Tacrolimus's Time Below Therapeutic Range Is Associated With Acute Pancreatic Graft Rejection and the Development of De Novo Donor-specific Antibodies.

Tacrolimus is pivotal in pancreas transplants but poses challenges in maintaining optimal levels due to recipient differences. This study aimed to explore the utility of time spent below the therapeutic range and intrapatient variability in predicting rejection and de novo donor-specific antibody (dnDSA) development in pancreas graft recipients. This retrospective unicentric study included adult pancreas transplant recipients between January 2006 and July 2020. Recorded variables included demographics, immunosuppression details, HLA matching, biopsy results, dnDSA development, and clinical parameters. Statistical analysis included ROC curves, sensitivity, specificity, and predictive values. A total of 131 patients were included. Those with biopsy-proven acute rejection (BPAR, 12.2%) had more time (39.9% ± 24% vs. 25.72% ± 21.57%, p = 0.016) and tests (41.95% ± 13.57% vs. 29.96% ± 17.33%, p = 0.009) below therapeutic range. Specific cutoffs of 31.5% for time and 34% for tests below the therapeutic range showed a high negative predictive value for BPAR (93.98% and 93.1%, respectively). Similarly, patients with more than 34% of tests below the therapeutic range were associated with dnDSA appearance (38.9% vs. 9.4%, p = 0.012; OR 6.135, 1.346-27.78). In pancreas transplantation, maintaining optimal tacrolimus levels is crucial. Suboptimal test percentages below the therapeutic range prove valuable in identifying acute graft rejection risk.

Pseudodiproline (Pro-Cyp) Oligomers Fold into Helical Polyproline Type secondary structures.

The synthesis and conformational properties of oligo-proline mimetics composed of dimeric and tetrameric Pro-Cyp constructs linked by a hydroxymethylene unit are reported. Oligomers were studied both in the solid state and in solution, unveiling right-handed helical conformation depending on the configuration of the vicinally substituted trans-cyclopentane carboxylic acid unit (Cyp). Unlike polyproline oligomers, the alternating synthetic Pro-Cyp counterparts are not stabilized by n-π* interactions but rely instead on the steric demands of the extended backbone conformation within the hydroxymethylene-linked Pro-Cyp repeating units.

A humanized IL-2 mutein expands Tregs and prolongs transplant survival in preclinical models.

Long-term organ transplant survival remains suboptimal, and life-long immunosuppression predisposes transplant recipients to an increased risk of infection, malignancy, and kidney toxicity. Promoting the regulatory arm of the immune system by expanding Tregs may allow immunosuppression minimization and improve long-term graft outcomes. While low-dose IL-2 treatment can expand Tregs, it has a short half-life and off-target expansion of NK and effector T cells, limiting its clinical applicability. Here, we designed a humanized mutein IL-2 with high Treg selectivity and a prolonged half-life due to the fusion of an Fc domain, which we termed mIL-2. We showed selective and sustainable Treg expansion by mIL-2 in 2 murine models of skin transplantation. This expansion led to donor-specific tolerance through robust increases in polyclonal and antigen-specific Tregs, along with enhanced Treg-suppressive function. We also showed that Treg expansion by mIL-2 could overcome the failure of calcineurin inhibitors or costimulation blockade to prolong the survival of major-mismatched skin grafts. Validating its translational potential, mIL-2 induced a selective and sustainable in vivo Treg expansion in cynomolgus monkeys and showed selectivity for human Tregs in vitro and in a humanized mouse model. This work demonstrated that mIL-2 can enhance immune regulation and promote long-term allograft survival, potentially minimizing immunosuppression.

Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as biomarkers to prognosticate survival in advanced gastric cancer patients in the era of immunotherapy: a systematic review and meta-analysis.

Background: Gastric cancer (GC) remains an important global health concern with limited treatment options for advanced cases. Immunotherapy has shown promising results, but identifying predictive biomarkers for treatment efficacy is challenging. Novel inflammatory markers, such as the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR), derived from complete blood count measurements, have gained attention as potential prognostic indicators. This systematic review and meta-analysis investigates the roles of the PLR and NLR as predictors of overall survival (OS) and progression-free survival (PFS) in advanced GC and gastroesophageal junction cancer (GEJC) patients treated with immunotherapy. Methods: A comprehensive search of the literature was conducted through PubMed, Embase, and Cochrane Library to identify relevant studies. A total of 16 studies involving NLR and 8 studies involving PLR were included. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to assess the association between high biomarker values and poor OS and PFS. Subgroup analyses were performed to explore potential sources of heterogeneity. Poor OS, PFS were defined by each study as statistically significant shorter survival. Results: A high NLR was significantly associated with worse OS (HR: 2.11; 95% CI: 1.70-2.62) and PFS (HR: 1.76; 95% CI: 1.43-2.17). High PLR was also significantly associated with poorer OS (HR: 1.77; 95% CI: 1.44-2.17) and PFS (HR: 1.61; 95% CI: 1.33-1.96). Subgroup analyses and sensitivity analyses supported the robustness of these findings. Publication bias was noted in NLR analysis for OS but not for PFS. PLR analysis showed low publication bias. Conclusions: Elevated NLR and PLR are associated with unfavorable OS and PFS outcomes in advanced GC/GEJC patients on immunotherapy. These findings imply the utility of these easily accessible biomarkers in prognostic assessment. However, standardized cutoff values and further research on interactions with the tumor microenvironment and comorbidities are needed. Additional prospective studies are warranted to validate these findings for both biomarkers.

Physiotherapists' barriers and facilitators to the implementation of a behaviour change-informed exercise intervention to promote the adoption of regular exercise practice in patients at risk of recurrence of low back pain: a qualitative study.

BACKGROUND: Recurrences of low back pain (LBP) are frequent and associated with high levels of disability and medical costs. Regular exercise practice may be an effective strategy to prevent recurrences of LBP, however, the promotion of this behaviour by physiotherapists seems to be challenging. This study aims to explore physiotherapists' perceived barriers and facilitators to the implementation of a behaviour change-informed exercise intervention to promote the adoption of regular exercise practice by patients at risk of recurrence of low back pain. METHODS: Two focus groups with primary healthcare physiotherapists were conducted, based on a semi-structured interview schedule informed by the Behaviour Change Wheel, including the Capability, Opportunity, Motivation-Behaviour (COM-B) model and the Theoretical Domains Framework (TDF). All focus groups were held through videoconference, audio and video recorded and transcribed verbatim. A deductive content analysis, using a coding matrix based on the COM-B and TDF, was performed by two independent researchers. A third researcher was approached to settle disagreements. RESULTS: In total, 14 physiotherapists participated in the focus groups. The analysis revealed a total of 13 barriers (4 COM-B components and 7 TDF domains) and 23 facilitators (5 COM-B and 13 TDF) to physiotherapists' implementation of a behaviour change-informed exercise intervention. The most common barriers were the lack of skills and confidence to implement the proposed intervention. These were explained by the fact that it differs from the usual practice of most participants and requires the learning of new skills applied to their contexts. However, for those who had already implemented other similar interventions or whose rationale is aligned with the new intervention, there seemed to exist more positive determinants, such as potential benefits for physiotherapists and the profession, improvement of quality of care and willingness to change clinical practice. For others who did not previously succeed in implementing these types of interventions, more context-related barriers were mentioned, such as lack of time to implement the intervention, schedule incompatibilities and lack of material and human resources. CONCLUSIONS: This study identified modifiable barriers and facilitators to physiotherapists' implementation of a behaviour change-informed exercise intervention for patients at risk of recurrence of LBP in primary healthcare. The findings of this study will allow the systematic and theory-based development of a behaviour change-informed training programme, aimed at physiotherapists and supporting the successful implementation of the exercise intervention.

Cross-cultural adaptation, validation and establishment of the minimal clinically important change score of the European Portuguese core outcome measures index in patients with lumbar degenerative spine disease.

PURPOSE: The core outcome measures index (COMI) for the back is a questionnaire that evaluates five domains and has been translated into several languages and validated for different populations. We aimed to translate, cross-culturally adapt and validate it in European Portuguese for use in patients with degenerative lumbar disease. Additionally, we aimed to establish the minimal clinically important change score (MCIC). METHODS: The translation and cultural adaptation were done according to published guidelines. Patients awaiting surgery at a neurosurgical center completed the COMI, Oswestry Disability Index (ODI), EQ-5D questionnaires and a pain visual analog scale (VAS). To evaluate COMI's reproducibility, patients completed the questionnaire twice within two weeks, preoperatively, in addition to answering a transition question. The MCIC was determined by analysis of postoperative changes in total COMI score, using the anchor method, with a question ascertaining surgical outcome as perceived by the patient. RESULTS: The first set of questionnaires was answered by 108 patients and the second, by 98 patients. COMI's construct validity was confirmed by demonstrating the hypothesized correlation between each domain's score (Spearman Rho > 0.4) and the corresponding questionnaire score (ODI, EQ-5D and VAS) and through adequate correlation (Spearman > 0.6) between COMI's total score and ODI and EQ-5D total scores. Intraclass correlation coefficients between each domain and COMI's total score were > 0.8. The MCIC was calculated as 2.1. CONCLUSION: The cross-culturally adapted COMI questionnaire is a valid clinical assessment tool for European Portuguese-speaking patients with degenerative lumbar disease, with an MCIC of 2.1 points.

Banff 2022 pancreas transplantation multidisciplinary report: Refinement of guidelines for T cell-mediated rejection, antibody-mediated rejection and islet pathology. Assessment of duodenal cuff biopsies and noninvasive diagnostic methods.

The Banff pancreas working schema for diagnosis and grading of rejection is widely used for treatment guidance and risk stratification in centers that perform pancreas allograft biopsies. Since the last update, various studies have provided additional insight regarding the application of the schema and enhanced our understanding of additional clinicopathologic entities. This update aims to clarify terminology and lesion description for T cell-mediated and antibody-mediated allograft rejections, in both active and chronic forms. In addition, morphologic and immunohistochemical tools are described to help distinguish rejection from nonrejection pathologies. For the first time, a clinicopathologic approach to islet pathology in the early and late posttransplant periods is discussed. This update also includes a discussion and recommendations on the utilization of endoscopic duodenal donor cuff biopsies as surrogates for pancreas biopsies in various clinical settings. Finally, an analysis and recommendations on the use of donor-derived cell-free DNA for monitoring pancreas graft recipients are provided. This multidisciplinary effort assesses the current role of pancreas allograft biopsies and offers practical guidelines that can be helpful to pancreas transplant practitioners as well as experienced pathologists and pathologists in training.

Midnight Cortisol is Associated with Changes in Systolic Blood Pressure and Diabetic Neuropathy in Subjects with Type 1 Diabetes Undergoing Simultaneous Kidney-Pancreas Transplantation.

INTRODUCTION: An increased midnight cortisol (MC) has been described in end-stage kidney disease (ESKD) and type 1 diabetes (T1D). Lower circulating levels of the cytokine soluble tumor necrosis factor (TNF)-like weak inducer of apoptosis (sTWEAK) have been found in T1D and ESKD and associated with cardiovascular (CV) events in the latter. We aimed to study MC and sTWEAK in simultaneous pancreas-kidney transplant (SPKT) recipients, and the association of these markers with CV risk factors and transplant outcomes. METHODS: This was a retrospective cohort study including subjects with T1D who received a first SPKT between 2008 and 2020. MC and sTWEAK at baseline were correlated with CV risk factors and evolution 1 year after SPKT. RESULTS: We included 29 subjects (58.6% women, mean age 43.5 ± 7.5 years, diabetes duration 31.9 ± 9.4 years). Systolic blood pressure (SBP) increased directly with MC quartiles, despite similar hypertension prevalence (p < 0.05). At 1 year, antihypertensive treatment was deintensified in those in lower MC quartiles (p < 0.05). Diabetic neuropathy prevalence decreased progressively in higher cortisol quartiles (p for trend = 0.005). Low MC was associated with delayed kidney graft function (p for trend = 0.044), and high sTWEAK with kidney graft rejection (p for trend = 0.018). In multivariate analyses, MC (standardized-ß 0.505, p = 0.004) and age (standardized-ß - 0.460, p = 0.040) were independently correlated with SBP, and MC was independently associated with the presence of diabetic neuropathy (OR 0.633, 95% CI 0.425-0.944, p = 0.025), adjusted for confounders. CONCLUSIONS: In this exploratory study, lower MC was associated with a lower baseline SBP, an improvement of antihypertensive treatment 1 year after transplant, and a higher diabetic neuropathy prevalence in SPKT recipients.

Requests, Issuing, and Hospital Admissions Regarding Mental Health Warrants Before and During the COVID-19 Pandemic in a Region in Portugal.

INTRODUCTION: Mental health warrants exist in most countries and are issued when patients have severe mental illness, refuse treatment, and present a serious risk to themselves or others. We describe the epidemiology of mental health warrant requests received, and warrants issued by a Public Health Unit in a Portuguese region, as well as subsequent hospital admissions before and during the COVID-19 pandemic. METHODS: We used routine administrative data of mental health warrant request entries from a Public Health Unit serving a population of 219 739 individuals and compared the average of monthly requests, issued warrants, and hospital admissions during two separate periods (January 2013 to January 2021 and February 2021 to October 2022) as well as the proportion of warrants issued, hospital admissions among requests, and other patient characteristics. We identified factors associated with hospital admissions among the requests using logistic regression. RESULTS: Monthly average warrant requests, issued warrants and hospital admissions increased after February 2021 (x̄ 2.87 vs 7.09 p < 0.001; x̄ 2.67 vs 6.42 p < 0.001; x̄ 1.55 vs 3.58 p < 0.001). We found no differences by period in the proportion of requests with issued warrants (92.8% vs 90.6% p = 0.42) nor the proportion of requests with subsequent hospital admissions (54.0% vs 49.0% p = 0.33). In the second period, there were differences in the proportion of patients with a previously diagnosed mental health disorder (95.3% vs 90.4% p = 0.049). There were significant differences in the distribution of the origin of requests. Being unemployed (OR:2.5 CI:1.2 - 5.2), not having completed high school (OR:2.01 CI:1.12 - 3.77) and having university education (OR:3.67 CI:1.27 - 10.57) degree were associated with hospital admission. CONCLUSION: Severe mental illness with criteria for mental health warrants may require more resources and different approaches due to a possible increase during and after the COVID-19 pandemic. Community based mental healthcare, incentivized follow-up by primary care and ambulatory treatment may be considered. Further research should evaluate both the national and international trends and associated factors.

Validation of the Back-table Graft Arterial Anastomosis between the Splenic Artery and Superior Mesenteric Artery: Arterial Complications after a 21-year Single-center Experience of Pancreas Transplantation.

OBJECTIVE: To determine the role of the arterial splenomesenteric anastomosis (ASMA) vascular reconstruction technique in terms of arterial vascular complications in pancreas transplant (PT) recipients. SUMMARY BACKGROUND DATA: The ASMA technique was first described in 1992 by Hospital Clínic Barcelona group. Regardless that the iliac Y-graft technique is the most frequently used worldwide, evidence of arterial complications and implications of using a different back-table reconstruction is conspicuously absent in the literature. METHODS: Descriptive review of 407 PTs performed at a single center (1999-2019) by analyzing the type of arterial reconstruction technique, focusing on ASMA. The endpoints were the management of arterial complications and long-term patient and graft survival. RESULTS: ASMA was performed in 376 cases (92.4%) and a Y-graft in 31 cases (7.6%). A total of 34 arterial complications (8.3%) were diagnosed. In the ASMA group (n=30, 7.9%) they comprised: 15 acute thrombosis; 4 stenosis; 1 pseudoaneurysm and 10 diverse chronic arterial complications while in the Y-graft group (n=4, 12.9%) 3 acute thrombosis and 1 chronic artery-duodenal fistula occurred. Graft salvage was achieved in 16 patients (53.3%) from the ASMA group and in 2 (50%) from the Y-graft. After a median follow-up of 129.2 (IQR 25-75%, 77.2 -182) months the overall graft and patient survival for the whole cohort at 1, 5, and 10 years was 86.7%, 79.5%, 70.5%, and 98.5%, 95.3%, 92.5%, respectively. CONCLUSIONS: The ASMA proves to be a safe and more easily reproducible technique and should therefore be considered for first-line back-table reconstruction in the PT population.

The Evolution of Cystic Echinococcosis in Humans and Ruminants in Portugal-A One Health Approach.

Cystic echinococcosis, also known as hydatid disease, is a significant parasitic zoonosis with public health implications, albeit often neglected. In Portugal, data on this zoonosis are scarce despite being a mandatory notifiable disease in both humans and animals. To assess the impact of cystic echinococcosis on both livestock and humans, we compiled data from slaughterhouse records of ruminants, human hospitalizations, and confirmed cases of human echinococcosis. Overall, a total of 298 cases of cystic echinococcosis were identified in ruminants slaughtered from national farms for human consumption in Portugal between 2008 and 2022, comprising 192 cases in ovines, 95 in bovines, and 11 in caprines. Echinococcosis led to 582 hospitalizations in Portuguese public hospitals, with an average hospital stay of 11 days (±15.66), and resulted in 13 deaths (2.23%) from 2008 to 2018. Each infected animal was associated with a 7% increase in the incidence rate of human hospitalization (p = 0.002, IRR = 1.070, 95% CI: 1.025-1.117). Additionally, for every 100,000 person-years observed between 2008 and 2018, the total number of hospitalizations was 0.528. Residence in the Alentejo region was associated with a 5.3-fold increase in the incidence rate of human hospitalizations and an 8-fold higher risk of death from echinococcosis.

Bariatric Surgery Outcomes in Patients with Chronic Kidney Disease.

Obesity increases the risk of developing chronic kidney disease (CKD), which has a major negative impact on global health. Bariatric surgery (BS) has demonstrated a substantial improvement of obesity-related comorbidities and thus, it has emerged as a potential therapeutic tool in order to prevent end-stage renal disease. A limited number of publications to date have examined the beneficial effects and risks of BS in patients with non-advanced stages of CKD. We aimed to investigate the safety of BS in patients with CKD stages 3-4 (directly related or not to obesity) and both the metabolic/renal outcomes post-BS. A total of 57 individuals were included (n = 19 for CKD-group; n = 38 for patients with obesity, but normal eGFR [control-group]). Weight loss and obesity comorbidities resolution after BS were similar in both groups. Renal function (eGFR [CKD-EPI]) improved significantly at the 1-year follow-up: Δ10.2 (5.2-14.9) (p < 0.001) for CKD-group and Δ4.0 (-3.9-9.0) mL/min/1.73 m2 (p = 0.043) for controls. Although this improvement tended to decrease in the 5-year follow-up, eGFR remained above its basal value for the CKD-group. Noteworthy, eGFR also improved in those patients who presented CKD not directly attributed to obesity. For patients with CKD, BS appears to be safe and effective regarding weight loss and obesity comorbidities resolution, irrespective of the main cause of CKD (related or not to obesity).

Opening a Pandora's Flask on a Prototype Catalytic Direct Arylation Reaction of Pentafluorobenzene: The Ag2CO3/Pd(OAc)2/PPh3 System.

Direct C-H functionalization reactions have opened new avenues in catalysis, removing the need for prefunctionalization of at least one of the substrates. Although C-H functionalization catalyzed by palladium complexes in the presence of a base is generally considered to proceed by the CMD/AMLA-6 mechanism, recent research has shown that silver(I) salts, frequently used as bases, can function as C-H bond activators instead of (or in addition to) palladium(II). In this study, we examine the coupling of pentafluorobenzene 1 to 4-iodotoluene 2a (and its analogues) to form 4-(pentafluorophenyl)toluene 3a catalyzed by palladium(II) acetate with the commonplace PPh3 ligand, silver carbonate as base, and DMF as solvent. By studying the reaction of 1 with Ag2CO3/PPh3 and with isolated silver (triphenylphosphine) carbonate complexes, we show the formation of C-H activation products containing the Ag(C6F5)(PPh3)n unit. However, analysis is complicated by the lability of the Ag-PPh3 bond and the presence of multiple species in the solution. The speciation of palladium(II) is investigated by high-resolution-MAS NMR (chosen for its suitability for suspensions) with a substoichiometric catalyst, demonstrating the formation of an equilibrium mixture of Pd(Ar)(κ1-OAc)(PPh3)2 and [Pd(Ar)(µ-OAc)(PPh3)]2 as resting states (Ar = Ph, 4-tolyl). These two complexes react stoichiometrically with 1 to form coupling products. The catalytic reaction kinetics is investigated by in situ IR spectroscopy revealing a two-term rate law and dependence on [Pdtot/nPPh3]0.5 consistent with the dissociation of an off-cycle palladium dimer. The first term is independent of [1], whereas the second term is first order in [1]. The observed rates are very similar with Pd(PPh3)4, Pd(Ph)(κ1-OAc)(PPh3)2, and [Pd(Ph)(µ-OAc)(PPh3)]2 catalysts. The kinetic isotope effect varied significantly according to conditions. The multiple speciation of both AgI and PdII acts as a warning against specifying the catalytic cycles in detail. Moreover, the rapid dynamic interconversion of AgI species creates a level of complexity that has not been appreciated previously.

Early kinetics of donor-derived cell-free DNA after transplantation predicts renal graft recovery and long-term function.

BACKGROUND: Ischemia-reperfusion injury (IRI) upon transplantation is one of the most impactful events that the kidney graft suffers during its life. Its clinical manifestation in the recipient, delayed graft function (DGF), has serious prognostic consequences. However, the different definitions of DGF are subject to physicians' choices and centers' policies, and a more objective tool to quantify IRI is needed. Here, we propose the use of donor-derived cell-free DNA (ddcfDNA) for this scope. METHODS: ddcfDNA was assessed in 61 kidney transplant recipients of either living or deceased donors at 24 h, and 7, 14 and 30 days after transplantation using the AlloSeq cfDNA Kit (CareDx, San Francisco, CA, USA). Patients were followed-up for 6 months and 7-year graft survival was estimated through the complete and functional iBox tool. RESULTS: Twenty-four-hour ddcfDNA was associated with functional DGF [7.20% (2.35%-15.50%) in patients with functional DGF versus 2.70% (1.55%-4.05%) in patients without it, P = .023] and 6-month estimated glomerular filtration rate (r = -0.311, P = .023). At Day 7 after transplantation, ddcfDNA was associated with dialysis duration in DGF patients (r = 0.612, P = .005) and worse 7-year iBox-estimated graft survival probability (ß -0.42, P = .001) at multivariable analysis. Patients with early normalization of ddcfDNA (<0.5% at 1 week) had improved functional iBox-estimated probability of graft survival (79.5 ± 16.8%) in comparison with patients with 7-day ddcfDNA ≥0.5% (67.7 ± 24.1%) (P = .047). CONCLUSIONS: ddcfDNA early kinetics after transplantation reflect recovery from IRI and are associated with short-, medium- and long-term graft outcome. This may provide a more objective estimate of IRI severity in comparison with the clinical-based definitions of DGF.

Challenges and opportunities in building a health economic framework for personalized medicine in oncology.

Personalized medicine has allowed for knowledge at an individual level for several diseases and this has led to improvements in prevention and treatment of various types of neoplasms. Despite the greater availability of tests, the costs of genomic testing and targeted therapies are still high for most patients, especially in low- and middle-income countries. Although value frameworks and health technology assessment are fundamental to allow decision-making by policymakers, there are several concerns in terms of personalized medicine pharmacoeconomics. A global effort may improve these tools in order to allow access to personalized medicine for an increasing number of patients with cancer.

Osteoarticular Infections: Younger Children With Septic Arthritis and Low Inflammatory Patterns Have a Better Prognosis in a European Cohort.

BACKGROUND: Osteoarticular infections (OAI) are associated with complications and sequelae in children, whose prediction are of great importance in improving outcomes. We aimed to design risk prediction models to identify early complications and sequelae in children with OAI. METHODS: This observational study included children (>3 months-17 years old) with acute OAI admitted to a tertiary-care pediatric hospital between 2008 and 2018. Clinical treatment, complications and sequelae were recorded. We developed a multivariable logistic predictive model for an acute complicated course (ACC) and another for sequelae. RESULTS: A total of 240 children were identified, 17.5% with ACC and 6.0% and 3.6% with sequelae at 6 and 12 months of follow-up, respectively. In the multivariable logistic predictive model for ACC, predictors were fever at admission [adjusted odds ratio (aOR): 2.98; 95% confidence interval (CI): 1.10-8.12], C-reactive protein ≥100 mg/L (aOR: 2.37; 95% CI: 1.05-5.35), osteomyelitis (aOR: 4.39; 95% CI: 2.04-9.46) and Staphylococcus aureus infection (aOR: 3.50; 95% CI: 1.39-8.77), with an area under the ROC curve of 0.831 (95% CI: 0.767-0.895). For sequelae at 6 months, predictors were age ≥4 years (aOR: 4.08; 95% CI: 1.00-16.53), C-reactive protein ≥110 mg/L (aOR: 4.59; 95% CI: 1.25-16.90), disseminated disease (aOR: 9.21; 95% CI: 1.82-46.73) and bone abscess (OR: 5.46; 95% CI: 1.23-24.21), with an area under the ROC curve of 0.887 (95% CI: 0.815-0.959). CONCLUSIONS: In our model we could identify patients at low risk for complications and sequelae, probably requiring a less aggressive approach.

Effectiveness of antimicrobial interventions directed at tackling antimicrobial resistance in animal production: A systematic review and meta-analysis.

BACKGROUND: In the last decades, a more prudent and rational use of antimicrobials has been progressively directed towards animal production to reduce antimicrobial selective pressure and antimicrobial resistance (AMR) in microorganisms and safeguard the antimicrobial efficacy of treatments in human medicine. This systematic review evaluated the effectiveness of interventions that have been applied to reduce or improve veterinary antimicrobial usage and aimed at decreasing resistant bacteria in chicken broiler and pig production contexts. METHODS: Original articles were identified by searching PubMed™, Scopus™, The Cochrane Library™, and Web of Science™, and grey literature by searching DANS EASY™, WorldCat™ and RCAAP™. Inclusion criteria included: chicken broiler or pig populations (predestined for meat production), interventions intended to reduce/improve antimicrobial use, comparator with standard or no use of antimicrobials, outcomes related to prevalence of resistant bacteria, farm level studies, original data, and analytical observational studies. Data was extracted from eligible studies and meta-analysis using random or fixed effects models was conducted for combinations including type of intervention, bacterial species, production type and animal populations. Models were selected according to heterogeneity between studies. The effectiveness of interventions was assessed using pooled odds ratio of resistance to antimicrobial substances/classes by bacteria for associations between animal populations with and without intervention. RESULTS: A total of 46 studies were eligible for review. For chicken broilers, most interventions were identified as antimicrobial restrictions on all non-therapeutic use (46%), complete restriction (27%), and prohibition on antimicrobials used for growth promotion (23%). As for pig populations, restrictions were mainly observed on all non-therapeutic use (37%), complete restriction (37%) and group treatments (22%). For meta-analysis, 21 studies were pooled after assessment of existing combinations. These combinations demonstrated a protective effect for most antimicrobial classes in Escherichia coli, Campylobacter and Enterococcus isolates from samples of chicken broilers as well in Escherichia coli and Campylobacter spp. from samples of pigs, compared to animals raised under conventional production or without intervention. Increased odds of resistance were only observed for cephalosporins in E. coli and broilers raised without antimicrobials, and to fluoroquinolones and quinolones in Campylobacter and pigs raised without antimicrobials, compared to conventional production. CONCLUSIONS: Our study indicates that organic production, antimicrobial-free farms, and group treatment restrictions are recommended for AMR reduction, providing information that may support decision-making to tackle AMR and better reporting to improve comparability of results between studies.