Risk Factors of In-Hospital Mortality in Patients Treated for Pneumonia at a Tertiary Care Centre in Switzerland.

BACKGROUND: Little is known about risk factors upon hospital admission that are associated with in-hospital death of patients hospitalized for bacterial pneumonia. Identifying such factors may help to optimize the treatment and lower the mortality of these patients. OBJECTIVES: The aim of the study was to characterize baseline characteristics of patients hospitalized for bacterial pneumonia in Switzerland and to identify risk factors associated with all-cause in-hospital mortality. METHODS: Routinely collected electronic health record data of patients discharged from a large Swiss tertiary care hospital between August 2009 and 2017 were analysed. Potential risk factors such as patient demographics, physical examination findings, vital signs, laboratory results, and comorbidities were considered within ±24 h of admission. Univariable and multivariable logistic regression models identified risk factors for in-hospital death. The area under the receiver operating characteristic (ROC) curve was used to compare the identified factors to existing pneumonia scoring systems. RESULTS: Out of 1,781 hospital stays with initial and main diagnosis of bacterial pneumonia, 85 patients (4.85%) died (33.9% female, median age 62.3 years [interquartile range, 52-75]). Age, low systolic blood pressure, underweight, a missing value for body mass index, decreased haemoglobin level, raised C-reactive protein, high urea, high lactate dehydrogenase, concomitant pleural effusion, and cancer were independently associated with in-hospital death. The area under the ROC curve was 0.89 for the multivariable model containing the identified predictors. CONCLUSIONS: Our data are consistent with previous trials characterizing patients hospitalized for pneumonia. Additionally, we identified new and independent risk factors associated with in-hospital death among patients treated for bacterial pneumonia. Findings need to be further validated in larger multicentre cohorts.

The TransFLUas influenza transmission study in acute healthcare - recruitment rates and protocol adherence in healthcare workers and inpatients.

BACKGROUND: Detailed knowledge about viral respiratory disease transmission dynamics within healthcare institutions is essential for effective infection control policy and practice. In the quest to study viral transmission pathways, we aimed to investigate recruitment rates and adherence of healthcare workers (HCWs) and hospital inpatients with a study protocol that involves prospective surveillance based on daily mid-turbinate nasal swabs and illness diaries. METHODS: Single center prospective surveillance of patients and HCWs in three different hospital departments of a tertiary care center during an entire influenza season in Switzerland. Inpatients and acute care HCWs were asked to provide mid-turbinate nasal swabs and illness diaries on a daily basis. Study protocol adherence and recruitment rates were the primary outcomes of interest. RESULTS: A total 251 participants (59 (23.5%) health care workers and 192 (76.5%) inpatients) were recruited from three different hospital wards. Recruitment rates differed between HCWs (62.1% of eligible HCWs) and inpatients (32.5%; P < 0.001), but not within HCWs (P = 0.185) or inpatients (P = 0.301) of the three departments. The total number of study-days was 7874; 2321 (29.5%) for inpatients and 5553 (70.5%) for HCWs. HCWs were followed for a median of 96 days (range, 71-96 days) and inpatients for 8 days (range, 3-77 days). HCWs provided swabs on 73% (range, 0-100%) of study days, and diaries on 77% (range 0-100%). Inpatients provided swabs and diaries for 83% (range, 0-100%) of days in hospital. In HCWs, increasing age, working in internal medicine and longer duration of total study participation were positively associated with the proportion of swabs and diaries collected. Adherence to the study protocol was significantly lower in physicians as compared to nurses for both swabs (P = 0.042) and diaries (P = 0.033). In inpatients, no association between demographic factors and adherence was detected. Conclusions Prospective surveillance of respiratory viral disease was feasible in a cohort of inpatients and HCWs over an entire influenza season, both in terms of recruitment rates and adherence to a study protocol that included daily specimen collection and illness diaries. TRIAL REGISTRATION: clinicaltrials.gov NCT02478905 . Date of registration June 23, 2015.

Basal mTORC2 activity and expression of its components display diurnal variation in mouse perivascular adipose tissue.

In adipose tissue mTOR complex 2 (mTORC2) contributes to the regulation of glucose/lipid metabolism and inflammatory molecule expression. Both processes display diurnal variations during the course of the day. RICTOR and mSIN1 are unique and essential components of mTORC2, which is activated by growth factors including insulin. To assess whether mTORC2 components display diurnal variations, we analyzed steady state mRNA expression levels of Rictor, mSin1, and mTor in various adipose tissues during a 24 h period. Diurnally regulated expression of Rictor was detected in brown adipose tissues displaying highest mRNA expression levels at the beginning of the 12 h light period (zeitgeber time 2, ZT2). Gene expression patterns of mSin1 and mTor displayed a similar diurnal regulation as Rictor in PVAT while smaller changes were detected for these genes in aorta during the course of the day. Basal mTORC2 activity was measured by phosphorylation of protein kinase C (PKC) α at serine 657 was higher at ZT14 as compared with ZT2 in PVAT. In line, gene expression of inflammatory molecules nitric oxide synthase 2 and tumor necrosis factor α was lower at ZT 14 compared to ZT2. Our findings provide evidence for a diurnal regulation of expression of mTORC2 components and activity. Hence, mTORC2 is possibly an integral part of diurnally regulated signaling pathways in PVAT and possibly in other adipose tissues.

Tracing the decision-making process of physicians with a Decision Process Matrix.

BACKGROUND: Decision-making processes in a medical setting are complex, dynamic and under time pressure, often with serious consequences for a patient's condition. OBJECTIVE: The principal aim of the present study was to trace and map the individual diagnostic process of real medical cases using a Decision Process Matrix [DPM]). METHODS: The naturalistic decision-making process of 11 residents and a total of 55 medical cases were recorded in an emergency department, and a DPM was drawn up according to a semi-structured technique following four steps: 1) observing and recording relevant information throughout the entire diagnostic process, 2) assessing options in terms of suspected diagnoses, 3) drawing up an initial version of the DPM, and 4) verifying the DPM, while adding the confidence ratings. RESULTS: The DPM comprised an average of 3.2 suspected diagnoses and 7.9 information units (cues). The following three-phase pattern could be observed: option generation, option verification, and final diagnosis determination. Residents strove for the highest possible level of confidence before making the final diagnoses (in two-thirds of the medical cases with a rating of practically certain) or excluding suspected diagnoses (with practically impossible in half of the cases). DISCUSSION: The following challenges have to be addressed in the future: real-time capturing of emerging suspected diagnoses in the memory of the physician, definition of meaningful information units, and a more contemporary measurement of confidence. CONCLUSIONS: DPM is a useful tool for tracing real and individual diagnostic processes. The methodological approach with DPM allows further investigations into the underlying cognitive diagnostic processes on a theoretical level and improvement of individual clinical reasoning skills in practice.

Hypoxia potentiates tumor necrosis factor-α induced expression of inducible nitric oxide synthase and cyclooxygenase-2 in white and brown adipocytes.

Obesity involves hypoxic adipose tissue and low-grade chronic inflammation. We investigated the impact of hypoxia on inflammatory response to TNF-α in white and brown adipocytes. In response to TNF-α, the expression of the inducible enzymes iNOS and COX-2 was prominently and selectively potentiated during hypoxia while only moderately under normoxia. Levels of their products, nitrite and prostaglandinE2 were elevated accordingly. NS398, a selective COX-2 inhibitor, reduced nitrite levels. The expression of PGC-1α, a transcriptional co-activator involved in mitochondrial biogenesis, and PPARγ, a transcription factor involved in adipocyte homeostasis, was reduced by TNF-α during hypoxia. These results suggest that hypoxia potentiates the inflammatory response by TNF-α in both white and brown adipocytes and downregulates the transcription factors involved in adipocyte function.

[Competences in telemedicine are essential]. / Kompetenzen in der Telemedizin sind essentiell.

The measurement and collection of health and fitness data as well as the telemedicine consultation supports the autonomy and self-determination of the responsible citizen concerning his health issues and promotes patient empowerment. However the patient is often over extended by an increasing and extensive data and information overload. He needs the help and the advice of a trustworthy doctor for guidance. While telemedical consultation, care or intervention is carried out, the telemedicine application represents a favored option and provides an immediate consequence of action for the patient's health issue. The quality stands and falls with training, continuing education and in particular with the telemedical expertise of the doctors involved

[Swiss recommendations for the check-up in the doctor's office]. / Schweizer Empfehlungen für den Check-up in der Arztpraxis.

Prevention and screening of diseases belong to the role of each primary care physician. Recommendations have been developed in the EviPrev programme, which brings together members of all five academic ambulatory general internal medicine centers in Switzerland (Lausanne, Bern, Geneva, Basel and Zürich). Several questions must be addressed before realising a prevention intervention: Do we have data demonstrating that early intervention or detection is effective? What are the efficacy and adverse effects of the intervention? What is the efficiency (cost-effectiveness) of the intervention? What are the patient's preferences concerning the intervention and its consequences? The recommendations aim at answering these questions independently, taking into account the Swiss context and integrating the patient's perspective in a shared decision-making encounter.

Rictor in perivascular adipose tissue controls vascular function by regulating inflammatory molecule expression.

OBJECTIVE: Perivascular adipose tissue (PVAT) wraps blood vessels and modulates vasoreactivity by secretion of vasoactive molecules. Mammalian target of rapamycin complex 2 (mTORC2) has been shown to control inflammation and is expressed in adipose tissue. In this study, we investigated whether adipose-specific deletion of rictor and thereby inactivation of mTORC2 in PVAT may modulate vascular function by increasing inflammation in PVAT. APPROACH AND RESULTS: Rictor, an essential mTORC2 component, was deleted specifically in mouse adipose tissue (rictor(ad-/-)). Phosphorylation of mTORC2 downstream target Akt at Serine 473 was reduced in PVAT from rictor(ad-/-) mice but unaffected in aortic tissue. Ex vivo functional analysis of thoracic aortae revealed increased contractions and impaired dilation in rings with PVAT from rictor(ad-/-) mice. Adipose rictor knockout increased gene expression and protein release of interleukin-6, macrophage inflammatory protein-1α, and tumor necrosis factor-α in PVAT as shown by quantitative real-time polymerase chain reaction and Bioplex analysis for the cytokines in the conditioned media, respectively. Moreover, gene and protein expression of inducible nitric oxide synthase was upregulated without affecting macrophage infiltration in PVAT from rictor(ad-/-) mice. Inhibition of inducible nitric oxide synthase normalized vascular reactivity in aortic rings from rictor(ad-/-) mice with no effect in rictor(fl/fl) mice. Interestingly, in perivascular and epididymal adipose depots, high-fat diet feeding induced downregulation of rictor gene expression. CONCLUSIONS: Here, we identify mTORC2 as a critical regulator of PVAT-directed protection of normal vascular tone. Modulation of mTORC2 activity in adipose tissue may be a potential therapeutic approach for inflammation-related vascular damage.

The lower quality of preventive care among forced migrants in a country with universal healthcare coverage.

OBJECTIVE: To assess the association between socio-demographic factors and the quality of preventive care and chronic care of cardiovascular (CV) risk factors in a country with universal health care coverage. METHODS: Our retrospective cohort assessed a random sample of 966 patients aged 50-80years followed over 2years (2005-2006) in 4 Swiss university primary care settings (Basel/Geneva/Lausanne/Zürich). We used RAND's Quality Assessment Tools indicators and examined recommended preventive care among different socio-demographic subgroups. RESULTS: Overall patients received 69.6% of recommended preventive care. Preventive care indicators were more likely to be met among men (72.8% vs. 65.4%; p<0.001), younger patients (from 71.0% at 50-59years to 66.7% at 70-80years, p for trend=0.03) and Swiss patients (71.1% vs. 62.7% in forced migrants; p=0.001). This latter difference remained in multivariate analysis adjusted for gender, age, civil status and occupation (OR 0.68; 95% CI 0.54-0.86). Forced migrants had lower scores for physical examination and breast and colon cancer screening (all p≤0.02). No major differences were seen for chronic care of CV risk factors. CONCLUSION: Despite universal healthcare coverage, forced migrants receive less preventive care than Swiss patients in university primary care settings. Greater attention should be paid to forced migrants for preventive care.

Clinically relevant quality measures for risk factor control in primary care: a retrospective cohort study.

BACKGROUND: Assessment of the proportion of patients with well controlled cardiovascular risk factors underestimates the proportion of patients receiving high quality of care. Evaluating whether physicians respond appropriately to poor risk factor control gives a different picture of quality of care. We assessed physician response to control cardiovascular risk factors, as well as markers of potential overtreatment in Switzerland, a country with universal healthcare coverage but without systematic quality monitoring, annual report cards on quality of care or financial incentives to improve quality. METHODS: We performed a retrospective cohort study of 1002 randomly selected patients aged 50-80 years from four university primary care settings in Switzerland. For hypertension, dyslipidemia and diabetes mellitus, we first measured proportions in control, then assessed therapy modifications among those in poor control. "Appropriate clinical action" was defined as a therapy modification or return to control without therapy modification within 12 months among patients with baseline poor control. Potential overtreatment of these conditions was defined as intensive treatment among low-risk patients with optimal target values. RESULTS: 20% of patients with hypertension, 41% with dyslipidemia and 36% with diabetes mellitus were in control at baseline. When appropriate clinical action in response to poor control was integrated into measuring quality of care, 52 to 55% had appropriate quality of care. Over 12 months, therapy of 61% of patients with baseline poor control was modified for hypertension, 33% for dyslipidemia, and 85% for diabetes mellitus. Increases in number of drug classes (28-51%) and in drug doses (10-61%) were the most common therapy modifications. Patients with target organ damage and higher baseline values were more likely to have appropriate clinical action. We found low rates of potential overtreatment with 2% for hypertension, 3% for diabetes mellitus and 3-6% for dyslipidemia. CONCLUSIONS: In primary care, evaluating whether physicians respond appropriately to poor risk factor control, in addition to assessing proportions in control, provide a broader view of the quality of care than relying solely on measures of proportions in control. Such measures could be more clinically relevant and acceptable to physicians than simply reporting levels of control.

Do Positive Psychosocial Factors Contribute to the Prediction of Coronary Artery Disease? A UK Biobank-Based Machine Learning Approach.

AIM: Most prediction models for coronary artery disease (CAD) compile biomedical and behavioural risk factors, using linear multivariate models. This study explored the potential of integrating positive psychosocial factors (PPFs), including happiness, satisfaction with life, and social support, into conventional and machine learning-based CAD prediction models. METHODS: We included UK Biobank participants without CAD at baseline. First, we estimated associations of individual PPFs with subsequent acute myocardial infarction (AMI) and chronic ischaemic heart disease (CIHD) using logistic regression. Then, we compared the performances of logistic regression and eXtreme Gradient Boosting (XGBoost) prediction models when adding PPFs as predictors to the Framingham Risk Score (FRS). RESULTS: Based on a sample size between 160,226 and 441,419 of UK Biobank participants, happiness, satisfaction with health and life, and participation in social activities were linked to lower AMI and CIHD risk (all p-for-trend ≤ 0.04), while social support was not. In a validation sample, adding PPFs to the FRS using logistic regression and XGBoost prediction models improved neither AMI (AUC change: 0.02% and 0.90%, respectively) nor CIHD (AUC change: -1.10% and -0.88%, respectively) prediction. CONCLUSIONS: PPFs were individually linked to CAD risk, in line with previous studies, and as reflected by the new European Society of Cardiology guidelines on cardiovascular disease prevention. However, including available PPFs in CAD-prediction models did not improve prediction compared to the FRS alone. Future studies should explore whether PPFs may act as CAD-risk modifiers, especially if the individual's risk is close to a decision threshold.

Positive psychosocial factors like happiness, satisfaction with health and life, social support and social activities can aid in successfully managing life's challenges, stress and disease. Consequently, they may help lower the risk and progression of cardiovascular disease. The study confirmed that positive psychosocial factors were associated with lower risks of myocardial infarction and chronic ischaemic heart disease. These findings underscore the role of positive psychosocial factors as risk modifiers for coronary artery disease, as recom-mended by the 2021 ESC Guidelines on cardiovascular disease prevention. This means that the individual risk of getting a coronary artery disease can be shifted to the next lower risk category by higher levels of happiness, satisfaction with health and life, and social support.

Sprouty2 expression controls endothelial monolayer integrity and quiescence.

Vascular integrity is fundamental to the formation of mature blood vessels and depends on a functional, quiescent endothelial monolayer. However, how endothelial cells enter and maintain quiescence in the presence of angiogenic factors is still poorly understood. Here we identify the fibroblast growth factor (FGF) antagonist Sprouty2 (Spry2) as a key player in mediating endothelial quiescence and barrier integrity in mouse aortic endothelial cells (MAECs): Spry2 knockout MAECs show spindle-like shapes and are incapable of forming a functional, impermeable endothelial monolayer in the presence of FGF2. Whereas dense wild type cells exhibit contact inhibition and stop to proliferate, Spry2 knockout MAECs remain responsive to FGF2 and continue to proliferate even at high cell densities. Importantly, the anti-proliferative effect of Spry2 is absent in sparsely plated cells. This cell density-dependent Spry2 function correlates with highly increased Spry2 expression in confluent wild type MAECs. Spry2 protein expression is barely detectable in single cells but steadily increases in cells growing to high cell densities, with hypoxia being one contributing factor. At confluence, Spry2 expression correlates with intact cell-cell contacts, whereas disruption of cell-cell contacts by EGTA, TNFα and thrombin decreases Spry2 protein expression. In confluent cells, high Spry2 levels correlate with decreased extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation. In contrast, dense Spry2 knockout MAECs exhibit enhanced signaling by Erk1/2. Moreover, inhibiting Erk1/2 activity in Spry2 knockout cells restores wild type cobblestone monolayer morphology. This study thus reveals a novel Spry2 function, which mediates endothelial contact inhibition and barrier integrity.

Intravenous iron for the treatment of fatigue in nonanemic, premenopausal women with low serum ferritin concentration.

This is the first study to investigate the efficacy of intravenous iron in treating fatigue in nonanemic patients with low serum ferritin concentration. In a randomized, double-blinded, placebo-controlled study, 90 premenopausal women presenting with fatigue, serum ferritin ≤ 50 ng/mL, and hemoglobin ≥ 120 g/L were randomized to receive either 800 mg of intravenous iron (III)-hydroxide sucrose or intravenous placebo. Fatigue and serum iron status were assessed at baseline and after 6 and 12 weeks. Median fatigue at baseline was 4.5 (on a 0-10 scale). Fatigue decreased during the initial 6 weeks by 1.1 in the iron group compared with 0.7 in the placebo group (P = .07). Efficacy of iron was bound to depleted iron stores: In patients with baseline serum ferritin ≤ 15 ng/mL, fatigue decreased by 1.8 in the iron group compared with 0.4 in the placebo group (P = .005), and 82% of iron-treated compared with 47% of placebo-treated patients reported improved fatigue (P = .03). Drug-associated adverse events were observed in 21% of iron-treated patients and in 7% of placebo-treated patients (P = .05); none of these events was serious. Intravenous administration of iron improved fatigue in iron-deficient, nonanemic women with a good safety and tolerability profile. The efficacy of intravenous iron was bound to a serum ferritin concentration ≤ 15 ng/mL. This study was registered at the International Standard Randomized Controlled Trial Number Register (www.isrctn.org) as ISRCTN78430425.

When the cause of death does not exist: time for the WHO to close the ICD classification gap for Medical Aid in Dying.

Medical aid in dying (MAID) is a highly controversial ethical issue in the global medical community. Unfortunately, the International Classification of Diseases (ICD) of the World Health Organization (WHO) lacks coding for MAID. Therefore, no robust data adequately monitors worldwide trends that include information on diseases and conditions underlying the patients' request for assisted dying ("MAID gap"). Countries with legalised MAID observe substantial increases in cases, and likely additional countries will allow MAID in the near future. Hence, we encourage the WHO to create specific ICD codes for MAID. According to internationally established practices, a revised classification would require separate MAID-codes for (1) assisted suicide and (2) voluntary active euthanasia including supplemental codings of diseases, clusters of symptoms and function-oriented categories. By addressing these concerns, the WHO could close the "MAID gap" with new codes providing urgently necessary insights to society, public health decision-makers and regulators on this comparatively new social and medical ethical phenomenon. Search strategy and selection criteria: Data for this Viewpoint were identified by searches of MEDLINE, PubMed, and references from relevant articles using the search terms "Medical Aid in Dying", "Assisted Dying", "Assisted suicide", "Voluntary active euthanasia", "End of life decisions" and "Cause of death statistics". Only articles and sources published in English between 1997 and 2023 were included."

Clinical practice guidelines for cardiovascular disease: how is depression addressed? Protocol for a systematic review.

INTRODUCTION: Depression frequently affects patients with cardiovascular disease (CVD). When these conditions co-occur, outcomes such as quality of life and life expectancy worsen. In everyday practice, this specific and prevalent disease-disease interaction complicates patient management. Clinical practice guidelines (CPGs) aim to provide the best available advice for clinical decision-making to improve patient care. This study will aim to evaluate how CPGs specifically address depression in patients with CVD, and whether they provide any operational guidance for screening and management of depression in the primary care and outpatient setting. METHODS AND ANALYSIS: We will conduct a systematic review of CPGs on CVD management published from 2012 to 2023. A broad literature search for guidelines will be performed through electronic medical databases, grey literature search tools, and websites of national and professional medical organisations.Based on the inclusion criteria, two independent reviewers will evaluate eligible guidelines for screening and management recommendations on depression in patients with CVD. Additional points to be evaluated will be any mention of drug-drug or drug-disease interactions, other aspects of specific relevance to treating physicians, as well as general information on mental health. We will assess the quality of CPGs with a recommendation regarding depression in CVD patients using the Appraisal of Guidelines for Research and Evaluation II. ETHICS AND DISSEMINATION: As this systematic review is based on available published data, ethics approval and consent are not applicable. Our intent is that our results will be published in a peer-reviewed journal, presented at international scientific meetings, and distributed to healthcare providers. PROSPERO REGISTRATION NUMBER: CRD42022384152.

A Telemedicine Center Reduces the Comprehensive Carbon Footprint in Primary Care: A Monocenter, Retrospective Study.

INTRODUCTION: Telemedicine reduces greenhouse gas emissions (CO2eq); however, results of studies vary extremely in dependence of the setting. This is the first study to focus on effects of telemedicine on CO2 imprint of primary care. METHODS: We conducted a comprehensive retrospective study to analyze total CO2eq emissions of kilometers (km) saved by telemedical consultations. We categorized prevented and provoked patient journeys, including pharmacy visits. We calculated CO2eq emission savings through primary care telemedical consultations in comparison to those that would have occurred without telemedicine. We used the comprehensive footprint approach, including all telemedical cases and the CO2eq emissions by the telemedicine center infrastructure. In order to determine the net ratio of CO2eq emissions avoided by the telemedical center, we calculated the emissions associated with the provision of telemedical consultations (including also the total consumption of physicians' workstations) and subtracted them from the total of avoided CO2eq emissions. Furthermore, we also considered patient cases in our calculation that needed to have an in-person visit after the telemedical consultation. We calculated the savings taking into account the source of the consumed energy (renewable or not). RESULTS: 433 890 telemedical consultations overall helped save 1 800 391 km in travel. On average, 1 telemedical consultation saved 4.15 km of individual transport and consumed 0.15 kWh. We detected savings in almost every cluster of patients. After subtracting the CO2eq emissions caused by the telemedical center, the data reveal savings of 247.1 net tons of CO2eq emissions in total and of 0.57 kg CO2eq per telemedical consultation. The comprehensive footprint approach thus indicated a reduced footprint due to telemedicine in primary care. DISCUSSION: Integrating a telemedical center into the health care system reduces the CO2 footprint of primary care medicine; this is true even in a densely populated country with little use of cars like Switzerland. The insight of this study complements previous studies that focused on narrower aspects of telemedical consultations.

Translational longevity medicine: a Swiss perspective in an ageing country.

Breakthroughs in medical research in the last century have led to a significant extension of the human lifespan, resulting in a shift towards an elderly population worldwide. Due to the ongoing progress of global development towards elevated standards of living, this study specifically examines Switzerland as a representative nation to explore the socioeconomic and healthcare ramifications associated with an ageing population, thereby highlighting the tangible impact experienced in this context. Beyond the exhaustion of pension funds and medical budgets, by reviewing the literature and analysing publicly available data, we observe a "Swiss Japanification". Old age is associated with late-life comorbidities and an increasing proportion of time spent in poor health. To address these problems, a paradigm shift in medical practice is needed to improve health rather than respond to existing diseases. Basic ageing research is gaining momentum to be translated into therapeutic interventions and provides machine learning tools driving longevity medicine. We propose that research focus on closing the translational gap between the molecular mechanisms of ageing and a more prevention-based medicine, which would help people age better and prevent late-life chronic diseases.

ICD-Based Cause of Death Statistics Fail to Provide Reliable Data for Medical Aid in Dying.

Objectives: To evaluate the most recent developments of medical aid in dying (MAID) in Switzerland and to test the reliability of reporting this phenomenon in cause of death statistics. Methods: By reviewing the MAID cases between 2018 and 2020, we compared the diseases and conditions underlying MAID reported by the ICD-based statistics provided by the Swiss Federal Statistical Office (FSO, n = 3,623) and those provided by the largest right-to-die organization EXIT (n = 2,680). Results: EXIT reported the motivations underlying the desire for death in a mixture of disease-specific and symptom-oriented categories; the latter including, for example, multimorbidity (26% of cases), and chronic pain (8%). Symptom-oriented categories were not included in the ICD-based FSO statistics. This led to the fact that the distribution of the diseases/conditions underlying MAID differed in 30%-40% of cases between both statistics. Conclusion: In order to reliably follow developments and trends in MAID, the diseases/conditions underlying the wish to die must be accurately recorded. Current methods of data collection using the ICD classification do not capture this information thoroughly ("MAID gap"). Newly created ICD codes for MAID must include both disease-specific and symptom-oriented categories.

Loss of pim1 imposes a hyperadhesive phenotype on endothelial cells.

BACKGROUND: PIM1 is a constitutively active serine-threonine kinase regulating cell survival and proliferation. Increased PIM1 expression has been correlated with cancer metastasis by facilitating migration and anti-adhesion. Endothelial cells play a pivotal role in these processes by contributing a barrier to the blood stream. Here, we investigated whether PIM1 regulates mouse aortic endothelial cell (MAEC) monolayer integrity. METHODS: Pim1-/-MAEC were isolated from Pim1 knockout mice and used in trypsinization-, wound closure assays, electrical cell-substrate sensing, immunostaining, cDNA transfection and as RNA source for microarray analysis. RESULTS: Pim1-/-MAEC displayed decreased migration, slowed cell detachment and increased electrical resistance across the endothelial monolayer. Reintroduction of Pim1- cDNA into Pim1-/-MAEC significantly restored wildtype adhesive characteristics. Pim1-/--MAEC displayed enhanced focal adhesion and adherens junction structures containing vinculin and ß-catenin, respectively. Junctional molecules such as Cadherin 13 and matrix components such as Collagen 6a3 were highly upregulated in Pim1-/- cells. Intriguingly, extracellular matrix deposited by Pim1-/- cells alone was sufficient to induce the hyperadhesive phenotype in wildtype endothelial cells. CONCLUSION: Loss of Pim1 induces a strong adhesive phenotype by enhancing endothelial cell-cell and cell-matrix adhesion by the deposition of a specific extracellular matrix. Targeting PIM1 function therefore might be important to promote endothelial barrier integrity.

Nuclear PIM1 confers resistance to rapamycin-impaired endothelial proliferation.

The PIM serine/threonine kinases and the mTOR/AKT pathway integrate growth factor signaling and promote cell proliferation and survival. They both share phosphorylation targets and have overlapping functions, which can partially substitute for each other. In cancer cells PIM kinases have been reported to produce resistance to mTOR inhibition by rapamycin. Tumor growth depends highly on blood vessel infiltration into the malignant tissue and therefore on endothelial cell proliferation. We therefore investigated how the PIM1 kinase modulates growth inhibitory effects of rapamycin in mouse aortic endothelial cells (MAEC). We found that proliferation of MAEC lacking Pim1 was significantly more sensitive to rapamycin inhibition, compared to wildtype cells. Inhibition of mTOR and AKT in normal MAEC resulted in significantly elevated PIM1 protein levels in the cytosol and in the nucleus. We observed that truncation of the C-terminal part of Pim1 beyond Ser 276 resulted in almost exclusive nuclear localization of the protein. Re-expression of this Pim1 deletion mutant significantly increased the proliferation of Pim1(-/-) cells when compared to expression of the wildtype Pim1 cDNA. Finally, overexpression of the nuclear localization mutant and the wildtype Pim1 resulted in complete resistance to growth inhibition by rapamycin. Thus, mTOR inhibition-induced nuclear accumulation of PIM1 or expression of a nuclear C-terminal PIM1 truncation mutant is sufficient to increase endothelial cell proliferation, suggesting that nuclear localization of PIM1 is important for resistance of MAEC to rapamycin-mediated inhibition of proliferation.