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Contains fulltext : 248865.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions. METHODS: The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6-30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features. RESULTS: In addition to significant between-group differences in "core" ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals' total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission. CONCLUSIONS: The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.

Background: The role of adjuvant therapy in patients with oesophagogastric adenocarcinoma treated by neoadjuvant chemotherapy (NAC) and surgery is contentious. In UK practice, surgical resection margin status is often used to classify patients into receiving adjuvant treatment. This study aimed to assess any survival benefit of adjuvant therapy in patients with clear resection margins. Methods: This was a retrospective collaborative cohort study combining two prospectively collected UK institutional databases of patients with oesophageal adenocarcinoma. Multivariable Cox regression and propensity matched analyses were used to compare overall and recurrence-free survival according to the adjuvant treatment. Results: Of 374 patients with clear resection margins, 221 patients (59%) had no adjuvant treatment, 137 patients (37%) had adjuvant chemotherapy and 16 patients (4%) had adjuvant chemoradiotherapy. For patients who had received NAC (290, 76%), when adjuvant chemotherapy was compared to no adjuvant treatment, hazard ratios (HRs) favoured adjuvant chemotherapy but did not reach independent significance (overall survival [OS] HR 0.65 95% confidence interval [CI] 0.40–1.06; p.0.087). Responders to NAC (Mandard 1–3) were seemingly more likely to demonstrate a survival benefit from adjuvant chemotherapy (HR 0.42 95% CI 0.15–1.11; p.1.081). Conclusions: Although no independent survival benefit was observed, the point estimates favoured adjuvant treatment, predominantly in patients with chemo-responsive tumours. Refereed/Peer-reviewed

Background: Experiences of African/Afro-Caribbean men on active surveillance (AS) for prostate cancer (PCa) in the United Kingdom (UK) are not well documented. We compared follow-up appointments, adherence, and clinical outcomes among African/Afro-Caribbean men on AS at a high-volume UK hospital with other ethnicities. Methods: Men with confirmed low-intermediate risk Pca who attended the AS clinic (2005–2016) and had undergone ≥1 follow-up biopsy (n = 458) were included. Non-adherence (defined as >20% missed appointments), suspicion of disease progression (any upgrading, >30% positive cores, cT-stage > 3, PIRADS > 3), any upgrading from diagnostic biopsy and conversion to active treatment (prostatectomy, radiotherapy or hormone therapy) according to ethnicity (African/Afro-Caribbean versus other ethnicities) were assessed using multivariable regression analysis. Results: Twenty-three percent of eligible men were recorded as African/Afro-Caribbean, while the remainder were predominantly Caucasian. African/Afro-Caribbean men had slightly lower PSA at diagnosis (median 5.0 vs. 6.0 ng/mL) and more positive cores at diagnosis (median 2 vs. 1). They had a substantially higher rate of non-attendance at scheduled follow-up visits (24% vs. 10%, p < 0.001). Adjusted analyses suggest African/Afro-Caribbean men may be at increased risk of disease progression (hazard ratio [HR]: 1.38; 95% confidence interval [CI] 0.99–1.91, P = 0.054) and upgrading (HR: 1.29; 95% CI 0.87–1.92, P = 0.305), though neither reached statistical significance. No difference in risk of conversion to treatment was observed between ethnic groups (HR: 1.03; 95% CI 0.64–1.47, P = 0.873). Conclusions: African/Afro-Caribbean men on AS for PCa in the UK are less likely to adhere to scheduled appointments, suggesting a more tailored service addressing their specific needs may be required. While African/Afro-Caribbean men were no more likely to convert to treatment than Caucasian/other men, findings of a potentially higher risk of disease progression signal the need for careful selection and monitoring of African/Afro-Caribbean men on AS. Larger prospective, multicentre studies with longer follow-up are required to provide more definitive conclusions. Refereed/Peer-reviewed

Background: The impact of adjuvant radiotherapy (RT) to the vulva with regard to prognosis and local recurrence in patients with vulvar squamous cell cancer (VSCC) is poorly described.Patients and methods: In the AGO-CaRE-1 study 1618 patients with primary VSCC FIGO stage ≥ IB, treated between 1998-2008, were documented. In this retrospective subanalysis, 360 patients were included based on the following criteria: nodal involvement (pN+), known RT treatment and known radiation fields.Results: The majority had pT1b/pT2 tumors (n=299; 83.1%). In 76.7%, R0 resection was achieved. 57/360 (15.8%) N+ patients were treated with adjuvant RT to the groins/pelvis and 146/360 (40.5%) received adjuvant RT to the vulva and groins/pelvis. 157/360 (43.6%) patients did not receive any adjuvant RT. HPV status was available in 162/360 patients (45.0%), 75/162 tumors were HPV+(46.3%), 87/162 (53.7%) HPV-. During a median follow-up of 17.2 months, recurrence at the vulva only occurred in 25.5% of patients without adjuvant RT, in 22.8% of patients with adjuvant RT to groins/pelvis and in 15.8% of patients with adjuvant RT to the vulva and groins/pelvis respectively. The risk reducing effect of local RT was independent of the resection margin status. 50% disease free survival time (50% DFST) indicated a stronger impact of adjuvant RT to the vulva in HPV+ compared to HPV- patients (50% DFST 20.7 months vs. 17.8 months).Conclusion: Adjuvant RT to the vulva was associated with a lower risk for local recurrence in N+ VSCC independent of the resection margin status. This observation was more pronounced in patients with HPV+ tumors in comparison to HPV– tumors.

Which is the optimal extraction method for isolating and quantifying circulating cell-free DNA (ccfDNA) from patients with endometriosis? Endometriosis is a common benign disease, associated with pain, infertility and reduced quality of life. Endometriosis is also a known risk factor for various cancers. Robust biomarkers for early detection and prediction of prognosis, however, are lacking. CcfDNA is an easy to obtain biomarker associated with prognosis of cancer patients and enables non-invasive analysis of somatic mutations. Recently, elevated levels of ccfDNA were detected in patients with endometriosis.Two different ccfDNA extraction methods were compared: Maxwell RSC ccfDNA plasma kit (Maxwell) and QiAamp minElute ccfDNA mini kit (QIAamp). The ccfDNA and circulating mitochondrial DNA (mtDNA) quantities from 34 patients diagnosed with endometriosis were analysed. Fluorometric measurement and quantitative reverse transcription polymerase chain reaction (qRT-PCR) of short and long ALU and mtDNA fragments were used to quantiy ccfDNA.The yield of ccfDNA isolated with the Maxwell method was significantly higher compared with the QIAamp method (P0.0001). Integrity of ccfDNA was significantly higher in the QIAamp isolate (P0.0001). Recovered mtDNA was not significantly different between both extraction methods used.The choice of extraction method can significantly influence the ccfDNA output and integrity. Both methods, however, enabled isolation of sufficient ccfDNA for further downstream applications. With this approach, isolation of ccfDNA could enable the non-invasive detection and analysis of somatic mutation within endometriosis tissue.

Context Dipeptidylpeptidase (DPP)-4 is a key regulator of the incretin system. It exists in a membrane-bound form and a soluble form (sDPP-4). Initial human studies suggested sDPP-4 to be an adipokine involved in metabolic inflammation. However, recent mechanistic data in genetically modified mice has questioned these findings. Objectives We examined circulating sDPP-4 in a cohort of n = 451 humans with different metabolic phenotypes and during 3 different weight loss interventions (n = 101) to further clarify its role in human physiology and metabolic diseases. Design sDPP-4 serum concentrations were measured by enzyme-linked immunosorbent assay and related to several phenotyping data including gut microbiome analysis. Results sDPP-4 increased with age and body weight and was positively associated with insulin resistance and hypertriglyceridemia but was reduced in manifest type 2 diabetes. In addition, we found reduced serum concentrations of sDPP-4 in subjects with arterial hypertension. In contrast to earlier reports, we did not identify an association with systemic markers of inflammation. Impaired kidney and liver functions significantly altered sDPP-4 concentrations while no relation to biomarkers for heart failure was observed. Having found increased levels of sDPP-4 in obesity, we studied surgical (gastric bypass and sleeve gastrectomy) and nonsurgical interventions, revealing a significant association of sDPP-4 with improvement of liver function tests but not with changes in body weight. Conclusions Our data suggest that sDPP-4 is related to hepatic abnormalities in obesity rather than primarily functioning as an adipokine and that sDPP-4 is implicated both in glucose and in lipid metabolism, but not fundamentally in systemic inflammation.

Background and purpose: To investigate associations between socio-demographic characteristics and radiotherapy patterns of care in non-metastatic prostate cancer [nmPCa] in South Australia [SA] between 2005–2015 and document practice patterns over time. Materials and methods: Men with nmPCa receiving primary curative radiotherapy were identified from SA Prostate Cancer Clinical Outcomes Collaborative database. Adjuvant, salvage and palliative therapies were excluded. Associations between socio-demographic factors (age, residence, socio-economic status, diagnostic period) and radiotherapy mode (external beam radiotherapy [EBRT] vs. brachytherapy [BT]) and technique (low-dose-rate vs. high-dose-rate brachytherapy) were investigated using multivariable logistic regression with separate models for clinical risk categories. Results: Of the 1874 men who underwent primary RT, 80% received EBRT and 20% BT. For low and intermediate risk disease, likelihood of receiving EBRT was higher among older men (ORlow = 3.08; 95% CI 1.82–5.22 and ORintermediate = 3.48; 2.28–5.31 for 65–74 yrs vs.

European spine journal 31(4), 1013-1021 (2021). doi:10.1007/s00586-021-07035-4, Published by Springer, Berlin ; Heidelberg ; New York

Purpose Assessment of HER2 overexpression using immunohistochemistry (IHC) and/or in situ hybridisation (ISH) for the detection of HER2 amplifications is standard to identify patients for established HER2-directed treatments. Patients with lower HER2 expression levels have recently also become candidates for novel therapies targeting HER2. This study aimed to assess tumour and patient characteristics and prognosis in patients with advanced breast cancer (aBC), relative to low HER2 expression levels. Methods PRAEGNANT is a prospective aBC registry (NCT02338167), focusing on molecular biomarkers. Patients in all therapy lines receiving any kind of treatment are eligible. This analysis includes patients with conventionally HER2-negative aBC. Clinical outcome was compared in the groups with no (IHC score 0) or with low HER2 expression (IHC 1+, or IHC 2+/ISH negative). Results Low HER2 expression levels in triple-negative aBC patients did not influence progression-free survival. Overall survival appeared poorer in patients with IHC 2+ compared with patients with no HER2 expression in the unadjusted analysis (hazard ratio 2.24, 95% confidence interval 0.1.12–4.47). However, this effect was not maintained in the adjusted analysis. In HER2-negative, hormone receptor–positive patients, low HER2 expression appeared to have no effect on prognosis, neither progression-free survival nor overall survival. Conclusions We could not demonstrate that HER2 expression at a low level and assessed in clinical routine can differentiate patients into prognostic groups. However, the prevalence of patients with a low expression makes this population interesting for clinical trials with potentially active treatments using HER2 as a target.

Antiparkinsonian drugs especially dopamine agonists have many side effects. Dopamine agonists have been linked with compulsive inappropriate behaviours such as gambling, compulsive shopping, hobbyism, other repetitive or purposeless behaviours such as punding, compulsive eating and hypersexuality. However pathological hypersexuality has rarely surfaced in routine Parkinson’s disease practice. We present clinical findings of a seventy-three year old male Parkinson’s disease patient with diagnosis of hypersexuality as a side effect of pramipexole. After pramipexole was withdrawn, dopamine agonist was changed to ropinirole and full remission was observed. Prevalence of psychiatric disorders in patients suffering from Parkinson’s disease varies from 12 to 90%. Hypersexuality is a common impulse control disorder seen in Parkinson’s disease and noted in these patients taking a variety of dopaminergic agents; including levodopa, dopamine agonists or MAO inhibitors. In our patient, pramipexole caused hypersexuality unexpectedly. Since this case constitutes interesting findings in two different points, one is hypersexuality with pramipexole, the other is no hypersexuality with use of ropinirole after pramipexole withdrawal, it is chosen to be presented here.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity. ADHD has been related to differences in white matter (WM) microstructure. However, much remains unclear regarding the nature of these WM differences and which clinical aspects of ADHD they reflect. We systematically investigated whether fractional anisotropy (FA) is associated with current and/or lifetime categorical diagnosis, impairment in daily life, and continuous ADHD symptom measures.METHODS: Diffusion-weighted imaging data were obtained from 654 participants (322 unaffected, 258 affected, 74 subthreshold; 7-29 years of age). We applied automated global probabilistic tractography on 18 major WM pathways. Linear mixed-effects regression models were used to examine associations of clinical measures with overall brain and tract-specific FA.RESULTS: There were significant interactions of tract with all ADHD variables on FA. There were no significant associations of FA with current or lifetime diagnosis, nor with impairment. Lower FA in the right cingulum angular bundle was associated with higher hyperactivity-impulsivity symptom severity (pfamilywise error = .045). There were no significant effects for other tracts.CONCLUSIONS: This is the first time global probabilistic tractography has been applied to an ADHD dataset of this size. We found no evidence for altered FA in association with ADHD diagnosis. Our findings indicate that associations of FA with ADHD are not uniformly distributed across WM tracts. Continuous symptom measures of ADHD may be more sensitive to FA than diagnostic categories. The right cingulum angular bundle in particular may play a role in symptoms of hyperactivity and impulsivity.

Background Marked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Efforts to unravel sex differences in the brain organization of autism have, however, been challenged by the limited availability of female data. Methods We addressed this gap by using a large sample of males and females with autism and neurotypical (NT) control individuals (ABIDE; Autism: 362 males, 82 females; NT: 409 males, 166 females; 7–18 years). Discovery analyses examined main effects of diagnosis, sex and their interaction across five resting-state fMRI (R-fMRI) metrics (voxel-level Z > 3.1, cluster-level P Results Discovery analyses in ABIDE revealed significant main effects of diagnosis and sex across the intrinsic functional connectivity of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical regions, largely converging in the default network midline. Sex-by-diagnosis interactions were confined to the dorsolateral occipital cortex, with reduced VMHC in females with autism. All findings were robust to different pre-processing steps. Replicability in independent samples varied by R-fMRI measures and effects with the targeted sex-by-diagnosis interaction being replicated in the larger of the two replication samples—EU-AIMS LEAP. Limitations Given the lack of a priori harmonization among the discovery and replication datasets available to date, sample-related variation remained and may have affected replicability. Conclusions Atypical cross-hemispheric interactions are neurobiologically relevant to autism. They likely result from the combination of sex-dependent and sex-independent factors with a differential effect across functional cortical networks. Systematic assessments of the factors contributing to replicability are needed and necessitate coordinated large-scale data collection across studies.

Objective This study aimed to provide an overview of the extent to which women with endometriosis are informed about, interested in, and make use of CAM, and to evaluate which of the methods are most often applied. Study Design A retrospective, two-center cohort study was conducted using a validated questionnaire among women with laparoscopically confirmed endometriosis at two urban teaching hospitals, certified as endometriosis centres. Results A total of 592 patients were included in the study and received the questionnaire; 114 (19.3 %) were included in the data analysis. Most of the women were not receiving hormone therapy at the time of the study (n = 60, 52.6 %). Most (n = 75, 65.8 %) were interested in CAM, but only a minority (n = 12, 10.5 %) had detailed knowledge about it. A total of 81 patients (71.1 %) had used at least one CAM method for disease management; the five most frequently used CAM methods were exercise (n = 55, 48.2 %), vitamins (n = 40, 35.1 %), yoga (n = 38, 33.3 %), homeopathy (n = 32, 28.1 %), and trace elements (n = 27, 23.7 %). Conclusions In our study population, women with endometriosis are strongly interested in using CAM, but have only limited information about it. Nevertheless, a majority of the patients had used at least one CAM method to relieve symptoms associated with the disease and the most often used was exercise.

Introduction Total knee arthroplasty (TKA) has historically been the preferred solution for any type of knee osteoarthritis, independently of the number of compartments involved. In these days of patient-specific medicine, mono-compartmental disease could also be approached with a more individualized treatment, such as partial knee arthroplasty (PKA). Off-the-shelf (OTS) implants are often the compromise of averages and means of a limited series of anatomical parameters retrieved from patients and the pressure of cost control by limited inventory. Personalized medicine requires respect and interest for the individual shape and alignment of each patient. Materials and methods A Pubmed and Google Scholar search were performed with the following terms: “patient-specific knee” and “arthroplasty” and “custom implant” and “total knee replacement” and “partial knee replacement” and “patellofemoral knee replacement” and “bicompartmental knee replacement”. The full text of 90 articles was used to write this narrative review. Results Unicondylar, patellofemoral and bicompartmental knee arthroplasty are successful treatment options, which can be considered over TKA for their bone and ligament sparing character and the superior functional outcome that can be obtained with resurfacing procedures. For TKA, where compromises dominate our choices, especially in patients with individual variations of their personal anatomy outside of the standard, a customized implant could be a preferable solution. Conclusion TKA might not be the only solution for every patient with knee osteoarthritis, if personalized medicine wants to be offered. Patient-specific mono-compartmental resurfacing solutions, such as partial knee arthroplasty, can be part of the treatment options proposed by the expert surgeon. Customized implants and personalized alignment options have the potential to further improve clinical outcome by identifying the individual morphotype and respecting the diversity of the surgical population.

Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. Results: We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10–8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15–1.34; P = 1.47 × 10–8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. Impact: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options. See related commentary by Peres and Monteiro, p. 1604

Background: Complicated diverticulitis of the sigmoid colon typically is treated by resection after initial antibiotic treatment. Third-generation cephalosporins are the drugs of choice but are not effective against enterococci and can induce colonic colonization by Enterococcus faecium within hours. Infections caused by enterococci, especially E. faecium, are difficult to treat but should be considered in the strategic treatment planning of hospital-acquired peritonitis (e.g., anastomotic leakage), especially in immunocompromised patients. Methods: To determine whether the duration of pre-operative ceftriaxone treatment in complicated diverticulitis increases the incidence of intra-abdominal E. faecium detection, we analyzed all patients operated on for diverticulitis of the sigmoid colon in our department between 2008 and 2016. Results: Analyzing 516 resections performed for complicated diverticulitis, we found that E. faecium generally was detected intra-abdominally more often in the group that underwent longer pre-operative ceftriaxone treatment (≥ 4 days). During primary resection, E. faecium was detected in 2.7%, 11.1%, and 37.0% cases in the group undergoing immediate operation, 1-3 days of antibiotic treatment, and ≥4 days of antibiotic treatment, respectively. Enterococcus faecium was detected in 0, 25.0%, and 70.6% of surgical revisions and 28.6%, 14.3%, and 56.0%, respectively, of incisional surgical site infections with identified pathogens. A multivariable analysis discovered anastomotic leakage and antibiotic treatment lasting ≥4 days to be independent risk factors for intra-abdominal isolation of E. faecium. Conclusion: A ceftriaxone treatment ≥4 days led to a higher incidence of intra-abdominal E. faecium. Our data further suggested that empiric coverage of E. faecium in the treatment of hospital-acquired peritonitis could be beneficial after a long duration of ceftriaxone treatment.

Background More and more information about complementary and integrative medicine is becoming available, especially among cancer patients. However, little is known about the use of herbal medicine by patients with gynecologic cancers. This study aimed to assess the use of herbal products by gynecologic cancer patients compared with healthy controls. Methods This cross-sectional study was conducted at the Department for Gynecology and Obstetrics of Erlangen University Hospital and included 201 patients with gynecologic cancer and 212 healthy controls. Use of herbal medicines was evaluated using a standardized questionnaire. Medical information on cancer patients was collected from hospital records. Group comparisons were done using a logistic regression model. Risk ratios were assessed using a Poisson regression model. Results Gynecologic cancer patients used herbal medicine significantly less often than healthy persons. 69% of gynecologic cancer patients and 81% of healthy participants reported using herbal products. 40% of cancer patients and 56% of healthy persons reported using plants for medicinal purposes. Motives of cancer patients for using herbal medicine included treatment of cancer-related symptoms. The major source of information for both groups was family and friends. Conclusions Although herbal medicine was used less by patients with gynecologic cancer, herbal products were used by both cancer patients and healthy individuals. To provide cancer patients with optimal therapy, oncologists should be informed about the herbal products used by their patients as this will allow them to take their patientsʼ self-medication with herbal medicine into account. Counseling by oncologists on the use of herbal medicine should be encouraged.

Purpose Villoglandular adenocarcinoma (VGA) of the uterine cervix has been classified as a rare subtype of cervical adenocarcinoma with good prognosis. A conservative surgical approach is considered feasible. The main risk factor is the presence of other histologic types of cancer. In this largest systematic review to date, we assess oncological outcomes associated with conservative therapy compared to those associated with invasive management in the treatment of stage Ia and Ib1 VGA. Methods Case series and case reports identified by searching the PubMed database were eligible for inclusion in this review (stage Ia–Ib1). Results A total of 271 patients were included in our literature review. 54 (20%) patients were treated by “conservative management” (conization, simple hysterectomy, and trachelectomy) and 217 (80%) by “invasive management” (radical hysterectomy ± radiation, hysterectomy, and radiation). Recurrences of disease (RODs) were found in the conservative group in two (4%) cases and in the invasive group in nine (4%) cases. There was no significant difference in disease-free survival (DFS) according to conservative or invasive treatment (p = 0.75). The histology of VGA may be complex with underlying usual adenocarcinoma (UAC) combined with VGA. Conclusion The excellent prognosis of pure VGA and the young age of the patients may justify the management of this tumor using a less radical procedure. The histological diagnosis of VGA is a challenge, and pretreatment should not be based solely on a simple punch biopsy but rather a conization with wide tumor-free margins.

Nerve root enlargement with increased contrast uptake has been reported in dogs and humans secondary to nerve root compression. In cats, nerve root enlargement and contrast uptake only have been reported in association with inflammatory and neoplastic diseases, but not as a sequela to nerve root compression. An 8‐year‐old oriental short hair cat was presented with acute neurologic deficits consistent with left‐sided sciatic nerve deficit and possible L6‐S1 myelopathy. Magnetic resonance imaging (MRI) was performed and identified compression of the cauda equina and L7 nerve root associated with intervertebral disc herniation (IVDH) at L6‐L7 as well as widespread sciatic nerve enlargement with moderate rim enhancement. A hemilaminectomy was performed to evacuate herniated disc material. The nerve root was biopsied and submitted for histological evaluation. Interstitial nerve edema was diagnosed. Follow‐up MRI 3 months postoperatively showed complete remission of the changes. Nerve root thickening together with contrast enhancement may represent nerve edema in cats secondary to IVDH.

RATIONALE: A growing body of research suggests that substance use disorder (SUD) may be characterized as disorders of decision making. However, drug-choice studies assessing drug-associated decision making often lack more complex and dynamic conditions that better approximate contexts outside the laboratory and may lead to incomplete conclusions regarding the nature of drug-associated value. OBJECTIVES: The current study assessed isomorphic (choice between identical food options) and allomorphic (choice between remifentanil [REMI] and food) choice across dynamically changing reward probabilities, magnitudes, and differentially reward-predictive stimuli in male rats to better understand determinants of drug value. Choice data were analyzed at aggregate and choice-by-choice levels using quantitative matching and reinforcement learning (RL) models, respectively. RESULTS: Reductions in reward probability or magnitude independently reduced preferences for food and REMI commodities. Inclusion of reward-predictive cues significantly increased preference for food and REMI rewards. Model comparisons revealed that reward-predictive stimuli significantly altered the economic substitutability of food and REMI rewards at both levels of analysis. Furthermore, model comparisons supported the reformulation of reward value updating in RL models from independent terms to a shared, relative term, more akin to matching models. CONCLUSIONS: The results indicate that value-based quantitative choice models can accurately capture choice determinants within complex decision-making contexts and corroborates drug choice as a multidimensional valuation process. Collectively, the present study indicates commonalities in decision making for drug and non-drug rewards, validates the use of economic-based SUD therapies (e.g. contingency management), and implicates the neurobehavioral processes underlying drug-associated decision making as a potential avenue for future SUD treatment.

BACKGROUND: Compressive symptoms are common in thyroid disease. Many studies have focused on the size of the gland and its effects on patients. However, few have taken into account the body mass of the patient. The aim of our study was to examine whether or not a patient’s body mass index (BMI) influences symptomatic outcomes following thyroid surgery for benign disease. METHODS: We conducted a prospective analysis evaluating 60 patients that underwent thyroidectomy for benign goiter (single or multinodular) disease. Patients were classified as obese, overweight, or normal based on BMI. Pre- and post-operative surveys were administered including the MRC breathlessness scale, M.D. Anderson Dysphagia Inventory (MDADI), and the ThyPRO quality of life questionnaire to evaluate dysphagia, dyspnea, and quality of life respectively. RESULTS: Patients classified as obese (n=37) scored significantly worse pre-operatively on MRC, MDADI, and ThyPRO surveys when compared to overweight (n=13) or normal weight (n=10) counterparts. Subjects in the obese group, but not the other groups, showed post-surgical improvement on both the MRC and MDADI surveys (P

Zusammenfassung Hintergrund Infolge der zunehmend individualisierten, multimodalen Therapie gibt es eine Vielzahl von potenziellen, therapieinduzierten Folgestörungen bei Mammakarzinom-Patientinnen. Die zunehmend verbesserte Langzeitprognose, das häufig junge Erkrankungsalter und die hohe Inzidenz der Erkrankung unterstreichen die Bedeutung dieser teils chronischen Nebenwirkungen für die berufliche und soziale Teilhabe. Methoden Im Rahmen dieser retrospektiven Analyse wurden bei 8000 Brustkrebspatientinnen (Durchschnittsalter 55,7 ± 10,4J) klinische Parameter und therapieinduzierte Toxizitäten und Folgestörungen im zeitlichen Verlauf analysiert und mit Daten aus der Literatur verglichen. Ergebnisse In 23,6% der Fälle wurde eine Mastektomie, in 89% eine Radiatio durchgeführt. Zudem erfolgte in den meisten eine zusätzliche systemische Therapie (57,6% CTX, 15,1% anti-Her2, 71% Antihormontherapie). In 8,1% lag ein Rezidiv bzw. eine metastasierte Erkrankung vor. Als häufigste Folgestörungen infolge der multimodalen Therapie ließen sich Kraftlosigkeit/Fatigue (73,6%), Schlafstörungen (51,9%), CIPN (33%), Lymphödeme (13,9%) und medikamentös-induzierte Arthralgien (24,8%) nachweisen. Zudem berichteten 60,4% der Frauen über einen hohen, psychischen Distress. Während kurz nach Akutbehandlung (AHB) signifikant häufiger CTX-induzierte Toxizitäten dokumentiert wurden (Leukopenie, p Diskussion Nach multimodaler Brustkrebstherapie lassen sich zwischen AHB- gegenüber Patientinnen im Regelheilverfahren teils signifikant unterschiedliche rehabilitationsrelevante Folgestörungen dokumentieren. Die Vielzahl und Vielfältigkeit somatischer sowie psychovegetativer Störungen unterstreichen die Notwendigkeit nach individualisierten, multimodalen Therapiekonzepten in der onkologischen Rehabilitation.

Aims The aim of this official guideline published and coordinated by the German Society of Gynaecology and Obstetrics (DGGG) in cooperation with the Austrian Society for Gynaecology and Obstetrics (OEGGG) and the Swiss Society for Gynaecology and Obstetrics (SGGG) was to provide consensus-based recommendations for the diagnosis and treatment of endometriosis based on an evaluation of the relevant literature. Methods This S2k guideline represents the structured consensus of a representative panel of experts with different professional backgrounds commissioned by the Guideline Committee of the DGGG, OEGGG and SGGG. Recommendations Recommendations on the epidemiology, aetiology, classification, symptomatology, diagnosis and treatment of endometriosis are given and special situations are discussed.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus 0– Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

Background REM sleep behaviour disorder (RBD) is a common non-motor feature of Parkinson's disease (PD). Cannabidiol (CBD) is one of the main non-psychoactive components of Cannabis sativa and may represent an alternative route for treating RBD. Objective This study assessed the efficacy and safety of CBD for RBD in PD. Methods We conducted a phase II/III, double-blind, placebo-controlled clinical trial in 33 patients with RBD and PD. Patients were randomized 1:1 to CBD in doses of 75 to 300mg or matched capsules placebo and were followed up for 14 weeks. The primary outcomes were the frequency of nights with RBD, CGI-I, and CGI-S. Results CBD showed no difference to placebo for primary outcomes. Regarding secondary outcomes, we observed a significant improvement in average sleep satisfaction from the 4th to 8th week in the CBD versus placebo group with P = 0.049 and P = 0.038, respectively. Conclusion CBD, as an adjunct therapy, showed no reduction in RBD manifestations in PD patients. A transient improvement in sleep satisfaction with a dose of 300mg has been noted. © 2021 International Parkinson and Movement Disorder Society.

Background Based on a quality assurance initiative of the German Society for Thoracic and Cardiovascular Surgery (DGTHG) and the German Society for Pediatric Cardiology and Congenital Heart Defects (DGPK), a voluntary registry was founded for assessment of treatment and outcomes of patients with congenital heart disease in Germany. This evaluation by the German Registry for cardiac operations and interventions in patients with congenital heart disease reports the data and the outcome over a 6-year period in patients undergoing invasive treatment. Methods This real-world database collects clinical characteristics, in-hospital complications, and medium-term outcome of patients who underwent cardiac surgical and interventional procedures within the prospective, all-comers registry. Patients were followed-up for up to 90 days. Results In the period from 2013 to 2018, a total of 35,730 patients, 39,875 cases, respectively 46,700 procedures were included at up to 31 German institutions. The cases could be subcategorized according to the treatment intention into 21,027 (52.7%) isolated operations, 17,259 (43.3%) isolated interventions, and 1,589 (4.0%) with multiple procedures. Of these, 4,708 (11.8%) were performed in neonates, 10,047 (25.2%) in infants, 19,351 (48.5%) in children of 1 to 18 years, and 5,769 (14.5%) in adults. Also, 15,845 (33.9%) cases could be allocated to so-called index procedures which underwent a more detailed evaluation to enable meaningful comparability. The mean unadjusted in-hospital mortality of all cases in our registry ranged from 0.3% in patients with isolated interventions and 2.0% in patients with surgical procedures up to 9.1% in patients undergoing multiple procedures. Conclusion This annually updated registry of both scientific societies represents voluntary public reporting by accumulating actual information for surgical and interventional procedures in patients with congenital heart disease (CHD) in Germany. It describes advancements in cardiac medicine and is a basis for internal and external quality assurance for all participating institutions. In addition, the registry demonstrates that in Germany, both interventional and surgical procedures for treatment of CHD are offered with high medical quality.

OBJECTIVES Total aortic arch replacement is an invasive procedure with significant risks for complications. These risks are even higher in older, multimorbid patients. The current trends in demographic changes in western countries with an ageing population will aggravate this issue. In this study, we present our experience with total aortic arch replacement using the frozen elephant trunk (FET) technique in septuagenarians. We compared the results of septuagenarians with those of younger patients and analysed if there was an improvement in outcome over time. METHODS Between August 2001 and March 2020, 225 patients underwent non-urgent FET procedure at our institution. There were 75 patients aged ≥70 years (mean age 74 ± 4) who were assigned to group A, and 150 patients aged RESULTS The rate for temporary dialysis was significantly higher in group A than in group B (29% vs 13%, P = 0.003), although the majority recovered kidney function. Rates for re-exploration for bleeding and stroke were comparable in both groups. In-hospital mortality was significantly higher in group A than in group B (24% vs 13%, P = 0.037). Logistic regression analysis showed that age >70 years was an independent statistically significant risk factor for in-hospital mortality (odds ratio = 2.513, 95% confidence interval = 1.197–5.278, P-value = 0.015). Follow-up was complete for 100% of patients and comprised a total of 1073 patient-years with a mean follow-up time of 4.8 ± 4.5 years. The 1- and 5-year survival rates were 68% and 49% in group A, and 85% and 71% in group B, respectively (log rank, P Discussion Total aortic arch replacement using the FET technique has a significantly higher risk for perioperative morbidity and mortality in septuagenarians than in younger patients. Long-term survival is significantly impaired in older patients. We recommend thorough patient selection of those who require total aortic arch replacement, and optimization of perioperative management to improve outcomes.

BACKGROUNDGenetic testing for breast cancer susceptibility is widely used, but for many genes,evidence of an association with breast cancer is weak, underlying risk estimatesare imprecise, and reliable subtype-specific risk estimates are lacking.METHODSWe used a panel of 34 putative susceptibility genes to perform sequencing onsamples from 60,466 women with breast cancer and 53,461 controls. In separateanalyses for protein-truncating variants and rare missense variants in these genes,we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluatedmissense-variant associations according to domain and classification of pathogenicity.RESULTSProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2)were associated with a risk of breast cancer overall with a P value of less than0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D,and TP53) were associated with a risk of breast cancer overall with a P value ofless than 0.05 and a Bayesian false-discovery probability of less than 0.05. Forprotein-truncating variants in 19 of the remaining 25 genes, the upper limit ofthe 95% confidence interval of the odds ratio for breast cancer overall was lessthan 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios werehigher for estrogen receptor (ER)–positive disease than for ER-negative disease;for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, andRAD51D, odds ratios were higher for ER-negative disease than for ER-positivedisease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 wereassociated with a risk of breast cancer overall with a P value of less than 0.001.For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a riskof breast cancer overall, with the risk being similar to that of protein-truncatingvariants.CONCLUSIONSThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimatesof the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)

Introduction Patients with Philadelphia-negative myeloproliferative neoplasms (MPNs), particularly those carrying the JAK2V617F mutation, are at increased risk of thrombosis. While an association of MPNs with autoimmune disorders has been established, the prevalence of inherited or acquired thrombophilias in JAK2V617F-positive patients remains obscure. We therefore investigated the coincidence of the JAK2V617F mutation with additional thrombogenic risk factors. Methods In a retrospective study, we analyzed all patients referred for thrombophilia work-up between 01/2011 and 08/2019, in whom additional JAK2V617F mutation analysis was performed because of thromboembolic events that were recurrent, atypically located and/or associated with abnormal blood counts. Results Of 472 tested patients, 49 (10.4%) were JAK2V617F-positive. While the frequency of inherited thrombophilias (factor V Leiden and prothrombin G20210A mutation, deficiency of antithrombin, protein C, protein S) was not different between the two groups, the prevalence of definite antiphospholipid syndrome (APS), mostly associated with a moderate- or high-risk antibody profile, was significantly higher in patients with (22.4%) than in those without (8.4%) JAK2V617F mutation (p Conclusion We found a significant association between JAK2V617F-positive MPN and definite APS. The presence of concomitant APS in patients carrying the JAK2V617F mutation may lead to earlier manifestation of thromboembolic events and may warrant more aggressive antithrombotic treatment strategies to prevent recurrence.

Background Whether chronic inflammation increases prostate cancer risk remains unclear. This study investigated whether chronic inflammatory diseases (CID) or anti-inflammatory medication use (AIM) were associated with prostate cancer risk. Methods Fifty-five thousand nine hundred thirty-seven cases (all prostate cancer, 2007–2012) and 279,618 age-matched controls were selected from the Prostate Cancer Database Sweden. CIDs and AIMs was determined from national patient and drug registers. Associations were investigated using conditional logistic regression, including for disease/drug subtypes and exposure length/dose. Results Men with a history of any CID had slightly increased risk of any prostate cancer diagnosis (OR: 1.08; 95%CI: 1.04–1.12) but not ‘unfavourable’ (high-risk or advanced) prostate cancer. Generally, risk of prostate cancer was highest for shorter exposure times. However, a positive association was observed for asthma > 5 years before prostate cancer diagnosis (OR: 1.21; 95%CI: 1.05–1.40). Risk of prostate cancer was increased with prior use of any AIMs (OR: 1.26; 95%CI: 1.24–1.29). A positive trend with increasing cumulative dose was only observed for inhaled glucocorticoids (p

OBJECTIVES Chronic kidney disease (CKD) is a key risk factor in patients undergoing transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR). We analysed the impact of estimated glomerular filtration rate (eGFR) and CKD stages on their mid-term survival. METHODS Data from 29 893 patients enrolled in the German Aortic Valve registry from January 2011 to December 2015 receiving TAVI (n = 12 834) or SAVR (n = 17 059) at 88 sites were included. The impact of renal impairment, as measured by eGFR and CKD stages, was investigated. The primary end-point was 1-year cumulative all-cause mortality. RESULTS Higher CKD stages were significantly associated to lower in-hospital, 30-day- and 1-year survival rates. Both TAVI- and SAVR-treated patients in CKD 3a, 3b, 4 and 5 stages showed significant and gradually increasing HR values for 1-year all-cause mortality. The same trend persisted in multivariable analysis, although HR values for CKD 3a and 5 did not reach significance in TAVI patients, whereas CKD 4 + 5 did not reach statistical significance in SAVR. Likewise, eGFR as a continuous variable was a significant predictor for 1-year mortality, with the best cut-off points being 47.4 ml/min/1.73 m2 for TAVI and 59.8 ml/min/1.73 m2 for SAVR. Significant 8.6% and 9.0% increases in 1-year mortality were observed for every 5-ml reduction in eGFR for TAVI and SAVR, respectively. CONCLUSIONS CKD ≥3b and CKD ≥3a are the independent major risk factors for mortality in patients undergoing TAVI and SAVR, respectively. In the overall population of patients with severe aortic stenosis, an appropriate stratification based on CKD substage may contribute to a better selection of patients suitable for such therapies.

Contains fulltext : 237700.pdf (Publisher’s version ) (Open Access) Pathological aggression is a debilitating feature of many neuropsychiatric disorders, and cingulate cortex is one of the brain areas centrally implicated in its control. Here we explore the specific role of midcingulate cortex (MCC) in the development of pathological aggression. To this end, we investigated the structural and functional degeneration of MCC in the BALB/cJ strain, a mouse model for pathological aggression. Compared to control animals from the BALB/cByJ strain, BALB/cJ mice expressed consistently heightened levels of aggression, as assessed by the resident-intruder test. At the same time, immunohistochemistry demonstrated stark structural degradation in the MCC of aggressive BALB/cJ mice: Decreased neuron density and widespread neuron death were accompanied by increased microglia and astroglia concentrations and reactive astrogliosis. cFos staining indicated that this degradation had functional consequences: MCC activity did not differ between BALB/cJ and BALB/cByJ mice at baseline, but unlike BALB/cByJ mice, BALB/cJ mice failed to activate MCC during resident-intruder encounters. This suggests that structural and functional impairments of MCC, triggered by neuronal degeneration, may be one of the drivers of pathological aggression in mice, highlighting MCC as a potential key area for pathologies of aggression in humans.

Contains fulltext : 234086.pdf (Publisher’s version ) (Closed access) Controlling aggression is a crucial skill in social species like rodents and humans and has been associated with anterior cingulate cortex (ACC). Here, we directly link the failed regulation of aggression in BALB/cJ mice to ACC hypofunction. We first show that ACC in BALB/cJ mice is structurally degraded: neuron density is decreased, with pervasive neuron death and reactive astroglia. Gene-set enrichment analysis suggested that this process is driven by neuronal degeneration, which then triggers toxic astrogliosis. cFos expression across ACC indicated functional consequences: during aggressive encounters, ACC was engaged in control mice, but not BALB/cJ mice. Chemogenetically activating ACC during aggressive encounters drastically suppressed pathological aggression but left species-typical aggression intact. The network effects of our chemogenetic perturbation suggest that this behavioral rescue is mediated by suppression of amygdala and hypothalamus and activation of mediodorsal thalamus. Together, these findings highlight the central role of ACC in curbing pathological aggression. 13 p.

Since the publication of the updated German guideline in 2015, the recommendations for performing pelvic lymphadenectomy (LAE) in patients with vulvar cancer (VSCC) have changed considerably. The guideline recommends surgical lymph node staging in all patients with a higher risk of pelvic lymph node involvement. However, the current data do not allow the population at risk to be clearly defined, therefore, the indication for pelvic lymphadenectomy is still not clear. There are currently two published German patient populations who had pelvic LAE which can be used to investigate both the prognostic effect of histologically verified pelvic lymph node metastasis and the relation between inguinal and pelvic lymph node involvement. A total of 1618 patients with primary FIGO stage ≥ IB VSCC were included in the multicenter AGO CaRE-1 study (1998 – 2008), 70 of whom underwent pelvic LAE. During a retrospective single-center evaluation carried out at the University Medical Center Hamburg-Eppendorf (UKE), a total of 514 patients with primary VSCC treated between 1996 – 2018 were evaluated, 21 of whom underwent pelvic LAE. In both cohorts, around 80% of the patients who underwent pelvic LAE were inguinally node-positive, with a median number of three affected groin lymph nodes. There were no cases of pelvic lymph node metastasis without inguinal lymph node metastasis in either of the two cohorts. Between 33 – 35% of the inguinal node-positive patients also had pelvic lymph node metastasis; the median number of affected groin lymph nodes in these patients was high (> 4), and the maximum median diameter of the largest inguinal metastasis was > 40 mm in both cohorts. Pelvic lymph node staging and pelvic radiotherapy is therefore probably not necessary for the majority of node-positive patients with VSCC, as the relevant risk of pelvic lymph node involvement was primarily found in node-positive patients with high-grade disease. More, ideally prospective data collections are necessary to validate the relation between inguinal and pelvic lymph node involvement.

Objectives This study sought to compare patient characteristics, procedural outcomes, and valve hemodynamics of surgical aortic valve replacement (SAVR) with current-generation rapid-deplo...

Introdução: O Granuloma Piogênico (GP) é uma lesão proliferativa não neoplásica e quando acomete a região bucal é comumente encontrada na gengiva, mas em casos mais raros o GP pode incidir nos lábios superiores e por conta disto poucos casos foram relatados no literatura. Objetivo: O presente estudo tem como objetivo, relatar um caso incomum de Granuloma Piogênico em lábio superior em paciente do sexo masculino. Relato de caso: Paciente melanoderma, sexo masculino, 20 anos de idade, sem complicações sistêmicas prévias e histórico de alergia compareceu a uma faculdade de odontologia no norte do Brasil com a queixa principal de um nódulo no lábio superior direito que havia aparecido aproximadamente 8 meses atrás. Clinicamente observou-se uma lesão de aspecto nodular com base séssil localizada no lábio superior direito e com tamanho aproximado de 8x5x4 centímetros, apresentava coloração rósea eritematosa, formato irregular, superfície ulcerada devido aos recorrentes traumas, ademais havia ausência de sintomatologia dolorosa, sangramento ou supuração. Após os procedimentos clínicos a biópsia excisional foi realizada e o material coletado foi colocado em um frasco contendo formol tamponado a 10%, oexame histopatológico revelou fragmento de mucosa revestido por epitélio pavimentoso estratificado paraqueratinizado. O controle pós-operatório foi realizado e paciente não apresentou nenhum sintoma ou sinal clínico de recidivas da lesão. Conclusão: Concluímos que o Granuloma Piogênico é uma lesão comum de ocorre na cavidade oral. Contudo este artigo é relevante a literatura científica pois apresenta-se o relato de um caso do GP na sua área de incidência mais rara e em um paciente do sexo masculino. E através da descrição deste raro caso, esperamos que cirurgiões dentistas fiquem atentos aos dados clínicos de lesões labiais e tenham exames histopatológico como uma ferramenta em seu diagnóstico.

Persistent Inflammation, Immune Suppression, and Catabolism Syndrome (PICS) is a disease state affecting patients who have a prolonged recovery after the acute phase of a large inflammatory insult. Trauma and sepsis are two pathologies after which such an insult evolves. In this review, we will focus on the key clinical determinants of PICS: Immunosuppression and cellular dysfunction. Currently, relevant immunosuppressive functions have been attributed to both innate and adaptive immune cells. However, there are significant gaps in our knowledge, as for trauma and sepsis the immunosuppressive functions of these cells have mostly been described in acute phase of inflammation so far, and their clinical relevance for the development of prolonged immunosuppression is mostly unknown. It is suggested that the initial immune imbalance determines the development of PCIS. Additionally, it remains unclear what distinguishes the onset of immune dysfunction in trauma and sepsis and how this drives immunosuppression in these cells. In this review, we will discuss how regulatory T cells (Tregs), innate lymphoid cells, natural killer T cells (NKT cells), TCR-a CD4- CD8- double-negative T cells (DN T cells), and B cells can contribute to the development of post-traumatic and septic immunosuppression. Altogether, we seek to fill a gap in the understanding of the contribution of lymphocyte immunosuppression and dysfunction to the development of chronic immune disbalance. Further, we will provide an overview of promising diagnostic and therapeutic interventions, whose potential to overcome the detrimental immunosuppression after trauma and sepsis is currently being tested.

BACKGROUND Drinking alcohol during pregnancy is considered a risk factor for child development; however, child biomarkers of prenatal alcohol exposure have been rarely studied. We examined whether a meconium alcohol metabolite (ethyl glucuronide, EtG) was associated with child cortisol concentrations at primary school age. METHODS For 137 children, prenatal alcohol exposure was operationalized by the meconium biomarker EtG and by maternal self-reports during pregnancy. Two EtG cut-offs (EtG ≥10 ng/g and EtG ≥112 ng/g) were applied. Cortisol concentrations were measured in saliva and hair samples. RESULTS Children with EtG ≥10 ng/g showed significantly reduced hair cortisol concentrations (HCCs) (p = .050, ηp2 = 0.042). For children with EtG ≥112 ng/g, the cortisol awakening response (CAR) was significantly decreased (p = .025, ηp2 = 0.070). These effects were also present in correlational analyses with continuous EtG data, speaking for partly dose-dependent effects. Especially, within the EtG ≥112 ng/g group, the basal (CAR: rp = -.642, p = .120) and cumulative (HCC: rp = -.660, p = .107) cortisol parameters were associated with child emotional symptoms at medium effect size. CONCLUSIONS The present study showed both the biological association of intrauterine alcohol exposure with the cortisol stress system, partly dose-dependent, and the functional association with emotional and behavioral symptoms.

Hypertensive pregnancy disorders and preeclampsia are major causes of maternal and fetal morbidity and mortality worldwide. Many different organs are involved in the diseases’ clinical phenotype. The underlying mechanism is still unknown, with a possible genetic component. This case–control study investigated effects on the risk of preeclampsia of genetic variations (single nucleotide polymorphisms, SNPs) in the estrogen and progesterone pathway genes. The study included 167 patients with preeclampsia and 115 healthy controls from the “Franconian Maternal Health Evaluation Studies” (FRAMES). All patients completed an epidemiological questionnaire, data from which were correlated with prospective data on pregnancy and labor. DNA was isolated from blood samples and genotyping was done by PCR. Variants in the aromatase gene CYP19A1 (rs10046, rs4646), progesterone receptor gene (rs1042838, rs10895068), and estrogen receptor-α gene (rs488133) were examined, and the genotype distribution in the two groups was analyzed statistically. A significant difference in the distribution frequency of genotypes between preeclampsia patients and controls was identified in one of the five SNPs. For rs10895068 in the progesterone receptor gene, genotype G/A was significantly more frequent among cases than controls (P = 0.023). No significant differences between the two cohorts were found in the other SNPs. This study showed a significant association between only one SNP in the progesterone receptor and preeclampsia. Other studies have also noted genetic aspects of preeclampsia. The underlying mechanism and causal relationship are not yet known, and further research is needed to explain the extent of genetic variations and the causal relationship in preeclampsia.

The aim of this study was to compare outcomes of transcatheter and surgical aortic valve implantation in chronic dialysis patients with aortic valve stenosis (AS). Chronic dialysis patients undergoing heart valve surgery are at higher risk for morbidity and mortality. Whether interventional techniques can reduce this risk is unclear because dialysis patients have thus far been excluded from randomized trials. Chronic dialysis patients with AS enrolled in the German Aortic Valve Registry (GARY) between 2012 and 2015 were analyzed to compare transcatheter aortic valve implantation (TAVI n = 661) with surgical aortic valve replacement (SAVR n = 457). Propensity scores for inverse probability of treatment weighting (IPTW) were used to adjust the comparison of the two treatment groups for potential confounders. TAVI patients were older (78 ± 7.3 vs. 69 ± 10.2 years, p

The disease burden of sepsis continues to increase, with intraabdominal contamination being a significant source of infection. Sepsis is a syndrome involving both an increase in systemic inflammation as well as a regulatory component. We have previously demonstrated that neutrophils are significant IL-10 producers in the abdomen during sepsis. Here, we sought to further characterize these neutrophils and elucidate potential underlying mechanisms resulting in IL-10 generation. Using transcriptional reporter mice, we observed that IL-10 producing neutrophils were activated, non-apoptotic, and expressed C-X-C chemokine receptor type 4-expressing. Further, we observed that active Signal Transducer and Activator of Transcription 1 expression was significantly increased in IL-10 producing versus non-IL-10 producing neutrophils. During sepsis, IFN-γ blockade lead to a decrease of neutrophil IL-10 production, while peritoneal CD4 T cells were found to be the most numerous acute producers of IFN-γ. Altogether, this report demonstrates that during sepsis, mature neutrophils can potentially dampen local inflammation by IL-10 production and this can be orchestrated by CD4 T cells through an IFN-γ dependent manner.

Several studies have revealed that the hyper-inflammatory response induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of disease severity and death. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α and IL-1β in hospitalized patients with coronavirus disease 2019 (COVID-19) upon admission to the Mount Sinai Health System in New York. Patients (n = 1,484) were followed up to 41 d after admission (median, 8 d), and clinical information, laboratory test results and patient outcomes were collected. We found that high serum IL-6, IL-8 and TNF-α levels at the time of hospitalization were strong and independent predictors of patient survival (P

International audience; Strong and ongoing artificial selection in domestic animals has resulted in amazing phenotypic responses that benefit humans, but often at a cost to an animal's health, and problems related to inbreeding depression, including a higher incidence of cancer. Despite high rates of cancer in domesticated species, little attention has been devoted to exploring the hypothesis that persistent artificial selection may also favour the evolution of compensatory anticancer defences. Indeed, there is evidence for effective anti‐cancer defences found in several domesticated species associated with different cancer types. We also suggest that artificial selection can favour the “domestication” of inherited oncogenic mutations in rare instances, retaining those associated to late and/or less aggressive cancers, and that by studying these seemingly rare anticancer adaptations, novel cancer treatments may be found.

The new guideline on organized cancer screening programs has been in force in Germany since January 1st, 2020. The guideline has amended earlier recommendations on cytological examinations, which were previously carried out annually during screening. The guidelines-based recommendations on the appropriate follow-up for preinvasive and invasive lesions of the uterine cervix and endometrium are briefly outlined and differentiated from screening cytology and Pap/HPV co-testing as described in the guideline on organized cancer screening programs (oKFE-RL).

Aims Impaired myocardial sympathetic innervation assessed by 123Iodine-Metaiodobenzylguanidine (123I-MIBG) scintigraphy is associated with cardiac events. Since regional disparities of structural abnormalities are common in inherited arrhythmia syndromes (iAS), a chamber-specific innervation assessment of the right (RV) and left ventricle (LV) could provide important insights for a patient-individual therapy. Aim of this study was to evaluate chamber-specific patterns of autonomic innervation by Single-photon emission computed tomography/computed tomography (SPECT/CT) in patients with iAS with respect to clinical outcome regarding cardiac events. Methods and results We assessed ventricular sympathetic innervation (LV, RV and planar heart/mediastinum-ratios, and washout-rates) by 123I-MIBG-SPECT/CT in 48 patients (arrhythmogenic right ventricular cardiomyopathy [ARVC], n = 26; laminopathy, n = 8; idiopathic ventricular fibrillation [iVF], n = 14) in relation to a composite clinical endpoint (ventricular arrhythmia; cardiac death; cardiac hospitalization). RV tracer uptake was lower in patients with ARVC than in laminopathy and iVF patients (1.7 ± 0.4 vs. 2.1 ± 0.7 and 2.1 ± 0.5, respectively). Over a median follow-up of 2.2 years, the combined endpoint was met in 18 patients (n = 12 ventricular tachyarrhythmias, n = 5 hospitalizations, n = 1 death). LV, but not RV H/M ratio was associated with the combined endpoint (hazard-ratio 2.82 [1.30–6.10], p Conclusion We demonstrated that chamber-specific 123MIBG-SPECT/CT imaging is feasible and that reduced LV sympathetic innervation was associated with worse outcome in iAS. These findings provide novel insights into the potential role of regional autonomic nervous system heterogeneity for the evolution of life-threatening cardiac events in iAS.

According to the Valve Academic Resortium, underweight is one parameter in the definition of frailty, which is associated with increased mortality after transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR). Aims of our study were (1) to examine the impact of underweight on mortality after TAVI and SAVR and (2) to determine the effect of intervention mode (TAVI vs SAVR) on mortality in underweight patients from the German Aortic Valve Registry. Overall, 35,109 patients treated with TAVI or SAVR were studied. Outcomes of underweight (body mass index [BMI]

Cortical atrophy has been identified using magnetic resonance imaging (MRI) in humans and dogs with Lafora disease (LD). In humans, proton magnetic resonance spectroscopy (1HMRS) of the brain indicates decreased N‐acetyl‐aspartate (NAA) relative to other brain metabolites. Brain 1HMRS findings in dogs with LD are lacking. A 6‐year‐old female Beagle was presented with a history of a single generalized tonic‐clonic seizure and episodic reflex myoclonus. Clinical, hematological, and neurological examination findings and 3‐Tesla MRI of the brain were unremarkable. Brain 1HMRS with voxel positioning in the thalamus was performed in the affected Beagle. It identified decreased amounts of NAA, glutamate‐glutamine complex, and increased total choline and phosphoethanolamine relative to water and total creatine compared with the reference range in healthy control Beagles. A subsequent genetic test confirmed LD. Abnormalities in 1HMRS despite lack of changes with conventional MRI were identified in a dog with LD.

In haemophilia, thrombin generation and fibrin deposition upon vascular injury critically depend on the tissue factor (TF)-driven coagulation pathway. TF expression by monocytes/macrophages and circulating microvesicles contributes to haemostasis, thrombosis and inflammation. Inflammation is a hallmark of blood-induced joint disease. The aim of this study is to correlate TF production by whole-blood monocytes with inflammatory markers and clinical parameters in patients with moderate-to-severe haemophilia A or B (n = 43) in comparison to healthy males (n = 23). Monocyte TF antigen and microvesicle-associated TF procoagulant activity (MV TF PCA) were measured immediately after blood draw (baseline) and following incubation of whole blood with buffer or lipopolysaccharide (LPS) using two-colour flow cytometry and chromogenic FXa generation assay, respectively. Patients with HIV or uncontrolled HBV/HCV infections were excluded. TF was hardly detectable and not different in baseline and buffer-treaded samples from both groups. Stimulation with LPS, however, induced monocyte TF production, with increased TF-specific mean fluorescence intensity (P = 0.08) and MV TF PCA (P P n = 16), who were older and also had a significantly worse orthopaedic joint score than patients with no history of viral hepatitis (P

Diagnosing schizoaffective disorder poses unique challenges due to both its history as a “catch-all” diagnosis and recent changes to the diagnostic criteria. The Diagnostic and Statistical Manual of Mental Disorder s, fifth edition, helps to clarify the diagnosis, but issues related to validity and reliability remain. The fundamental approach to diagnosis must be done positively (as opposed to being a diagnosis of exclusion), looking at each feature of a patient's presentation and ensuring that criteria for schizoaffective disorder are met, without symptoms being better explained by a phenomenologically similar yet different psychiatric conditions (and assuming that no medical or toxic condition is responsible). This article presents a straightforward approach to generating and critically assessing a differential diagnosis when schizoaffective disorder is suspected. [ Psychiatr Ann . 2020;50(5):195–199.]