Cell Adhesion by Integrins.

Integrins are heterodimeric cell surface receptors ensuring the mechanical connection between cells and the extracellular matrix. In addition to the anchorage of cells to the extracellular matrix, these receptors have critical functions in intracellular signaling, but are also taking center stage in many physiological and pathological conditions. In this review, we provide some historical, structural, and physiological notes so that the diverse functions of these receptors can be appreciated and put into the context of the emerging field of mechanobiology. We propose that the exciting journey of the exploration of these receptors will continue for at least another new generation of researchers.

Influenza A virus exploits transferrin receptor recycling to enter host cells.

Influenza A virus (IAV) enters host cells mostly through clathrin-dependent receptor-mediated endocytosis. A single bona fide entry receptor protein supporting this entry mechanism remains elusive. Here we performed proximity ligation of biotin to host cell surface proteins in the vicinity of attached trimeric hemagglutinin-HRP and characterized biotinylated targets using mass spectrometry. This approach identified transferrin receptor 1 (TfR1) as a candidate entry protein. Genetic gain-of-function and loss-of-function experiments, as well as in vitro and in vivo chemical inhibition, confirmed the functional involvement of TfR1 in IAV entry. Recycling deficient mutants of TfR1 do not support entry, indicating that TfR1 recycling is essential for this function. The binding of virions to TfR1 via sialic acids confirmed its role as a directly acting entry factor, but unexpectedly even headless TfR1 promoted IAV particle uptake in trans. TIRF microscopy localized the entering virus-like particles in the vicinity of TfR1. Our data identify TfR1 recycling as a revolving door mechanism exploited by IAV to enter host cells.

ConFERMing the role of talin in integrin activation and mechanosignaling.

Talin (herein referring to the talin-1 form), is a cytoskeletal adapter protein that binds integrin receptors and F-actin, and is a key factor in the formation and regulation of integrin-dependent cell-matrix adhesions. Talin forms the mechanical link between the cytoplasmic domain of integrins and the actin cytoskeleton. Through this linkage, talin is at the origin of mechanosignaling occurring at the plasma membrane-cytoskeleton interface. Despite its central position, talin is not able to fulfill its tasks alone, but requires help from kindlin and paxillin to detect and transform the mechanical tension along the integrin-talin-F-actin axis into intracellular signaling. The talin head forms a classical FERM domain, which is required to bind and regulate the conformation of the integrin receptor, as well as to induce intracellular force sensing. The FERM domain allows the strategic positioning of protein-protein and protein-lipid interfaces, including the membrane-binding and integrin affinity-regulating F1 loop, as well as the interaction with lipid-anchored Rap1 (Rap1a and Rap1b in mammals) GTPase. Here, we summarize the structural and regulatory features of talin and explain how it regulates cell adhesion and force transmission, as well as intracellular signaling at integrin-containing cell-matrix attachment sites.

Akt-driven TGF-ß and DKK1 Secretion Impairs F508del Cystic Fibrosis Airway Epithelium Polarity.

Epithelial polarity is fundamental in maintaining barrier integrity and tissue protection. In cystic fibrosis (CF), apicobasal polarity of the airway epithelium is altered, resulting in increased apical fibronectin deposition and enhanced susceptibility to bacterial infections. Here, we evaluated the effect of highly effective modulator treatment (HEMT) on fibronectin apical deposition and investigated the intracellular mechanisms triggering the defect in polarity of the CF airway epithelium. To this end, primary cultures of CF (F508del variant) human airway epithelial cells (HAECs) and a HAEC line, Calu-3, knocked down for CFTR (CF transmembrane conductance regulator) were compared with control counterparts. We show that CFTR mutation in primary HAECs and CFTR knockdown cells promote the overexpression and oversecretion of TGF-ß1 and DKK1 when cultured at an air-liquid interface. These dynamic changes result in hyperactivation of the TGF-ß pathway and inhibition of the Wnt pathway through degradation of ß-catenin leading to imbalanced proliferation and polarization. The abnormal interplay between TGF-ß and Wnt signaling pathways is reinforced by aberrant Akt signaling. Pharmacological manipulation of TGF-ß, Wnt, and Akt pathways restored polarization of the F508del CF epithelium, a correction that was not achieved by HEMT. Our data shed new insights into the signaling pathways that fine-tune apicobasal polarization in primary airway epithelial cells and may provide an explanation to the mitigated efficacy of HEMT on lung infection in people with CF.

Phosphorylated paxillin and phosphorylated FAK constitute subregions within focal adhesions.

Integrin-mediated adhesions are convergence points for multiple signaling pathways. Their inner structure and diverse functions can be studied with super-resolution microscopy. Here, we examined the spatial organization within focal adhesions by analyzing several adhesion proteins with structured illumination microscopy (SIM). Paxillin (Pax) serves as a scaffold protein and signaling hub in focal adhesions, and focal adhesion kinase (FAK, also known as PTK2) regulates the dynamics of adhesions. We found that their phosphorylated forms, pPax and pFAK, form spot-like, spatially defined clusters within adhesions in several cell lines and confirmed these findings with additional super-resolution techniques. These clusters showed a more regular separation from each other compared with more randomly distributed signals for FAK or paxillin. Mutational analysis indicated that the active (open) FAK conformation is a prerequisite for the pattern formation of pFAK. Live-cell super-resolution imaging revealed that organization in clusters is preserved over time for FAK constructs; however, distance between clusters is dynamic for FAK, while paxillin is more stable. Combined, these data introduce spatial clusters of pPax and pFAK as substructures in adhesions and highlight the relevance of paxillin-FAK binding for establishing a regular substructure in focal adhesions.

Adherence and potential factors of adherence to a resistance, coordination and endurance training in older retirement home residents over 6 months.

INTRODUCTION: High exercise adherence is a key factor for effective exercise programmes. However, little is known about predictors of exercise adherence to a multimodal machine-based training in older retirement home residents. AIMS: To assess exercise adherence and potential predictors of adherence. Furthermore, to evaluate user acceptance of the multimodal training and the change in exercise self-efficacy. METHODS: In this sub-analysis of the bestform-F study, a total of 77 retirement home residents ≥65 years (mean age: 85.6 ± 6.6 years, 77.9% female) participated in a 6-month machine-based resistance, coordination and endurance training. Attendance to the training was documented for each training session. To identify potential predictors a multiple linear regression model was fitted to the data. Analyzed predictors included age, sex, body mass index (BMI), physical function, exercise self-efficacy, and physical activity history. Different domains of user acceptance (e.g. safety aspects, infrastructure) and exercise self-efficacy were assessed by a questionnaire and the exercise self-efficacy scale (ESES), respectively. RESULTS: Mean exercise adherence was 67.2% (median: 74.4%). The regression model (R2 = 0.225, p = 0.033) revealed that the 6-minute walk test (6-MWT) at baseline significantly predicted exercise adherence (ß: 0.074, 95% confidence interval (CI): 0.006-0.142, p = 0.033). Different user domains were rated at least as good by 83.9%-96.9% of participants, reflecting high acceptance. No statistically significant change was found for exercise self-efficacy over 6 months (mean change: 0.47 ± 3.08 points, p = 0.156). CONCLUSION: Retirement home residents attended more than two thirds of offered training sessions and physical function at baseline was the key factor for predicting adherence. User acceptance of the training devices was highly rated. These findings indicate good potential for implementation of the exercise programme.

Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation.

BACKGROUND: Post-COVID-19 syndrome (PCS) is a lingering disease with ongoing symptoms such as fatigue and cognitive impairment resulting in a high impact on the daily life of patients. Understanding the pathophysiology of PCS is a public health priority, as it still poses a diagnostic and treatment challenge for physicians. METHODS: In this prospective observational cohort study, we analyzed the retinal microcirculation using Retinal Vessel Analysis (RVA) in a cohort of patients with PCS and compared it to an age- and gender-matched healthy cohort (n = 41, matched out of n = 204). MEASUREMENTS AND MAIN RESULTS: PCS patients exhibit persistent endothelial dysfunction (ED), as indicated by significantly lower venular flicker-induced dilation (vFID; 3.42% ± 1.77% vs. 4.64% ± 2.59%; p = 0.02), narrower central retinal artery equivalent (CRAE; 178.1 [167.5-190.2] vs. 189.1 [179.4-197.2], p = 0.01) and lower arteriolar-venular ratio (AVR; (0.84 [0.8-0.9] vs. 0.88 [0.8-0.9], p = 0.007). When combining AVR and vFID, predicted scores reached good ability to discriminate groups (area under the curve: 0.75). Higher PCS severity scores correlated with lower AVR (R = - 0.37 p = 0.017). The association of microvascular changes with PCS severity were amplified in PCS patients exhibiting higher levels of inflammatory parameters. CONCLUSION: Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients. As potential therapies for PCS emerge, RVA parameters may become relevant as clinical biomarkers for diagnosis and therapy management. TRIAL REGISTRATION: This study was previously registered at ClinicalTrials ("All Eyes on PCS-Analysis of the Retinal Microvasculature in Patients with Post-COVID-19 Syndrome". NCT05635552. https://clinicaltrials.gov/ct2/show/NCT05635552 ). Persistent endothelial dysfunction in post-COVID-19 syndrome. Acute SARS-CoV-2 infection indirectly or directly causes endotheliitis in patients. N = 41 PCS patients were recruited and retinal vessel analysis was performed to assess microvascular endothelial function. Images of SVA and DVA are illustrative for RVA data analysis. For each PCS patient and healthy cohort, venular vessel diameter of the three measurement cycles was calculated and plotted on a diameter-time curve. Patients exhibited reduced flicker-induced dilation in veins (vFID) measured by dynamic vessel analysis (DVA) and lower central retinal arteriolar equivalent (CRAE) and arteriolar-venular ratio (AVR) and a tendency towards higher central retinal venular equivalent (CRVE) when compared to SARS-CoV-2 infection naïve participants. Created with BioRender.com.

Assessment of glenoid bone loss and other osseous shoulder pathologies comparing MR-based CT-like images with conventional CT.

OBJECTIVES: To evaluate and compare the diagnostic performance of CT-like images based on a 3D T1-weighted spoiled gradient-echo sequence (T1 GRE), an ultra-short echo time sequence (UTE), and a 3D T1-weighted spoiled multi-echo gradient-echo sequence (FRACTURE) with conventional CT in patients with suspected osseous shoulder pathologies. MATERIALS AND METHODS: Patients with suspected traumatic dislocation of the shoulder (n = 46, mean age 40 ± 14.5 years, 19 women) were prospectively recruited and received 3-T MR imaging including 3D T1 GRE, UTE, and 3D FRACTURE sequences. CT was performed in patients with acute fractures and served as standard of reference (n = 25). Agreement of morphological features between the modalities was analyzed including the glenoid bone loss, Hill-Sachs interval, glenoid track, and the anterior straight-line length. Agreement between the modalities was assessed using Bland-Altman plots, Student's t-test, and Pearson's correlation coefficient. Inter- and intrareader assessment was evaluated with weighted Cohen's κ and intraclass correlation coefficient. RESULTS: All osseous pathologies were detected accurately on all three CT-like sequences (n = 25, κ = 1.00). No significant difference in the percentage of glenoid bone loss was found between CT (mean ± standard deviation, 20.3% ± 8.0) and CT-like MR images (FRACTURE 20.6% ± 7.9, T1 GRE 20.4% ± 7.6, UTE 20.3% ± 7.7, p > 0.05). When comparing the different measurements on CT-like images, measurements performed using the UTE images correlated best with CT. CONCLUSION: Assessment of bony Bankart lesions and other osseous pathologies was feasible and accurate using CT-like images based on 3-T MRI compared with conventional CT. Compared to the T1 GRE and FRACTURE sequence, the UTE measurements correlated best with CT. CLINICAL RELEVANCE STATEMENT: In an acute trauma setting, CT-like images based on a T1 GRE, UTE, or FRACTURE sequence might be a useful alternative to conventional CT scan sparing associated costs as well as radiation exposure. KEY POINTS: • No significant differences were found for the assessment of the glenoid bone loss when comparing measurements of CT-like MR images with measurements of conventional CT images. • Compared to the T1 GRE and FRACTURE sequence, the UTE measurements correlated best with CT whereas the FRACTURE sequence appeared to be the most robust regarding motion artifacts. • The T1 GRE sequence had the highest resolution with high bone contrast and detailed delineation of even small fractures but was more susceptible to motion artifacts.

Efficacy and Safety of Cold Snare Polypectomy of Colorectal Polyps 10-15 mm with a Hybrid Snare: A Prospective Observational Pilot Study.

INTRODUCTION: Cold snare polypectomy (CSP) is a safe and effective procedure for small colorectal polyps ≤9 mm. There are only limited data regarding CSP of larger neoplastic lesions. This study evaluated the efficacy and safety of CSP for polyps between 10 and 15 mm in size. METHODS: In this prospective single-arm observational pilot study, patients with a least one polyp 10-15 mm were included. These polyps were preferably removed by CSP using a dedicated hybrid snare. The primary outcome was the histological complete resection rate (CRR) determined by pathologically negative margins of the specimen and no neoplastic tissue obtained from biopsies of the resection site margin. Secondary outcomes were en bloc resection rate, failure of CSP, and incidence of adverse events. RESULTS: A total of 61 neoplastic polyps were removed from 39 patients. Overall CRR was 80.3% (49/61). CSP was feasible in 78.7% (48/61) of polyps and the CRR in this group was 85.4% (41/48). When CSP failed (13/61; 21.3%), lesions were successfully resected by immediate HSP using the same snare with a CRR of 61.5% (8/13) in this group. One patient presented delayed hemorrhage after HSP of a polyp but successful hemostasis was achieved with two hemoclips. No other adverse events occurred. No recurrence was seen on follow-up colonoscopy in cases with incomplete resected polyps. CONCLUSION: CSP seems to be efficient and safe in removing colorectal polyps up to 15 mm. A hybrid snare seems to be particularly advantageous for these polyps as it allows immediate conversion to HSP if CSP might fail in larger polyps. This trial is registered at ClinicalTrials.gov (NCT04464837).

Student mistakes and teacher reactions in bedside teaching.

We analyse interactions between teachers and students during video-recorded bedside teaching sessions in internal medicine, orthopaedics and neurology. Multiple raters used a high-inference categorical scheme on 36 sessions. Our research questions concern the types of student mistakes, clinical teachers' reactions to them and if they use different strategies to address different types of mistakes. We used a Poisson model and generalized mixed models to analyse these research questions. Most frequently, students made reproduction mistakes. Relatively high rates of rejection and a similar prevalence of low and high levels of elaboration and correction time for students were observed. Reproduction mistakes were associated with the highest level of rejection and the lowest level of elaboration. High levels of elaboration were observed when students were applying skills in new situations. Students were most often allowed time to correct when mistakes in the areas of analysis or application of skills and knowledge had occurred. There is a decrease in the rate of making mistakes for neurology and orthopaedics compared to internal medicine. Reproduction mistakes influence significantly the outcome feedback compared to application mistakes. Analytic and reproduction mistakes influence elaboration significantly compared to application mistakes. We found a significant effect whether the lecturer allows time for correction of reproduction mistakes compared to application mistakes. These results contribute to the understanding of interactive, patient-centred clinical teaching as well as student mistakes and how teachers are reacting to them. Our descriptive findings provide an empirical basis for clinical teachers to react to student mistakes in didactically fruitful ways.

Crystal structure of the FERM-folded talin head reveals the determinants for integrin binding.

Binding of the intracellular adapter proteins talin and its cofactor, kindlin, to the integrin receptors induces integrin activation and clustering. These processes are essential for cell adhesion, migration, and organ development. Although the talin head, the integrin-binding segment in talin, possesses a typical FERM-domain sequence, a truncated form has been crystallized in an unexpected, elongated form. This form, however, lacks a C-terminal fragment and possesses reduced ß3-integrin binding. Here, we present a crystal structure of a full-length talin head in complex with the ß3-integrin tail. The structure reveals a compact FERM-like conformation and a tightly associated N-P-L-Y motif of ß3-integrin. A critical C-terminal poly-lysine motif mediates FERM interdomain contacts and assures the tight association with the ß3-integrin cytoplasmic segment. Removal of the poly-lysine motif or disrupting the FERM-folded configuration of the talin head significantly impairs integrin activation and clustering. Therefore, structural characterization of the FERM-folded active talin head provides fundamental understanding of the regulatory mechanism of integrin function.

Perinatal Outcome and its Prediction Using Longitudinal Feto-Maternal Doppler Follow-Up in Late Onset Small for Gestational Age Fetuses - A Prospective Cohort Study.

PURPOSE: To describe the perinatal outcome of a prospective cohort of late-onset small-for-gestational-age (SGA) fetuses and to test adverse perinatal outcome (APO) prediction using Doppler measurements. METHODS: Singleton pregnancies from 32 weeks with suspicion of SGA (followed-up each 2 weeks) and randomly selected healthy controls at a university hospital were included. The whole SGA group was divided into the FGR subgroup or SGA percentile 3-10 subgroup. The following Doppler measurements were evaluated prospectively: umbilical artery (UA) pulsatility index (PI), middle cerebral artery (MCA) PI, cerebro-placental ratio (CPR), and mean uterine artery (mUtA) PI. APO was defined as arterial cord blood pH ≤ 7.15 and/or 5-minute Apgar ≤ 7 and/or emergency operative delivery and/or admission to the neonatal unit. Induction of labor was indicated according to a stage-based protocol. RESULTS: A total of 149 SGA and 143 control fetuses were included. The number of operative deliveries was similar between both groups (control: 29 %, SGA: 28 %), especially the cesarean delivery rate after the onset of labor (11 % vs. 10 %). Most SGA cases ended up in induction of labor (61 % vs. 31 %, p < 0.001). The areas under the curve (AUC) for APO prediction were similar using the last UA PI, MCA PI, CPR, and mUtA PI and barely reached 0.60. The AUC was best for the FGR subgroup, using the minimal CPR or maximum mUtA PI z-score of all longitudinal measurements (AUC = 0.63). CONCLUSION: SGA fetuses do not have a higher rate of operative delivery if managed according to a risk stratification protocol. Prediction of APO is best for SGA and FGR using the "worst" CPR or mUtA PI but it remains moderate.

The synovial fluid calprotectin lateral flow test for the diagnosis of chronic prosthetic joint infection in failed primary and revision total hip and knee arthroplasty.

PURPOSE: The diagnostic criteria of prosthetic joint infection (PJI) recommended by the most commonly used diagnostic algorithms can be obscured or distorted by other inflammatory processes or aseptic pathology. Furthermore, the most reliable diagnostic criteria are garnered during revision surgery. A robust, reliable addition to the preoperative diagnostic cascade is warranted. Calprotectin has been shown to be an excellent diagnostic marker for PJI. In this study, we aimed to evaluate a lateral flow test (LFT) in the challenging patient cohort of a national referral centre for revision arthroplasty. METHODS: Beginning in March 2019, we prospectively included patients scheduled for arthroplasty exchange of a total hip (THA) or knee arthroplasty (TKA). Synovial fluid samples were collected intra-operatively. We used the International Consensus Meeting of 2018 (ICM) score as the gold standard. We then compared the pre-operative ICM score with the LFT result to calculate its diagnostic accuracy as a standalone pre-operative marker and in combination with the ICM score as part of an expanded diagnostic workup. RESULTS: A total of 137 patients with a mean age of 67 (± 13) years with 53 THA and 84 TKA were included. Ninety-nine patients (72.8%) were not infected, 34 (25.0) were infected, and four (2.9%) had an inconclusive final score and could not be classified after surgery. The calprotectin LFT had a sensitivity (95% confidence interval) of 0.94 (0.80-0.99) and a specificity of 0.87 (0.79-0.93). The area under the receiver operating characteristic curve (AUC) for the calprotectin LFT was 0.94 (0.89-0.99). In nine cases with an inconclusive pre-operative ICM score, the calprotectin LFT would have led to the correct diagnosis of PJI. CONCLUSIONS: The synovial fluid calprotectin LFT shows excellent diagnostic metrics both as a rule-in and a rule-out test, even in a challenging patient cohort with cases of severe osteolysis, wear disease, numerous preceding surgeries, and poor soft tissue conditions, which can impair the common diagnostic criteria. As it is available pre-operatively, this test might prove to be a very useful addition to the diagnostic algorithm.

Infection Control Measures and Prevalence of SARS-CoV-2 IgG among 4,554 University Hospital Employees, Munich, Germany.

Hospital staff are at high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the coronavirus disease (COVID-19) pandemic. This cross-sectional study aimed to determine the prevalence of SARS-CoV-2 infection in hospital staff at the University Hospital rechts der Isar in Munich, Germany, and identify modulating factors. Overall seroprevalence of SARS-CoV-2-IgG in 4,554 participants was 2.4%. Staff engaged in direct patient care, including those working in COVID-19 units, had a similar probability of being seropositive as non-patient-facing staff. Increased probability of infection was observed in staff reporting interactions with SARS-CoV-2‒infected coworkers or private contacts or exposure to COVID-19 patients without appropriate personal protective equipment. Analysis of spatiotemporal trajectories identified that distinct hotspots for SARS-CoV-2‒positive staff and patients only partially overlap. Patient-facing work in a healthcare facility during the SARS-CoV-2 pandemic might be safe as long as adequate personal protective equipment is used and infection prevention practices are followed inside and outside the hospital.

Induction of ligand promiscuity of αVß3 integrin by mechanical force.

αVß3 integrin can bind to multiple extracellular matrix proteins, including vitronectin (Vn) and fibronectin (Fn), which are often presented to cells in culture as homogenous substrates. However, in tissues, cells experience highly complex and changing environments. To better understand integrin ligand selection in such complex environments, we employed binary-choice substrates of Fn and Vn to dissect αVß3 integrin-mediated binding to different ligands on the subcellular scale. Super-resolution imaging revealed that αVß3 integrin preferred binding to Vn under various conditions. In contrast, binding to Fn required higher mechanical load on αVß3 integrin. Integrin mutations, structural analysis and chemical inhibition experiments indicated that the degree of hybrid domain swing-out is relevant for the selection between Fn and Vn; only a force-mediated, full hybrid domain swing-out facilitated αVß3-Fn binding. Thus, force-dependent conformational changes in αVß3 integrin increased the diversity of available ligands for binding and therefore enhanced the ligand promiscuity of this integrin.This article has an associated First Person interview with the first author of the paper.

The F1 loop of the talin head domain acts as a gatekeeper in integrin activation and clustering.

Integrin activation and clustering by talin are early steps of cell adhesion. Membrane-bound talin head domain and kindlin bind to the ß integrin cytoplasmic tail, cooperating to activate the heterodimeric integrin, and the talin head domain induces integrin clustering in the presence of Mn2+ Here we show that kindlin-1 can replace Mn2+ to mediate ß3 integrin clustering induced by the talin head, but not that induced by the F2-F3 fragment of talin. Integrin clustering mediated by kindlin-1 and the talin head was lost upon deletion of the flexible loop within the talin head F1 subdomain. Further mutagenesis identified hydrophobic and acidic motifs in the F1 loop responsible for ß3 integrin clustering. Modeling, computational and cysteine crosslinking studies showed direct and catalytic interactions of the acidic F1 loop motif with the juxtamembrane domains of α- and ß3-integrins, in order to activate the ß3 integrin heterodimer, further detailing the mechanism by which the talin-kindlin complex activates and clusters integrins. Moreover, the F1 loop interaction with the ß3 integrin tail required the newly identified compact FERM fold of the talin head, which positions the F1 loop next to the inner membrane clasp of the talin-bound integrin heterodimer.This article has an associated First Person interview with the first author of the paper.

A bitter pill to swallow - Polypharmacy and psychotropic treatment in people with advanced dementia.

BACKGROUND: Polypharmacy is common in people with dementia. The use of psychotropic drugs (PDs) and other, potentially inappropriate medications is high. The aims of this cross-sectional study were 1) to investigate the use of drugs in people with advanced dementia (PWAD), living at home or in long term care (LTC); 2) to focus on PD use; and 3) to identify determinants of PD use. METHODS: The study was performed in the context of EPYLOGE (IssuEs in Palliative care for people in advanced and terminal stages of YOD and LOD in Germany). 191 PWAD were included. All drugs that were administered at the date of the examination were recorded. Multiple logistic regression analysis identified determinants of PD use. RESULTS: 96% of PWAD received medication with a median number of four drugs. 49.7% received five or more drugs. According to the Beers Criteria 39% of PWAD ≥ 65 years received at least one potentially inappropriate medication. 79% of PWAD were treated with PDs. Older PWAD and PWAD living in LTC facilities received significantly more drugs than younger PWAD, and PWAD living at home, respectively. Dementia etiology was significantly associated with the use of antipsychotics, antidepressants and sedative substances. Place of living was associated with the use of pain medication. Behavioral disturbances were associated with the use of antipsychotics and sedative substances. CONCLUSIONS: To mitigate the dangers of polypharmacy and medication related harm, critical examination is required, whether a drug is indicated or not. Also, the deprescribing of drugs should be considered on a regular basis. TRIAL REGISTRATION: Clinicaltrial.gov, NCT03364179 . Registered 6 December 2017.

Myocardial deformation analysis in late-onset small-for-gestational-age and growth-restricted fetuses using two-dimensional speckle tracking echocardiography: a prospective cohort study.

OBJECTIVES: An association between fetal growth restriction (FGR) and increased predisposition to cardiovascular disease (CVD) is suggested. The aim of this study was to evaluate subclinical signs of fetal cardiac remodeling in late-onset small-for-gestational-age (SGA) and growth-restricted fetuses using two-dimensional speckle tracking echocardiography (2D-STE). METHODS: This is a prospective cohort study, including 117 late-onset (≥32 weeks) SGA (birthweight≤10th centile) fetuses and 102 gestational age matched controls. A subgroup analysis was performed: FGR was defined based on either BW (0.05). Regarding global and segmental LPSS and LSR values of LV/RV, subgroup analysis revealed no significant difference between the FGR (n=81), SGA centile 3-10 (n=36) and control group. CONCLUSIONS: A mild degree of placental dysfunction seems not to influence myocardial deformation properties measured by 2D-STE.

Cardiovascular outcome of former late-onset small-for-gestational-age children at 1 year of age: CURIOSA study.

OBJECTIVE: Late-onset small-for-gestational-age (SGA) fetuses usually show normal uterine artery Doppler and were long considered to have a good peri- and postnatal outcome. Recently, these fetuses were identified to have a risk factor for cardiovascular disease. The aim of our study was to evaluate former SGA children concerning their cardiovascular risk and nutrition behavior at the age of 1 year. METHODS: We performed a prospective longitudinal cohort study at the University Hospital "Klinikum rechts der Isar" of the Technical University of Munich. Singleton pregnancies from 32 weeks with suspicion of SGA and healthy control pregnancies were included. RESULTS: A total of 100 former SGA children and 113 controls with normal weight (AGA) were examined at 1 year of age. Drop-out for 1-year follow-up was 27%. SGA children had significantly higher systolic (92.8 ± 9.8 mmHg vs. 87.5 ± 10.7 mmHg, p = 0.001), diastolic (63.1 ± 8.5 mmHg vs. 60.0 ± 10.3 mmHg, p = 0.028) and mean (73.0 ± 7.8 vs. 69.2 ± 9.7 mmHg, p = 0.004) blood pressure than AGA children. Comparing two breastfeeding periods (0-4 months vs. > 7 months), a downward trend in blood pressure values for longer breastfeeding periods was shown. CONCLUSION: Our study showed that even late-onset small-for-gestational-age fetuses seem to have cardiovascular problems, although they were previously thought to be "healthy". Up to now, blood pressure measurement is not part of indicated health checks in former SGA or even fetal growth-restricted children which should be changed. Further studies are needed to investigate cardiovascular prevention programs in children.