Body mass index and Mini Nutritional Assessment-Short Form as predictors of in-geriatric hospital mortality in older adults with COVID-19.

BACKGROUND & AIMS: Overweight and obesity have been consistently reported to carry an increased risk for poorer outcomes in coronavirus disease 2019 (COVID-19) in adults. Existing reports mainly focus on in-hospital and intensive care unit mortality in patient cohorts usually not representative of the population with the highest mortality, i.e. the very old and frail patients. Accordingly, little is known about the risk patterns related to body mass and nutrition in very old patients. Our aim was to assess the relationship between body mass index (BMI), nutritional status and in-geriatric hospital mortality among geriatric patients treated for COVID-19. As a reference, the analyses were performed also in patients treated for other diagnoses than COVID-19. METHODS: We analyzed up to 10,031 geriatric patients with a median age of 83 years of which 1409 (14%) were hospitalized for COVID-19 and 8622 (86%) for other diagnoses in seven geriatric hospitals in the Stockholm region, Sweden during March 2020-January 2021. Data were available in electronic hospital records. The associations between 1) BMI and 2) nutritional status, assessed using the Mini-Nutritional Assessment - Short Form (MNA-SF) scale, and short-term in-geriatric hospital mortality were analyzed using logistic regression. RESULTS: After adjusting for age, sex, comorbidity, polypharmacy, frailty and the wave of the pandemic (first vs. second), underweight defined as BMI<18.5 increased the risk of in-hospital mortality in COVID-19 patients (odds ratio [OR] = 2.30; confidence interval [CI] = 1.17-4.31). Overweight and obesity were not associated with in-hospital mortality. Malnutrition; i.e. MNA-SF 0-7 points, increased the risk of in-hospital mortality in patients treated for COVID-19 (OR = 2.03; CI = 1.16-3.68) and other causes (OR = 6.01; CI = 2.73-15.91). CONCLUSIONS: Our results indicate that obesity is not a risk factor for very old patients with COVID-19, but emphasize the role of underweight and malnutrition for in-hospital mortality in geriatric patients with COVID-19.

Detecting long-range interactions between migrating cells.

Chemotaxis enables cells to systematically approach distant targets that emit a diffusible guiding substance. However, the visual observation of an encounter between a cell and a target does not necessarily indicate the presence of a chemotactic approach mechanism, as even a blindly migrating cell can come across a target by chance. To distinguish between the chemotactic approach and blind migration, we present an objective method that is based on the analysis of time-lapse recorded cell migration trajectories: For each movement step of a cell relative to the position of a potential target, we compute a p value that quantifies the likelihood of the movement direction under the null-hypothesis of blind migration. The resulting distribution of p values, pooled over all recorded cell trajectories, is then compared to an ensemble of reference distributions in which the positions of targets are randomized. First, we validate our method with simulated data, demonstrating that it reliably detects the presence or absence of remote cell-cell interactions. In a second step, we apply the method to data from three-dimensional collagen gels, interspersed with highly migratory natural killer (NK) cells that were derived from two different human donors. We find for one of the donors an attractive interaction between the NK cells, pointing to a cooperative behavior of these immune cells. When adding nearly stationary K562 tumor cells to the system, we find a repulsive interaction between K562 and NK cells for one of the donors. By contrast, we find attractive interactions between NK cells and an IL-15-secreting variant of K562 tumor cells. We therefore speculate that NK cells find wild-type tumor cells only by chance, but are programmed to leave a target quickly after a close encounter. We provide a freely available Python implementation of our p value method that can serve as a general tool for detecting long-range interactions in collective systems of self-driven agents.

Prediction of individual prosthesis size for valve-sparing aortic root reconstruction based on geometric features.

Valve-sparing aortic root reconstruction is an up- and-coming approach for patients suffering from aortic valve insufficiencies which promises to significantly reduce complications. However, the success of the treatment strongly depends on the challenging task of choosing the correct size of the prosthesis, for which, up to now, surgeons solely have to rely on their experience. Here, we present a novel machine learning based approach, which might make it possible to predict the size of the prosthesis from pre-operatively acquired ultrasound images. We utilize support vector regression to train a prediction model on three geometric features extracted from the ultrasound data. In order to evaluate the accuracy and robustness of our approach we created a large data base of porcine aortic root geometries in a healthy state and an artificially dilated state. Our results indicate that prediction of correct prosthesis sizes is feasible. Furthermore, they suggest that it is crucial that the training data set faithfully represents the diversity of aortic root geometries.

Hypophysitis caused by ipilimumab in cancer patients: hormone replacement or immunosuppressive therapy.

Ipilimumab is besides the BRAF inhibitor vemurafenib the first officially approved medical treatment for metastatic melanoma, which results in improved survival. Ipilimumab leads to a release of a CTLA4-mediated inhibition of T-cell immunoreactions. Therefore, patients may also suffer from immune-related adverse events affecting different organs, which are typically treated by high-dose corticosteroids. Ipilimumab-induced hypophysitis (iH) has been reported in up to 17% of melanoma patients in clinical trials.Here we present 5 patients with metastatic melanoma and 2 patients with prostate cancer who developed hypophysitis after ipilimumab therapy. Patients were treated by high-dose corticosteroid therapy resulting in the resolution of local inflammation but not of pituitary deficiencies. Partial or complete hypopituitarism remained in all patients. Pharmacotherapy with high-dose corticosteroids caused complications in 5 patients, necessitating hospitalization in 4. 2 of the 3 patients with progressive disease died, while 3 patients had stable disease and 1 patient showed tumor regression after discontinuation of ipilimumab.In summary, with regard to safety and simplicity of hormonal substitution therapy we have to scrutinize high-dose corticosteroid therapy, though it only improves inflammation but not neuro-endocrine function and may cause further morbidity. Regression of the tumor depends on the ipilimumab-mediated immune events, in which high-dose and long-term corticosteroid therapy for iH appears to be counter-intuitive. Herein, we discuss screening and the diagnostic as well as therapeutic management of iH in metastatic cancer patients from an endocrinologic perspective.

Change in the fatty acid pattern of erythrocyte membrane phospholipids after oral supplementation of specific fatty acids in patients with gastrointestinal diseases.

BACKGROUND/OBJECTIVES: The fatty acid pattern of membrane phospholipids is suggested to affect membrane fluidity and epithelial barrier function as a result of membrane fatty acid unsaturation. The incorporation of n-3 polyunsaturated fatty acids (PUFAs) into membrane phospholipids may diminish inflammatory potential in patients with gastrointestinal diseases. The aim of this study was to improve the fatty acid profile of erythrocyte membrane phospholipids after oral supplementation of specific fatty acids in patients with maldigestion and/or malabsorption. SUBJECTS/METHODS: We conducted a randomized, double-blind, controlled trial. A total of 48 patients with gastrointestinal diseases received either fat-soluble vitamins A,D,E,K (ADEK) or ADEK plus fatty acids alpha-linolenic acid (ALA), docosahexaenoic acid (DHA) and medium-chain triglycerides (FA-ADEK) for 12 weeks. The fatty acid profile of erythrocyte membrane phospholipids, dietary intake, plasma antioxidant vitamins and serum gamma-glutamyl transferase (GGT) were evaluated at baseline, 8 and 12 weeks after supplementation. RESULTS: Supplementation with FA-ADEK increased ALA, DHA and eicosapentaenoic acid (EPA) concentrations of erythrocyte membrane phospholipids by 0.040, 1.419 and 0.159%, respectively, compared with ADEK supplementation (-0.007, 0.151 and 0.002%, respectively) after 12 weeks (all P

Fluctuations of cytoskeleton-bound microbeads--the effect of bead-receptor binding dynamics.

The cytoskeleton (CSK) of living cells is a crosslinked fiber network, subject to ongoing biochemical remodeling processes that can be visualized by tracking the spontaneous motion of CSK-bound microbeads. The bead motion is characterized by anomalous diffusion with a power-law time evolution of the mean square displacement (MSD), and can be described as a stochastic transport process with apparent diffusivity D and power-law exponent ß: MSD ∼ D (t/t(0))(ß). Here we studied whether D and ß change with the time that has passed after the initial bead-cell contact, and whether they are sensitive to bead coating (fibronectin, integrin antibodies, poly-L-lysine, albumin) and bead size (0.5-4.5 µm). The measurements are interpreted in the framework of a simple model that describes the bead as an overdamped particle coupled to the fluctuating CSK network by an elastic spring. The viscous damping coefficient characterizes the degree of bead internalization into the cell, and the spring constant characterizes the strength of the binding of the bead to the CSK. The model predicts distinctive signatures of the MSD that change with time as the bead couples more tightly to the CSK and becomes internalized. Experimental data show that the transition from the unbound to the tightly bound state occurs in an all-or-nothing manner. The time point of this transition shows considerable variability between individual cells (2-30 min) and depends on the bead size and bead coating. On average, this transition occurs later for smaller beads and beads coated with ligands that trigger the formation of adhesion complexes (fibronectin, integrin antibodies). Once the bead is linked to the CSK, however, the ligand type and bead size have little effect on the MSD. On longer timescales of several hours after bead addition, smaller beads are internalized into the cell more readily, leading to characteristic changes in the MSD that are consistent with increased viscous damping by the cytoplasm and reduced binding strength.

Noise and critical phenomena in biochemical signaling cycles at small molecule numbers.

Biochemical reaction networks in living cells usually involve reversible covalent modification of signaling molecules, such as protein phosphorylation. Under conditions of small molecule numbers, as is frequently the case in living cells, mass-action theory fails to describe the dynamics of such systems. Instead, the biochemical reactions must be treated as stochastic processes that intrinsically generate concentration fluctuations of the chemicals. We investigate the stochastic reaction kinetics of covalent modification cycles (CMCs) by analytical modeling and numerically exact Monte Carlo simulation of the temporally fluctuating concentration. Depending on the parameter regime, we find for the probability density of the concentration qualitatively distinct classes of distribution functions including power-law distributions with a fractional and tunable exponent. These findings challenge the traditional view of biochemical control networks as deterministic computational systems and suggest that CMCs in cells can function as versatile and tunable noise generators.

Simple model of cytoskeletal fluctuations.

The spontaneous motion of microbeads bound to the cytoskeleton of living cells is not an ordinary random walk. Unlike Brownian motion, the mean-square displacement undergoes a transition from subdiffusive to superdiffusive behavior with time. This transition is associated with characteristic changes of the turning angle distribution. Recent experimental data demonstrated that force fluctuations measured in an elastic hydrogel matrix beneath the cell correlate with the bead motion [C. Raupach, Phys. Rev. E 76, 011918 (2007)]. These data indicate that the bead trajectory is driven by motor forces originating from the actomyosin network and that cytoskeletal remodeling processes with short- and long-time dynamics are mainly responsible for the non-Brownian behavior. We show that the essential statistical properties of the spontaneous bead motion can be reproduced by a particle diffusing in a potential well with a slowly drifting minimum position. Based on this simple model, which can be solved analytically, we develop a biologically plausible numerical model of a tensed and continuously remodeling actomyosin network that accounts quantitatively for the measured data.

[Bone metastasis of prostatic cancer imitating Paget's sarcoma]. / Ossäre Metastase eines Prostatakarzinoms simuliert ein Paget-Sarkom.

HISTORY AND CLINICAL FINDINGS: A 74-year-old man presented with bone pain of the right hip, night sweat and weight loss for 18 months. The diagnosis of Paget's disease was confirmed four months before admission, but pain and elevated serum alkaline phosphatase levels remained despite treatment with i.v. bisphosphonates. The physical examination showed no specific abnormalities. INVESTIGATIONS: Laboratory findings were elevated levels of serum alkaline phosphatase (AP), CA 19-9 and CEA. Radiological and tomographic images showed an aggressive periostal reaction consistent with Paget's sarcoma. The bone biopsy revealed the presence of prostatic cancer which was confirmed in a subsequent prostate biopsy. TREATMENT AND COURSE: Because of the multiple bone and lung metastases the disease proved to be incurable and the patient received palliative therapy with flutamide. He died 12 months later. CONCLUSION: In patients with Paget's disease lacking of response to bisphosphonate administration (permanently increased AP and sustained pain) radiological and clinical re-assessment of the diagnosis is indicated and may sometimes also include bone biopsy.

Mood and affect during detoxification of opiate addicts: a comparison of buprenorphine versus methadone.

Twenty-six in-patients with Diagnostic and Statistical Manual version IV (DSM-IV) criteria for opioid dependence were selected at random to receive either a combination of an 11-day low-dose buprenorphine and a 14-day carbamazepine regimen (n = 14) or a combination of an 11-day methadone and a 14-day carbamazepine regimen (n = 12) in a double-blind, randomized 14-day in-patient detoxification treatment. Patients with buprenorphine and carbamazepine showed a significantly better psychological state after the first and second weeks of treatment. Above all, the buprenorphine-treated patients demonstrated a less marked tiredness, sensitiveness and depressive state as well as a more prominent elevated mood during the detoxification process. Seven non-completers (after 7 days: four of 12 = 33.3%; after 14 days: seven of 12 = 58.3%) were treated with methadone and carbamazepine and five non-completers (after 7 days: two of 14 = 14.3%; after 14 days: five of 14 = 35.7%) received buprenorphine and carbamazepine. The difference in the overall dropout rate after day 14 was not significant. The present study supports the hypothesis that the combination of buprenorphine and carbamazepine leads to a better clinical outcome than does a combination of methadone and carbamazepine in the detoxification of opioid addicts with additional multiple drug abuse. The buprenorphine and carbamazepine-regimen provides a more effective short-term relief of affective disturbances than does methadone and carbamazepine. No severe side effects occurred during the treatment period in both groups.

[Accidental intraartrial injection of diacethylmorphine (heroin) in drug addicts -- three case reports]. / Akzidentelle intraarterielle Injektion von Diacetylmorphin (Heroin) bei Drogenabhängigen -- 3 Fallberichte.

Accidental intrarterial injections are not uncommon in medical treatments. This is also true for uncontrolled injections by drug-addicts. Since 2002 a number of 600 heavy opiate addicts in Germany are substituted in a country-wide study with pure diacetylmorphine (Heroine). We report the course and outcome of three cases of accidental intraarterial injections of pure diacetylmorphine under controlled conditions. After initial symptoms of vasospasms, all cases were without symptoms within one hour and no obvious loss of tissue was observed. After discussing the literature about medical literature and treatment options in intraarterial injections it is concluded, that the cause of major complications after intraarterial injections may not be the pure diacetylmorphine but additional substances in impure "street-heroin" samples.

Treatment of alcohol withdrawal: chlormethiazole vs. carbamazepine and the effect on memory performance--a pilot study.

Although relatively little attention has been paid to the question how acute alcohol withdrawal might affect cognitive functions, this factor remains of particular interest because it influences psychotherapeutic treatment during detoxification. The clinical outcome and neuropsychological state of 37 inpatients with alcohol withdrawal was investigated in a randomized single-blind approach. Two different medical strategies [chlormethiazole (CMZ) vs. carbamazepine (CBZ)] in the treatment of inpatients with alcohol withdrawal syndrome were compared. Among comparable groups (related to gender, age, initial alcohol level, severity of abuses, severity of initial withdrawal symptoms such as tremor, perspiration, psychomotor agitation, hallucinations, orientation, intelligence, patient demographics), CBZ is just as potent as CMZ in therapy of withdrawal symptoms (circulatory function, vegetative function, psychomotor activity). Patients in both groups showed initial impairments in some neuropsychological tests (d2, Zahlen-Verbundings test, Beck Depression Inventory, Anxiety Sensitivity Index) with significant improvement during detoxification. Additionally, CBZ-treated patients showed significantly better verbal memory performance during the first days of treatment. Without any addictive potential, CBZ therapy could be very supportive in alcohol detoxification. In addition a higher verbal memory performance state could be favourable for a psychotherapeutic approach.

Detoxification of opiate addicts with multiple drug abuse: a comparison of buprenorphine vs. methadone.

Over the last few years, there has been a growing tendency for opioid addicts to abuse multiple drugs, although many patients are in substitution therapy with methadone. Abuse of multiple drugs leads to a more complicated withdrawal syndrome; it is therefore necessary to investigate new drug strategies as a treatment for detoxification. Buprenorphine appears to be an effective and safe drug in opioid-addicted patient detoxification. In this study, we have compared the short-term efficacy of an 11-day low-dose buprenorphine/14-day carbamazepine regime [BPN/CBZ] (n = 14) to an 11-day methadone/14-day carbamazepine regime [MET/CBZ] (n = 12) in a double-dummy, randomized 14-day inpatient detoxification treatment study. Twenty-six inpatients met the DSM-IV criteria for opioid dependence and were included in this study. All patients abused various additional drugs. Fourteen of 26 patients (53.8 %) completed the study. Seven non-completers (seven of 12 = 58.3 %) were treated with methadone/carbamazepine and five non-completers (five of 14 = 35.7 %) received buprenorphine/carbamazepine, but the difference in the dropout rate was not significant. However, patients with buprenorphine/carbamazepine showed significantly fewer withdrawal symptoms after the first two weeks of treatment. The present study supports the hypothesis that buprenorphine/carbamazepine is more effective than methadone/carbamazepine in detoxification strategies for opioid addict with additional multiple drug abuse. No severe side effects occurred during treatment in either group.

Effect of vitamin E and vitamin C on the DNA synthesis of human umbilical arterial endothelial cells.

BACKGROUND: Endothelial cell growth and reendothealization after vascular injury protect the vessel wall against endothelial dysfunction which is believed to play a major role in the pathogenesis of atherosclerosis. AIM: of the study To investigate a possible protective role of antioxidant vitamins in the present study, the effect of vitamin E (alpha-tocopherol) alone and in combination with vitamin C on the DNA synthesis of human umbilical arterial endothelial cells (HUAEC) was examined. Furthermore, because oxidized low-density lipoprotein (ox-LDL) is thought to be involved in atherogenesis, the combined effect of vitamin E and vitamin C with ox-LDL and the influence of vitamin-pretreated LDL on HUAEC proliferation were investigated. METHODS: DNA-synthesis was determined by measurement of [3H]thymidine incorporation into the cell DNA. RESULTS: Vitamin E alone and in combination with vitamin C resulted in an increase in [3H]thymidine incorporation into cell DNA, especially in the presence of basic fibroblast growth factor (bFGF). All vitamin-pretreated LDL samples and ox-LDL led to a nearly complete inhibition of endothelial DNA-synthesis. The ox-LDL-induced effect could not be prevented by vitamin E alone nor in combination with vitamin C. CONCLUSIONS: It seems that once LDL oxidation is in process, vitamin E alone and in combination with vitamin C is ineffective to exert its antioxidative capacity under the conditions used. Thus, vitamin E alone and combined with vitamin C may act as antiatherogens by inducing endothelial cell growth.

Emergency carotid thromboendarterectomy: safe and effective.

Whether to perform emergency carotid thromboendarterectomy (CTEA) in the presence of crescendo transient ischemic attacks or stroke-in-evolution is controversial, with the operative mortality in some reports exceeding 20% and improvement in neurologic deficit of less than 40% in others. Our anecdotal experience with emergency CTEA for acute, persistent, or crescendo neurologic deficit had been strikingly better than published reports. Accordingly, we carried out a restrospective comparison of 43 such patients undergoing emergency CTEA with 237 patients concurrently undergoing elective CTEA for conventional indications. A standard protocol followed in emergency CTEA patients included carotid Doppler ultrasonography, computed cerebral tomography (CT), four-vessel cerebral arteriography, and intravenous heparin. Exclusions from emergency CTEA included coma or cerebral CT scan evidence for either hemorrhagic or ischemic infarction with edema. Operative techniques included standard carotid endarterectomy with Dacron patch or direct suture, eversion endarterectomy, or shortening resection. No mortality or central neurologic complications resulted among the 43 emergency CTEA patients, in comparison to no deaths and one temporary hemiparesis (0.4% central neurologic morbidity) in the 237 elective CTEA patients. Our results suggest that in the absence of coma or cerebral CT scan evidence for an unstable blood-brain barrier, emergency carotid reconstruction can be performed safely and with excellent outcome notwithstanding the magnitude and severity of the acute preoperative neurologic deficit.

[MR angiography of the lower extremities with an automatic table translation (Mobitrak) compared to i.a. DSA]. / MR-Angiographie der unteren Extremitäten mit automatischer Tischverschiebung ("MobiTrak") im Vergleich zur i.a. DSA.

PURPOSE: Comparison of the diagnostic information obtained by MRA using a moving bed ("MobiTrak") with i.a.DSA for angiography of the lower extremities. MATERIALS AND METHODS: In 20 patients, i.a.DSA and MRA were performed within a few days. The image quality and diagnostic information were evaluated by two radiologists and two surgeons. RESULTS: The radiologists assessed the quality of MRA higher for 18%, for 79% image quality was equal, for 3% the quality was graded as lower in comparison to i.a.DSA. The surgeons found the quality of MRA higher for 16%, equal for 75% and lower for 9%. In all cases, MRA was sufficient for planning of further treatment. CONCLUSIONS: For examinations of the arterial vessels of the lower extremities, MRA with a moving bed ("MobiTrak") can be used instead of i.a.DSA. The diagnostic information from MRA is sufficient for planning the further treatment. The advantages of MRA (no radiation, no i.a. puncture, no contrast medium with iodine) will lead to an increasing application of this method.

Cell-density-dependent repression of discoidin in Dictyostelium discoideum.

When Dictyostelium discoideum cells are grown on bacteria, their natural food source, the discoidin genes are induced by cell-density-sensing factors before the food supply is exhausted [11, 18], and expression increases continuously thereafter. This regulation pattern is changed when cells are grown in axenic medium: the discoidins are induced at a considerably lower cell density and are no longer expressed in stationary phase [13]. We have investigated this phenomenon further and show that repression begins when cells are still in exponential growth. It occurs at the level of transcription and involves an element of the discoidin I gamma promoter for which no function has previously been described. Since the effect of high cell density can be mimicked by conditioned medium, it appears that the repression is due to an extracellular signal. This signal is neither ammonia, nor folate, nor cAMP, the known repressors of discoidin expression.