Intensive care units (ICU) are often overflooded with alarms from monitoring devices which constitutes a hazard to both staff and patients. To date, the suggested solutions to excessive monitoring ...alarms have remained on a research level. We aimed to identify patient characteristics that affect the ICU alarm rate with the goal of proposing a straightforward solution that can easily be implemented in ICUs. Alarm logs from eight adult ICUs of a tertiary care university-hospital in Berlin, Germany were retrospectively collected between September 2019 and March 2021. Adult patients admitted to the ICU with at least 24 h of continuous alarm logs were included in the study. The sum of alarms per patient per day was calculated. The median was 119. A total of 26,890 observations from 3205 patients were included. 23 variables were extracted from patients' electronic health records (EHR) and a multivariable logistic regression was performed to evaluate the association of patient characteristics and alarm rates. Invasive blood pressure monitoring (adjusted odds ratio (aOR) 4.68, 95%CI 4.15-5.29, p < 0.001), invasive mechanical ventilation (aOR 1.24, 95%CI 1.16-1.32, p < 0.001), heart failure (aOR 1.26, 95%CI 1.19-1.35, p < 0.001), chronic renal failure (aOR 1.18, 95%CI 1.10-1.27, p < 0.001), hypertension (aOR 1.19, 95%CI 1.13-1.26, p < 0.001), high RASS (aOR 1.22, 95%CI 1.18-1.25, p < 0.001) and scheduled surgical admission (aOR 1.22, 95%CI 1.13-1.32, p < 0.001) were significantly associated with a high alarm rate. Our study suggests that patient-specific alarm management should be integrated in the clinical routine of ICUs. To reduce the overall alarm load, particular attention regarding alarm management should be paid to patients with invasive blood pressure monitoring, invasive mechanical ventilation, heart failure, chronic renal failure, hypertension, high RASS or scheduled surgical admission since they are more likely to have a high contribution to noise pollution, alarm fatigue and hence compromised patient safety in ICUs.
spp. are rarely considered pathogens, but data on
spp. as a cause of orthopedic infections are sparse. Therefore, we asked how often
spp. caused an infection in a defined cohort of orthopedic ...patients with a positive culture. In addition, we aimed to determine the species variety and the susceptibility of isolated strains to define potential treatment strategies. We retrospectively assessed all bone and joint samples that were collected between 2006 and 2015 from an orthopedic ward and that were positive for
spp. by culture. The isolates were considered relevant to an infection if the same
sp. was present in at least two samples. We found 97 orthopedic cases with isolation of
spp. (128 positive samples). These were mainly
(
= 26),
(
= 17),
(
= 13), and
(
= 11). Compared to the species found in a cohort of patients with positive blood cultures hospitalized in nonorthopedic wards, we found significantly more
- and
-positive cases but no
-positive cases in our orthopedic cohort. Only 16 out of 66 cases (24.2%) with an available diagnostic set of at least two samples had an infection. Antibiotic susceptibility testing (AST) showed various susceptibility results for all antibiotics except vancomycin and linezolid, to which 100% of the isolates were susceptible. The rates of susceptibility of corynebacteria isolated from orthopedic samples and of isolates from blood cultures were comparable. In conclusion, our study results confirmed that a
sp. is most often isolated as a contaminant in a cohort of orthopedic patients. AST is necessary to define the optimal treatment in orthopedic infections.
Antibody–drug conjugates (ADCs) have emerged as an important class of therapeutics for cancer treatment that combine the target specificity of antibodies with the killing activity of anticancer ...chemotherapeutics. Early conjugation technologies relied upon random conjugation to either lysine or cysteine residues, resulting in heterogeneous ADCs. Recent technology advancements have resulted in the preparation of homogeneous ADCs through the site-specific conjugation at engineered cysteines, glycosylated amino acids, and bioorthogonal unnatural amino acids. Here we describe for the first time the conjugation of an anti-mitotic drug to an antibody following the mild and selective oxidation of a serine residue engineered at the N-terminus of the light chain. Using an alkoxyamine-derivatized monomethyl auristatine E payload, we have prepared a hydrolytically stable ADC that retains binding to its antigen and displays potent in vitro cytotoxicity and in vivo tumor growth inhibition.
Antibody-drug conjugates (ADCs) are among the most promising empowered biologics for cancer treatment. ADCs are commonly prepared by chemical conjugation of small molecule cytotoxic anti-cancer drugs ...to antibodies through either lysine side chains or cysteine thiols generated by the reduction of interchain disulfide bonds. Both methods yield heterogeneous conjugates with complex biophysical properties and suboptimal serum stability, efficacy, and pharmacokinetics. To limit the complexity of cysteine-based ADCs, we have engineered and characterized in vitro and in vivo antibody cysteine variants that allow precise control of both site of conjugation and drug load per antibody molecule. We demonstrate that the chemically-defined cysteine-engineered antibody-tubulysin conjugates have improved ex vivo and in vivo stability, efficacy, and pharmacokinetics when compared to conventional cysteine-based ADCs with similar drug-to-antibody ratios. In addition, to limit the non-target FcγRs mediated uptake of the ADCs by cells of the innate immune system, which may result in off-target toxicities, the ADCs have been engineered to lack Fc-receptor binding. The strategies described herein are broadly applicable to any full-length IgG or Fc-based ADC and have been incorporated into an ADC that is in phase I clinical development.
Site-specific ADCs have improved efficacy compared to conventional ADCs with same drug load. Display omitted
The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) is the largest food supplement program in the United States, serving almost 7 500 000 participants in 2002. Because ...the program is a grant program, rather than an entitlement program, Congress is not mandated to allocate funds to serve all eligible participants. Little is known about the effects of WIC on infant growth, health, and food security.
To examine associations between WIC participation and indicators of underweight, overweight, length, caregiver-perceived health, and household food security among infants < or =12 months of age, at 6 urban hospitals and clinics.
A multisite study with cross-sectional surveys administered at urban medical centers in 5 states and Washington, DC, from August 1998 though December 2001.
A total of 5923 WIC-eligible caregivers of infants < or =12 months of age were interviewed at hospital clinics and emergency departments.
Weight-for-age, length-for-age, weight-for-length, caregiver's perception of infant's health, and household food security.
Ninety-one percent of WIC-eligible families were receiving WIC assistance. Of the eligible families not receiving WIC assistance, 64% reported access problems and 36% denied a need for WIC. The weight and length of WIC assistance recipients, adjusted for age and gender, were consistent with national normative values. With control for potential confounding family variables (site, housing subsidy, employment status, education, and receipt of food stamps or Temporary Assistance for Needy Families) and infant variables (race/ethnicity, birth weight, months breastfed, and age), infants who did not receive WIC assistance because of access problems were more likely to be underweight (weight-for-age z score = -0.23 vs 0.009), short (length-for-age z score = -0.23 vs -0.02), and perceived as having fair or poor health (adjusted odds ratio: 1.92; 95% confidence interval: 1.29-2.87), compared with WIC assistance recipients. Rates of overweight, based on weight-for-length of >95th percentile, varied from 7% to 9% and did not differ among the 3 groups but were higher than the 5% expected from national growth charts. Rates of food insecurity were consistent with national data for minority households with children. Families that did not receive WIC assistance because of access problems had higher rates of food insecurity (28%) than did WIC participants (23%), although differences were not significant after covariate control. Caregivers who did not perceive a need for WIC services had more economic and personal resources than did WIC participants and were less likely to be food-insecure, but there were no differences in infants' weight-for-age, perceived health, or overweight between families that did not perceive a need for WIC services and those that received WIC assistance.
Infants < or =12 months of age benefit from WIC participation. Health care providers should promote WIC utilization for eligible families and advocate that WIC receive support to reduce waiting lists and eliminate barriers that interfere with access.
MEDI-565 (also known as MT111) is a bispecific T-cell engager (BiTE®) antibody in development for the treatment of patients with cancers expressing carcinoembryonic antigen (CEA). MEDI-565 binds CEA ...on cancer cells and CD3 on T cells to induce T-cell mediated killing of cancer cells. To understand the molecular basis of human CEA recognition by MEDI-565 and how polymorphisms and spliced forms of CEA may affect MEDI-565 activity, we mapped the epitope of MEDI-565 on CEA using mutagenesis and homology modeling approaches. We found that MEDI-565 recognized a conformational epitope in the A2 domain comprised of amino acids 326-349 and 388-410, with critical residues F(326), T(328), N(333), V(388), G(389), P(390), E(392), I(408), and N(410). Two non-synonymous single-nucleotide polymorphisms (SNPs) (rs10407503, rs7249230) were identified in the epitope region, but they are found at low homozygosity rates. Searching the National Center for Biotechnology Information GenBank® database, we further identified a single, previously uncharacterized mRNA splice variant of CEA that lacks a portion of the N-terminal domain, the A1 and B1 domains, and a large portion of the A2 domain. Real-time quantitative polymerase chain reaction analysis of multiple cancers showed widespread expression of full-length CEA in these tumors, with less frequent but concordant expression of the CEA splice variant. Because the epitope was largely absent from the CEA splice variant, MEDI-565 did not bind or mediate T-cell killing of cells solely expressing this form of CEA. In addition, the splice variant did not interfere with MEDI-565 binding or activity when co-expressed with full-length CEA. Thus MEDI-565 may broadly target CEA-positive tumors without regard for expression of the short splice variant of CEA. Together our data suggest that MEDI-565 activity will neither be impacted by SNPs nor by a splice variant of CEA.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Thoracolumbar spine fractures in multiple-injured patients are a common injury pattern. The appropriate timing for the surgical stabilization of vertebral fractures is still ...controversial. The purpose of this study was to analyse the impact of the timing of spinal surgery in multiple-injured patients both in general and in respect to spinal injury severity. Methods: A retrospective analysis of multiple-injured patients with an associated spinal trauma within the thoracic or lumbar spine (injury severity score (ISS) >16, age >16 years) was performed from January 2012 to December 2016 in two Level I trauma centres. Demographic data, circumstances of the accident, and ISS, as well as time to spinal surgery were documented. The evaluated outcome parameters were length of stay in the intensive care unit (ICU) (iLOS) and length of stay (LOS) in the hospital, duration of mechanical ventilation, onset of sepsis, and multiple organ dysfunction syndrome (MODS), as well as mortality. Statistical analysis was performed using SPSS. Results: A total of 113 multiple-injured patients with spinal stabilization and a complete dataset were included in the study. Of these, 71 multiple-injured patients (63%) presented with an AOSpine A-type spinal injury, whereas 42 (37%) had an AOSpine B-/C-type spinal injury. Forty-nine multiple-injured patients (43.4%) were surgically treated for their spinal injury within 24 h after trauma, and showed a significantly reduced length of stay in the ICU (7.31 vs. 14.56 days; p < 0.001) and hospital stay (23.85 vs. 33.95 days; p = 0.048), as well as a significantly reduced prevalence of sepsis compared to those surgically treated later than 24 h (3 vs. 7; p = 0.023). These adverse effects were even more pronounced in the case where cutoffs were increased to either 72 h or 96 h. Independent risk factors for a delay in spinal surgery were a higher ISS (p = 0.036), a thoracic spine injury (p = 0.001), an AOSpine A-type spinal injury (p = 0.048), and an intact neurological status (p < 0.001). In multiple-injured patients with AOSpine A-type spinal injuries, an increased time to spinal surgery was only an independent risk factor for an increased LOS; however, in multiple-injured patients with B-/C-type spinal injuries, an increased time to spinal surgery was an independent risk factor for increased iLOS, LOS, and the development of sepsis. Conclusion: Our data support the concept of early spinal stabilization in multiple-injured patients with AOSpine B-/C-type injuries, especially of the thoracic spine. However, in multiple-injured patients with AOSpine A-type injuries, the beneficial impact of early spinal stabilization has been overemphasized in former studies, and the benefit should be weighed out against the risk of patients’ deterioration during early spinal stabilization.
We previously reported an association between 5HTTLPR genotype and outcome following cognitive-behavioural therapy (CBT) in child anxiety (Cohort 1). Children homozygous for the low-expression ...short-allele showed more positive outcomes. Other similar studies have produced mixed results, with most reporting no association between genotype and CBT outcome.
To replicate the association between 5HTTLPR and CBT outcome in child anxiety from the Genes for Treatment study (GxT Cohort 2, n = 829).
Logistic and linear mixed effects models were used to examine the relationship between 5HTTLPR and CBT outcomes. Mega-analyses using both cohorts were performed.
There was no significant effect of 5HTTLPR on CBT outcomes in Cohort 2. Mega-analyses identified a significant association between 5HTTLPR and remission from all anxiety disorders at follow-up (odds ratio 0.45, P = 0.014), but not primary anxiety disorder outcomes.
The association between 5HTTLPR genotype and CBT outcome did not replicate. Short-allele homozygotes showed more positive treatment outcomes, but with small, non-significant effects. Future studies would benefit from utilising whole genome approaches and large, homogenous samples.
Most strategies used to prepare homogeneous site-specific antibody-drug conjugates (ADCs) result in ADCs with a drug-to-antibody ratio (DAR) of two. Here, we report a disulfide re-bridging strategy ...to prepare homogeneous ADCs with DAR of one using a dual-maleimide pyrrolobenzodiazepine (PBD) dimer (SG3710) and an engineered antibody (Flexmab), which has only one intrachain disulfide bridge at the hinge. We demonstrate that SG3710 efficiently re-bridge a Flexmab targeting human epidermal growth factor receptor 2 (HER2), and the resulting ADC was highly resistant to payload loss in serum and exhibited potent anti-tumor activity in a HER2-positive gastric carcinoma xenograft model. Moreover, this ADC was tolerated in rats at twice the dose compared to a site-specific ADC with DAR of two prepared using a single-maleimide PBD dimer (SG3249). Flexmab technologies, in combination with SG3710, provide a platform for generating site-specific homogenous PBD-based ADCs with DAR of one, which have improved biophysical properties and tolerability compared to conventional site-specific PBD-based ADCs with DAR of two.
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