High-Dose Rate Brachytherapy Combined with PD-1 Blockade as a Treatment for Metastatic Adrenocortical Carcinoma - A Single Center Case Series.

The response rate of advanced adrenocortical carcinoma (ACC) to standard chemotherapy with mitotane and etoposide/doxorubicin/cisplatin (EDP-M) is unsatisfactory, and benefit is frequently short lived. Immune checkpoint inhibitors (CPI) have been examined in patient's refractory to EDP-M, but objective response rates are only approximately 15%. High-dose rate brachytherapy (HDR-BT) is a catheter-based internal radiotherapy and expected to favorably combine with immunotherapies. Here we describe three cases of patients with advanced ACC who were treated with HDR-BT and the CPI pembrolizumab. None of the tumors were positive for established response markers to CPI. All patients were female, had progressed on EDP-M and received external beam radiation therapy for metastatic ACC. Pembrolizumab was initiated 7 or 23 months after brachytherapy in two cases and prior to brachytherapy in one case. Best response of lesions treated with brachytherapy was complete (n=2) or partial response (n=1) that was ongoing at last follow up after 23, 45 and 4 months, respectively. Considering all sites of tumor, response was complete and partial remission in the two patients with brachytherapy prior to pembrolizumab. The third patient developed progressive disease with severe Cushing's syndrome and died due to COVID-19. Immune-related adverse events of colitis (grade 3), gastroduodenitis (grade 3), pneumonitis (grade 2) and thyroiditis (grade 1) occurred in the two patients with systemic response. HDR-BT controlled metastases locally. Sequential combination with CPI therapy may enhance an abscopal antitumoral effect in non-irradiated metastases in ACC. Systematic studies are required to confirm this preliminary experience and to understand underlying mechanisms.

Clinical outcomes and perioperative morbidity and mortality following segmental resections of the colon for Crohn's colitis.

INTRODUCTION: Crohn's disease (CD) is a chronic inflammatory bowel disease of a multifactorial pathogenesis. Recently numerous genetic variants linked to an aggressive phenotype were identified, leading to a progress in therapeutic options, resulting in a decreased necessity for surgery. Nevertheless, surgery is often inevitable. The aim of the study was to evaluate possible risk factors for postoperative complications and disease recurrence specifically after colonic resections for CD. PATIENTS AND METHODS: A total of 241 patients who underwent colonic and ileocaecal resections for CD at our instiution between 2008 and 2018 were included. All data was extracted from clinical charts. RESULTS: Major complications occurred in 23.8% of all patients. Patients after colonic resections showed a significantly higher rate of major postoperative complications compared to patients after ICR (p = < 0.0001). The most common complications after colonic resections were postoperative bleeding (22.2%), the need for revision surgery (27.4%) and ICU (17.2%) or hospital readmission (15%). As risk factors for the latter, we identified time interval between admission and surgery (p = 0.015) and the duration of the surgery (p = 0.001). Isolated distal resections had a higher risk for revision surgery and a secondary stoma (p = 0.019). Within the total study population, previous bowel resections (p = 0.037) were identified as independent risk factors for major perioperative complications. CONCLUSION: The results indicate that both a complex surgical site and a complex surgical procedure lead to a higher perioperative morbidity in colonic resections for Crohn's colitis.

The changing clinical presentation of COVID-19 in children during the course of the pandemic.

AIM: To investigate the evolution of clinical symptoms of COVID-19 in children throughout the pandemic. METHODS: In this national prospective surveillance study, symptoms in children hospitalised with COVID-19 were collected from all paediatric hospitals in Switzerland between March 2020 and March 2023. Data was analysed across four time periods, according to the predominantly circulating SARS-CoV-2 variant: T1 (wild-type), T2 (Alpha), T3 (Delta) and T4 (Omicron), as well as by age group. RESULTS: The study included 1323 children. The proportion of children admitted to an intensive care unit remained stable throughout the pandemic. However, the pattern and frequency of clinical manifestations changed over time. Respiratory symptoms were less prevalent during T1 (wild-type), fever during T2 (Alpha) and rash during T4 (Omicron). In contrast, fever and neurological symptoms were more prevalent during T4 (Omicron). Newly described symptoms during T4 (Omicron) included conjunctivitis, laryngotracheitis and seizures. Fever was more prevalent among neonates and infants whereas respiratory symptoms were more common among infants. Gastrointestinal symptoms were more frequent among toddlers, while both toddlers and school-aged children presented with neurological symptoms more often than other age groups. CONCLUSION: Continuous surveillance is required to detect changes in manifestations and there by be prepared for the optimal management of complications in children with COVID-19.

Fifteen-minute consultation: Management of mammalian bites in children - from local wound care to prophylactic antibiotics.

Animal and human bites are a common reason for emergency consultation, especially in children. The most common complication of bite wounds is local infection. Systemic infections are much rarer. The key in reducing the risk of infection after a mammalian bite is local wound management with either primary or delayed closure. The benefit of administering prophylactic antibiotics is controversial.In this review, we provide a summary of the current evidence for the management of mammalian bites in children, including recommendations for appropriate investigations, wound management, administration of prophylactic and therapeutic antibiotics and the prevention of systemic infections.

Molecular interactions between the intestinal microbiota and the host.

The intestine is the most densely colonized region of the body, inhabited by a diverse community of microbes. The functional significance of the intestinal microbiota is not yet fully understood, but it is known that the microbiota is implicated in numerous physiological processes of the host, such as metabolism, nutrition, the immune system, and regulation of behavior and mood. This article reviews recent findings on how bacteria of the intestinal microbiota interact with the host. Microbiota-microbiota and microbiota-host interactions are mediated by direct cell contact and by metabolites either produced by bacteria or produced by the host or the environment and metabolized by bacteria. Among them are short-chain fatty, including butyrate, propionate, and acetate. Other examples include polyamines, linoleic acid metabolites, tryptophan metabolites, trimethylamine-N-oxide, vitamins, and secondary bile acids. These metabolites are involved in regulating the cell cycle, neurobiological signaling, cholesterol and bile acid metabolism, immune responses, and responses to antioxidants. Understanding the host-microbiota pathways and their modulation will allow the identification of individualized therapeutic targets for many diseases. This overview helps to facilitate and promote further research in this field.

Predictors of outcome for treatment of enterovaginal fistula : Therapeutical strategies for treatment.

BACKGROUND: Enterovaginal fistulas represent a serious complication of various diseases and therapeutic procedures, often associated with complicated clinical courses and massive impairment of quality of life. As underlying conditions and procedures are multifarious, therapeutic approaches are challenging and have to be tailored individually. As the therapeutic management is complex and individualized, multiple surgical interventions might be necessary. METHODS: The aim of this study was to identify possible predictors for outcome in the treatment enterovaginal fistula patients. The study was realized as a retrospective analysis. Ninety-two patients treated with enterovaginal fistulas between 2004 and 2016 were analyzed. Patient characteristics, therapeutic data, and endoscopic findings were stratified according to etiology, closure rate and time, as well as recurrence of fistula. Main outcome measure was the overall rate of fistula closure. RESULTS: Overall therapeutic success rate was 67.4%. Postoperatively derived fistulas were most frequent (40.2%), mainly after rectal surgery (59.5%). Postoperative and non-IBD-inflammation associated fistulas had better outcome than IBD-, radiotherapy-, and tumor-related fistulas (p = 0.001). Successful fistula closure was observed more frequently after radical surgical interventions, best results observed after transabdominal surgery (p < 0.001). Fistula recurrence was also less frequently observed after radical surgical therapies (p = 0.029). A temporary stoma was associated with higher incidence of fistula closure (p = 0.013) and lower incidence of fistula recurrence (p = 0.042) in the postoperative subgroup, as well as shortened therapy period in all groups (p = 0.031). CONCLUSION: Enterovaginal fistulas are a result of various etiologies, and treatment should be adjusted accordingly. A very sustainable, rapid, and persistent therapeutic success can be expected after radical surgical approaches with temporary diverting stoma. This is especially true for postoperatively derived fistulas.

Smoking as a risk factor for colorectal neoplasms in young individuals? A systematic meta-analysis.

BACKGROUND AND AIMS: Early-onset colorectal neoplasms (EoCRN) include both benign and malign colorectal tumors, which occur before the age of 50. The incidence of EoCRN is rising worldwide. Tobacco smoking has previously been proven to be related to the development of various tumor types. However, its relationship with EoCRN is not clearly defined. Hence, we carried out a systematic review and a meta-analysis to evaluate the relationship between smoking status and the risk of EoCRN. METHODS: A systematic search of PubMed, EMBASE, and Web of Science up to September 7, 2022, was performed for studies that evaluated the association of smoking status with EoCRN. The quality of the case-control study was evaluated with the Newcastle‒Ottawa Scale. The quality of the cross-sectional studies was evaluated with the American Health Care Research and Quality checklist. Fixed-effects models were used to pool odds ratios (ORs) to evaluate the relationship between the risk of developing EoCRN and smoking status. The meta-analyses were performed with Review Manager version 5.4, and funnel plots and publication bias tests were produced by STATA software. RESULTS: A total of six studies were included in this meta-analysis. After pooling the results of these six studies, we found that current smokers carry a relatively high risk of developing EoCRN (OR, 1.33; 95% confidence interval [CI], 1.17-1.52) compared to never-smokers. Ex-smokers were not at a significantly increased risk for developing EoCRN (OR, 1.00; 95% CI, 0.86-1.18). DISCUSSION: Smoking behavior is significantly associated with an increased risk for developing EoCRN and might be one of the reasons for the increasing incidence. Ex-smokers who quit are not at significant risk of developing EoCRN.

Diagnosis and treatment of Lyme disease in children.

Lyme disease is a zoonotic infection caused by the spirochete Borrelia burgdorferi sensu lato which is transmitted to humans mainly by tick bites. The global incidence of Lyme disease is rising, and children are more frequently affected. The disease can manifest in various organs causing non-specific symptoms. The lack of sensitive and specific diagnostic tests makes the management of Lyme disease challenging. This article offers up-to-date clinical algorithms for the management of children with suspected or diagnosed Lyme disease.

It is not NOD2 - genetic and clinical risk factors for postoperative complications following ileocolic resection in Crohn's disease.

PURPOSE: To evaluate the role of the nucleotide oligomerization domain 2 (NOD2) mutation status and other risk factors for the incidence of postoperative complications after ileocolic resection for Crohn's disease (CD). METHODS: Data of 138 patients consecutively undergoing ileocolic resection for CD at a tertiary academic referral center were retrospectively analyzed including single nucleotide polymorphism (SNP) data of the NOD2 gene. Uni- and multivariate regression analysis was performed to identify factors associated with increased risk of severe postoperative complications. RESULTS: From 114 patients (83%), the NOD2 mutation status was available. Of these, 60 (53%) had a NOD2 wildtype, whereas eleven (10%) were homozygous for the high risk p.Leu1007fsX1008 (rs2066847) variant. Major postoperative complications occurred in 28 patients (20%). Twenty-seven of these (96%) were intraabdominal septic complications such as anastomotic leakage or abscess. Male gender (P = 0.029; OR 3.052, the duration of CD (time [months] from initial diagnosis of CD to surgery; P = 0.001; OR 1.009), previous abdominal surgery for CD (P = 0.017; OR 3.49), and the presence of enteric fistulas (P = 0.023; OR 3.21) were identified as independent risk factors for major postoperative complications. Homozygosity for the NOD2 high-risk variant p.Leu1007fsX1008 did not show increased postoperative morbidity in the short and long-term outcome. CONCLUSIONS: We could detect independent risk factors for major postoperative complications after ileocolic resection for Crohn's disease. However, patients with the high-risk variant p.Leu1007fsX1008 of the NOD2 gene did not show increased postoperative morbidity.

Endoscopic vacuum therapy for the treatment of colorectal leaks - a systematic review and meta-analysis.

BACKGROUND: During the last two decades, vacuum-assisted wound therapy has been successfully transferred to an endoscopic treatment approach of various upper and lower gastrointestinal leaks called endoscopic vacuum therapy (EVT). As mostly small case series are published in this field, the aim of our systematic review and meta-analysis was to evaluate the efficacy and safety of EVT in the treatment of colorectal leaks. METHODS: A systematic search of MEDLINE/PubMed and Cochrane databases was performed using search terms related to EVT and colorectal defects (anastomotic leakage, rectal stump insufficiency) according to the PRISMA guidelines. Randomized controlled trials (RCTs), observational studies, and case series published by December 2020 were eligible for inclusion. A meta-analysis was conducted on the success of EVT, stoma reversal rate after EVT as well as procedure-related complications. Statistical interferences were based on pooled estimates from random effects models using DerSimonian-Laird estimator. RESULTS: Only data from observational studies and case series were available. Twenty-four studies reporting on 690 patients with colorectal defects undergoing EVT were included. The mean rate of success was 81.4% (95% CI: 74.0%-87.1%). The proportion of diverted patients was 76.4% (95% CI: 64.9%-85.0%). The mean rate of ostomy reversal across the studies was 66.7% (95% CI: 58.0%-74.4%). Sixty-four patients were reported with EVT-associated complications, the weighted mean complication rate across the studies was 12.1% (95% CI: 9.7%-15.2%). CONCLUSIONS: Current medical evidence on EVT in patients with colorectal leaks lacks high quality data from RCTs. Based on the data available, EVT can be seen as a feasible treatment option with manageable risks for selected patients with colorectal leaks.

Immunogenicity and safety of routine vaccines in children and adolescents with rheumatic diseases on immunosuppressive treatment - a systematic review.

The immunogenicity of vaccines in children with juvenile autoimmune rheumatic diseases (JARDs) can be reduced, there are additional safety concerns around vaccination, and there is a potential for worsening in disease activity. In this systematic review, we summarise studies that investigated the immunogenicity and safety of routine vaccines in children and adolescents with JARD on immunosuppressive treatment. We identified 37 studies investigating 2571 children and adolescents with JARD on immunosuppressive treatment and 4895 control children. Of the 56 geometric mean antibody titres measured, 19 (34%) were lower, six (11%) higher, and 31 (55%) similar; of the 39 seroprotection rates measured, 10 (26%) were lower, two (5%) higher, and 27 (69%) similar; and of the 27 seroconversion rates measured, nine (33%) were lower, two (8%) higher, and 16 (59%) similar in children with JARD on immunosuppressive treatment compared with control children. However, many of the studies were underpowered, and not designed to show non-inferiority between children with JARD and controls. Subgroup analysis for different types of immunosuppressive treatments was not feasible, as most studies did not report results by treatment. Severe adverse events were reported in 38 children (33 with juvenile idiopathic arthritis, four with systemic lupus erythematosus, and one in a healthy child); most of them were likely not related to the vaccination (e.g. elective hospitalisation or surgery). A worsening in disease activity was reported in 44 (2%) children with JARD; again, many of them were likely not related to the vaccination. There were no safety concerns with live attenuated vaccines; however, only few studies reported results for this. CONCLUSION: Vaccination in children with JARD on immunosuppressive treatment is safe and should be promoted, especially since these children are at increased risk for infection. The importance for the completion of vaccination schedules should be stressed. Strategies to compensate for the lower vaccine responses, which are found in approximately one-third of these children, include measuring antibody levels to determine the optimal timing for the administration of additional booster doses. WHAT IS KNOWN: • Children with juvenile autoimmune rheumatic diseases (JARDs) are at higher risk for infections, due to their underlying disease and their immunosuppressive treatment. • In children with JARD, the immunogenicity of vaccines might be reduced, and concerns about safety or the potential for worsening in disease activity after vaccination exist. WHAT IS NEW: • Our systematic review shows that vaccines in children with JARDs on immunosuppressive treatment are safe and immunogenic. • There are several limitations of the currently published studies, including random timing of measuring vaccine responses and age differences between children with JARD and control groups. Many of the studies were underpowered, and not designed to show non-inferiority between children with JARD and controls.

Factors associated with hospital and intensive care admission in paediatric SARS-CoV-2 infection: a prospective nationwide observational cohort study.

Coronavirus disease 2019 (COVID-19) is usually less severe in children compared to adults. This study describes detailed clinical characteristics, treatment and outcomes of children with COVID-19 in a non-hospitalised and hospitalised setting and quantifies factors associated with admission to hospital and intensive care unit in children with SARS-CoV-2 infection on a nationwide level. Data were collected through the Swiss Paediatric Surveillance Unit from children < 18 years with confirmed SARS-CoV-2 infection. All 33 paediatric hospitals in Switzerland reported non-hospitalised and hospitalised cases from March 1 to October 31, 2020 during both pandemic peaks. In total, 678 children were included. The median age was 12.2 years (IQR 5.0-14.6), 316 (46.6%) were female and 106 (15.6%) had comorbidities. Overall, 126 (18.6%) children were hospitalised of whom 16 (12.7%) required ICU admission. Comorbidities were the only factor associated with hospital admission in a multivariable regression analysis (odds ratio 3.23, 95%CI 1.89 to 5.50; p-value < 0.01). Children with preexisting comorbidities did not require ICU admission more often. Hospitalised children more often presented with fever (96 [76.2%] vs 209 [38.1%], p-value < 0.01) and rash (16 [12.8%] vs 6 [1.1%], p-value < 0.01). Anosmia/dysgeusia was more prevalent in non-hospitalised children (73 [13.3%] vs 3 [2.4%], p-value < 0.01). In hospitalised children, oxygen treatment was required in 34 (27.0%), inotropes in nine (7.3%) and mechanical ventilation in eight (6.3%) cases. Complications were reported in 28 (4.1%) children with cardiovascular complications being most frequent (12 [1.8%]). Three deaths were recorded.Conclusion: This study confirms that COVID-19 is mostly a mild disease in children. Fever, rash and comorbidities are associated with higher admission rates. Continuous observation is necessary to further understand paediatric COVID-19, guide therapy and evaluate the necessity for vaccination in children. What is Known: • Clinical manifestations of SARS-CoV-2 infection in children vary from asymptomatic to critical disease requiring intensive care unit admission. • Most studies are based on hospitalised children only; currently, there is limited data on non-hospitalised children. What is New: • The clinical spectrum and severity of COVID-19 is influenced by age: in children less than 2 years, fever, cough and rhinorrhoea are the most common symptoms and in adolescents, fever, cough and headache are more common. • Hospitalised children more often presented with fever and rash, while anosmia/dysgeusia is more prevalent in non-hospitalised children. • Children with pre-existing comorbidities are more frequently hospitalised but do not require ICU admission more often.

Oral antibiotic bowel decontamination in open and laparoscopic sigmoid resections for diverticular disease.

PURPOSE: There is an ongoing debate on whether or not to use oral antibiotic bowel decontamination in colorectal surgery, despite the numerous different regimens in terms of antibiotic substances and duration of application. As we routinely use oral antibiotic bowel decontamination (selective decontamination of the digestive tract (SDD) regimen and SDD regimen plus vancomycin since 2016) in surgery for diverticular disease, our aim was to retrospectively analyze the perioperative outcome in two independent centers. METHODS: Data from two centers with a routine use of oral antibiotic bowel decontamination for up to 20 years of experience were analyzed for the perioperative outcome of 384 patients undergoing surgery for diverticular disease. RESULTS: Overall morbidity was 12.8%, overall mortality was 0.3%, the overall rate of anastomotic leakage (AL) was 1.0%, and surgical site infections (SSIs) were 5.5% and 7.8% of all infectious complications including urinary tract infections and pneumonia. No serious adverse events were related to use of oral antibiotic bowel decontamination. Most of the patients (93.8%) completed the perioperative regimen. Additional use of vancomycin to the SDD regimen did not show a further reduction of infectious complications, including SSI and AL. CONCLUSION: Oral antibiotic decontamination appears to be safe and effective with low rates of AL and infectious complications in surgery for diverticular disease.

Swiss consensus recommendations on urinary tract infections in children.

The kidneys and the urinary tract are a common source of infection in children of all ages, especially infants and young children. The main risk factors for sequelae after urinary tract infections (UTI) are congenital anomalies of the kidney and urinary tract (CAKUT) and bladder-bowel dysfunction. UTI should be considered in every child with fever without a source. The differentiation between upper and lower UTI is crucial for appropriate management. Method of urine collection should be based on age and risk factors. The diagnosis of UTI requires urine analysis and significant growth of a pathogen in culture. Treatment of UTI should be based on practical considerations regarding age and presentation with adjustment of the initial antimicrobial treatment according to antimicrobial sensitivity testing. All children, regardless of age, should have an ultrasound of the urinary tract performed after pyelonephritis. In general, antibiotic prophylaxis is not recommended.Conclusion: Based on recent data and in line with international guidelines, multidisciplinary Swiss consensus recommendations were developed by members of Swiss pediatric infectious diseases, nephrology, and urology societies giving the clinician clear recommendations in regard to diagnosis, type and duration of therapy, antimicrobial treatment options, indication for imaging, and antibiotic prophylaxis. What is Known: • Urinary tract infections (UTI) are a common and important clinical problem in childhood. Although children with pyelonephritis tend to present with fever, it can be difficult on clinical grounds to distinguish cystitis from pyelonephritis, particularly in young children less than 2 years of age. • Method of urine collection is based on age and risk factors. The diagnosis of UTI requires urine analysis and significant growth of a pathogen in culture. What is New: • Vesicoureteric reflux (VUR) remains a risk factor for UTI but per se is neither necessary nor sufficient for the development of renal scars. Congenital anomalies of the kidney and urinary tract (CAKUT) and bladder-bowel dysfunction play a more important role as causes of long-term sequelae. In general, antibiotic prophylaxis is not recommended. • A switch to oral antibiotics should be considered already in young infants. Indications for invasive imaging are more restrictive and reserved for patients with abnormal renal ultrasound, complicated UTI, and infections with pathogens other than E. coli.

Factors That Influence the Immune Response to Vaccination.

There is substantial variation between individuals in the immune response to vaccination. In this review, we provide an overview of the plethora of studies that have investigated factors that influence humoral and cellular vaccine responses in humans. These include intrinsic host factors (such as age, sex, genetics, and comorbidities), perinatal factors (such as gestational age, birth weight, feeding method, and maternal factors), and extrinsic factors (such as preexisting immunity, microbiota, infections, and antibiotics). Further, environmental factors (such as geographic location, season, family size, and toxins), behavioral factors (such as smoking, alcohol consumption, exercise, and sleep), and nutritional factors (such as body mass index, micronutrients, and enteropathy) also influence how individuals respond to vaccines. Moreover, vaccine factors (such as vaccine type, product, adjuvant, and dose) and administration factors (schedule, site, route, time of vaccination, and coadministered vaccines and other drugs) are also important. An understanding of all these factors and their impacts in the design of vaccine studies and decisions on vaccination schedules offers ways to improve vaccine immunogenicity and efficacy.

Acute Stress-Induced Coagulation Activation in Patients With Remitted Major Depression Versus Healthy Controls and the Role of Stress-Specific Coping.

BACKGROUND: Depressed patients have an increased risk of myocardial infarction, for which acute stress is a frequent trigger. Prothrombotic changes could be one involved mechanism that can be modulated by psychological coping. PURPOSE: We examined the effects of remitted major depression and situation-specific coping strategies on stress-induced coagulation activation. METHODS: Forty patients with remitted depression and 23 healthy controls underwent the Trier Social Stress Test, rating applied coping strategies thereafter. Blood was sampled at baseline and 15 and 45 min poststress to measure fibrinogen, von Willebrand factor (VWF) and D-dimer. Coagulation activation over time was quantified as area under the curve (AUC) with respect to baseline activity. Standardized z-scores of individual coagulation AUC measures were added up to a prothrombotic index. RESULTS: Stress provoked significant VWF (p = .024) and D-dimer (p = .002) responses. Remitted depressed patients used positive distraction coping more frequently than controls did (p = .030). Coagulation AUC measures were similar in both groups. In all participants, higher positive coping total (p = 0.009), driven by devaluation/defense (p = .022) and distraction (p = .004) coping, was associated with a lower prothrombotic index. In controls, but not in remitted depressed patients, higher positive coping total (p = .008), driven by higher devaluation/defense (p = .010) and distraction (p = .023) coping, was associated with lower VWF AUC. CONCLUSIONS: Despite the use of favorable coping strategies in a specific stress situation, remitted depressed patients may benefit less from a positive effect of positive situational coping on coagulation activation than controls. Such a mechanism could partially explain the increased risk of myocardial infarction in depressed individuals.

Schema therapy versus cognitive behavioral therapy versus individual supportive therapy for depression in an inpatient and day clinic setting: study protocol of the OPTIMA-RCT.

BACKGROUND: Major depressive disorder represents (MDD) a major cause of disability and disease burden. Beside antidepressant medication, psychotherapy is a key approach of treatment. Schema therapy has been shown to be effective in the treatment of psychiatric disorders, especially personality disorders, in a variety of settings and patient groups. Nevertheless, there is no evidence on its effectiveness for MDD in an inpatient nor day clinic setting and little is known about the factors that drive treatment response in such a target group. METHODS: In the current protocol, we outline OPTIMA (OPtimized Treatment Identification at the MAx Planck Institute): a single-center randomized controlled trial of schema therapy as a treatment approach for MDD in an inpatient and day clinic setting. Over the course of 7 weeks, we compare schema therapy with cognitive behavioral therapy and individual supportive therapy, conducted in individual and group sessions and with no restrictions regarding concurrent antidepressant medication, thus approximating real-life treatment conditions. N = 300 depressed patients are included. All study therapists undergo a specific training and supervision and therapy adherence is assessed. Primary outcome is depressive symptom severity as self-assessment (Beck Depression Inventory-II) and secondary outcomes are clinical ratings of MDD (Montgomery-Asberg Depression Rating Scale), recovery rates after 7 weeks according to the Munich-Composite International Diagnostic Interview, general psychopathology (Brief Symptom Inventory), global functioning (World Health Organization Disability Assessment Schedule), and clinical parameters such as dropout rates. Further parameters on a behavioral, cognitive, psychophysiological, and biological level are measured before, during and after treatment and in 2 follow-up assessments after 6 and 24 months after end of treatment. DISCUSSION: To our knowledge, the OPTIMA-Trial is the first to investigate the effectiveness of schema therapy as a treatment approach of MDD, to investigate mechanisms of change, and explore predictors of treatment response in an inpatient and day clinic setting by using such a wide range of parameters. Insights from OPTIMA will allow more integrative approaches of psychotherapy of MDD. Especially, the identification of intervention-specific markers of treatment response can improve evidence-based clinical decision for individualizing treatment. TRIAL REGISTRATION: Identifier on clinicaltrials.gov : NCT03287362 ; September, 12, 2017.

Biological sex influences antibody responses to routine vaccinations in the first year of life.

AIM: We investigated the effect of early-life factors, namely sex, delivery mode, feeding method and antibiotic exposure, on antibody responses to routine vaccinations administered during the first year of life. METHODS: One and seven months after the primary course of routine vaccines and 1 month after routine vaccines at 12 months of age, antibodies against 26 vaccine antigens were measured in 398 healthy infants. The geometric mean concentration (GMC) of antibodies (adjusted for effect modifiers with multiple linear regression) and the seroprotection rate for each vaccine were compared for each early-life factor. RESULTS: Sex had an influence on GMCs. Antibody concentrations were significantly lower at 7 months of age in females for tetanus and filamentous haemagglutinin and at 13 months of age for pertactin. In contrast, at 13 months of age, antibody concentrations were significantly higher in females for polio type 3, pneumococcal serotype 6A and measles. Sex did not have an influence on seroprotection rates. Delivery mode, feeding method and antibiotic exposure did not exert a substantial influence on vaccine antibody concentrations. CONCLUSION: There is a difference between males and females in the humoral response to routine vaccinations in the first year of life.

Association between the intestinal microbiota and allergic sensitization, eczema, and asthma: A systematic review.

The intestinal microbiota plays an important role in development of the immune system and regulation of immune responses. This review summarizes the association between the intestinal microbiota and the development of allergic sensitization, eczema, and asthma in neonates and children. Overall, a greater relative abundance of Bacteroidaceae, Clostridiaceae, and Enterobacteriaceae and a lower relative abundance of Bifidobacteriaceae and Lactobacillaceae is associated with the development of allergic sensitization, eczema, or asthma. Reduced bacterial diversity can be associated with the development of allergic disease. The association between the composition of the intestinal microbiota and the development of allergic disease or asthma is less consistent in older children than in neonates, suggesting that early-life microbial exposure plays a more important role. Inconsistencies in the results reported from different studies might partly be explained by heterogeneity in design, study populations, diagnostic criteria, microbiota analysis methods, and reporting on different taxonomic levels. Larger studies that better account for antenatal and postnatal factors will further help determine specific microbial intestinal signatures associated with increased risk of allergy and asthma. This will enable the early identification of infants at high risk and facilitate novel strategies and interventions to prevent and treat these conditions, including modifying the intestinal microbiota early in life.

The immunomodulatory effects of measles-mumps-rubella vaccination on persistence of heterologous vaccine responses.

It is proposed that measles-containing vaccines have immunomodulatory effects which include a reduction in all-cause childhood mortality. The antibody response to heterologous vaccines provides a means to explore these immunomodulatory effects. This is the first study to investigate the influence of measles-mumps-rubella (MMR) vaccine on the persistence of antibodies to a broad range of heterologous infant vaccinations given in the first year of life. In total, 319 children were included in the study. All infants received routine vaccinations at 6 weeks, 4 and 6 months of age. At 12 months of age, 212 children were vaccinated with MMR and Haemophilus influenzae type b-meningococcus C (Hib-MenC) vaccines while the remaining 99 children had not yet received these vaccines. In the MMR/Hib-MenC-vaccinated group, blood was taken 28 ± 14 days after receiving these vaccines. Antibodies against diphtheria, tetanus, pertussis [pertussis toxin (PT), filamentous hemagglutinin, pertactin], poliomyelitis (type 1, 2, 3) and 13 pneumococcal serotypes were measured. Seroprotection rates and geometric mean antibody concentrations were compared between MMR/MenC-Hib-vaccinated and MMR/MenC-Hib-naïve participants. In the final analysis, 311 children were included. Seroprotection rates were lower in MMR/Hib-MenC-vaccinated children against PT and pneumococcal serotype 19A. After adjustment for prespecified factors, MMR/Hib-MenC-vaccinated infants had significantly higher antibody concentrations against tetanus (likely explained by a boosting effect of the carrier protein, a tetanus toxoid), while for the other vaccine antigens there was no difference in antibody concentrations between the two groups. MMR vaccination given at 12 months of age in a developed country does not significantly influence antibody concentrations to heterologous vaccines received in the first year of life.