Intraperitoneal activation of myeloid cells clears ascites and reveals IL27-dependent regression of metastatic ovarian cancer.

Patients with metastatic ovarian cancer (OvCa) have a 5-year survival rate of less than 30% due to persisting dissemination of chemoresistant cells in the peritoneal fluid and the immunosuppressive microenvironment in the peritoneal cavity. Here, we report that intraperitoneal administration of ß-glucan and IFNγ (BI) induced robust tumor regression in clinically relevant models of metastatic OvCa. BI induced tumor regression by controlling fluid tumor burden and activating localized antitumor immunity. ß-glucan alone cleared ascites and eliminated fluid tumor cells by inducing intraperitoneal clotting in the fluid and Dectin-1-Syk-dependent NETosis in the omentum. In omentum tumors, BI expanded a novel subset of immunostimulatory IL27+ macrophages and neutralizing IL27 impaired BI efficacy in vivo. Moreover, BI directly induced IL27 secretion in macrophages where single agent treatment did not. Finally, BI extended mouse survival in a chemoresistant model and significantly improved chemotherapy response in a chemo-sensitive model. In summary, we propose a new therapeutic strategy for the treatment of metastatic OvCa.

Correlations of Postural Stability to Proprioception, Tactile Sensation, and Strength Among People With Chronic Ankle Instability.

OBJECTIVES: The static and dynamic correlations of postural stability to its three potential contributors, namely, proprioception, tactile sensation, and strength remain unclear among people with chronic ankle instability (CAI). This study aimed to compare static and dynamic postural stability, along with proprioception, tactile sensation, and strength between people with and without CAI and explore their correlations. METHODS: Sixty-seven participants with CAI and 67 participants without CAI were enrolled in this study. Ankle proprioception, plantar tactile sensation, and lower limb strength were measured by a proprioception test device, a set of monofilaments, and a strength testing system, respectively. Static and dynamic postural stability were measured during standing and jump landing on a force plate and indicated by the root mean square of center of pressure and time to stability. RESULTS: Compared to people without CAI, people with CAI had poorer postural stability, proprioception, tactile sensation, and strength. Both groups demonstrated correlation between proprioception and static postural stability, but only people without CAI showed correlation between proprioception and dynamic postural stability. Both groups demonstrated a correlation between tactile sensation and static postural stability, but not with dynamic stability. Both groups demonstrated a correlation between strength and both static and dynamic postural stability. CONCLUSIONS: People with CAI had deficits in static and dynamic postural stability, proprioception, tactile sensation, and strength. Among people with CAI, proprioception, tactile sensation, and strength can help maintain static postural stability; strength can help maintain dynamic postural stability, whereas proprioception may not provide sufficient information for dynamic postural stability.

Salvianolic acid B inhibits thrombosis and directly blocks the thrombin catalytic site.

Background: Salvianolic acid B (SAB) is a major component of Salvia miltiorrhiza root (Danshen), widely used in East/Southeast Asia for centuries to treat cardiovascular diseases. Danshen depside salt, 85% of which is made up of SAB, is approved in China to treat chronic angina. Although clinical observations suggest that Danshen extracts inhibited arterial and venous thrombosis, the exact mechanism has not been adequately elucidated. Objective: To delineate the antithrombotic mechanisms of SAB. Methods: We applied platelet aggregation and coagulation assays, perfusion chambers, and intravital microscopy models. The inhibition kinetics and binding affinity of SAB to thrombin are measured by thrombin enzymatic assays, intrinsic fluorescence spectrophotometry, and isothermal titration calorimetry. We used molecular in silico docking models to predict the interactions of SAB with thrombin. Results: SAB dose-dependently inhibited platelet activation and aggregation induced by thrombin. SAB also reduced platelet aggregation induced by adenosine diphosphate and collagen. SAB attenuated blood coagulation by modifying fibrin network structures and significantly decreased thrombus formation in mouse cremaster arterioles and perfusion chambers. The direct SAB-thrombin interaction was confirmed by enzymatic assays, intrinsic fluorescence spectrophotometry, and isothermal titration calorimetry. Interestingly, SAB shares key structural similarities with the trisubstituted benzimidazole class of thrombin inhibitors, such as dabigatran. Molecular docking models predicted the binding of SAB to the thrombin active site. Conclusion: Our data established SAB as the first herb-derived direct thrombin catalytic site inhibitor, suppressing thrombosis through both thrombin-dependent and thrombin-independent pathways. Purified SAB may be a cost-effective agent for treating arterial and deep vein thrombosis.

Changes in cannabis involvement in emergency department visits for anxiety disorders after cannabis legalization: a repeated cross-sectional study.

Background: An increasing number of countries have or are considering legalizing cannabis. One concern is that legalization of cannabis will result in increased cannabis use and in turn a higher prevalence of anxiety disorders. We examined changes in emergency department (ED) visits for anxiety disorders with cannabis involvement in Ontario, over a period that involved medical and non-medical cannabis legalization. Methods: This repeated cross-sectional population-based study identified all ED visits for anxiety disorders from residents of Ontario, Canada aged 10-105 between 2008 and 2022 (n = 15.7 million individuals). We used interrupted time series analyses to examine immediate and gradual changes in cannabis-involvement and alcohol-involvement (control condition) over four policy periods: medical cannabis legalization (January 2008-November 2015), expanded medical access (December 2015-September 2018), non-medical cannabis legalization with restrictions (October 2018-February 2020), and commercialization which overlapped with the COVID-19 pandemic (March 2020-December 2022). Poisson models were used to generate incidence rate ratios with 95% confidence intervals. Findings: Over the 14-year study, there were 438,700 individuals with one or more ED visits for anxiety disorders of which 3880 (0.89%) individuals had cannabis involvement and 6329 (1.45%) individuals had alcohol involvement. During the commercialization/COVID-19 period monthly rates of anxiety disorders with cannabis-involvement were 156% higher (0.11 vs 0.29 per 100,000 individuals) relative to the pre-legalization period, compared to a 27% increase for alcohol-involvement (0.27 vs 0.35 per 1100,000 individuals). Rates of anxiety ED visits with cannabis involvement per 100,000 individuals increased gradually over the study period with no immediate or gradual changes after expanded medical access, legalization with restrictions or commercialization/COVID-19. However, during the commercialization/COVID-19 period there were large declines in total anxiety disorder ED visits and anxiety disorder ED visits with alcohol-involvement. Consequently, during this period there was an immediate 31.4% relative increase in the proportion of anxiety visits with cannabis-involvement (incidence rate ratio [IRR], 1.31; 95% CI 1.05-1.65). Interpretation: We found large relative increases in anxiety disorder ED visits with cannabis involvement over a 14-year period involving medical and non-medical cannabis legalization. These findings may reflect increasing anxiety disorder problems from cannabis use, increasing self-medication of anxiety disorders with cannabis use, or both. The proportion of anxiety ED visits with cannabis involvement increased during the final period of the study but could have been the results of the market commercialization, COVID-19 or both and ongoing monitoring is indicated. Funding: Canadian Institutes of Health Research (grant #452360).

Sclerosing Mesenteritis Presenting With Small Bowel Obstruction in a Patient With Systemic Lupus Erythematosus: A Case Report.

Sclerosing mesenteritis (SM) is a rare inflammatory disorder characterized by chronic inflammation and fibrosis of the mesenteric adipose tissue. While SM can manifest with various gastrointestinal symptoms, its association with small bowel obstruction (SBO) is infrequent. We present a case of a 78-year-old male with a history of systemic lupus erythematosus (SLE) who presented with acute abdominal pain and distention. The patient had multiple admissions with the same symptoms. A CT scan showed swirling of the proximal central mesentery, small bowel malrotation with volvulus, and high-grade mechanical obstruction of the proximal jejunum. The patient underwent exploratory laparotomy, with findings significant for multiple inflammatory nodules in the mesentery. These were causing adhesions between the bowel and mesentery, resulting in a volvulus of the bowel. One segment was resected, and subsequent histopathological examination revealed subserosal fibrosis and chronic inflammation. The clinical scenario was consistent with a diagnosis of SM. This case highlights the challenges of diagnosing and managing SBO in the presence of SM and SLE. Further research is needed to understand the underlying pathophysiological mechanisms and improve management techniques for this rare clinical condition.

Extra-articular proximal tibia fracture fixation with locked plating versus intramedullary nailing: A meta-analysis.

OBJECTIVES: This study compared outcomes of locked plating (LP) versus intramedullary nailing (IMN) techniques for treatment of extra-articular proximal-third tibia fractures. METHODS: Data Sources: PubMed, Ovid MEDLINE STUDY SELECTION: Studies were included if they compared LP and IMN fixation for proximal one third tibial shaft fractures without articular extension or with simple articular extension into the tibial plateau. Minimum 1 year of clinical and radiographic follow up was used. DATA EXTRACTION: Outcomes assessed included operative duration, postoperative knee range of motion (ROM), union outcomes (time to union, nonunion, malunion, delayed union), and incidence of postoperative complications (superficial and deep infection, secondary surgical intervention, compartment syndrome). DATA SYNTHESIS: Separate random-effects meta-analyses were conducted for each outcome. For categorical data, relative risks were used whereas the standardized mean difference was used for continuous variables, with corresponding 95 % confidence intervals. RESULTS: 7 studies were included reporting the outcomes of 319 patients treated with LP and 300 treated with IMN. IMN fixation had significantly shorter time to union (p = 0.049) and lower risk for superficial infection (p = 0.028). However, LP conferred a significantly lower risk for malunion (p = 0.017) and postoperative compartment syndrome (p = 0.018). CONCLUSION: IMN demonstrated significantly shorter time to union and lower risk of superficial infection when treating extra-articular proximal tibia fractures, while LP fixation demonstrated significantly lower risk for malunion and postoperative compartment syndrome. Although successful results can be achieved with good technique in LP and IMN fixation, a significant complication profile exists with these fractures regardless of construct choice. LEVEL OF EVIDENCE: Therapeutic Level III.

Stereotactic Body Radiation Therapy (SBRT) for Pancreatic Cancer: A Radiosurgery Society Case-Based Practical Guidelines to Challenging Cases.

The use of radiation therapy (RT) for pancreatic cancer continues to be controversial despite recent technical advances. Improvements in systemic control have created an evolving role for RT and the need for improved local tumor control but currently no standardized approach exists. Advances in stereotactic body radiation therapy (SBRT), motion management, real time image guidance and adaptive therapy have renewed hopes of improved outcomes in this devastating disease with one of the lowest survival rates. This case-based guide provides a practical framework for delivering SBRT for locally advanced pancreatic cancer. In conjunction with multidisciplinary care, an intradisciplinary approach should guide treatment of the high-risk cases outlined within these guidelines for prospective peer review and treatment safety discussions.

Lisfranc Open Reduction and Internal Fixation.

VIDEO AVAILABLE AT: https://ota.org/education/ota-online-resources/video-library-procedures-techniques/lisfranc-open-reduction-and.

Precise in vivo RNA base editing with a wobble-enhanced circular CLUSTER guide RNA.

Recruiting the endogenous editing enzyme adenosine deaminase acting on RNA (ADAR) with tailored guide RNAs for adenosine-to-inosine (A-to-I) RNA base editing is promising for safely manipulating genetic information at the RNA level. However, the precision and efficiency of editing are often compromised by bystander off-target editing. Here, we find that in 5'-UAN triplets, which dominate bystander editing, G•U wobble base pairs effectively mitigate off-target events while maintaining high on-target efficiency. This strategy is universally applicable to existing A-to-I RNA base-editing systems and complements other suppression methods such as G•A mismatches and uridine (U) depletion. Combining wobble base pairing with a circularized format of the CLUSTER approach achieves highly precise and efficient editing (up to 87%) of a disease-relevant mutation in the Mecp2 transcript in cell culture. Virus-mediated delivery of the guide RNA alone realizes functional MeCP2 protein restoration in the central nervous system of a murine Rett syndrome model with editing yields of up to 19% and excellent bystander control in vivo.

Mother's Milk Donation to a Human Milk Bank During Bereavement: Circumstances Associated with Completing the Donation Process.

Background: Bereaved mothers describe positive experiences donating breast milk and negative experiences when not informed of opportunities to donate. Predictors of whether mothers donate milk are unknown, impairing efforts to optimize support in completing donation. Objective: To define circumstances associated with completing mother's milk (MM) donation during bereavement. Methods: A retrospective cohort study included dyads of bereaved mothers and their deceased children if a child's death occurred on-site at a quaternary care children's hospital during 2016-2020, the child had documentation of MM availability, and age at death <24 months. The primary outcome was the completion of MM donation to the milk bank. Multivariate logistic regression measured associations between clinical variables and odds of completion. Results: Of 124 deceased children with documented MM exposure, 34 mothers (28%) of 35 of those children completed MM donation, donating a mean of 13.7 liters (SD 16.8). The child's race/ethnicity documented in the medical record was White for 25 (71%), Black/African American (AA) for 1 (3%), Asian for 1 (3%), and Hispanic/Latino for 8 (23%). Referenced to mothers of White children, being a mother of an AA [OR 0.05 (95% CI: 0.01-0.43)] or Asian [0.08 (0.01-0.75)] child was associated with lower odds of donation. Referenced to mothers delivering full term (≥37 weeks'), mothers delivering <34 weeks showed higher odds [5.0 (1.5-17.5)] of donation. Conclusion: Relatively few bereaved mothers of children with indicators of MM exposure completed donation. The results suggest an opportunity to ensure bereaved mothers are uniformly informed and supported in donating.

Corrigendum: Translatability of findings from cynomolgus monkey to human suggests a mechanistic role for IL-21 in promoting immunogenicity to an anti-PD-1/IL-21 mutein fusion protein.

[This corrects the article DOI: 10.3389/fimmu.2024.1345473.].

Enhancing running injury prevention strategies with real-time biofeedback: A systematic review and meta-analysis.

The number of runners and the incidence of running-related injuries (RRIs) are on the rise. Real-time biofeedback gait retraining offers a promising approach to RRIs prevention. However, due to the diversity in study designs and reported outcomes, there remains uncertainty regarding the efficacy of different forms of feedback on running gait biomechanics. Three databases: MEDLINE, PUBMED, and SPORTDiscus were searched to identify relevant studies published up to March 2024, yielding 4646 articles for review. The quality of the included studies was assessed using the Downs and Black Quality checklist. Primary outcomes, including Peak Tibial Acceleration (PTA), Vertical Average Loading Rate (VALR), and Vertical Instantaneous Loading Rate (VILR), were analysed through meta-analysis. 24 studies met the inclusion criteria and were analysed in this review.17 used visual biofeedback (VB) while 14 chose auditory biofeedback (AB). The meta-analysis revealed a reduction in loading variables both immediately following the intervention and after extended training, with both visual and auditory feedback. Notably, the decrease in loading variables was more pronounced post-training and VB proved to be more effective than AB. Real-time biofeedback interventions are effective in lowering loading variables associated with RRIs. The impact is more substantial with sustained training, and VB outperforms AB in terms of effectiveness.

Visceral adiposity index, fitness and clustered cardiovascular disease risk in adolescents.

BACKGROUND:  Clustering of cardiovascular disease (CVD) risk factors have been observed in children and adolescents, but its association with visceral adiposity index (VAI) and cardiorespiratory fitness (CRF) in adolescents has rarely been studied. AIM:  This study determines the independent associations of VAI and CRF with the clustering of cardiovascular disease risk (CVDr) among Nigerian adolescents. SETTING:  Adolescents from specific secondary schools in Kogi East, North Central Nigeria participated in the study. METHODS:  A cross-sectional sample of 403 adolescents (202 boys and 201 girls) aged 11 years - 19 years were evaluated for VAI, CRF and CVDr. Using identified risk factors, a clustered CVDr score was generated. The association between VAI, CRF and clustered CVDr was evaluated using regression models that controlled for age, gender and maturity status. RESULTS:  Fitness was negatively associated with CVDr (ß = -0.268, p  0.001), while VAI was positively correlated with CVDr (ß = 0.379, p  0.001). After CRF or VAI adjustment, the independent association with the dependent variable remained significant. The odds of an adolescent with elevated VAI being at risk of CVD was 4.7 times higher than his peers. Unfit adolescents were 2.1 times more likely to develop CVDr. CONCLUSION:  Both VAI and CRF were independently associated with the clustering of CVDr in Nigerian adolescents. The findings suggest that health promotion efforts focusing on healthy diet and aerobic-type physical activity programmes should be encouraged among the youth to reduce the risk of CVD.Contribution: This study shows that improving visceral adipose tissue and fitness may lower CVD risk factors in adolescents, which is significant for public health.

Urban birds' tolerance towards humans was largely unaffected by COVID-19 shutdown-induced variation in human presence.

The coronavirus disease 2019 (COVID-19) pandemic and respective shutdowns dramatically altered human activities, potentially changing human pressures on urban-dwelling animals. Here, we use such COVID-19-induced variation in human presence to evaluate, across multiple temporal scales, how urban birds from five countries changed their tolerance towards humans, measured as escape distance. We collected 6369 escape responses for 147 species and found that human numbers in parks at a given hour, day, week or year (before and during shutdowns) had a little effect on birds' escape distances. All effects centered around zero, except for the actual human numbers during escape trial (hourly scale) that correlated negatively, albeit weakly, with escape distance. The results were similar across countries and most species. Our results highlight the resilience of birds to changes in human numbers on multiple temporal scales, the complexities of linking animal fear responses to human behavior, and the challenge of quantifying both simultaneously in situ.

Raoultella ornithinolytica Urinary Tract Infection in a Patient With Triple-Negative Breast Cancer.

Due to the challenges associated with accurately identifying Raoultella ornithinolytica as the causative agent in urinary tract infections (UTIs), coupled with limited guidance on treatment protocols, reports of similar cases still need to be made publicly available because of their increasing emergence. In this article, we present the first documented case of a UTI caused by Raoultella ornithinolytica in a patient with triple-negative breast cancer undergoing neoadjuvant chemotherapy. This case report highlights Raoultella ornithinolytica as an uncommon yet significant pathogen, particularly in immunocompromised patients. Given the bacterium's antibiotic resistance patterns, it emphasizes the importance of prompt, accurate identification methods and tailored treatment strategies, especially in vulnerable populations undergoing chemotherapy.

Netrin signaling mediates survival of dormant epithelial ovarian cancer cells.

Dormancy in cancer is a clinical state in which residual disease remains undetectable for a prolonged duration. At a cellular level, rare cancer cells cease proliferation and survive chemotherapy and disseminate disease. We created a suspension culture model of high-grade serous ovarian cancer (HGSOC) dormancy and devised a novel CRISPR screening approach to identify survival genes in this context. In combination with RNA-seq, we discovered the Netrin signaling pathway as critical to dormant HGSOC cell survival. We demonstrate that Netrin-1, -3, and its receptors are essential for low level ERK activation to promote survival, and that Netrin activation of ERK is unable to induce proliferation. Deletion of all UNC5 family receptors blocks Netrin signaling in HGSOC cells and compromises viability during the dormancy step of dissemination in xenograft assays. Furthermore, we demonstrate that Netrin-1 and -3 overexpression in HGSOC correlates with poor outcome. Specifically, our experiments reveal that Netrin overexpression elevates cell survival in dormant culture conditions and contributes to greater spread of disease in a xenograft model of abdominal dissemination. This study highlights Netrin signaling as a key mediator HGSOC cancer cell dormancy and metastasis.

High-grade serous ovarian cancer (or HGSOC for short) is the fifth leading cause of cancer-related deaths in women. It is generally diagnosed at an advanced stage of disease when the cancer has already spread to other parts of the body. Surgical removal of tumors and subsequent treatment with chemotherapy often reduces the signs and symptoms of the disease for a time but some cancer cells tend to survive so that patients eventually relapse. The HGSOC cells typically spread from the ovaries by moving through the liquid surrounding organs in the abdomen. The cells clump together and enter an inactive state known as dormancy that allows them to survive chemotherapy and low-nutrient conditions. Understanding how to develop new drug therapies that target dormant cancer cells is thought to be an important step in prolonging the life of HGSOC patients. Cancer cells are hardwired to multiply and grow, so Perampalam et al. reasoned that becoming dormant poses challenges for HGSOC cells, which may create unique vulnerabilities not shared by proliferating cancer cells. To find out more, the researchers used HGSOC cells that had been isolated from patients and grown in the laboratory. The team used a gene editing technique to screen HGSOC cells for genes required by the cells to survive when they are dormant. The experiments found that genes involved in a cell signaling pathway, known as Netrin signaling, were critical for the cells to survive. Previous studies have shown that Netrin signaling helps the nervous system form in embryos and inhibits a program of controlled cell death in some cancers. Perampalam et al. discovered that Netrins were present in the environment immediately surrounding dormant HGSOC cells. Human HGSOC patients with higher levels of Netrin gene expression had poorer prognoses than patients with lower levels of Netrin gene expression. Further experiments demonstrated that Netrins help dormant HGSOC cells to spread around the body. These findings suggest that Netrin signalling may provide useful targets for future drug therapies against dormant cells in some ovarian cancers. This could include repurposing drugs already in development or creating new inhibitors of this pathway.

Molecular testing for gastrointestinal pathogens in intestinal tissue of infants with necrotizing enterocolitis or spontaneous intestinal perforation.

OBJECTIVE: The objective of this study was to determine the frequency of common gastrointestinal bacterial, parasitic, and viral pathogen detection in necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP) -associated intestinal tissue. STUDY DESIGN: Retrospective cohort study examined formalin fixed, paraffin embedded (FFPE) surgical or autopsy intestinal tissue from NEC or SIP specimens. DNA and RNA were extracted and analyzed by multiplex PCR panel (GIFA Biofire). DNA or RNA from stool samples containing each pathogen were extracted for positive controls. RESULTS: The total number of intestinal tissue samples were 193 from 310 infants (156 NEC, 37 SIP). Six (3%) infants with stage III NEC tested positive for a target pathogen; 2, C. difficile; 3, Enteroaggregtive E. coli; and 1, Giardia. No gastrointestinal viral pathogens were detected. CONCLUSION: Molecular testing yielded few GI pathogens suggesting that these organisms are likely not major causes or facilitators of NEC or SIP.

Pharmacokinetic and neuroimmune pharmacogenetic impacts on slow-release morphine cancer pain control and adverse effects.

The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in patients without pain control (median (interquartile range) 1.2 (0.7-2.3) versus 1.0 (0.5-1.9) µM, P = 0.006), whereas morphine concentrations were higher in patients with cognitive dysfunction (40 (20-81) versus 29 (14-60) nM, P = 0.02). TLR2 rs3804100 variant carriers had reduced odds (adjusted odds ratio (95% confidence interval) 0.42 (0.22-0.82), P = 0.01) of opioid adverse events. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02-0.63)) and IL6R rs8192284 carrier (0.55 (0.34-0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2-9.3)), odds of sickness response (P ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients.

Epidemiology and multiple colonization of gastrointestinal pathogens in rural Tanzanian children with and without diarrhea: A case-control study.

Diarrheal diseases are important causes of morbidity and mortality, worldwide. The occurrence of multiple pathogens in stool samples of symptomatic and asymptomatic individuals in resource-limited countries have been repeatedly described. In this study, we assessed the differentiated effects of combined pathogen detections on recorded symptoms. A case-control study was conducted among 620 under-five-year-old children in rural northeastern Tanzania with emphasis of multiple detection. The median age of children was 11 months (IQR = 7, 20), and 52.1% were male. Cases (50.2%, n = 157) were less likely than controls (64.5%, n = 198) to have multiple colonization with gastrointestinal tract (GIT) pathogens. The children's age was positively associated with the likelihood of harboring multiple GIT pathogens [OR, 1.02, 95% CI = 1.01, 1.04]. Shigella spp./enteroinvasive Escherichia coli (EIEC) [OR = 2.80, 95% CI 1.62, 4.83] and norovirus [OR = 2.04, 95% CI 1.23, 3.39] were more common in cases and were strongly associated with diarrhea, while enteroaggregative E. coli (EAEC) [OR = 0.23, 95%CI 0.17-0.33] were more common in controls. Diarrheal diseases in under-five children from rural Tanzania are likely to be due to infections with Shigella spp./EIEC, and norovirus with strongly age-dependent associations.