Household transmission of SARS-CoV-2 in a rural area in South Africa.

BACKGROUND: Patterns of SARS-CoV-2 spread have varied by geolocation, with differences in seroprevalence between urban and rural areas, and between waves. Household spread of SARS-CoV-2 is a known source of new COVID-19 infections, with rural areas in sub-Saharan Africa being more prone than urban areas to COVID-19 transmission because of limited access to water in some areas, delayed health- seeking behaviour and poor access to care. OBJECTIVES: To explore SARS-CoV-2 infection incidence and transmission in rural households in South Africa (SA). METHODS: We conducted a prospective household cluster investigation between 13 April and 21 July 2021 in the Matjhabeng subdistrict, a rural area in Free State Province, SA. Adults with SARS-CoV-2 confirmed by polymerase chain reaction (PCR) tests (index cases, ICs) and their household contacts (HCs) were enrolled. Household visits conducted at enrolment and on days 7, 14 and 28 included interviewer- administered questionnaires and respiratory and blood sample collection for SARS-CoV-2 PCR and SARS-CoV-2 immunoglobulin G serological testing, respectively. Co-primary cases were HCs with a positive SARS-CoV-2 PCR test at enrolment. The incidence rate (IR), using the Poisson distribution, was HCs with a new positive PCR and/or serological test per 1 000 person-days. Associations between outcomes and HC characteristics were adjusted for intra-cluster correlation using robust standard errors. The secondary infection rate (SIR) was the proportion of new COVID-19 infections among susceptible HCs. RESULTS: Among 23 ICs and 83 HCs enrolled, 10 SARS-CoV-2 incident cases were identified, giving an IR of 5.8 per 1 000 person-days (95% confidence interval (CI) 3.14 - 11.95). Households with a co-primary case had higher IRs than households without a co-primary case (crude IR 14.16 v. 1.75, respectively; p=0.054). HIV infection, obesity and the presence of chronic conditions did not materially alter the crude IR. The SIR was 15.9% (95% CI 7.90 - 29.32). Households with a lower household density (fewer household members per bedroom) had a higher IR (IR 9.58; 95% CI 4.67 - 21.71) than households with a higher density (IR 3.06; 95% CI 1.00 - 12.35). CONCLUSION: We found a high SARS-CoV-2 infection rate among HCs in a rural setting, with 48% of households having a co-primary case at the time of enrolment. Households with co-primary cases were associated with a higher seroprevalence and incidence of SARS-CoV-2. Sociodemographic and health characteristics were not associated with SARS-CoV-2 transmission in this study, and we did not identify any transmission risks inherent to a rural setting.

The differences in the anatomy of the thoracolumbar and sacral autonomic outflow are quantitative.

PURPOSE: We have re-evaluated the anatomical arguments that underlie the division of the spinal visceral outflow into sympathetic and parasympathetic divisions. METHODOLOGY: Using a systematic literature search, we mapped the location of catecholaminergic neurons throughout the mammalian peripheral nervous system. Subsequently, a narrative method was employed to characterize segment-dependent differences in the location of preganglionic cell bodies and the composition of white and gray rami communicantes. RESULTS AND CONCLUSION: One hundred seventy studies were included in the systematic review, providing information on 389 anatomical structures. Catecholaminergic nerve fibers are present in most spinal and all cranial nerves and ganglia, including those that are known for their parasympathetic function. Along the entire spinal autonomic outflow pathways, proximal and distal catecholaminergic cell bodies are common in the head, thoracic, and abdominal and pelvic region, which invalidates the "short-versus-long preganglionic neuron" argument. Contrary to the classically confined outflow levels T1-L2 and S2-S4, preganglionic neurons have been found in the resulting lumbar gap. Preganglionic cell bodies that are located in the intermediolateral zone of the thoracolumbar spinal cord gradually nest more ventrally within the ventral motor nuclei at the lumbar and sacral levels, and their fibers bypass the white ramus communicans and sympathetic trunk to emerge directly from the spinal roots. Bypassing the sympathetic trunk, therefore, is not exclusive for the sacral outflow. We conclude that the autonomic outflow displays a conserved architecture along the entire spinal axis, and that the perceived differences in the anatomy of the autonomic thoracolumbar and sacral outflow are quantitative.

Modifiable Risk Factors for Accelerated Decline in Processing Speed: Results from Three Dutch Population Cohorts.

BACKGROUND: Several lifestyle, cardiovascular and psychosocial factors are associated with risk of cognitive decline and dementia. We studied the independent associations of a broad set of modifiable risk factors with decline in processing speed in three large population-based cohorts with up to 23 years of follow-up. METHODS: We used data of 9,666 participants from the Doetinchem Cohort Study, the Longitudinal Aging Study Amsterdam, and the Maastricht Aging Study. Decline in processing speed was measured with the letter digit substitution task or the alphabet coding task and modeled using quadratic latent growth curves. Associations of modifiable risk factors with level and rate of decline in processing speed were investigated by estimating associations with level of processing speed at different centering ages. RESULTS: Latent growth curves showed that decline in processing speed accelerated with age. Smoking, not drinking alcohol and depressive symptoms were associated with a lower level of processing speed in all cohorts. In two of the cohorts, more physical activity, drinking more than two glasses of alcohol per day, higher BMI and diabetes were associated with a lower level of processing speed. Depressive symptoms and diabetes were also associated with faster decline in processing speed. CONCLUSION: Several modifiable risk factors are associated with the level of processing speed in older age, while few are also related to the rate of decline.

What makes community-based, multilevel physical activity promotion last? A systematic review with narrative synthesis on factors for sustainable implementation.

AIM: To follow the need for more research and strategies to enhance the knowledge of sustainable implementation, we examined cases of community-based, multilevel physical activity-related health promotion after initial funding has ceased and aimed to identify factors that influence their sustainable implementation. METHODS: Five scientific databases (PubMed; Scopus; Ebsco Host with CINAHL, PsychInfo, and Sportdiscus; ProQuest and Web of Science) were systematically searched for relevant literature in December 2021. Three reviewers performed a title/abstract screening and independently screened the full texts of the remaining papers, followed by a quality assessment. A narrative synthesis method, including qualitative text analysis, was used to synthesise retrieved articles. As starting point, the framework of Schell et al. containing nine domains for sustainability capacity was used and new emerging themes were inductively added. RESULTS: The search revealed 270 potentially eligible articles out of 27,652 hits. After the systematic review process, 14 studies were included. In the synthesis, 14 factors influencing the sustainablity of community-based, multilevel physical activity-related health promotion were identified of which six are new factors compared to Schell et al. In particular, our findings bring forth a novel understanding of the importance of the factors 'Participation and Partnerships', 'Empowerment and Capacity Building' and 'Community Support'. A dynamic interplay and high connectedness between factors were visible. CONCLUSION: The identified factors can help establish a better understanding of sustainability processes within whole-system approaches intervening on multiple levels in the community with the aim of systems change. They are relevant for practitioners, researchers and policy makers alike. Future research should more closely examine based on further theoretical elaboration how an interplay between the factors can promote sustainability and which interdependencies are of particular importance in facilitating sustainable and equitable change.

Second language learning role-play: effects of patient and doctor roles on motivation and competence.

Objectives: Role-playing has motivated foreign language learners for decades. In doctor-patient medical consultation role-plays, the doctor role has always been considered an important learning opportunity, whilst the patient role remained obscured. Our study, therefore, had a dual focus. We first explored how intrinsic motivation changes medical second-language (L2) learning through the lens of self-determination theory. We subsequently examined if playing the role of the patient provides additional value to medical L2 learning. Methods: We performed a mixed-methods study using a one-group pretest-posttest design. Participants were 15 student volunteers learning medical Dutch through peer role-play in medical consultations. Students completed a questionnaire before and after the course that measured changes in their intrinsic motivation to experience stimulation (IMES), feeling of relatedness, and feeling of competence. We also measured students' competence through a peer-rated checklist and the final course grades. At the end of the course, the students participated in semi-structured interviews to discuss their experience acting as patients. The data were subjected to the Wilcoxon signed-rank test and a thematic analysis. Results: The pre- and post-questionnaires revealed that students' IMES as well as their feeling of relatedness increased. Their self-perceptions, feeling of competence, peer assessments, and final course grades demonstrated that students were competent in medical L2. Our thematic analysis led to the identification of five themes of the role-play exercise for medical L2 learning: (1) motivational experience, (2) supportive peer interaction, (3) setting up a role-play environment for medical L2 learning, (4) utilizing the patient role to benefit medical L2 learning, and (5) a novel patient perspective on the doctor's role. Discussion: Our study found that role-play, by enhancing students' intrinsic motivation, feeling of relatedness, and competence development, aids the medical L2 learning process. Interestingly, playing a patient role in medical consultation was also found to support this process. We welcome future controlled experiments to confirm the positive impact of playing the role of the patient in medical consultation.

Cognitive Functioning in Survivors of Hematopoietic Stem Cell Transplantation Compared With a Matched General Population Sample-The Maastricht Observational Study of Late Effects After Stem Cell trAnsplantation Study.

Although cognitive problems can recover over time, a subgroup of hematopoietic stem cell transplantation (HCT) survivors experience persistent cognitive problems in the long term. Despite these implications, studies assessing cognitive functioning in HCT survivors are limited. The aim of the present study was (1) to quantify the prevalence of cognitive impairment in patients treated with HCT who survived at least 2 years and to compare these with a matched reference group representing the general population; (2) to identify potential determinants of cognitive functioning within the HCT survivor group. Within the single-center Maastricht Observational study of late effects after Stem cell trAnsplantation, cognitive performance was assessed by a neuropsychological test battery divided into 3 cognitive domains: memory, information processing speed, and executive function and attention. An overall cognition score was calculated as the average of the domain scores. A total of 115 HCT survivors were group-matched on a 1:4 ratio to the reference group by age, sex, and level of education. Regression analyses adjusted for different sets of covariates including demographic and health- and lifestyle-related factors were used to test for differences in cognition between HCT survivors and the reference group resembling the general population. A limited set of clinical characteristics (diagnosis, type of transplant, time since treatment, conditioning regimen with total body irradiation and age at time of transplantation) were assessed as potential determinants of neurocognitive dysfunction among HCT survivors. Cognitive impairment was defined as scores in the cognitive domains < -1.5 standard deviation (SD) from what can be expected based on someone's age, sex, and education. The mean age at time of transplantation was 50.2 (SD ± 11.2) years, and the mean number of years after transplant was 8.7 (SD ± 5.7) years. The majority of HCT survivors were treated with autologous HCT (n = 73 [64%]). The prevalence of cognitive dysfunction was 34.8% in HCT survivors and 21.3% in the reference group (p = .002.) When adjusted for age, sex, and level of education, HCT survivors had a worse overall cognition score (b = -0.35; 95% confidence interval [CI], -0.55 to -0.16; p < .001), translating into 9.0 years of higher cognitive age. Analyses of specific cognitive domain scores showed that HCT survivors scored worse on memory (b = -0.43; 95% CI, -0.73 to -0.13; p = .005), information processing speed (b = -0.33; 95% CI, -0.55 to -0.11; p = .003), and executive function and attention (b = -0.29; 95% CI, -.55 to -.03; p = .031) than the reference group. The odds of cognitive impairment were on average 2.4 times higher among HCT survivors than the reference group (odd ratio = 2.44; 95% CI, 1.47-4.07; p = .001). Within the HCT survivor group none of the tested clinical determinants of cognitive impairment were significantly associated with cognition. This cohort study showed evidence for worse cognitive functioning in HCT survivors encompassing all three cognitive domains, respectively memory, information processing speed, and executive and attention compared to a reference group that represents the general population translating into nine years of faster cognitive ageing in HCT survivors than can be expected based on their chronological age. It is important to increase awareness for signs of neurocognitive dysfunction after HCT in clinicians and HCT survivors.

Screening over Speech in Unselected Populations for Clinical Trials in AD (PROSPECT-AD): Study Design and Protocol.

BACKGROUND: Speech impairments are an early feature of Alzheimer's disease (AD) and consequently, analysing speech performance is a promising new digital biomarker for AD screening. Future clinical AD trials on disease modifying drugs will require a shift to very early identification of individuals at risk of dementia. Hence, digital markers of language and speech may offer a method for screening of at-risk populations that are at the earliest stages of AD, eventually in combination with advanced machine learning. To this end, we developed a screening battery consisting of speech-based neurocognitive tests. The automated test performs a remote primary screening using a simple telephone. OBJECTIVES: PROSPECT-AD aims to validate speech biomarkers for identification of individuals with early signs of AD and monitor their longitudinal course through access to well-phenotyped cohorts. DESIGN: PROSPECT-AD leverages ongoing cohorts such as EPAD (UK), DESCRIBE and DELCODE (Germany), and BioFINDER Primary Care (Sweden) and Beta-AARC (Spain) by adding a collection of speech data over the telephone to existing longitudinal follow-ups. Participants at risk of dementia are recruited from existing parent cohorts across Europe to form an AD 'probability-spectrum', i.e., individuals with a low risk to high risk of developing AD dementia. The characterization of cognition, biomarker and risk factor (genetic and environmental) status of each research participants over time combined with audio recordings of speech samples will provide a well-phenotyped population for comparing novel speech markers with current gold standard biomarkers and cognitive scores. PARTICIPANTS: N= 1000 participants aged 50 or older will be included in total, with a clinical dementia rating scale (CDR) score of 0 or 0.5. The study protocol is planned to run according to sites between 12 and 18 months. MEASUREMENTS: The speech protocol includes the following neurocognitive tests which will be administered remotely: Word List [Memory Function], Verbal Fluency [Executive Functions] and spontaneous free speech [Psychological and/ or behavioral symptoms]. Speech features on the linguistic and paralinguistic level will be extracted from the recordings and compared to data from CSF and blood biomarkers, neuroimaging, neuropsychological evaluations, genetic profiles, and family history. Primary candidate marker from speech will be a combination of most significant features in comparison to biomarkers as reference measure. Machine learning and computational techniques will be employed to identify the most significant speech biomarkers that could represent an early indicator of AD pathology. Furthermore, based on the analysis of speech performances, models will be trained to predict cognitive decline and disease progression across the AD continuum. CONCLUSION: The outcome of PROSPECT-AD may support AD drug development research as well as primary or tertiary prevention of dementia by providing a validated tool using a remote approach for identifying individuals at risk of dementia and monitoring individuals over time, either in a screening context or in clinical trials.

Anxiety and cognitive functioning in the Maastricht study: A cross-sectional population study.

BACKGROUND: Higher anxiety levels in older adults are associated with worse executive functioning and an increased risk for dementia. In this study individual anxiety disorders and clinically relevant generalized anxiety symptoms are studied in relation to multiple cognitive domains. METHOD: This cross-sectional study includes 7344 community-dwelling participants of The Maastricht Study aged 40-75 years and oversampling of type 2 diabetes. Panic disorder with and without agoraphobia, agoraphobia and lifetime panic disorder were measured with the Mini International Neuropsychiatric Interview. Generalized anxiety symptoms were measured with the Generalized Anxiety Disorder 7-item scale (GAD-7). Multiple cognitive domains (executive functioning, memory and processing speed) and cognitive impairment were assessed. Multivariable linear and logistic regression analyses were used with adjustment for potential confounders. Interaction analyses were performed to test the moderation of age, sex and type 2 diabetes (due to oversampling). RESULTS: Agoraphobia was associated with worse scores on all cognitive domains (range B = -0.12 to -0.10; range 95%CI = -0.20 to -0.04) and with higher odds of cognitive impairment (OR = 1.51, 95%CI = 1.18-1.93). High scores on the GAD-7 were associated with worse scores on processing speed (B = -0.11, 95%CI = -0.20 to -0.03) and higher odds of cognitive impairment (OR = 1.42, 95%CI = 1.02-1.97). Panic disorder was significantly associated with worse scores on memory tasks (B = -0.25, 95%CI = -0.48 to -0.02). Associations were stronger in the younger participants and for agoraphobia and GAD-7 scores also in those with type 2 diabetes. CONCLUSION: Multiple anxiety disorders and generalized anxiety symptoms were associated with worse cognitive functioning on several cognitive domains.

The role of cognitive and social leisure activities in dementia risk: assessing longitudinal associations of modifiable and non-modifiable risk factors.

AIMS: With the projected surge in global dementia cases and no curative treatment available, research is increasingly focusing on lifestyle factors as preventive measures. Social and cognitive leisure activities are promising targets, but it is unclear which types of activities are more beneficial. This study investigated the individual and joint contribution of cognitive and social leisure activities to dementia risk and whether they modify the risks associated with other potentially modifiable and non-modifiable risk factors. METHODS: We used data from the English Longitudinal Study of Ageing (ELSA) from 7917 participants, followed up from 2008/2009 (Wave 4) until 2018/2019 (Wave 9) for incident dementia. Self-reported baseline cognitive activities (e.g. 'reading the newspaper'), the number of social memberships (e.g. being a member of a social club) and social participation (e.g. 'going to the cinema') were clustered into high and low based on a median split. Subsequently, their individual and joint contribution to dementia risk, as well as their interaction with other dementia risk factors, were assessed with Cox regression models, adjusting for age, sex, level of education, wealth and a composite score of 11 lifestyle-related dementia risk factors. RESULTS: After a median follow-up period of 9.8 years, the dementia incidence rate was 54.5 cases per 10.000 person-years (95% CI 49.0-60.8). Adjusting for demographic and other lifestyle-related risk factors, higher engagement in cognitive activities (HR = 0.58; 95% CI 0.40-0.84), a greater number of social memberships (HR = 0.65; 95% CI 0.51-0.84) and more social participation (HR = 0.71; 95% CI 0.54-0.95) were associated with lower dementia risk. In a joint model, only engagement in cognitive activities (HR = 0.60; 95% CI 0.40-0.91) and social memberships (HR = 0.75; 95% CI 0.56-0.99) independently explained dementia risk. We did not find any interaction with other modifiable and non-modifiable risk factors. CONCLUSIONS: Engagement in cognitive and social leisure activities may be beneficial for overall dementia risk, independent of each other and other risk factors. Both types of activities may be potential targets for dementia prevention measures and health advice initiatives.

A pictorial account of the human embryonic heart between 3.5 and 8 weeks of development.

Heart development is topographically complex and requires visualization to understand its progression. No comprehensive 3-dimensional primer of human cardiac development is currently available. We prepared detailed reconstructions of 12 hearts between 3.5 and 8 weeks post fertilization, using Amira® 3D-reconstruction and Cinema4D®-remodeling software. The models were visualized as calibrated interactive 3D-PDFs. We describe the developmental appearance and subsequent remodeling of 70 different structures incrementally, using sequential segmental analysis. Pictorial timelines of structures highlight age-dependent events, while graphs visualize growth and spiraling of the wall of the heart tube. The basic cardiac layout is established between 3.5 and 4.5 weeks. Septation at the venous pole is completed at 6 weeks. Between 5.5 and 6.5 weeks, as the outflow tract becomes incorporated in the ventricles, the spiraling course of its subaortic and subpulmonary channels is transferred to the intrapericardial arterial trunks. The remodeling of the interventricular foramen is complete at 7 weeks.

Ethical dilemma for healthcare professionals facing elderly dementia patients during the COVID-19 pandemic.

The management of elderly patients with dementia and COVID-19 infections without access to an intensive care unit gives rise to serious ethical conflicts. Therapeutic decisions have been made in psychogeriatric units, leaving a heavy moral burden on staff. They had to deal with the most difficult patients without the support of appropriate guidelines. The gap between established rules and hospital reality led to psychological distress and burnout. Managing uncertainty in medical decisions is a skill that doctors and staff learn through experience. However, with the COVID-19 pandemic, uncertainty about patient outcomes seems no longer acceptable. Geriatric triage has challenged professional conscience, emotions and values. The principle of distributive justice, which consists of giving each person in society what is rightfully his or hers, is not being respected during this pandemic. Charity has been reduced to patient survival. Staffs need to make decisions together, and it is important to allow all carers access to a space for reflection. In our unit, the involvement of nurses and care assistants in the decision-making process for patient care is crucial especially for refusal of care. Their view of the patient's condition is different from that of the doctors, as they provide daily care to the patient and stay in the wards for several hours with them. By including as many people as possible in the reflection, we could avoid moral or personal prejudices related to these difficult decisions. The current pandemic can give new meaning to team thinking, giving everyone a voice without hierarchical barriers. With these new waves of COVID-19, we need to rethink our therapeutic conduct for elderly patients with dementia to avoid ethical failure.

Effect of a multi-domain intervention on the quality of life in older adults with major neurocognitive disorder: A pilot study.

PURPOSE: Major neurocognitive disorders (MND) have multiple negative consequences on patients' lives and on their caregivers' health. Occupational therapy and cognitive stimulation have failed to show any significant efficacy on quality of life (QoL), cognitive functioning and behavioural symptoms. Bretonneau Hospital's Day Care Unit offers personalized and structured multi-domain interventions to cognitively impaired older patients on a weekly basis, for a 3-month period. OBJECTIVES: Our objective was to determine whether a specific rehabilitation day care unit (RDCU) could influence the QoL of cognitively impaired community-dwelling elderly patients. We also aimed to better understand the characteristics of patients who had the most benefited from the RDCU. METHODS: Retrospective study based on a sample of outpatients participating in RDCU during three months. All patients underwent a cognitive (MMS), functional (IADl, ADL) and behavioral (NPI) assessment. We compared QoL using the QoL-Alzheimer's Disease (QoL-AD) scale before and after RDCU. RESULTS: Overall, we included 60 outpatients in our study (mean age 83.3±5.8; women=70%). We found a statistically significant improvement of QoL-AD scores after RDCU (31.8±4.9 to 32.9±5.2, P=0.008). Patients who benefitted the most from RDCU were older (P=0.01) and had lower baseline QoL (P=0.04). We did not find any other characteristics associated with QoL-AD score improvement in our population. CONCLUSION: RDCU showed positive effects on QoL in this uncontrolled pilot study of older adults with MND. These findings should be confirmed in a future randomized controlled trial to corroborate the potential benefits of RDCU on QoL in older cognitively impaired patients.

Development of the sympathetic trunks in human embryos.

Although the development of the sympathetic trunks was first described >100 years ago, the topographic aspect of their development has received relatively little attention. We visualised the sympathetic trunks in human embryos of 4.5-10 weeks post-fertilisation, using Amira 3D-reconstruction and Cinema 4D-remodelling software. Scattered, intensely staining neural crest-derived ganglionic cells that soon formed longitudinal columns were first seen laterally to the dorsal aorta in the cervical and upper thoracic regions of Carnegie stage (CS)14 embryos. Nerve fibres extending from the communicating branches with the spinal cord reached the trunks at CS15-16 and became incorporated randomly between ganglionic cells. After CS18, ganglionic cells became organised as irregular agglomerates (ganglia) on a craniocaudally continuous cord of nerve fibres, with dorsally more ganglionic cells and ventrally more fibres. Accordingly, the trunks assumed a "pearls-on-a-string" appearance, but size and distribution of the pearls were markedly heterogeneous. The change in position of the sympathetic trunks from lateral (para-aortic) to dorsolateral (prevertebral or paravertebral) is a criterion to distinguish the "primary" and "secondary" sympathetic trunks. We investigated the position of the trunks at vertebral levels T2, T7, L1 and S1. During CS14, the trunks occupied a para-aortic position, which changed into a prevertebral position in the cervical and upper thoracic regions during CS15, and in the lower thoracic and lumbar regions during CS18 and CS20, respectively. The thoracic sympathetic trunks continued to move further dorsally and attained a paravertebral position at CS23. The sacral trunks retained their para-aortic and prevertebral position, and converged into a single column in front of the coccyx. Based on our present and earlier morphometric measurements and literature data, we argue that differential growth accounts for the regional differences in position of the sympathetic trunks.

[Innovative outpatient models]. / Innovative ambulante Modelle.

Innovative, multimodal, cross-professional and cross-sectoral approaches to outpatient care have been funded in Germany since 2004 when the integrated care (IV) according to § 140 ff Social Security Code V (SGB V) and selective contracts according to § 73 SGB V were introduced. As a result, almost 7000 IV contracts were established providing psychiatric care; however, most of them were short-term contracts and only 1-2% of the total number of patients were treated by means of IV contracts. Great attention has been paid to the multiprofessional care of patients in all service models. Here we present two service models that were permanently established: the network of the Psychiatry Initiative Berlin Brandenburg (PIBB), certified according to § 87b SGB V, and the project Neuropsychiatric and Psychotherapeutic Care (NPPV) North Rhine funded by the Innovation Fund. The care projects described show new opportunities by exploiting previously unused networking resources at various levels of care and by coordinating the necessary treatment steps. Furthermore, a better coordination of patients enables, among other things, the organization of group therapy. This form of treatment in particular offers the possibility of treating more patients by applying different treatment intensities and contents. Moreover, it intensifies the guideline-based treatment itself through an interactive, therapeutically desired exchange. In addition, the formation of medical networks, which are entitled to relevant financial support according to their statutory certification, is a special opportunity to use complex outpatient psychiatric treatment and thus to improve care.

Extrinsic innervation of the pelvic organs in the lesser pelvis of human embryos.

Realistic models to understand the developmental appearance of the pelvic nervous system in mammals are scarce. We visualized the development of the inferior hypogastric plexus and its preganglionic connections in human embryos at 4-8 weeks post-fertilization, using Amira 3D reconstruction and Cinema 4D-remodelling software. We defined the embryonic lesser pelvis as the pelvic area caudal to both umbilical arteries and containing the hindgut. Neural crest cells (NCCs) appeared dorsolateral to the median sacral artery near vertebra S1 at ~5 weeks and had extended to vertebra S5 1 day later. Once para-arterial, NCCs either formed sympathetic ganglia or continued to migrate ventrally to the pre-arterial region, where they formed large bilateral inferior hypogastric ganglionic cell clusters (IHGCs). Unlike more cranial pre-aortic plexuses, both IHGCs did not merge because the 'pelvic pouch', a temporary caudal extension of the peritoneal cavity, interposed. Although NCCs in the sacral area started to migrate later, they reached their pre-arterial position simultaneously with the NCCs in the thoracolumbar regions. Accordingly, the superior hypogastric nerve, a caudal extension of the lumbar splanchnic nerves along the superior rectal artery, contacted the IHGCs only 1 day later than the lumbar splanchnic nerves contacted the inferior mesenteric ganglion. The superior hypogastric nerve subsequently splits to become the superior hypogastric plexus. The IHGCs had two additional sources of preganglionic innervation, of which the pelvic splanchnic nerves arrived at ~6.5 weeks and the sacral splanchnic nerves only at ~8 weeks. After all preganglionic connections had formed, separate parts of the inferior hypogastric plexus formed at the bladder neck and distal hindgut.

Development of extrinsic innervation in the abdominal intestines of human embryos.

Compared to the intrinsic enteric nervous system (ENS), development of the extrinsic ENS is poorly documented, even though its presence is easily detectable with histological techniques. We visualised its development in human embryos and foetuses of 4-9.5 weeks post-fertilisation using Amira 3D-reconstruction and Cinema 4D-remodelling software. The extrinsic ENS originated from small, basophilic neural crest cells (NCCs) that migrated to the para-aortic region and then continued ventrally to the pre-aortic region, where they formed autonomic pre-aortic plexuses. From here, nerve fibres extended along the ventral abdominal arteries and finally connected to the intrinsic system. Schwann cell precursors (SCPs), a subgroup of NCCs that migrate on nerve fibres, showed region-specific differences in differentiation. SCPs developed into scattered chromaffin cells of the adrenal medulla dorsolateral to the coeliac artery (CA) and into more tightly packed chromaffin cells of the para-aortic bodies ventrolateral to the inferior mesenteric artery (IMA), with reciprocal topographic gradients between both fates. The extrinsic ENS first extended along the CA and then along the superior mesenteric artery (SMA) and IMA 5 days later. Apart from the branch to the caecum, extrinsic nerves did not extend along SMA branches in the herniated parts of the midgut until the gut loops had returned in the abdominal cavity, suggesting a permissive role of the intraperitoneal environment. Accordingly, extrinsic innervation had not yet reached the distal (colonic) loop of the midgut at 9.5 weeks development. Based on intrinsic ENS-dependent architectural remodelling of the gut layers, extrinsic innervation followed intrinsic innervation 3-4 Carnegie stages later.

Sex-opposed inflammatory effects of 27-hydroxycholesterol are mediated via differences in estrogen signaling.

Despite the increased awareness of differences in the inflammatory response between men and women, only limited research has focused on the biological factors underlying these sex differences. The cholesterol derivative 27-hydroxycholesterol (27HC) has been shown to have opposite inflammatory effects in independent experiments using mouse models of atherosclerosis and non-alcoholic steatohepatitis (NASH), pathologies characterized by cholesterol-induced inflammation. As the sex of mice in these in vivo models differed, we hypothesized that 27HC exerts opposite inflammatory effects in males compared to females. To explore whether the sex-opposed inflammatory effects of 27HC translated to humans, plasma 27HC levels were measured and correlated with hepatic inflammatory parameters in obese individuals. To investigate whether 27HC exerts sex-opposed effects on inflammation, we injected 27HC into female and male Niemann-Pick disease type C1 mice (Npc1nih ) that were used as an extreme model of cholesterol-induced inflammation. Finally, the involvement of estrogen signaling in this mechanism was studied in bone marrow-derived macrophages (BMDMs) that were treated with 27HC and 17ß-estradiol (E2). Plasma 27HC levels showed opposite correlations with hepatic inflammatory indicators between female and male obese individuals. Likewise, hepatic 27HC levels oppositely correlated between female and male Npc1nih mice. Twenty-seven hydroxycholesterol injections reduced hepatic inflammation in female Npc1nih mice in contrast to male Npc1nih mice, which showed increased hepatic inflammation after 27HC injections. Furthermore, 27HC administration also oppositely affected inflammation in female and male BMDMs cultured in E2-enriched medium. Remarkably, female BMDMs showed higher ERα expression compared to male BMDMs. Our findings identify that the sex-opposed inflammatory effects of 27HC are E2-dependent and are potentially related to differences in ERα expression between females and males. Hence, the individual's sex needs to be taken into account when 27HC is employed as a therapeutic tool as well as in macrophage estrogen research in general. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Iatrogenesis and neurological manifestations in the elderly.

Older people are often exposed to polypharmacy in a multimorbidity context. Inappropriate polypharmacy is often harmful, increasing the risk of inappropriate prescriptions and therefore adverse drug events (ADEs). Five to 20% of all hospital admissions are related to ADE in older people, among which 40 to 70% could be prevented. However, identifying ADEs and drug-related admissions in the elderly is challenging because ADEs often present as common geriatric problems such as falls, delirium, which might be due to the aging process, underlying diseases, and/or medications. In the pharmacovigilance database of the World Health Organization, drug-related neurological manifestations are the third reported cause of ADEs in the elderly, and neurological drugs are the third leading class of medications involved in ADEs. We must therefore be particularly vigilant, both in our prescriptions but also in our diagnoses to avoid prescribing inappropriate treatments and detect ADEs. Even though multiple pharmacologic changes occur in the elderly (absorption, distribution, drug metabolism and excretion), most of medications are still often prescribed at the same daily dosage as in young adults. When prescribing any drug for old patients, we should remember that daily intake should be adapted to these specificities, keeping in mind the old well-known aphorism "start low, go slow". In this review, we describe the main drug-related neurological manifestations (drug-induced movement disorders, falls, seizures, delirium, hypoglycemia, stroke, hyponatremia, peripheral neuropathy and myopathy, and serotonin syndrome) and the main drugs associated with neurological manifestations (dopamine receptor blocking agents, antithrombotics, anticholinergics, beta-lactams, antidepressants, benzodiazepines, mood stabilizers).