Utility of a Benchmarking Report for Balancing Infection Prevention and Antimicrobial Stewardship in Children with Complicated Appendicitis.

OBJECTIVE: To develop a severity-adjusted, hospital-level benchmarking comparative performance report for postoperative organ space infection and antibiotic utilization in children with complicated appendicitis. BACKGROUND: No benchmarking data exist to aid hospitals in identifying and prioritizing opportunities for infection prevention or antimicrobial stewardship in children with complicated appendicitis. METHODS: This was a multicenter cohort study using NSQIP-Pediatric data from 16 hospitals participating in a regional research consortium, augmented with antibiotic utilization data obtained through supplemental chart review. Children with complicated appendicitis who underwent appendectomy from 07/01/2015 to 06/30/2020 were included. Thirty-day postoperative OSI rates and cumulative antibiotic utilization were compared between hospitals using observed-to-expected (O/E) ratios after adjusting for disease severity using mixed effects models. Hospitals were considered outliers if the 95% confidence interval for O/E ratios did not include 1.0. RESULTS: 1790 patients were included. Overall, the OSI rate was 15.6% (hospital range: 2.6-39.4%) and median cumulative antibiotic utilization was 9.0 days (range: 3.0-13.0). Across hospitals, adjusted O/E ratios ranged 5.7-fold for OSI (0.49-2.80, P=0.03) and 2.4-fold for antibiotic utilization (0.59-1.45, P<0.01). Three (19%) hospitals were outliers for OSI (1 high and 2 low performers), and eight (50%) were outliers for antibiotic utilization (5 high and 3 low utilizers). Ten (63%) hospitals were identified as outliers in one or both measures. CONCLUSIONS: A comparative performance benchmarking report may help hospitals identify and prioritize quality improvement opportunities for infection prevention and antimicrobial stewardship, as well as identify exemplar performers for dissemination of best practices.

Estimating the relative importance of epidemiological and behavioural parameters for epidemic mpox transmission: a modelling study.

BACKGROUND: Many European countries experienced outbreaks of mpox in 2022, and there was an mpox outbreak in 2023 in the Democratic Republic of Congo. There were many apparent differences between these outbreaks and previous outbreaks of mpox; the recent outbreaks were observed in men who have sex with men after sexual encounters at common events, whereas earlier outbreaks were observed in a wider population with no identifiable link to sexual contacts. These apparent differences meant that data from previous outbreaks could not reliably be used to parametrise infectious disease models during the 2022 and 2023 mpox outbreaks, and modelling efforts were hampered by uncertainty around key transmission and immunity parameters. METHODS: We developed a stochastic, discrete-time metapopulation model for mpox that allowed for sexual and non-sexual transmission and the implementation of non-pharmaceutical interventions, specifically contact tracing and pre- and post-exposure vaccinations. We calibrated the model to case data from Berlin and used Sobol sensitivity analysis to identify parameters that mpox transmission is especially sensitive to. We also briefly analysed the sensitivity of the effectiveness of non-pharmaceutical interventions to various efficacy parameters. RESULTS: We found that variance in the transmission probabilities due to both sexual and non-sexual transmission had a large effect on mpox transmission in the model, as did the level of immunity to mpox conferred by a previous smallpox vaccination. Furthermore, variance in the number of pre-exposure vaccinations offered was the dominant contributor to variance in mpox dynamics in men who have sex with men. If pre-exposure vaccinations were not available, both the accuracy and timeliness of contact tracing had a large impact on mpox transmission in the model. CONCLUSIONS: Our results are valuable for guiding epidemiological studies for parameter ascertainment and identifying key factors for success of non-pharmaceutical interventions.

Measuring Pectus Excavatum Severity, External Caliper, or Cross-Sectional Imaging: Family Perceptions.

INTRODUCTION: Patients with pectus excavatum (PE) often undergo cross-sectional imaging (CSI) to quantify severity for insurance authorization before surgical repair. The modified percent depth (MPD), an external caliper-based metric, was previously validated to be similar to the pectus index and correction index. This study explored family perceptions of CSI and MPD with respect to value and costs. METHODS: This is a cross-sectional survey study including families of patients enrolled in an ongoing prospective multicenter study evaluating the use of MPD as an alternative to CSI for quantifying PE severity. Families of PE patients who underwent both MPD and CSI completed a survey to determine their perceptions of MPD and costs of CSI. Responses were described and associations were evaluated using chi squared, Wilcoxon rank-sum test and logistic regression as appropriate. Statistical significance was set to 0.05. RESULTS: There were 136 surveys completed for a response rate of 88%. Respondents were confident in MPD (86%) and confident in its similarity to CSI (76%). Families of females were less confident in the measurements than males (55% versus 80%, P = 0.02; odds ratio 0.30 (0.11, 0.83). Obtaining CSI required time off work/school in 90% and a copay in 60%. Nearly half (49%) of respondents reported CSI was a time/financial hardship. Increasing copay led to decreased reassurance in CSI (55%: copay > $100 versus 77%: lower copay/75%: no copay; P = 0.04). CONCLUSIONS: From the family perspective, MPD is valuable in assessing the severity of PE. Obtaining CSI was financially burdensome, particularly for those with higher copays. MPD measurements provide high value at low cost in assessing the severity of PE.

Impact of Biotransformation on Internal Concentrations and Specificity Classification of Organic Chemicals in the Zebrafish Embryo (Danio rerio).

Internal concentrations (ICs) are crucial for linking exposure to effects in the development of New Approach Methodologies. ICs of chemicals in aquatic organisms are primarily driven by hydrophobicity and modulated by biotransformation and efflux. Comparing the predicted baseline to observed toxicity enables the estimation of effect specificity, but biological processes can lead to overestimating ICs and bias the specificity assessment. To evaluate the prediction of a mass balance model (MBM) and the impact of biotransformation on ICs, experimental ICs of 63 chemicals in zebrafish embryos were compared to predictions with physicochemical properties as input parameters. Experimental ICs of 79% (50 of 63) of the chemicals deviated less than 10-fold from predictions, and the remaining 13 deviated up to a factor of 90. Using experimental ICs changed the classification for 19 chemicals, with ICs 5 to 90 times lower than predicted, showing the bias of specificity classification. Uptake kinetics of pirinixic acid, genistein, dexamethasone, ethoprophos, atorvastatin, and niflumic acid were studied over a 96 h exposure period, and transformation products (TPs) were elucidated using suspect- and nontarget screening with UPLC-HRMS. 35 TPs (5 to 8 TPs per compound) were tentatively identified and semiquantified based on peak areas, suggesting that biotransformation may partly account for the overpredictions of ICs.

SAGES guideline for the diagnosis and treatment of appendicitis.

BACKGROUND: Appendicitis is an extremely common disease with a variety of medical and surgical treatment approaches. A multidisciplinary expert panel was convened to develop evidence-based recommendations to support clinicians and patients in decisions regarding the diagnosis and treatment of appendicitis. METHODS: A systematic review was conducted from 2010 to 2022 to answer 8 key questions relating to the diagnosis of appendicitis, operative or nonoperative management, and specific technical and post-operative issues for appendectomy. The results of this systematic review were then presented to a panel of adult and pediatric surgeons. Evidence-based recommendations were formulated using the GRADE methodology by subject experts. RESULTS: Conditional recommendations were made in favor of uncomplicated and complicated appendicitis being managed operatively, either delayed (>12h) or immediate operation (<12h), either suction and lavage or suction alone, no routine drain placement, treatment with short-term antibiotics postoperatively for complicated appendicitis, and complicated appendicitis previously treated nonoperatively undergoing interval appendectomy. A conditional recommendation signals that the benefits of adhering to a recommendation probably outweigh the harms although it does also indicate uncertainty. CONCLUSIONS: These recommendations should provide guidance with regard to current controversies in appendicitis. The panel also highlighted future research opportunities where the evidence base can be strengthened.

Analysis of vascular disruption in zebrafish embryos as an endpoint to predict developmental toxicity.

Inhibition of angiogenesis is an important mode of action for the teratogenic effect of chemicals and drugs. There is a gap in the availability of simple, experimental screening models for the detection of angiogenesis inhibition. The zebrafish embryo represents an alternative test system which offers the complexity of developmental differentiation of an entire organism while allowing for small-scale and high-throughput screening. Here we present a novel automated imaging-based method to detect the inhibition of angiogenesis in early life stage zebrafish. Video subtraction was used to identify the location and number of functional intersegmental vessels according to the detection of moving blood cells. By exposing embryos to multiple tyrosine kinase inhibitors including SU4312, SU5416, Sorafenib, or PTK787, we confirmed that this method can detect concentration-dependent inhibition of angiogenesis. Parallel assessment of arterial and venal aorta ruled out a potential bias by impaired heart or blood cell development. In contrast, the histone deacetylase inhibitor valproic acid did not affect ISV formation supporting the specificity of the angiogenic effects. The new test method showed higher sensitivity, i.e. lower effect concentrations, relative to a fluorescent reporter gene strain (Tg(KDR:EGFP)) exposed to the same tyrosine kinase inhibitors indicating that functional effects due to altered tubulogenesis or blood transport can be detected before structural changes of the endothelium are visible by fluorescence imaging. Comparison of exposure windows indicated higher specificity for angiogenesis when exposure started at later embryonic stages (24 h post-fertilization). One of the test compounds was showing particularly high specificity for angiogenesis effects (SU4312) and was, therefore, suggested as a model compound for the identification of molecular markers of angiogenic disruption. Our findings establish video imaging in wild-type strains as viable, non-invasive, high-throughput method for the detection of chemical-induced angiogenic disruption in zebrafish embryos.

Molecular signatures of angiogenesis inhibitors: a single-embryo untargeted metabolomics approach in zebrafish.

Angiogenesis is a key process in embryonic development, a disruption of this process can lead to severe developmental defects, such as limb malformations. The identification of molecular perturbations representative of antiangiogenesis in zebrafish embryo (ZFE) may guide the assessment of developmental toxicity from an endpoint- to a mechanism-based approach, thereby improving the extrapolation of findings to humans. Thus, the aim of the study was to discover molecular changes characteristic of antiangiogenesis and developmental toxicity. We exposed ZFEs to two antiangiogenic drugs (SU4312, sorafenib) and two developmental toxicants (methotrexate, rotenone) with putative antiangiogenic action. Molecular changes were measured by performing untargeted metabolomics in single embryos. The metabolome response was accompanied by the occurrence of morphological alterations. Two distinct metabolic effect patterns were observed. The first pattern comprised common effects of two specific angiogenesis inhibitors and the known teratogen methotrexate, strongly suggesting a shared mode of action of antiangiogenesis and developmental toxicity. The second pattern involved joint effects of methotrexate and rotenone, likely related to disturbances in energy metabolism. The metabolites of the first pattern, such as phosphatidylserines, pterines, retinol, or coenzyme Q precursors, represented potential links to antiangiogenesis and related developmental toxicity. The metabolic effect pattern can contribute to biomarker identification for a mechanism-based toxicological testing.

COVID-19 Vaccine Effectiveness and Digital Pandemic Surveillance in Germany (eCOV Study): Web Application-Based Prospective Observational Cohort Study.

BACKGROUND: The COVID-19 pandemic posed significant challenges to global health systems. Efficient public health responses required a rapid and secure collection of health data to improve the understanding of SARS-CoV-2 and examine the vaccine effectiveness (VE) and drug safety of the novel COVID-19 vaccines. OBJECTIVE: This study (COVID-19 study on vaccinated and unvaccinated subjects over 16 years; eCOV study) aims to (1) evaluate the real-world effectiveness of COVID-19 vaccines through a digital participatory surveillance tool and (2) assess the potential of self-reported data for monitoring key parameters of the COVID-19 pandemic in Germany. METHODS: Using a digital study web application, we collected self-reported data between May 1, 2021, and August 1, 2022, to assess VE, test positivity rates, COVID-19 incidence rates, and adverse events after COVID-19 vaccination. Our primary outcome measure was the VE of SARS-CoV-2 vaccines against laboratory-confirmed SARS-CoV-2 infection. The secondary outcome measures included VE against hospitalization and across different SARS-CoV-2 variants, adverse events after vaccination, and symptoms during infection. Logistic regression models adjusted for confounders were used to estimate VE 4 to 48 weeks after the primary vaccination series and after third-dose vaccination. Unvaccinated participants were compared with age- and gender-matched participants who had received 2 doses of BNT162b2 (Pfizer-BioNTech) and those who had received 3 doses of BNT162b2 and were not infected before the last vaccination. To assess the potential of self-reported digital data, the data were compared with official data from public health authorities. RESULTS: We enrolled 10,077 participants (aged ≥16 y) who contributed 44,786 tests and 5530 symptoms. In this young, primarily female, and digital-literate cohort, VE against infections of any severity waned from 91.2% (95% CI 70.4%-97.4%) at week 4 to 37.2% (95% CI 23.5%-48.5%) at week 48 after the second dose of BNT162b2. A third dose of BNT162b2 increased VE to 67.6% (95% CI 50.3%-78.8%) after 4 weeks. The low number of reported hospitalizations limited our ability to calculate VE against hospitalization. Adverse events after vaccination were consistent with previously published research. Seven-day incidences and test positivity rates reflected the course of the pandemic in Germany when compared with official numbers from the national infectious disease surveillance system. CONCLUSIONS: Our data indicate that COVID-19 vaccinations are safe and effective, and third-dose vaccinations partially restore protection against SARS-CoV-2 infection. The study showcased the successful use of a digital study web application for COVID-19 surveillance and continuous monitoring of VE in Germany, highlighting its potential to accelerate public health decision-making. Addressing biases in digital data collection is vital to ensure the accuracy and reliability of digital solutions as public health tools.

Increased Use and Large Variation in Strong Opioids and Metamizole (Dipyrone) for Minor and Major Musculoskeletal Injuries Between 2008 and 2018: An Analysis of a Representative Sample of Swiss Workers.

PURPOSE: Musculoskeletal (MSK) injuries are a major contributing factor for chronic pain. To date, little is known how pain medication use in MSK injuries has changed over time. We assessed pain medication prescription for MSK injuries in a representative sample of Swiss workers between 2008 and 2018. METHODS: Retrospective analysis of the Swiss Accident Insurance Fund (Suva) data. We calculated annual pain medication use, treatment days, and costs associated with pain medication use in minor and major MSK injuries. RESULTS: In total, 1,921,382 cases with MSK injuries with ≥ 1 pain medication were analyzed. Whereas MSK injuries with ≥ 1 pain medication increased by 9.4%, we observed a larger increase in metamizole (+ 254%), strong opioids (+ 88.4%), coxibs (+ 85.8%), and paracetamol (+ 28.1%). Strong opioids were increasingly used in minor (+ 91.4%) and major (+ 88.3%) injuries. The increase in metamizole (+ 390.6%) and coxibs (+ 115.5%) was larger in minor injuries compared to major injuries (+ 238.7% and + 80.6%, respectively). Medical expenses decreased in all medications except for strong opioids where a substantial increase was observed (+ 192.4% in minor; + 34% in major injuries). CONCLUSIONS: We observed a disproportionate increase in metamizole, strong opioids, coxibs, and paracetamol prescriptions even in minor MSK injuries between 2008 and 2018. Whereas treatment costs decreased for all pain medications, there was a substantial increase in strong opioids. A more liberal prescription practice of opioids conflict with current evidence-based practice recommendations and need to be addressed by physicians and policy makers.

Association Between Antibiotic Redosing Before Incision and Risk of Incisional Site Infection in Children With Appendicitis.

OBJECTIVE: To evaluate whether redosing antibiotics within an hour of incision is associated with a reduction in incisional surgical site infection (iSSI) in children with appendicitis. BACKGROUND: Existing data remain conflicting as to whether children with appendicitis receiving antibiotics at diagnosis benefit from antibiotic redosing before incision. METHODS: This was a multicenter retrospective cohort study using data from the Pediatric National Surgical Quality Improvement Program augmented with antibiotic utilization and operative report data obtained though supplemental chart review. Children undergoing appendectomy at 14 hospitals participating in the Eastern Pediatric Surgery Network from July 2016 to June 2020 who received antibiotics upon diagnosis of appendicitis between 1 and 6 hours before incision were included. Multivariable logistic regression was used to compare odds of iSSI in those who were and were not redosed with antibiotics within 1 hour of incision, adjusting for patient demographics, disease severity, antibiotic agents, and hospital-level clustering of events. RESULTS: A total of 3533 children from 14 hospitals were included. Overall, 46.5% were redosed (hospital range: 1.8%-94.4%, P <0.001) and iSSI rates were similar between groups [redosed: 1.2% vs non-redosed: 1.3%; odds ratio (OR) 0.84, (95%,CI, 0.39-1.83)]. In subgroup analyses, redosing was associated with lower iSSI rates when cefoxitin was used as the initial antibiotic (redosed: 1.0% vs nonredosed: 2.5%; OR: 0.38, (95% CI, 0.17-0.84)], but no benefit was found with other antibiotic regimens, longer periods between initial antibiotic administration and incision, or with increased disease severity. CONCLUSIONS: Redosing of antibiotics within 1 hour of incision in children who received their initial dose within 6 hours of incision was not associated with reduction in risk of incisional site infection unless cefoxitin was used as the initial antibiotic.

Use of Antipseudomonal Antibiotics is not Associated with Lower Rates of Postoperative Drainage Procedures or More Favorable Culture Profiles in Children with Complicated Appendicitis: Results from a Multicenter Regional Research Consortium.

OBJECTIVE: To compare rates of postoperative drainage and culture profiles in children with complicated appendicitis treated with the two most common antibiotic regimens with and without antipseudomonal activity (piperacillin-tazobactam [PT] and ceftriaxone with metronidazole [CM]). SUMMARY OF BACKGROUND DATA: Variation in use of antipseudomonal antibiotics has been driven by a paucity of multicenter data reporting clinically relevant, culture-based outcomes. METHODS: Retrospective cohort study of patients with complicated appendicitis (7/2015-6/2020) using NSQIP-Pediatric data from 15 hospitals participating in a regional research consortium. Operative report details, antibiotic utilization, and culture data were obtained through supplemental chart review. Rates of 30-day postoperative drainage and organism-specific culture positivity were compared between groups using mixed effects regression to adjust for clustering after propensity matching on measures of disease severity. RESULTS: 1002 children met criteria for matching (58.9% received CM and 41.1% received PT). In the matched sample of 778 patients, children treated with PT had similar rates of drainage overall (PT: 11.8%, CM: 12.1%; OR 1.44 [OR:0.71-2.94]) and higher rates of drainage associated with growth of any organism (PT: 7.7%, CM: 4.6%; OR 2.41 [95%CI:1.08-5.39]) and Escherichia coli (PT: 4.6%, CM: 1.8%; OR 3.42 [95%CI:1.07-10.92]) compared to treatment with CM. Rates were similar between groups for drainage associated with multiple organisms (PT: 2.6%, CM: 1.5%; OR 3.81 [95%CI:0.96-15.08]) and Pseudomonas (PT: 1.0%, CM: 1.3%; OR 3.42 [95%CI:0.55-21.28]). CONCLUSIONS AND RELEVANCE: Use of antipseudomonal antibiotics is not associated with lower rates of postoperative drainage procedures or more favorable culture profiles in children with complicated appendicitis.

Multicenter Assessment of Cryoanalgesia Use in Minimally Invasive Repair of Pectus Excavatum: A 20-center Retrospective Cohort Study.

OBJECTIVE: To assess the clinical implications of cryoanalgesia for pain management in children undergoing minimally invasive repair of pectus excavatum (MIRPE). BACKGROUND: MIRPE entails significant pain management challenges, often requiring high postoperative opioid use. Cryoanalgesia, which blocks pain signals by temporarily ablating intercostal nerves, has been recently utilized as an analgesic adjunct. We hypothesized that the use of cryoanalgesia during MIRPE would decrease postoperative opioid use and length of stay (LOS). MATERIALS AND METHODS: A multicenter retrospective cohort study of 20 US children's hospitals was conducted of children (age below 18 years) undergoing MIRPE from January 1, 2014, to August 1, 2019. Differences in total postoperative, inpatient, oral morphine equivalents per kilogram, and 30-day LOS between patients who received cryoanalgesia versus those who did not were assessed using bivariate and multivariable analysis. P value <0.05 is considered significant. RESULTS: Of 898 patients, 136 (15%) received cryoanalgesia. Groups were similar by age, sex, body mass index, comorbidities, and Haller index. Receipt of cryoanalgesia was associated with lower oral morphine equivalents per kilogram (risk ratio=0.43, 95% confidence interval: 0.33-0.57) and a shorter LOS (risk ratio=0.66, 95% confidence interval: 0.50-0.87). Complications were similar between groups (29.8% vs 22.1, P =0.07), including a similar rate of emergency department visit, readmission, and/or reoperation. CONCLUSIONS: Use of cryoanalgesia during MIRPE appears to be effective in lowering postoperative opioid requirements and LOS without increasing complication rates. With the exception of preoperative gabapentin, other adjuncts appear to increase and/or be ineffective at reducing opioid utilization. Cryoanalgesia should be considered for patients undergoing this surgery.

Uptake and Biotransformation of the Tire Rubber-derived Contaminants 6-PPD and 6-PPD Quinone in the Zebrafish Embryo (Danio rerio).

N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine (6-PPD) is a widely used antioxidant in tire rubber known to enter the aquatic environment via road runoff. The associated transformation product (TP) 6-PPD quinone (6-PPDQ) causes extreme acute toxicity in some fish species (e.g., coho salmon). To interpret the species-specific toxicity, information about biotransformation products of 6-PPDQ would be relevant. This study investigated toxicokinetics of 6-PPD and 6-PPDQ in the zebrafish embryo (ZFE) model. Over 96 h of exposure, 6-PPD and 6-PPDQ accumulated in the ZFE with concentration factors ranging from 140 to 2500 for 6-PPD and 70 to 220 for 6-PPDQ. A total of 22 TPs of 6-PPD and 12 TPs of 6-PPDQ were tentatively identified using liquid chromatography coupled to high-resolution mass spectrometry. After 96 h of exposure to 6-PPD, the TPs of 6-PPD comprised 47% of the total peak area (TPA), with 4-hydroxydiphenylamine being the most prominent in the ZFE. Upon 6-PPDQ exposure, >95% of 6-PPDQ taken up in the ZFE was biotransformed, with 6-PPDQ + O + glucuronide dominating (>80% of the TPA). Among other TPs of 6-PPD, a reactive N-phenyl-p-benzoquinone imine was found. The knowledge of TPs of 6-PPD and 6-PPDQ from this study may support biotransformation studies in other organisms.

Effect of risk status for severe COVID-19 on individual contact behaviour during the SARS-CoV-2 pandemic in 2020/2021-an analysis based on the German COVIMOD study.

BACKGROUND: One of the primary aims of contact restriction measures during the SARS-CoV-2 pandemic has been to protect people at increased risk of severe disease from the virus. Knowledge about the uptake of contact restriction measures in this group is critical for public health decision-making. We analysed data from the German contact survey COVIMOD to assess differences in contact patterns based on risk status, and compared this to pre-pandemic data to establish whether there was a differential response to contact reduction measures. METHODS: We quantified differences in contact patterns according to risk status by fitting a generalised linear model accounting for within-participant clustering to contact data from 31 COVIMOD survey waves (April 2020-December 2021), and estimated the population-averaged ratio of mean contacts of persons with high risk for a severe COVID-19 outcome due to age or underlying health conditions, to those without. We then compared the results to pre-pandemic data from the contact surveys HaBIDS and POLYMOD. RESULTS: Averaged across all analysed waves, COVIMOD participants reported a mean of 3.21 (95% confidence interval (95%CI) 3.14,3.28) daily contacts (truncated at 100), compared to 18.10 (95%CI 17.12,19.06) in POLYMOD and 28.27 (95%CI 26.49,30.15) in HaBIDS. After adjusting for confounders, COVIMOD participants aged 65 or above had 0.83 times (95%CI 0.79,0.87) the number of contacts as younger age groups. In POLYMOD, this ratio was 0.36 (95%CI 0.30,0.43). There was no clear difference in contact patterns due to increased risk from underlying health conditions in either HaBIDS or COVIMOD. We also found that persons in COVIMOD at high risk due to old age increased their non-household contacts less than those not at such risk after strict restriction measures were lifted. CONCLUSIONS: Over the course of the SARS-CoV-2 pandemic, there was a general reduction in contact numbers in the German population and also a differential response to contact restriction measures based on risk status for severe COVID-19. This differential response needs to be taken into account for parametrisations of mathematical models in a pandemic setting.

Application of AOPs to assist regulatory assessment of chemical risks - Case studies, needs and recommendations.

While human regulatory risk assessment (RA) still largely relies on animal studies, new approach methodologies (NAMs) based on in vitro, in silico or non-mammalian alternative models are increasingly used to evaluate chemical hazards. Moreover, human epidemiological studies with biomarkers of effect (BoE) also play an invaluable role in identifying health effects associated with chemical exposures. To move towards the next generation risk assessment (NGRA), it is therefore crucial to establish bridges between NAMs and standard approaches, and to establish processes for increasing mechanistically-based biological plausibility in human studies. The Adverse Outcome Pathway (AOP) framework constitutes an important tool to address these needs but, despite a significant increase in knowledge and awareness, the use of AOPs in chemical RA remains limited. The objective of this paper is to address issues related to using AOPs in a regulatory context from various perspectives as it was discussed in a workshop organized within the European Union partnerships HBM4EU and PARC in spring 2022. The paper presents examples where the AOP framework has been proven useful for the human RA process, particularly in hazard prioritization and characterization, in integrated approaches to testing and assessment (IATA), and in the identification and validation of BoE in epidemiological studies. Nevertheless, several limitations were identified that hinder the optimal usability and acceptance of AOPs by the regulatory community including the lack of quantitative information on response-response relationships and of efficient ways to map chemical data (exposure and toxicity) onto AOPs. The paper summarizes suggestions, ongoing initiatives and third-party tools that may help to overcome these obstacles and thus assure better implementation of AOPs in the NGRA.

Diagnosis and treatment of appendicitis: systematic review and meta-analysis.

BACKGROUND: The optimal diagnosis and treatment of appendicitis remains controversial. This systematic review details the evidence and current best practices for the evaluation and management of uncomplicated and complicated appendicitis in adults and children. METHODS: Eight questions regarding the diagnosis and management of appendicitis were formulated. PubMed, Embase, CINAHL, Cochrane and clinicaltrials.gov/NLM were queried for articles published from 2010 to 2022 with key words related to at least one question. Randomized and non-randomized studies were included. Two reviewers screened each publication for eligibility and then extracted data from eligible studies. Random effects meta-analyses were performed on all quantitative data. The quality of randomized and non-randomized studies was assessed using the Cochrane Risk of Bias 2.0 or Newcastle Ottawa Scale, respectively. RESULTS: 2792 studies were screened and 261 were included. Most had a high risk of bias. Computerized tomography scan yielded the highest sensitivity (> 80%) and specificity (> 93%) in the adult population, although high variability existed. In adults with uncomplicated appendicitis, non-operative management resulted in higher odds of readmission (OR 6.10) and need for operation (OR 20.09), but less time to return to work/school (SMD - 1.78). In pediatric patients with uncomplicated appendicitis, non-operative management also resulted in higher odds of need for operation (OR 38.31). In adult patients with complicated appendicitis, there were higher odds of need for operation following antibiotic treatment only (OR 29.00), while pediatric patients had higher odds of abscess formation (OR 2.23). In pediatric patients undergoing appendectomy for complicated appendicitis, higher risk of reoperation at any time point was observed in patients who had drains placed at the time of operation (RR 2.04). CONCLUSIONS: This review demonstrates the diagnosis and treatment of appendicitis remains nuanced. A personalized approach and appropriate patient selection remain key to treatment success. Further research on controversies in treatment would be useful for optimal management.

Modernizing persistence-bioaccumulation-toxicity (PBT) assessment with high throughput animal-free methods.

The assessment of persistence (P), bioaccumulation (B), and toxicity (T) of a chemical is a crucial first step at ensuring chemical safety and is a cornerstone of the European Union's chemicals regulation REACH (Registration, Evaluation, Authorization, and Restriction of Chemicals). Existing methods for PBT assessment are overly complex and cumbersome, have produced incorrect conclusions, and rely heavily on animal-intensive testing. We explore how new-approach methodologies (NAMs) can overcome the limitations of current PBT assessment. We propose two innovative hazard indicators, termed cumulative toxicity equivalents (CTE) and persistent toxicity equivalents (PTE). Together they are intended to replace existing PBT indicators and can also accommodate the emerging concept of PMT (where M stands for mobility). The proposed "toxicity equivalents" can be measured with high throughput in vitro bioassays. CTE refers to the toxic effects measured directly in any given sample, including single chemicals, substitution products, or mixtures. PTE is the equivalent measure of cumulative toxicity equivalents measured after simulated environmental degradation of the sample. With an appropriate panel of animal-free or alternative in vitro bioassays, CTE and PTE comprise key environmental and human health hazard indicators. CTE and PTE do not require analytical identification of transformation products and mixture components but instead prompt two key questions: is the chemical or mixture toxic, and is this toxicity persistent or can it be attenuated by environmental degradation? Taken together, the proposed hazard indicators CTE and PTE have the potential to integrate P, B/M and T assessment into one high-throughput experimental workflow that sidesteps the need for analytical measurements and will support the Chemicals Strategy for Sustainability of the European Union.

Post-COVID-19-associated morbidity in children, adolescents, and adults: A matched cohort study including more than 157,000 individuals with COVID-19 in Germany.

BACKGROUND: Long-term health sequelae of the Coronavirus Disease 2019 (COVID-19) are a major public health concern. However, evidence on post-acute COVID-19 syndrome (post-COVID-19) is still limited, particularly for children and adolescents. Utilizing comprehensive healthcare data on approximately 46% of the German population, we investigated post-COVID-19-associated morbidity in children/adolescents and adults. METHODS AND FINDINGS: We used routine data from German statutory health insurance organizations covering the period between January 1, 2019 and December 31, 2020. The base population included all individuals insured for at least 1 day in 2020. Based on documented diagnoses, we identified individuals with polymerase chain reaction (PCR)-confirmed COVID-19 through June 30, 2020. A control cohort was assigned using 1:5 exact matching on age and sex, and propensity score matching on preexisting medical conditions. The date of COVID-19 diagnosis was used as index date for both cohorts, which were followed for incident morbidity outcomes documented in the second quarter after index date or later.Overall, 96 prespecified outcomes were aggregated into 13 diagnosis/symptom complexes and 3 domains (physical health, mental health, and physical/mental overlap domain). We used Poisson regression to estimate incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs). The study population included 11,950 children/adolescents (48.1% female, 67.2% aged between 0 and 11 years) and 145,184 adults (60.2% female, 51.1% aged between 18 and 49 years). The mean follow-up time was 236 days (standard deviation (SD) = 44 days, range = 121 to 339 days) in children/adolescents and 254 days (SD = 36 days, range = 93 to 340 days) in adults. COVID-19 and control cohort were well balanced regarding covariates. The specific outcomes with the highest IRR and an incidence rate (IR) of at least 1/100 person-years in the COVID-19 cohort in children and adolescents were malaise/fatigue/exhaustion (IRR: 2.28, 95% CI: 1.71 to 3.06, p < 0.01, IR COVID-19: 12.58, IR Control: 5.51), cough (IRR: 1.74, 95% CI: 1.48 to 2.04, p < 0.01, IR COVID-19: 36.56, IR Control: 21.06), and throat/chest pain (IRR: 1.72, 95% CI: 1.39 to 2.12, p < 0.01, IR COVID-19: 20.01, IR Control: 11.66). In adults, these included disturbances of smell and taste (IRR: 6.69, 95% CI: 5.88 to 7.60, p < 0.01, IR COVID-19: 12.42, IR Control: 1.86), fever (IRR: 3.33, 95% CI: 3.01 to 3.68, p < 0.01, IR COVID-19: 11.53, IR Control: 3.46), and dyspnea (IRR: 2.88, 95% CI: 2.74 to 3.02, p < 0.01, IR COVID-19: 43.91, IR Control: 15.27). For all health outcomes combined, IRs per 1,000 person-years in the COVID-19 cohort were significantly higher than those in the control cohort in both children/adolescents (IRR: 1.30, 95% CI: 1.25 to 1.35, p < 0.01, IR COVID-19: 436.91, IR Control: 335.98) and adults (IRR: 1.33, 95% CI: 1.31 to 1.34, p < 0.01, IR COVID-19: 615.82, IR Control: 464.15). The relative magnitude of increased documented morbidity was similar for the physical, mental, and physical/mental overlap domain. In the COVID-19 cohort, IRs were significantly higher in all 13 diagnosis/symptom complexes in adults and in 10 diagnosis/symptom complexes in children/adolescents. IRR estimates were similar for age groups 0 to 11 and 12 to 17. IRs in children/adolescents were consistently lower than those in adults. Limitations of our study include potentially unmeasured confounding and detection bias. CONCLUSIONS: In this retrospective matched cohort study, we observed significant new onset morbidity in children, adolescents, and adults across 13 prespecified diagnosis/symptom complexes, following COVID-19 infection. These findings expand the existing available evidence on post-COVID-19 conditions in younger age groups and confirm previous findings in adults. TRIAL REGISTRATION: ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05074953.

A SAGES technology and value assessment and pediatric committee evaluation of mini-laparoscopic instrumentation.

BACKGROUND: The TAVAC and Pediatric Committees of SAGES evaluated the current use of mini-laparoscopic instrumentation to better understand the role this category of devices plays in the delivery of minimally invasive surgery today. METHODS: The role of mini-laparoscopic instrumentation, defined as minimally invasive instruments of between 1 and 4 mm in diameter, was assessed by an exhaustive review of the peer reviewed literature on the subject between 1990 and 2021. The instruments, their use, and their perceived value were tabulated and described. RESULTS: Several reported studies propose a value to using mini-laparoscopic instrumentation over the use of larger instruments or as minimally invasive additions to commonly performed procedures. Additionally, specifically developed smaller-diameter instruments appear to be beneficial additions to our minimally invasive toolbox. CONCLUSIONS: The development of small instrumentation for the effective performance of minimally invasive surgery, while perhaps best suited to pediatric populations, proves useful as adjuncts to a wide variety of adult surgical procedures. Mini-laparoscopic instrumentation thus proves valuable in selected cases.

Inhibition of neurite outgrowth and enhanced effects compared to baseline toxicity in SH-SY5Y cells.

Early life exposure to environmental chemicals can cause developmental neurotoxicity (DNT). The impairment of key neurodevelopmental processes such as neurite outgrowth inhibition can be used as endpoints for screening of DNT effects. We quantified neurite-specific effects using the ratio of effect concentrations for cytotoxicity and neurite outgrowth inhibition (SRcytotoxicity). Baseline cytotoxicity, the minimal toxicity of any chemical, was used to quantify enhanced cytotoxicity (toxic ratio, TR) and neuronal-specific toxicity (SRbaseline) by comparing baseline cytotoxicity with the effects on cell viability and neurite outgrowth, respectively. The effects on cell viability and neurite length were measured based on image analysis in human neuroblastoma SH-SY5Y cells. Baseline cytotoxicity was predicted from hydrophobicity descriptors using a previously published model for SH-SY5Y cells. Enhanced cytotoxicity and neuronal-specific toxicity were more often observed for hydrophilic chemicals, which indicates that they are more likely to act through specific modes of action (MOA) on cell viability and neurite outgrowth. Hydrophobic chemicals showed a tendency to act through baseline toxicity without showing specific or enhanced toxicity, but were highly potent considering their low effect concentrations for both cytotoxicity and neurite outgrowth inhibition. The endpoint-specific controls (narciclasine, colchicine, cycloheximide, and rotenone), two carbamates (3-hydroxycarbofuran and carbaryl), and two redox cyclers (diquat and paraquat) showed distinct neurite-specific effects (SRcytotoxicity > 4). By comparing neurite-specific effects with enhanced cytotoxicity, one can explain whether the observed effects involve specific inhibition of neurite outgrowth, other specific MOAs, or merely baseline toxicity arising from hydrophobicity.