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Background: Limited treatment options with a rapid onset of action are available to treat off episodes in Parkinson's disease (PD) patients. Therefore, the development of rapid onset formulations, for instance with levodopa, is warranted, which was the reason to investigate an inhalable formulation of levodopa., Objectives: The primary objective was to determine the duration until maximum effect is reached of inhaled levodopa on the improvement of motor function of PD patients. The secondary objective was to compare the time until maximal effect and the maximal effect of inhaled levodopa versus oral levodopa., Design: Open-label randomized two-way one-period crossover trial., Methods: Nine PD patients in the 'off state' received one dose of inhaled levodopa (90 mg) from Cyclops® and one dose of levodopa orodispersible tablet (100 mg) on two consecutive days in a randomized order. A timed tapping test, Timed Up and Go test (TUG test) and Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III score were performed pre-dose and on set time points up to 90 min post-dose as measure for motor function. In addition, blood samples were taken for a pharmacokinetic evaluation ( T max , C max and area under the concentration time curve (AUC) 0-3 h)., Results: The maximal effect of inhaled levodopa was reached at 30 min (tapping test), at 75 min (TUG test) and at 60 min (UPDRS III). The positive effect on the UPDRS was statistically significant within 20 min after inhalation. After oral administration, C max and AUC 0-3 h were found to be significant higher ( p  = 0.028 and p  = 0.028, respectively) than after pulmonary administration. T max was achieved significantly ( p  = 0.028) faster after inhalation. The motor function examinations showed a similar maximum clinical improvement after pulmonary and oral administration and although not significant, inhaled levodopa results in a shorter median duration to maximum clinical effect for the TUG and timed finger-tapping test compared with oral administration (TUG: inhalation 55.0 and oral 67.5 min, timed finger-tapping test: inhalation 35.0 and oral 57.5 min). After the levodopa inhalation, there were no adverse events observed and no significant differences found in long-function parameters., Conclusion: Inhaled levodopa from Cyclops ® shows promising data as a rescue therapy for PD patients with off episodes, not responsive to the current oral therapies., Trial Registration: The study protocol was approved by the local ethics board 'Regionale toetsingscommissie patiëntgebonden onderzoek' (RTPO) in Leeuwarden, The Netherlands (approval number RTPO1019). The study was registered in in the Dutch trial register (LTR) with identification number NL6876. From 5 March 2024 on, the research data on onderzoekmetmensen.nl are known as 'Overview of Medical Research in the Netherlands' (OMON). This means the use of the name LTR has thus been dropped. Now, it is registered in the OMON with the same identification number (NL6876, Effectiveness of inhaled levodopa in PD | Research with human participants (onderzoekmetmensen.nl)). All patients provided written informed consent., (© The Author(s), 2024.)

Background: Chylothorax is an uncommon condition defined by the escape of lymphatic fluid into the pleural space originating from the thoracic duct., Case Description: Our case involves a male patient in his 60s who developed traumatic chylothorax after being involved in a bicycle collision. The total body computed tomography (CT) showed multiple fractures of the ribs and spine, including a fracture of the anterior column of the Th12 vertebra. The patient was placed under observation in the intensive care unit and because of the instability of the Th12 fracture operative stabilization was performed with a percutaneous dorsal pedicle screw-rod spondylodesis. One day postoperatively, the patient suffered from acute respiratory distress; vital signs and hemoglobin levels remained stable. CT angiography was performed showing a large amount of fluid in the right pleural cavity. A chest tube was placed and a total of 3 L of fluid was evacuated. The next day a chylous production of 2 to 3 L per 24 hours was observed. Initiation of nutritional management for the patient involved a medium-chain triglyceride (MCT) diet in conjunction with total parenteral nutrition (TPN) administration. Due to the ongoing chylous leakage, despite the MCT diet and TPN, the patient underwent video-assisted thoracic surgery (VATS); the thoracic duct was identified and clipped. In addition, a VATS chemical pleurodesis with talc was performed. The chylous drainage ceased and after a total of 8 weeks the MCT diet was stopped., Conclusions: This case report encompasses relevant diagnostic evaluations and the array of medical treatments applicable to a chylothorax resulting from trauma., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-34/coif). The authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Introduction: The aim of our study was to validate the original Charlson Comorbidity Index (1987) (CCI) and adjusted CCI (2011) as a prediction model for 30-day and 1-year mortality after hip fracture surgery. The secondary aim of this study was to verify each variable of the CCI as a factor associated with 30-day and 1-year mortality., Methods: A prospective database of two-level II trauma teaching hospitals in the Netherlands was used. The original CCI from 1987 and the adjusted CCI were calculated based on medical history. To validate the original CCI and the adjusted CCI, the CCI was plotted against the observed 30-day and 1-year mortality, and the area under the curve (AUC) was calculated., Results: A total of 3523 patients were included in this cohort study. The mean of the original CCI in this cohort was 5.1 (SD ± 2.0) and 4.6 (SD ± 1.9) for the adjusted CCI. The AUCs of the prediction models were 0.674 and 0.696 for 30-day mortality for the original and adjusted CCIs, respectively. The AUCs for 1-year mortality were 0.705 and 0.717 for the original and adjusted CCIs, respectively., Conclusions: A higher original and adjusted CCI is associated with a higher mortality rate. The AUC was relatively low for 30-day and 1-year mortality for both the original and adjusted CCIs compared to other prediction models for hip fracture patients in our cohort. The CCI is not recommended for the prediction of 30-day and 1-year mortality in hip fracture patients., (© 2024. The Author(s).)

Background: Needs-based, patient-oriented palliative care includes palliative day care clinics as a specialized semi-inpatient care offer. However, the establishment and development of these facilities has been unsystematic. Research is needed to strengthen their transparency and ensure their accessibility, quality, and structural adequacy. A national Delphi study was conducted to generate appropriate recommendations for the establishment and development of palliative day care clinics in Germany., Methods: Recommendations were formulated from focus group data on the development and expansion of palliative day care clinics in Germany. Experts on in- and outpatient palliative care rated 28 recommendations for relevance and feasibility, respectively, using a 4-point Likert-type scale. Suggestions for improvement were captured via free text comments. Items were considered consented when more than 80% of the experts scored them 4 (strongly agree) or 3 (somewhat agree), regarding both relevance and feasibility., Results: A total of 23 experts (32% response rate) completed three Delphi rounds. Following the first round, 10 of 28 recommendations were revised according to participants' comments; 1 recommendation was rejected. After the second round, 3 of these 10 recommendations were revised, while 3 were rejected. Consensus was achieved after the third round for 22 of the initial recommendations., Conclusions: The Delphi-consented recommendations provide a basis for the targeted evidence- and needs-based development of palliative day care clinics. The findings show a need for standards setting and the meaningful integration of these clinics into existing structures., Trial Registration: The present study was prospectively registered on April 20, 2020, with the German Clinical Trials Register (DRKS00021446)., (© 2024. The Author(s).)

Background: Trio exome sequencing can be used to investigate congenital abnormalities identified on pregnancy ultrasound, but its use in an Australian context has not been assessed., Aims: Assess clinical outcomes and changes in management after expedited genomic testing in the prenatal period to guide the development of a model for widespread implementation., Materials and Methods: Forty-three prospective referrals for whole exome sequencing, including 40 trios (parents and pregnancy), two singletons and one duo were assessed in a tertiary hospital setting with access to a state-wide pathology laboratory. Diagnostic yield, turn-around time (TAT), gestational age at reporting, pregnancy outcome, change in management and future pregnancy status were assessed for each family., Results: A clinically significant genomic diagnosis was made in 15/43 pregnancies (35%), with an average TAT of 12 days. Gestational age at time of report ranged from 16 + 5 to 31 + 6 weeks (median 21 + 3 weeks). Molecular diagnoses included neuromuscular and skeletal disorders, RASopathies and a range of other rare Mendelian disorders. The majority of families actively used the results in pregnancy decision making as well as in management of future pregnancies., Conclusions: Rapid second trimester prenatal genomic testing can be successfully delivered to investigate structural abnormalities in pregnancy, providing crucial guidance for current and future pregnancy management. The time-sensitive nature of this testing requires close laboratory and clinical collaboration to ensure appropriate referral and result communication. We found the establishment of a prenatal coordinator role and dedicated reporting team to be important facilitators. We propose this as a model for genomic testing in other prenatal services., (© 2024 The Authors. Australian and New Zealand Journal of Obstetrics and Gynaecology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Background: Most tyrosine kinase inhibitors (TKIs) have failed in clinical trials for metastatic colorectal cancer (mCRC). To leverage the additional lower-affinity targets that most TKIs have, high-dose regimens that trigger efficacy are explored. Here, we studied unprecedented drug exposure-response relationships in vitro using mCRC patient-derived tumour organoids (PDTOs)., Methods: We investigated the cytotoxic anti-tumour effect of high-dose, short-term (HDST) TKI treatment on 5 PDTOs. Sunitinib, cediranib and osimertinib were selected based on favourable physicochemical and pharmacokinetic properties. Intra-tumoroid TKI concentrations were measured using a clinically validated LC/MS-MS method. Cell death was determined using an enzyme activity assay, immunofluorescent staining and western blotting., Results: Most PDTOs tested were sensitive to sunitinib and cediranib, but all to osimertinib. Furthermore, HDST osimertinib treatment effectively blocks organoid growth. This treatment led to markedly elevated intra-tumoroid TKI concentrations, which correlated with PDTO sensitivity. Mechanistically, HDST osimertinib treatment induced apoptosis in treated PDTOs., Conclusion: Our work provides a better understanding of TKI exposure vs response and can be used to determine patient-specific sensitivity. Additionally, these results may guide both mechanistic elucidation in organotypic translational models and the translation of target drug exposure to clinical dosing strategies. Moreover, HDST osimertinib treatment warrants clinical exploration for mCRC., (© 2024. The Author(s).)

Introduction: A needs-based and patient-oriented hospice and palliative care also includes day hospices as a specialised semi-inpatient care offer. The establishment and development of these facilities in Germany has been rather unsystematic. In order to ensure quality and adequacy of these structures, research is needed., Methods: A Delphi consensus study was conducted online from November 2022 to February 2023 aiming at generating recommendations for the development and expansion of day hospices in Germany. For each recommendation, the participants indicated on a four-point verbal rating scale how much they agreed upon a) the relevance and b) the feasibility of the recommendation. Items were considered consented when 80% of the participants (strongly) agreed with the recommendation regarding both criteria. If no consensus was reached, the recommendations were revised according to the participants' free text comments and presented in the next Delphi round. Descriptive analyses were applied., Results: A total of 64 experts participated in the first Delphi round and 44 in the second. In round 1, 34 recommendations and in round 2 six recommendations were consented. The final set contains a total of 40 recommendations: 18 on the tasks of day hospices, 13 on cooperation, 7 on funding, and 2 on public relations., Discussion: Recommendations for the development and expansion of day hospices in Germany were developed. Due to their highly rated feasibility, the recommendations should be directly transferable into care practice. It remains to be seen to what extent they will be taken into account in the renegotiation of the framework agreement for day hospices., Conclusion: The Delphi-consented recommendations provide a basis to guide action in the currently very dynamic development of hospice work and palliative care in Germany., (Copyright © 2024. Published by Elsevier GmbH.)

Purpose: The primary objective of this study was to identify new risk factors and to confirm previously reported risk factors associated with 30-day mortality after hip fracture surgery., Patients and Methods: A prospective hip fracture database was used to obtain data. In total, 3523 patients who underwent hip fracture surgery between 2011 and 2021 were included. Univariable and multivariable logistic regression was used to screen and identify candidate risk factors. Twenty-seven baseline factors and 16 peri-operative factors were included in the univariable analysis and 28 of those factors were included in multivariable analysis., Results: 8.6% of the patients who underwent hip fracture surgery died within 30 days after surgery. Prognostic factors associated with 30-day mortality after hip fracture surgery were as follows: age 90-100 years (OR = 4.7, 95% CI: 1.07-19.98, p = 0.041) and above 100 years (OR = 11.3, 95% CI: 1.28-100.26, p = 0.029), male gender (OR = 2.6, 95% CI: 1.97-3.33, p < 0.001), American Society of Anesthesiologists (ASA) 3 and ASA 4 (OR = 2.1, 95% CI: 1.44-3.14, p < 0.001), medical history of dementia (OR = 1.7, 95% CI: 1.25-2.36, p = 0.001), decreased albumin level (OR = 0.94, 95% CI: 0.92-0.97, p < 0.001), decreased glomerular filtration rate (GFR) (OR = 0.98, 95% CI: 0.98-0.99, p < 0.001), residential status of nursing home (OR = 2.1, 95% CI: 1.44-2.87, p < 0.001), higher Katz Index of Independence in Activities of Daily Living (KATZ-ADL) score (OR = 1.1, 95% CI: 1.01-1.16, p=0.018) and postoperative pneumonia (OR = 2.4, 95% CI: 1.72-3.38, p < 0.001)., Conclusion: A high mortality rate in patients after acute hip fracture surgery is known. Factors that are associated with an increased mortality are age above 90 years, male gender, ASA 3 and ASA 4, medical history of dementia, decreased albumin, decreased GFR, residential status of nursing home, higher KATZ-ADL score and postoperative pneumonia., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 de Haan et al.)

Purpose: In Germany, patients with incurable chronic diseases living at home increasingly have the option of using outpatient and day care hospice and specialized palliative care services. The present study examined and compared patients' and their relatives' preferences for end-of-life outpatient and day care services., Patients and Methods: The study used a questionnaire integrating a discrete choice experiment. For six scenarios, participants chose between two hypothetical end-of-life care offers, described by seven attributes. The model compared place of care, frequency and duration of care and support, specialized medical palliative care, accompanied activities, and relieving patient counselling. The model also included optional overnight care and willingness to pay. Patients and the relatives of patients suffering from incurable, chronic diseases who were not yet receiving palliative care were recruited via hospitals and self-help groups (06/2021-07/2022)., Results: The results were based on data from 436 questionnaires (patients: n=263, relatives: n=173). All attributes had a statistically significant impact on choice decisions, with place of care showing the greatest importance. All respondents highly preferred care in the patient's home over out-of-home care. Patients stressed the importance of special medical (palliative) care and valued accompanied activities, often facilitated by hospice volunteers. Relatives, but not patients, considered the frequency and duration of care highly relevant., Conclusion: The results suggest a higher demand for care in the patient's home than for out-of-home care. Patients' and relatives' high preference for special medical care and the relief of family caregiver burden should be considered in the design of day care services., Competing Interests: Dr Franziska Herbst reports spokesperson for the Research Working Group of the German Society for Palliative Medicine (DGP) and spokesperson for the Humanities and Social Sciences Professions Section of the German Society for Palliative Medicine (DGP). The authors declare that they have no other conflicts of interest in this work., (© 2024 Apolinarski et al.)

Background: FSHD is a highly prevalent inherited myopathy with a still poorly understood pathology., Objective: To investigate whether proinflammatory cytokines are associated with FSHD and which specific innate immune cells are involved in its pathology., Methods: First, we measured circulating cytokines in serum samples: IL-6 (FSHD, n = 150; HC, n = 98); TNF (FSHD, n = 150; HC, n = 59); IL-1α (FSHD, n = 150; HC, n = 66); IL-1β (FSHD, n = 150; HC, n = 98); MCP-1 (FSHD, n = 14; HC, n = 14); VEGF-A (FSHD, n = 14; HC, n = 14). Second, we tested trained immunity in monocytes (FSHD, n = 15; HC, n = 15) and NK cells (FSHD, n = 11; HC, n = 11). Next, we explored the cytokine production capacity of NK cells in response to different stimuli (FSHD, n = 39; HC, n = 22). Lastly, we evaluated the cytokine production of ex vivo stimulated MRI guided inflamed (TIRM+) and paired MRI guided non inflamed (TIRM-) muscle biopsies of 21 patients and of 8 HC muscle biopsies., Results: We included a total of 190 FSHD patients (N = 190, 48±14 years, 49% men) and of 135 HC (N = 135, 44±15 years, 47% men). We found that FSHD patients had higher concentrations of IL-6 and TNF measured (a) in the circulation, (b) after ex-vivo stimulation of NK cells, and (c) in muscle specimens. Besides, IL-6 circulating concentrations, as well as its production by NK cells and IL-6 content of FSHD muscle specimens, showed a mild correlation with disease duration, disease severity, and muscle weakness., Conclusion: These results show that IL-6 and TNF may contribute to FSHD pathology and suggest novel therapeutic targets. Additionally, the activation of NK cells in FSHD may be a novel pathway contributing to FSHD pathology.

Introduction/aims: Ultrasound imaging of muscle tissue conventionally results in two-dimensional sampling of tissue. For heterogeneously affected muscles, a sampling error using two-dimensional (2D) ultrasound can therefore be expected. In this study, we aimed to quantify and extend ultrasound imaging findings in neuromuscular disorders by using three-dimensional quantitative muscle ultrasound (3D QMUS)., Methods: Patients with facioscapulohumeral dystrophy (n = 31) and myotonic dystrophy type 1 (n = 16) were included in this study. After physical examination, including Medical Research Council (MRC) scores, the tibialis anterior muscle was scanned with automated ultrasound. QMUS parameters were calculated over 15 cm of the length of the tibialis anterior muscle and were compared with a healthy reference data set., Results: With 3D QMUS local deviations from the healthy reference could be detected. Significant Pearson correlations (P < .01) between MRC score and QMUS parameters in male patients (n = 23) included the mean echo intensity (EI) (0.684), the standard deviation of EI (0.737), and the residual attenuation (0.841). In 91% of all patients, mean EI deviated by more than 1 standard deviation from the healthy reference. In general, the proportion of muscle tissue with a Z score >1 was about 50%., Discussion: In addition to mean EI, multiple QMUS parameters reported in this study are potential biomarkers for pathology. Besides a moderate correlation of mean EI with muscle weakness, two other parameters showed strong correlations: standard deviation of EI and residual attenuation. Local detection of abnormalities makes 3D QMUS a promising method that can be used in research and potentially for clinical evaluation., (© 2023 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Introduction: Encounters for preoperative assessments are common within primary care offices, so it is imperative that family medicine residents learn how to perform preoperative evaluations. We assessed family medicine residents' knowledge of preoperative evaluation in preparation for surgery by providing a pre- and post-test alongside a didactic seminar., Methods: A didactic seminar on preoperative evaluations was presented at a family medicine resident didactics session by two senior anesthesiology residents. A 16-question, multiple choice test was used as both a pre-test and post-test to assess family medicine residents' knowledge., Results: A total of 31 participants took the pre-test (residents = 24; medical students = 7), and 30 participants took the post-test (residents = 23; medical students = 7). Mean scores and standard deviations were calculated for both tests with an average score of 37.50% ± 10.58% and 45.42% ± 11.12% on the pre- and post-test, respectively. Using the Kruskal-Wallis test, residents showed a significant improvement in test scores following the didactic presentation (p = 0.041), while overall results (residents and medical students) also reported a significant difference (p = 0.004)., Conclusions: Our results demonstrated that educating family medicine residents and medical students on preoperative evaluation showed significant, quantifiable gains in knowledge following a brief didactic presentation. Given the current gap between guidelines and practice, our results emphasize the need for a formal medical school and residency-based curriculum related to preoperative patient evaluation., (© 2023 The University of Kansas Medical Center.)

Objectives: To assess the comparative budget and health impact of lower-dose dabigatran versus reduced doses of apixaban and rivaroxaban in atrial fibrillation (AF) patients eligible for a lower-/reduced-dose due to individual patient characteristics in the Netherlands. Methods: A budget impact model was developed in accordance with ISPOR guidelines. A 3-year-time horizon was considered, and analyses were conducted from a Dutch healthcare payer's perspective. The model applies published data to local AF-epidemiology, allowing calculations to estimate clinical events (strokes and haemorrhages) and costs. The analyses were based on real-world outcomes from patients with AF receiving a first direct oral anticoagulant (DOAC) prescription for low-dose dabigatran (110 mg) and a reduced dose of apixaban (2.5 mg) or rivaroxaban (15 mg). Two situations of switching treatments from one to another DOAC were modelled: switching from apixaban to dabigatran and from rivaroxaban to dabigatran. Base case results were given as savings per 100 patient-year, per total Dutch population, and events avoided. A univariate sensitivity analysis was conducted to explore the uncertainty around epidemiological and event costs input data. Scenario analyses were performed to estimate the effect of different market shares and potential price reductions due to future patent expiry for the total real-world population from the Netherlands. Results: The 3-years outcomes of switching patients eligible for a lower-/reduced-dose due to individual patient characteristics from apixaban or rivaroxaban to dabigatran resulted in cost savings estimated at €157 or €72 thousand per 100 patient-years, respectively, or €146 million per total Dutch population. Looking into the clinical events, dabigatran reflected the lowest number of mortalities, ischemic strokes, major bleeding, non-major bleeding, and haemorrhagic stroke compared to apixaban and rivaroxaban. The sensitivity analysis consistently reflected cost savings, with the ischeamic stroke events having the biggest impact. Accounting for the Dutch situation, both scenarios showed total savings ranging from €45 to €229 million over 3 years. Conclusions: Switching eligible AF-patients from reduced-dose apixaban or rivaroxaban to lower-dose dabigatran has the potential to reduce healthcare payer's budget expenditures and provide health gains. Cost savings can potentially be further enhanced by market share adjustments and further price reductions., Competing Interests: CB and MJP reported receiving grants and honoraria from various pharmaceutical companies, including BI. They are both shareholders of Health-Ecore, the Netherlands. TF and LdJ are partly employed as consultants at Health – Ecore, the Netherlands. BK is employee at BI in the Netherlands. No other disclosures were reported., (© 2023 Health-Ecore B.V.Utrechtseweg 603704 HE ZeistThe Netherlands. Published by Informa UK Limited, trading as Taylor & Francis Group.)

Introduction: Mild intellectual disability or borderline intellectual functioning (MID/BIF) are common in people with severe mental health problems (SMHP). Despite this, there is a lack of treatments adapted for this group of clients., Methods: This qualitative study describes the development of a new intervention, guided by the principles of action research, for people with SMHP and MID/BIF and mental health professionals to help them talk about all aspects of the process of recovery. The intervention was developed in four cycles and in close cooperation with mental health professionals, experts by experience, other experts in the field of SMHP or MID/BIF, and clients. During all cycles there was a strong focus on the content of the intervention, exercises, understandable language, and drawings for visual support., Results: This resulted in the intervention "Routes to Recovery," which covers both complaints and strengths, coping strategies, helpful (social) activities, and how to determine future steps in a recovery plan., Discussion: Routes to Recovery is a first step in helping professionals and their clients with SMHP and MID/BIF to have a conversation about personal strengths and what the client needs to recover. Future research should investigate the effects of this intervention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Berger, Bruineberg, van Ewijk, de Jong, van der Hout, van Weeghel and van der Meer.)

Background: Informal care provided by family members, friends, or neighbors is a major pillar in the German long-term care system. As the number of care-dependent older adults grow, ensuring their future care still relies on the willingness of family members, friends, or neighbors to assume the role of an informal caregiver. This study aimed to investigate the impact on people's willingness to provide informal care to a close relative with predominately cognitive compared to physical impairments., Methods: An online survey was distributed to the general population in Germany, which resulted in 260 participants. A discrete choice experiment was created to elicit and quantify people's preferences. A conditional logit model was used to investigate preferences and marginal willingness-to-accept values were estimated for one hour of informal caregiving., Results: Increased care time per day (hours) and expected duration of caregiving were negatively valued by the participants and reduced willingness to care. Descriptions of the two care dependencies had a significant impact on participants' decisions. Having to provide care to a close relative with cognitive impairments was slightly preferred over caring for a relative with physical impairments., Conclusions: Our study results show the impact of different factors on the willingness to provide informal care to a close relative. How far the preference weights as well as the high willingness-to-accept values for an hour of caregiving can be explained by the sociodemographic structure of our cohort needs to be investigated by further research. Participants slightly preferred caring for a close relative with cognitive impairments, which might be explained by fear or discomfort with providing personal care to a relative with physical impairments or feelings of sympathy and pity towards people with dementia. Future qualitative research designs can help understand these motivations., (© 2023. The Author(s).)

Background: Among available breast biopsy techniques, ultrasound (US)-guided biopsy is preferable because it is relatively inexpensive and provides live imaging feedback. The availability of magnetic resonance imaging (MRI)-3D US image fusion would facilitate US-guided biopsy even for US occult lesions to reduce the need for expensive and time-consuming MRI-guided biopsy. In this paper, we propose a novel Automated Cone-based Breast Ultrasound Scanning and Biopsy System (ACBUS-BS) to scan and biopsy breasts of women in prone position. It is based on a previously developed system, called ACBUS, that facilitates MRI-3D US image fusion imaging of the breast employing a conical container filled with coupling medium., Purpose: The purpose of this study was to introduce the ABCUS-BS system and demonstrate its feasibility for biopsy of US occult lesions., Method: The biopsy procedure with the ACBUS-BS comprises four steps: target localization, positioning, preparation, and biopsy. The biopsy outcome can be impacted by 5 types of errors: due to lesion segmentation, MRI-3D US registration, navigation, lesion tracking during repositioning, and US inaccuracy (due to sound speed difference between the sample and the one used for image reconstruction). For the quantification, we use a soft custom-made polyvinyl alcohol phantom (PVA) containing eight lesions (three US-occult and five US-visible lesions of 10 mm in diameter) and a commercial breast mimicking phantom with a median stiffness of 7.6 and 28 kPa, respectively. Errors of all types were quantified using the custom-made phantom. The error due to lesion tracking was also quantified with the commercial phantom. Finally, the technology was validated by biopsying the custom-made phantom and comparing the size of the biopsied material to the original lesion size. The average size of the 10-mm-sized lesions in the biopsy specimen was 7.00 ± 0.92 mm (6.33 ± 1.16 mm for US occult lesions, and 7.40 ± 0.55 mm for US-visible lesions)., Results: For the PVA phantom, the errors due to registration, navigation, lesion tracking during repositioning, and US inaccuracy were 1.33, 0.30, 2.12, and 0.55 mm. The total error was 4.01 mm. For the commercial phantom, the error due to lesion tracking was estimated at 1.10 mm, and the total error was 4.11 mm. Given these results, the system is expected to successfully biopsy lesions larger than 8.22 mm in diameter. Patient studies will have to be carried out to confirm this in vivo., Conclusion: The ACBUS-BS facilitates US-guided biopsy of lesions detected in pre-MRI and therefore might offer a low-cost alternative to MRI-guided biopsy. We demonstrated the feasibility of the approach by successfully taking biopsies of five US-visible and three US-occult lesions embedded in a soft breast-shaped phantom., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Introduction: The proportion of people in need of care will continue to rise in Germany. In 2019, the majority of people in need of care was cared for at home. Reconciling caregiving and work poses a heavy burden for many caregivers. Therefore, a monetary compensation for care is being discussed politically in order to facilitate the reconciliation of work and care. The aim of this study was to investigate whether and under which circumstances a sample of the German population is willing to care for a close relative. A particular focus was placed on the willingness to reduce working hours, the importance of the expected period of caregiving, and monetary compensation., Methods: A primary data collection was conducted in two modes using a questionnaire. A self-completion postal survey was sent out via the AOK Lower Saxony and complemented with an online survey. Data was analysed descriptively and using logistic regression., Results: 543 participants were included. 90% of the sample surveyed was willing to provide care for a close relative, with the majority stating that their willingness depended on various factors: both the health status and the person of the family member needing care had the greatest influence. 34% of the employed respondents were not willing to reduce their working hours, mostly for financial reasons., Discussion and Conclusion: Many older adults want to stay in their homes for as long as possible. Thus, the willingness to provide and take over the role of informal caregiver is and will remain a central pillar of the German care system. Negotiating between informal caregiving and professional activities often creates a substantial burden. For people from lower income households monetary compensation might enhance their willingness to provide informal care. However, in order to increase the willingness to engage in informal care of people from different backgrounds and life stages, flexible approaches are needed that go beyond monetary compensation., (Copyright © 2023. Published by Elsevier GmbH.)

As the German population is continually aging and the majority of older adults still wish to 'age in place', the need for informal care provided by family and friends will correspondingly continue to increase. In addition, while the need for formal (professional) care services is also likely to increase, the supply already does not meet the demand in Germany today. The aim of our study is the elicitation of people's willingness to provide informal care by means of a discrete choice experiment. The self-complete postal survey was disseminated to a random sample of the German general population in Lower Saxony. Data cleansing resulted in a final sample size of 280 participants. A conditional logit and a latent class model were estimated. All attributes were judged as highly relevant by the respondents. The results revealed that an increase in the care hours per day had the greatest negative impact overall on the willingness to provide informal care in our sample. The marginal willingness-to-accept for 1 h of informal care was €14.54 when having to provide informal care for 8 h in reference to 2 h per day. This value is considerably higher than the national minimum wage of €9.82. A three-class latent class model revealed preference heterogeneity. While a monetary compensation is often discussed to increase the willingness and availability of informal care in a country, our results show that this statement could not be generalized within our entire sample., (© 2022. The Author(s).)

Purpose: The primary aim of this study was to identify risk factors for delirium after hip fracture surgery. The secondary purpose of this study was to verify peri-operative clinical outcomes, adverse events and mortality rates in delirium patients after hip fracture surgery., Patients and Methods: A prospective hip fracture database was used to obtain data. In total, 2051 patients older than 70 years undergoing a hip fracture surgery between 01-01-2018 and 01-01-2021 were included. A delirium was diagnosed by a geriatrician based on the DSM-V criteria., Results: The results showed that 16% developed a delirium during hospital admission. Multivariable analysis showed that male gender (OR: 1.99, p<0.001), age (OR: 1.06, p<0.001), dementia (OR: 1.66, p=0.001), Parkinson's disease (OR: 2.32, p=0.001), Δhaemoglobin loss (OR: 1.19, p=0.022), pneumonia (OR: 3.86, p<0.001), urinary tract infection (UTI) (OR: 1.97, p=0.001) and wound infection (OR: 3.02, p=0.007) were significant independent prognostic risk factors for the development of a delirium after hip surgery. The median length in-hospital stay was longer in patients with a delirium (9 days) vs patients without a delirium (6 days) (p<0.001). The 30-day mortality was 7% (with delirium 16% vs with no delirium 6% (p<0.001))., Conclusion: Significant independent prognostic factors associated with delirium after hip surgery were male gender, age, dementia, Parkinson's disease, Δhaemoglobin loss, pneumonia, UTI and wound infection., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 de Haan et al.)

In chlordecone (CLD)-contaminated soils of the French West Indies, if microbial remediation or a physicochemical remediation process, e.g., in situ chemical reduction, is implemented, concentrations of degradation byproducts, such as hydrochlordecones, are expected to increase in the ecosystems. To study their impact in mixtures with CLD, bioassays were carried out. They consisted in evaluating the regenerative capacity of hydra polyps, from a clone whose phylogenetic analysis confirmed that it belonged to the species Hydra vulgaris Pallas, 1766. Hydra gastric sections were exposed to CLD alone or CLD plus dechlorinated byproducts (CLD-BP) for 96 h to assess regeneration. Based on chromatographic analysis, the CLD-BP mix was composed of the 5-monohydrochlordecone isomer (CAS nomenclature), four dihydrochlordecone isomers, and one trihydrochlordecone isomer representing 50%, 47%, and 3% of the total chromatographic area, respectively. A total of 18 mixtures of CLD and CLD-BP were tested. Six environmental concentrations of CLD (2.10 -4 μM to 4.10 -2 μM) and a similar range of CLD-BP were used. Results from exposures to CLD alone showed the following: (i) a significant decrease in the regenerative capacity of hydra, except at the lowest concentration (2.10 -4 μM); (ii) a concentration-independent deleterious effect. The regeneration scores obtained after the exposure to the addition of CLD-BP were not significantly different from those obtained after exposure to CLD alone. Using an experimental design, a modeling of the regeneration scores of hydra exposed to mixtures is proposed. Interpreted carefully, since they are limited to only one type of bioassay, the present results suggest that the situation in the aquatic environments should not become worse in terms of toxicity, if soil remediation programs resulting in the formation of hydrochlordecones are put in place., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Factors associated with high mortality rates in geriatric hip fracture patients are frequently unmodifiable. Time to surgery, however, might be a modifiable factor of interest to optimize clinical outcomes after hip fracture surgery. This study aims to determine the influence of postponement of surgery due to non-medical reasons on clinical outcomes in acute hip fracture surgery., Methods: This observational cohort study enrolled consecutively admitted patients with a proximal femoral fracture, for which surgery was performed between 1 January 2018 and 11 January 2021 in two level II trauma teaching hospitals. Patients with medical indications to postpone surgery were excluded. A total of 1,803 patients were included, of whom 1,428 had surgery < 24 hours and 375 had surgery ≥ 24 hours after admission., Results: Prolonged total length of stay was found when surgery was performed ≥ 24 hours (median 6 days (interquartile range (IQR) 4 to 9) vs 7 days (IQR 5 to 10); p = 0.001) after admission. No differences in postoperative length of hospital stay nor in 30-day mortality rates were found. In subgroup analysis for time frames of 12 hours each, pressure sores and urinary tract infections were diagnosed more frequently when time to surgery increased., Conclusion: Longer time to surgery due to non-medical reasons was associated with a higher incidence of postoperative pressure sores and urinary tract infections when time to surgery was more than 48 hours after admission. No association was found between time to surgery and 30-day mortality rates or postoperative length of hospital stay.Cite this article: Bone Joint J  2022;104-B(12):1369-1378.

In the design of long-term care systems, preferences can serve as an essential indication to better tailor services to the needs, wishes and expectations of its consumers. The aim of this systematic review was to summarize and synthesize available evidence on long-term care preferences that have been elicited by quantitative stated-preference methods. The databases PubMed and Web of Science were searched for the period 2000 to 2020 with an extensive set of search terms. Two independent researchers judged the eligibility of studies. The final number of included studies was 66, conducted in 19 different countries. Studies were systematized according to their content focus as well as the survey method used. Irrespective of the heterogeneity of studies with respect to research focus, study population, sample size and study design, some consistent findings emerged. When presented with a set of long-term care options, the majority of study participants preferred to "age in place" and make use of informal or home-based care. With increasing severity of physical and cognitive impairments, preferences shifted toward the exclusive use of formal care. Next to the severity of care needs, the influence on preferences of a range of other independent variables such as income, family status and education were tested; however, none showed consistent effects across all studies. The inclusion of choice-based elicitation techniques provides an impression of how studies operationalized long-term care and measured preferences. Future research should investigate how preferences might change over time and generations as well as people's willingness and realistic capabilities of providing care., Competing Interests: Conflicts of interestThe authors declare that there is no conflict of interest., (© The Author(s) 2022.)

Background: Tranexamic acid (TXA) has shown to significantly reduce perioperative blood loss in elective orthopedic joint replacement surgery but is yet not implemented in acute hip fracture surgery for elderly patients who are particularly vulnerable to perioperative blood loss and postoperative anemia. Aim of this study is to answer the following questions: 1. Does TXA reduce bleeding associated complications in elderly patients? 2. Does TXA induce thromboembolic complications in elderly patients?, Hypothesis: TXA reduces perioperative blood loss and associated complications in acute hip fracture surgery in geriatric patients., Patients and Methods: In this observational cohort study with prospectively enrolled patients over 65 years of age who received an acute hip hemiarthroplasty, the primary outcome was blood loss, also described as Δ hemoglobin. Secondary outcomes were bleeding associated complications as hematomas. Also, the occurrence of thromboembolic events and mortality were examined., Results: In total 864 geriatric patients were included of which 235 received TXA and 629 did not. Multivariable analysis showed reduced Δ hemoglobin loss [-0.24 (-0.39; -0.09), p=0.002] and hematomas (OR 0.44 (0.21; 0.91), p=0.026). Pulmonary embolism were diagnosed more frequently after administration of TXA (2% versus 0.3%, p=0.008), without an association with increased 30-day mortality rate (6% versus 8%, p=0.3)., Discussion: TXA reduced perioperative blood loss and associated complications. However, adverse effects of TXA as pulmonary embolisms were found more frequently without effecting postoperative mortality rates. More research is needed to assess adverse effects of intravenous TXA and topical TXA as an alternative for systemic TXA to prevent systemic adverse effects., Level of Evidence: III, Observational cohort study., (Copyright © 2022. Published by Elsevier Masson SAS.)

We have quantum chemically explored the competition between the S N 2 and S N 2' pathways for X - + H 2 C═CHCH 2 Y (X, Y = F, Cl, Br, I) using a combined relativistic density functional theory and coupled-cluster theory approach. Bimolecular nucleophilic substitution reactions at allylic systems, i.e., C γ ═C β -C α -Y, bearing a leaving-group at the α-position, proceed either via a direct attack at the α-carbon (S N 2) or via an attack at the γ-carbon, involving a concerted allylic rearrangement (S N 2'), in both cases leading to the expulsion of the leaving-group. Herein, we provide a physically sound model to rationalize under which circumstances a nucleophile will follow either the aliphatic S N 2 or allylic S N 2' pathway. Our activation strain analyses expose the underlying physical factors that steer the S N 2/S N 2' competition and, again, demonstrate that the concepts of a reaction's "characteristic distortivity" and "transition state acidity" provide explanations and design tools for understanding and predicting reactivity trends in organic synthesis.

Purpose: The routine use of surgical drains in elective hip arthroplasty has been abandoned. Also in acute hip arthroplasty for femoral neck fractures drain use reduces. Question is, whether this is justified in geriatric patients, where the incidence of anticoagulation use is high. Therefore, the aim of this study is to compare the clinical outcomes in patients with and without the use of a wound drain after hip hemiarthroplasty., Methods: Data were extracted from a prospective hip fracture database and completed by retrospective review of the hospital records at two level II trauma centers between January 1st 2010 and May 16th 2016. Patients with a femoral neck fracture requiring hip hemiarthroplasty were included in the study., Results: This study cohort included 900 patients (68% female), with a median age of 83.5 (IQR 78-88), of which 544 (60%) had a wound drain. Patients with a wound drain needed more days to be ready for discharged (10.0 days (SD ± 43.3), P =  < 0.001) compared to patients without a drain (5.3 days (SD ± 4.2). With a drain more hemoglobin loss was found, 2.66 g/dL versus 2.4 g/dL (P = 0.008) and also more packed cells were supplemented, 0.29 versus 0.13 (P = 0.0016). Wound drain placement showed a statistically significant inverse relation with post-operative hematoma; odds ratio (OR 0.61, 95% CI 0.39; 0.94, P = 0.024), but no reduced risk of post-operative deep surgical site infection, (OR 1.09, 95% CI 0.43; 2.72, P = 0.862)., Conclusion: Surgical drain placement was not associated with a reduced risk of post-operative deep surgical site infections, nor one-year mortality. However, a decreased risk of post-operative wound hematoma was observed. Furthermore, patients with a drain needed more days to be ready for discharge, show more hemoglobin loss and need more packed cell supplementation during admission., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Age estimation is a key factor for identification procedure in forensic context. Based on anthropological findings, degenerative changes of the sternal extremity of the 4th rib are currently used for age estimation. These have been adapted to post-mortem computed tomography (PMCT). The aim of this study was to validate a post-mortem computed tomography method based on a revision of the Iscan's method on a French sample. A total of 250 PMCT (aged from 18-98 years (IQR 36-68 years, median 51 years); 68 (27%) females) from the Medicolegal Institute of Paris (MLIP) were analyzed by two radiologists. The sternal extremity of 4th right rib was scored using method adapted from Iscan et al. Weighted κ was used to evaluate intra- and inter-observer reliability and Spearman correlation was performed to evaluate relationship between age and score. Confidence intervals for individual prediction of age based on 4th rib score and sex were computed with bootstrapping. The intra-observer reliability and inter-observer reliability were almost perfect (weighted κ = 0.85 [95%CI: 0.78-0.93] and 0.82 [95%CI 0.70-0.96] respectively). We confirmed a high correlation between the 4th rib score and subject age (rho = 0.72, p < 0.001), although the confidence intervals for individual age prediction were large, spanning over several decades. This study confirms the high reliability of Iscan method applied to PMCT for age estimation, although future multimodal age prediction techniques may help reducing the span of confidence intervals for individual age estimation.Trial registration: INDS 0,509,211,020, October 2020, retrospectively registered., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

It is well known that certain non B-DNA structures, including G-quadruplexes, are key elements that can regulate gene expression. Here, we explore the theory that DNA modifications, such as methylation of cytosine, could act as a dynamic switch by promoting or alleviating the structural formation of G-quadruplex structures in DNA or RNA. The interaction between epigenetic DNA modifications, G4 formation, and the 3D architecture of the genome is a complex and developing area of research. Although there is growing evidence for such interactions, a great deal still remains to be discovered. In vivo, the potential effect that cytosine methylation may have on the formation of DNA structures has remained largely unresearched, despite this being a potential mechanism through which epigenetic factors could regulate gene activity. Such interactions could represent novel mechanisms for important biological functions, including altering nucleosome positioning or regulation of gene expression. Furthermore, promotion of strand-specific G-quadruplex formation in differentially methylated genes could have a dynamic role in directing X-inactivation or the control of imprinting, and would be a worthwhile focus for future research.

Alcohol intoxication is known to affect many aspects of human behavior and cognition; one of such affected systems is articulation during speech production. Although much research has revealed that alcohol negatively impacts pronunciation in a first language (L1), there is only initial evidence suggesting a potential beneficial effect of inebriation on articulation in a non-native language (L2). The aim of this study was thus to compare the effect of alcohol consumption on pronunciation in an L1 and an L2. Participants who had ingested different amounts of alcohol provided speech samples in their L1 (Dutch) and L2 (English), and native speakers of each language subsequently rated the pronunciation of these samples on their intelligibility (for the L1) and accent nativelikeness (for the L2). These data were analyzed with generalized additive mixed modeling. Participants' blood alcohol concentration indeed negatively affected pronunciation in L1, but it produced no significant effect on the L2 accent ratings. The expected negative impact of alcohol on L1 articulation can be explained by reduction in fine motor control. We present two hypotheses to account for the absence of any effects of intoxication on L2 pronunciation: (1) there may be a reduction in L1 interference on L2 speech due to decreased motor control or (2) alcohol may produce a differential effect on each of the two linguistic subsystems.

Introduction: The Nottingham Hip Fracture Score (NHFS) was developed to predict 30-day mortality for patients with hip fracture. This study aimed to validate the NHFS in a cohort with sufficient statistical power., Methods: Data were extracted from a prospective hip-fracture database (FAMMI). Patients were included between January 1, 2018 and January 11, 2021. All consecutively admitted patients ≥18 years of age with a hip fracture (ie, femoral neck fracture, intertrochanteric fracture, and subtrochanteric fracture) were included. Mann-Whitney's U values were calculated to find potential miscalibration of the NHFS formula. Discrimination evaluation was performed using the concordance statistic as an equivalent to area under the receiver-operating curve., Results: In total, 2,458 patients were included. Mean age was 80±12 years, and 66% were women (n=1,631). Median NHFS was 5 (4-6) and overall 30-day mortality 7.9% (n=195). Overall goodness of fit was tested with Pearson's ? 2 (11.8, df 10; P =0.297). No statistically significant signs of miscalibration were found (Mann-Whitney U , P =0.08). Discrimination was tested with area under the receiver- operating curve, which was 72.1% (95% CI 68.7%-75.4%). However, observed 30-day mortality in our population of hip-fracture patients was slightly higher than the NHFS prediction., Conclusion: The NHFS seemed to predict 30-day mortality with reasonable accuracy for patients with a hip fracture in a population within the Netherlands., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 van Rijckevorsel et al.)

Introduction: Geriatric hip fracture patients are characterized by frailty due to multiple comorbidities, such as cardiovascular disease, in which the use of antithrombotics is frequent. The aim of this study is to assess the effect of antithrombotics on perioperative care and patient outcomes after hip hemiarthroplasty following current guidelines., Materials and Methods: This observational cohort study included all consecutively admitted patients with a femoral neck fracture requiring hip hemiarthroplasty between January 1 st 2010, and May 16 th 2016, in two level II trauma teaching hospitals. Patients with multiple trauma injuries were excluded., Results: In total, n = 907 patients (68% female (n = 615), median age 84 years) were included of which n = 142 used a vitamin K antagonist (VKA) and n = 213 used antiplatelet (AP) therapy. Both were associated with more packed cell supplementation (.4 ± 1.1 units and .3 ± .8 units vs .2 ± .6 units, P < .001 and P = .03, respectively). VKA was associated with more hematomas compared no antithrombotics (23% vs 11%, P = .001). VKA had a longer time to surgery compared to no antithrombotics and AP (24 hours vs 19 and 20 hours, P < .001 and P < .001, respectively) and longer admission duration (9 days vs 7 days P < .001. There were no differences in 30 day mortality nor in 1-year mortality rates., Discussion: All modifiable causes for deep SSI, such as hematomas, should be prevented in acute hip fracture surgery. Since antithrombotics are associated with hematomas, an optimal handling in perioperative setting is necessary., Conclusion: VKA was associated with longer time to surgery, more hematomas, and longer admission duration. VKA and AP were associated with more packed cell supplementation., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Introduction/aims: Quantitative muscle ultrasound offers biomarkers that aid in the diagnosis, detection, and follow-up of neuromuscular disorders. At present, quantitative muscle ultrasound methods are 2D and are often operator and device dependent. The aim of this study was to combine an existing device independent method with an automated ultrasound machine and perform 3D quantitative muscle ultrasound, providing new normative data of healthy controls., Methods: In total, 123 healthy volunteers were included. After physical examination, 3D ultrasound scans of the tibialis anterior muscle were acquired using an automated ultrasound scanner. Image postprocessing was performed to obtain calibrated echo intensity values based on a phantom reference., Results: Tibialis anterior muscle volumes of 61.2 ± 24.1 mL and 53.7 ± 22.7 mL were scanned in males and females, respectively. Echo intensity correlated with gender**, age**, fat fraction*, histogram kurtosis**, skewness* and standard deviation** (*P < .05, **P < .01). Outcome measures did not differ significantly for different acquisition presets. The 3D quantitative muscle ultrasound revealed the non-uniformity of echo intensity values over the length of the tibialis anterior muscle., Discussion: Our method extended 2D measurements and confirmed previous findings. Our method and reported normative data of (potential) biomarkers can be used to study neuromuscular disorders., (© 2021 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Chemical cross-linking (CX) of proteins in vivo or in cell free extracts followed by mass spectrometric (MS) identification of linked peptide pairs (CXMS) can reveal protein-protein interactions (PPIs) both at a proteome wide scale and the level of cross-linked amino acid residues. However, error estimation at the level of PPI remains challenging in large scale datasets. Here we discuss recent advances in the recognition of spurious inter-protein peptide pairs and in diminishing the FDR for these PPI-signaling cross-links, such as the use of chromatographic retention time prediction, in order to come to a more reliable reporting of PPIs., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: To date, the establishment and development of palliative day-care clinics and day hospices in Germany have been completely unsystematic. Research is needed to gain insight into these services and to ensure their accessibility and quality. Accordingly, the ABPATITE research project aims at: (1) identifying the characteristics of palliative day-care clinics and day hospices in Germany, (2) determining demand and preferences for these services, and (3) proposing recommendations (with expert agreement) for the needs-based establishment and development of these services., Methods: The research is a multi-perspective, prospective, observational study following a mixed-methods approach across three study phases. In phase 1a, qualitative expert interviews will be conducted to capture the facility-related characteristics of palliative day-care clinics and day hospices in Germany; the results will feed into a questionnaire sent to all such institutions identified nationwide. In phase 1b, a questionnaire will be sent to local statutory health insurance providers, to gain insight into their contracts and accounting and remuneration models. In phase 2a, a service preference survey will be conducted with patients and family caregivers. In phase 2b, semi-structured interviews with management staff will explore the factors that promote and hinder the provision of service. In phase 2c, the external perspective will be surveyed via focus groups with local actors involved in hospice and palliative care. In phase 3a, focus groups with representatives from relevant areas will be conducted to develop recommendations. Finally, in phase 3b, recommendations will be agreed upon through a Delphi survey., Discussion: The empirically developed recommendations should enable the establishment and development of day hospices and palliative day-care clinics in Germany to be better managed, more oriented to actual demand, and more effectively integrated into wider health care services. Importantly, the findings are expected to optimize the overall development of hospice and palliative care services., Trial Registration: The study was prospectively registered in the German Clinical Trials Register (Deutsches Register Klinischer Studien) (Registration N° DRKS00021446; date of registration: April 20, 2020). The study is searchable under the International Clinical Trials Registry Platform Search Portal of the World Health Organization, under the German Clinical Trials Register number.

Purpose: For the safety and success of an ultrasound-guided percutaneous liver biopsy, needle visibility and needle tip identification are critical. The aim of this pilot study was to evaluate the influence of an innovative echogenic sheath placed over a standard biopsy needle on needle visibility in ultrasound imaging., Materials and Methods: Ultrasound videos of three sheaths with different coating characteristics (echogenicity) and one conventional liver biopsy needle were recorded at two angles (30° and 60°) and two depths (5 and 10 cm) in a human cadaver. The videos were blinded for needle type and presented to five independent radiologists who used Likert-scale scoring to rank each video for six characteristics on needle visibility. In addition, a phantom model was used to acquire standardized images for quantitative evaluation of the ultrasound visibility. Comparative statistical analysis consisted of a one-way ANOVA., Results: The three prototype sheaths were ranked higher than the control needle at 60° with 5 cm depth, with an equal performance for the other conditions. The radiologists expressed more confidence in taking a biopsy with the echogenic sheaths than with the control needle, with 1 Likert score difference at 30°. Contrast analysis in the phantom model showed a statistically significant effect of a sheath (p = 0.004) on echogenic intensity., Conclusion: This pilot study suggests that the use of an echogenic sheath may increase needle visibility, particularly for trajectories requiring steeper insertion angles. To investigate the superiority of the echogenic sheath over conventional needles, a clinical study is necessary.

Breast cancer is one of the most diagnosed types of cancer worldwide. Volumetric ultrasound breast imaging, combined with MRI can improve lesion detection rate, reduce examination time, and improve lesion diagnosis. However, to our knowledge, there are no 3D US breast imaging systems available that facilitate 3D US - MRI image fusion. In this paper, a novel Automated Cone-based Breast Ultrasound System (ACBUS) is introduced. The system facilitates volumetric ultrasound acquisition of the breast in a prone position without deforming it by the US transducer. Quality of ACBUS images for reconstructions at different voxel sizes (0.25 and 0.50 mm isotropic) was compared to quality of the Automated Breast Volumetric Scanner (ABVS) (Siemens Ultrasound, Issaquah, WA, USA) in terms of signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and resolution using a custom made phantom. The ACBUS image data were registered to MRI image data utilizing surface matching and the registration accuracy was quantified using an internal marker. The technology was also evaluated in vivo. The phantom-based quantitative analysis demonstrated that ACBUS can deliver volumetric breast images with an image quality similar to the images delivered by a currently commercially available Siemens ABVS. We demonstrate on the phantom and in vivo that ACBUS enables adequate MRI-3D US fusion. To our conclusion, ACBUS might be a suitable candidate for a second-look breast US exam, patient follow-up, and US guided biopsy planning.

Background: At present, the provision of informal care to older relatives is an essential pillar of the long-term care system in Germany. However, the impact of demographic and social changes on informal caregiving remains unclear., Methods: Thirty-three semi-structured interviews were conducted with care consultants, informal caregivers and people without any caregiving experience to explore if people are willing to provide older adult care and how prepared these are with regard to the possibility of becoming care dependent themselves., Results: In total, three main categories (willingness to provide care, willingness to receive care and information as preparation) with several sub-categories were identified during the content analysis. While almost all interviewees were willing to provide care for close family members, most were hesitant to receive informal care. Other factors such as the available housing space, flexible working hours and the proximity of relatives were essential indicators of a person's preparedness to provide informal care. It is, however, unclear if care preferences change over time and generations. Six out of 12 informal caregivers and nine out of 14 care consultants also reported an information gap. Because they do not possess adequate information, informal caregivers do not seek help until it is too late and they experience high physical and mental strain. Despite the increased efforts of care consultants in recent years, trying to inform caregivers earlier was seen as almost impossible., Conclusions: The very negative perception of caregiving as a burden was a reoccurring theme throughout all interviews and influenced people's willingness to receive care as well as seeking timely information. Despite recent political efforts to strengthen home-based care in Germany, it remains unclear whether political efforts will be effective in changing individuals' perceptions of informal caregiving and their willingness to be better prepared for the highly likely scenario of having to care for a close relative or becoming care dependent at a later stage in life.

In vivo chemical cross-linking combined with LCMSMS of digested extracts (in vivo CX-MS) can reveal stable and dynamic protein-protein interactions at proteome-wide scale and at peptide level. In vivo CX-MS requires a membrane permeable and cleavable cross-linker and a fast and sensitive search engine to identify the linked peptides. Here we explore the use of the search engine pLink 2 to identify cross-links induced in exponentially growing Bacillus subtilis cells treated in culture with bis(succinimidyl)-3-azidomethyl-glutarate (BAMG). Cross-linked peptide pairs were identified by pLink 2 in very short time at an overall FDR of <5%. To also obtain a FDR <5% for non-redundant inter-protein cross-linked peptide pairs additional threshold values were applied for matched fragment intensity and for the numbers of unambiguous y and b ions assigned to both composite peptides. Also the mass- and charge-dependent retention times of target peptides purified by diagonal strong cation exchange chromatography were used as a criterion to distinguish true from false positives. After application of the composite filter new protein-protein interactions were revealed among others between the global transcriptional repressor AbrB and elongation factor Tu and between the essential protein YlaN of unknown function and the ferric uptake repressor Fur. SIGNIFICANCE: Important for reliable identification of PPIs by chemical cross-linking in vivo is a low FDR of non-redundant inter-protein peptide pairs. Here we describe how to recognize the presence of spurious interactions in a dataset of cross-linked peptide pairs enriched by 2D strong cation exchange chromatography and identified by LCMSMS by taking into account chromatographic behavior of cross-linked peptide pairs and protein abundance of corresponding peptides. Based on these criteria we assessed that the FDR of the fraction of non-redundant inter-protein cross-linked peptide pairs was approx. 20-25% by interrogating an entire species specific database at an overall FDR of 5% or 0.1% with a search engine that otherwise scores best in sensitivity among other search engines. We have defined a composite filter to decrease this high FDR of inter-protein cross-linked peptide pairs to only about 2%., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Despite existing interventions, tobacco smoking and alcohol consumption during pregnancy are common. The Smoke and Alcohol Free with EHealth and Rewards (SAFER) pregnancy intervention combines monthly group sessions, access to a web-based platform and incentives upon biochemically validated cessation for a maximum duration of 6 months to promote cessation of smoking and alcohol use before and during pregnancy. To inform development of the SAFER pregnancy intervention, two focus groups with the target population were held beforehand, with results reported here alongside the final SAFER pregnancy study protocol. In a before-after study we aim to include 66 women who are pregnant or have a wish to become pregnant and who smoke and/or consume alcohol (i.e. target population of the SAFER pregnancy intervention). The primary outcome measure is cessation of smoking and/or alcohol use at 34-38 weeks of gestation, or after six group sessions if women did not become pregnant during the study period. Secondary outcomes focus on the barriers and facilitators for implementation of the SAFER pregnancy intervention.

Chlordecone (CLD) is an organochlorine pesticide widely used in the past to control pest insects in banana plantations in the French West Indies. Due to its persistence in the environment, CLD has contaminated the soils where it has been spread, as well as the waters, and is still present in them. The objective of our study was to evaluate the effects of chronic exposure to environmentally relevant CLD concentrations in an animal model, the freshwater hydra (Hydra circumcincta). In a multi-marker approach, we have studied the expression of some target stress genes, the morphology, and the asexual reproduction rates. Our data showed that exposure to low concentrations of chlordecone leads to (i) a modulation of the expression of target genes involved in oxidative stress, detoxification, and neurobiological processes, and (ii) morphological damages and asexual reproduction impairment. We have observed non-monotonic dose-response curves, which agree with endocrine-disrupting chemical effects. Thus, "U-shaped" dose-response curves were observed for SOD, GRed, Hym355, and potentially GST gene expressions; inverted "U-shaped" curves for GPx and CYP1A gene expressions and reproductive rates; and a biphasic dose-response curve for morphological damages. Therefore, in the range of environmental concentrations tested, very low concentrations of CLD can produce equally or more important deleterious effects than higher ones. Finally, to our knowledge, this study is the first one to fill the lack of knowledge concerning the effects of CLD in Hydra circumcincta and confirms that this diploblastic organism is a pertinent freshwater model in the risk assessment.

Objective: The role of treatment with renin-angiotensin-aldosterone system blockers at the onset of COVID-19 infection is not known in the geriatric population. The aim of this study was to assess the relationship between angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitor (ACEI) use and in-hospital mortality in geriatric patients hospitalized for COVID-19., Design: This observational retrospective study was conducted in a French geriatric department. Patients were included between March 17 and April 18, 2020., Setting and Participants: All consecutive 201 patients hospitalized for COVID-19 (confirmed by reverse-transcriptase polymerase chain reaction methods) were included. All nondeceased patients had 30 days of follow-up and no patient was lost to follow-up., Methods: Demographic, clinical, and biological data and medications were collected. In-hospital mortality of patients treated or not by ACEI/ARB was analyzed using multivariate Cox models., Results: Mean age of the population was 86.3 (8.0) years, 62.7% of patients were institutionalized, 88.6% had dementia, and 53.5% had severe disability (activities of daily living [ADL] score <2). Sixty-three patients were treated with ACEI/ARB and 138 were not. Mean follow-up was 23.4 (10.0) days, 66 (33.8%) patients died after an average of 10.0 days (6.0). Lower mortality rate was observed in patients treated with ACEI/ARB compared with patients not treated with ARB or ACEI (22.2% [14] vs 37.7% [52], hazard ratio [HR] 0.54; 95% confidence interval 0.30-0.97; P = .03). In a multivariate Cox regression model including age, sex, ADL score, Charlson index, renal function, dyspnea, C-reactive protein, and white blood cell count, use of ACEI/ARB was significantly associated with lower in-hospital mortality (HR 0.52 (0.27-0.99), P = .048)., Conclusion and Implications: In very old subjects hospitalized in geriatric settings for COVID-19, mortality was significantly lower in subjects treated with ARB or ACEI before the onset of infection. The continuation of ACEI/ARB therapy should be encouraged during periods of coronavirus outbreak in older subjects., (Copyright © 2020 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Clostridioides difficile is an anaerobic Gram-positive bacterium that can produce the large clostridial toxins toxin A and toxin B, encoded within the pathogenicity locus (PaLoc). The PaLoc also encodes the sigma factor TcdR, which positively regulates toxin gene expression, and TcdC, which is a putative negative regulator of toxin expression. TcdC is proposed to be an anti-sigma factor; however, several studies failed to show an association between the tcdC genotype and toxin production. Consequently, the TcdC function is not yet fully understood. Previous studies have characterized TcdC as a membrane-associated protein with the ability to bind G-quadruplex structures. The binding to the DNA secondary structures is mediated through the oligonucleotide/oligosaccharide binding fold (OB-fold) domain present at the C terminus of the protein. This domain was previously also proposed to be responsible for the inhibitory effect on toxin gene expression, implicating a cytoplasmic localization of the OB-fold. In this study, we aimed to obtain topological information on the C terminus of TcdC and demonstrate that the C terminus of TcdC is located extracellularly. In addition, we show that the membrane association of TcdC is dependent on a membrane-proximal cysteine residue and that mutating this residue results in the release of TcdC from the bacterial cell. The extracellular location of TcdC is not compatible with the direct binding of the OB-fold domain to intracellular nucleic acid or protein targets and suggests a mechanism of action that is different from that of the characterized anti-sigma factors. IMPORTANCE The transcription of C. difficile toxins TcdA and TcdB is directed by the sigma factor TcdR. TcdC has been proposed to be an anti-sigma factor. The activity of TcdC has been mapped to its C terminus, and the N terminus serves as the membrane anchor. Acting as an anti-sigma factor requires a cytoplasmic localization of the C terminus of TcdC. Using cysteine accessibility analysis and a HiBiT-based system, we show that the TcdC C terminus is located extracellularly, which is incompatible with its role as anti-sigma factor. Furthermore, mutating a cysteine residue at position 51 resulted in the release of TcdC from the bacteria. The codon-optimized version of the HiBiT (HiBiT opt ) extracellular detection system is a valuable tool for topology determination of membrane proteins, increasing the range of systems available to tackle important aspects of C. difficile development., (Copyright © 2020 American Society for Microbiology.)

Introduction: The primary aim is to validate earlier suggested risk factors and to find new associated risk factors for (30-day) mortality after a hip fracture in the frail population. The secondary aim is to determine the factors associated with perioperative complications. At last we want to develop and validate a more specific 30-day mortality prediction tool compared with the Nottingham Hip Fracture Score. The 30-day mortality prediction can help inform surgical risk and guide shared decision-making among patients, family and physicians., Methods and Analysis: The study is designed as a prospective multicentre cohort study within the area of Rotterdam, the Netherlands starting from January 2018. All patients over 65 years of age, with an acute proximal hip fracture, are included. Treatment of patients will be by standard practice of care using the latest national and international guidelines. Inclusion will be continued at least until January 2021 and including at least 2500 patients. In this large cohort we hope to have sufficient strength and quality to identify risk factors of 30-day mortality and to compare them to known risk factors in literature. Moreover, we plan to develop and validate a 30-day mortality prediction tool, which identifies patients with a high probability of 30-day mortality., Ethics and Dissemination: Ethical approval for this protocol was given by the Ethics Committee of the Maasstad Hospital (TWOR). Patient data are stored anonymously using the Castor data management system. No external funding is used for this study. Results will be published in peer-reviewed publications and at international conferences., Trial Registration Number: NL8313., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Smoking during pregnancy increases the risk of morbidity and mortality of the mother and child. The inability of the unborn child to protect itself, raises the social and academic responsibility to protect the child from the harmful effects of smoking. Interventions including rewards (incentives) for lifestyle changes are an upcoming trend and can encourage women to quit smoking. However, these incentives can, as we will argue, also have negative consequences, for example the restriction of personal autonomy and encouragement of smoking to become eligible for participation. To prevent these negative consequences, we developed an ethical framework that enables to assess and address unwanted consequences of incentive-based interventions whereby moral permissibility can be evaluated., Aims and Methods: The possible adverse consequences of incentives were identified through an extensive literature search. Subsequently, we developed ethical criteria to identify these consequences based on the biomedical ethical principles of Beauchamp and Childress., Results: Our framework consists of 12 criteria. These criteria concern (1) effectiveness, (2) support of a healthy lifestyle, (3) motivational for the target population, (4) stimulating unhealthy behavior, (5) negative attitudes, (6) personal autonomy, (7) intrinsic motivation, (8) privacy, (9) fairness, (10) allocation of incentives, (11) cost-effectiveness, and (12) health inequity. Based on these criteria, the moral permissibility of potential interventions can be evaluated., Conclusions: Incentives for smoking cessation are a response to the responsibility to protect the unborn child. But these interventions might have possible adverse effects. This ethical framework aims to identify and address ethical pitfalls in order to avoid these adverse effects., Implications: Although various interventions to promote smoking cessation during pregnancy exist, many women still smoke during pregnancy. Interventions using incentives for smoking cessation during pregnancy are a promising and upcoming trend but can have unwanted consequences. This ethical framework helps to identify and address ethical pitfalls in order to avoid these adverse effects.It can be a practical tool in the development and evaluation of these interventions and in evaluating the moral permissibility of interventions using incentives for smoking cessation during pregnancy., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.)

Tumor associated macrophages (TAMs) are important components of the tumor microenvironment (TME). They are characterized by a remarkable functional plasticity, thereby mostly promoting cancer progression. Changes in immune cell metabolism are paramount for this functional adaptation. Here, we review the functional consequences of the metabolic programming of TAMs and the influence of local and systemic targeted therapies on the metabolic characteristics of the TME that shape the functional phenotype of the TAMs. Understanding these metabolic changes within the context of the cross-talk between the different components of the TME including the TAMs and the tumor cells is an essential step that can pave the way towards identifications of ways to improve responses to different treatments, to overcome resistance to treatments, tumor progression and reduce treatment-specific toxicity., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-1114). The series “Tumor Associated Macrophages in Solid Tumor: Friend or Foe” was commissioned by the editorial office without any funding or sponsorship. RTNM reports grants from Netherlands Cancer Foundation (KWF), during the conduct of the study; non-financial support from SOBI, outside the submitted work; In addition, RTNM has a patent Biomarkers for follicular thyroid carcinoma and methods of use issued. The authors have no other conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Objectives: Automated ultrasound of the breast has the advantage to have the whole breast scanned by technicians. Consequently, feedback to the radiologist about concurrent focal abnormalities (e.g., palpable lesions) is lost. To enable marking of patient- or physician-reported focal abnormalities, we aimed to develop skin markers that can be used without disturbing the interpretability of the image., Methods: Disk-shaped markers were casted out of silicone. In this IRB-approved prospective study, 16 patients were included with a mean age of 57 (39-85). In all patients, the same volume was imaged twice using an automated breast ultrasound system, once with and once without a marker in place. Nine radiologists from two medical centers filled scoring forms regarding image quality, image interpretation, and confidence in providing a diagnosis based on the images., Results: Marker adhesion was sufficient for automated scanning. Observer scores showed a significant shift in scores from excellent to good regarding diagnostic yield/image quality (χ 2 , 15.99, p < 0.01), and image noise (χ 2 , 21.20, p < 0.01) due to marker presence. In 93% of cases, the median score of observers "agree" with the statement that marker-induced noise did not influence image interpretability. Marker presence did not interfere with confidence in diagnosis (χ 2 , 6.00, p = 0.20)., Conclusion: Inexpensive, easy producible skin markers can be used for accurate lesion marking in automated ultrasound examinations of the breast while image interpretability is preserved. Any marker-induced noise and decreased image quality did not affect confidence in providing a diagnosis., Key Points: • The use of a skin marker enables the reporting radiologist to identify a location which a patient is concerned about. • The developed skin marker can be used for accurate breast lesion marking in ultrasound examinations.

Introduction: Since the implementation of long-term care insurance in 1995, various reforms have contributed to the development of the German nursing care system in order to meet the structural and financial needs of the growing number of people in need of care. The aim of this paper is to present an assessment of care consultants on past legislation, challenges encountered during their work and suggestions to improve the current care system., Methods: 14 semi-structured, face-to-face interviews were conducted with care consultants. All interviews were transcribed verbatim and a qualitative content analysis was performed., Results: Care consultants perceived tangible improvements with regard to the scope of benefits as a direct result of recent legislation changes. The use of these benefits, however, is limited due to an insufficient growth of care infrastructure. Particularly frequent legislation changes, unclear responsibilities and dissimilar regulations between federal states were seen as challenges., Discussion and Conclusion: Complex dependencies within the German nursing care system were identified and the necessity for a public discourse on themes such as self-responsibility, equity and a comprehensive (nationwide) care supply was underlined. A central information platform was proposed in order to concretely improve information about services available locally., (Copyright © 2020. Published by Elsevier GmbH.)