid excessive peak exposures.
A pregnancy physiologically based pharmacokinetic (PBPK) model was used to predict fetal drug exposures. To allow prediction of the extent of betamethasone and dexamethasone exposure in the fetus, placenta perfusion experiments were conducted to determine placental transfer. Placental transfer rates were integrated in the PBPK model to predict fetal exposure and model performance was verified using published maternal and fetal pharmacokinetic data. The verified pregnancy PBPK models were then used to simulate alternative dosing regimens to establish a model-informed dose.
Ex vivo data showed that both drugs extensively cross the placenta. For betamethasone 15.7±1.7% and for dexamethasone 14.4±1.5%, the initial maternal perfusate concentration reached the fetal circulations at the end of the 3-hour perfusion period. Pregnancy PBPK models that include these ex vivo-derived placental transfer rates accurately predicted maternal and fetal exposures resulting from current dosing regimens. The dose simulations suggest that for betamethasone intramuscular, a dose reduction from 2 dosages 11.4 mg, 24 hours apart, to 4 dosages 1.425 mg, 12 hours apart would avoid excessive peak exposures and still meet the fetal response threshold. For dexamethasone, the dose may be reduced from 4 times 6 mg every 12 hours to 8 times 1.5 mg every 6 hours.
A combined placenta perfusion and pregnancy PBPK modeling approach adequately predicted both maternal and fetal drug exposures of 2 antenatal corticosteroids (ACSs). Strikingly, our PBPK simulations suggest that drug doses might be reduced drastically to still meet earlier proposed efficacy targets and minimize peak exposures. We propose the provided model-informed dosing regimens are used to support further discussion on an updated ACS scheme and design of clinical trials to confirm the effectiveness and safety of lower doses.
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