Effect of the COVID-19 pandemic on clinical characteristics and outcomes of adult pneumococcal meningitis patients - a Dutch prospective nationwide cohort study.

PURPOSE: To investigate clinical characteristics and outcomes of patients with pneumococcal meningitis during the COVID-19 pandemic. METHODS: In a Dutch prospective cohort, risk factors and clinical characteristics of pneumococcal meningitis episodes occurring during the COVID-19 pandemic (starting March 2020) were compared with those from baseline and the time afterwards. Outcomes were compared with an age-adjusted logistic regression model. RESULTS: We included 1,699 patients in 2006-2020, 50 patients in 2020-2021, and 182 patients in 2021-2023. After March 2020 relatively more alcoholism was reported (2006-2020, 6.1%; 2020-2021, 18%; 2021-2023, 9.7%; P = 0.002) and otitis-sinusitis was less frequently reported (2006-2020, 45%; 2020-2021, 22%; 2021-2023, 47%; P = 0.006). Other parameters, i.e. age, sex, symptom duration or initial C-reactive protein level, remained unaffected. Compared to baseline, lumbar punctures were more frequently delayed (on admission day, 2006-2020, 89%; 2020-2021, 74%; 2021-2022, 86%; P = 0.002) and outcomes were worse ('good recovery', 2020-2021, OR 0.5, 95% CI 0.3-0.8). CONCLUSION: During the COVID-19 pandemic, we observed worse outcomes in patients with pneumococcal meningitis. This may be explained by differing adherence to restrictions according to risk groups or by reduced health care quality.

Impact of an INtervention to increase MOBility in older hospitalized medical patients (INTOMOB): Study protocol for a cluster randomized controlled trial.

BACKGROUND: Low mobility during an acute hospitalization is frequent and associated with adverse effects, including persistent functional decline, institutionalization and death. However, we lack effective interventions to improve mobility that are scalable in everyday practice. The INTOMOB trial - INtervention to increase MOBility in older hospitalized medical patients - will test the effect of a multilevel intervention to improve mobility of older hospitalized patients on functional mobility. METHODS: The INTOMOB multicenter superiority parallel cluster randomized controlled trial will enroll in total 274 patients in Swiss hospitals. Community-dwelling adults aged ≥ 60 years, admitted to a general internal medicine ward with an anticipated length of hospital stay of ≥ 3 days, will be eligible for participation. Unit of randomization will be the wards. A multilevel mobility intervention will be compared to standard of care and target the patients (information and exercise booklets, mobility diary, iPad with exercise videos), healthcare professionals (e-learning, oral presentation, mobility checklist), and environment (posters and pictures on the wards). The primary outcome will be life-space level, measured by the University of Alabama at Birmingham Study of Aging Life-Space Assessment (LSA), at 30 days after enrollment. The LSA is a measure of functional mobility, i.e., how far participants move from bedroom to outside town. Secondary outcomes include, among others, LSA at 180 days, mobility and falls during hospitalization, muscle strength at discharge, and falls, emergency room visits, readmissions, and death within 180 days. DISCUSSION: This study has the potential to improve outcomes of older hospitalized patients through an intervention that should be scalable in clinical practice because it fosters patient empowerment and does not require additional resources. The tools provided to the patients can help them implement better mobility practices after discharge, which can contribute to better functional outcomes. The choice of a functional patient-reported outcome measure as primary outcome (rather than a "simple" objective mobility measure) reinforces the patient-centeredness of the study. TRIAL REGISTRATION: clinicaltrials.gov (NCT05639231, released on December 19 2022); Swiss National Clinical Trial Portal (SNCTP000005259, released on November 28 2022).

Feasibility and Acceptability of an INtervention TO Increase MOBility in Older Hospitalized Medical Patients (INTOMOB): A Mixed-Methods Pilot Study.

Background: To reduce adverse outcomes of low hospital mobility, we need interventions that are scalable in everyday practice. This study assessed the feasibility and acceptability of the INTOMOB multilevel intervention addressing barriers to hospital mobility without requiring unavailable resources. Methods: The INTOMOB intervention, targeting older patients, healthcare professionals (HCPs) and the hospital environment, was implemented on acute general internal medicine wards of three hospitals (12/2022-03/2023). Feasibility and acceptability of the intervention were assessed and two types of accelerometers compared in a mixed methods study (patient and HCP surveys and interviews). Quantitative data were analyzed descriptively and qualitative data using a deductive approach. Results were integrated through meta-inferences. Results: Of 20 patients (mean age 74.1 years), 90% found the intervention helpful and 82% said the environment intervention (posters) stimulated mobility. The majority of 44 HCPs described the intervention as clear and helpful. There was no major implementation or technical issue. About 60% of patients and HCPs preferred a wrist-worn over an ankle-worn accelerometer. Conclusions: The INTOMOB intervention is feasible and well accepted. Patients' and HCPs' feedback allowed to further improve the intervention that will be tested in a cluster randomized trial and provides useful information for future mobility-fostering interventions.

Factors associated with one-year mortality after hospital discharge: A multicenter prospective cohort study.

OBJECTIVES: 1) To identify predictors of one-year mortality in hospitalized medical patients using factors available during their hospital stay. 2) To evaluate whether healthcare system use within 30 days of hospital discharge is associated with one-year mortality. STUDY DESIGN AND SETTING: This prospective, observational study included adult patients from four mid-sized hospital general internal medicine units. During index hospitalization, we retrieved patient characteristics, including demographic and socioeconomic indicators, diagnoses, and early simplified HOSPITAL scores from electronic health records and patient interviews. Data on healthcare system use was collected using telephone interviews 30 days after discharge. Survival status at one year was collected by telephone and from health records. We used a univariable analysis including variables available from the hospitalization and 30-day post-discharge periods. We then performed multivariable analyses with one model using index hospitalization data and one using 30-day post-discharge data. RESULTS: Of 934 patients, 123 (13.2%; 95% CI 11.0-15.4%) were readmitted or died within 30 days. Of 814 patients whose primary outcome was available, 108 died (13.3%) within one year. Using factors obtained during hospitalization, the early simplified HOSPITAL score (OR 1.50; 95% CI 1.31-1.71; P < 0.001) and not living at home (OR 4.0; 95% CI 1.8-8.3; P < 0.001) were predictors of one-year mortality. Using 30-day post-discharge predictors, hospital readmission was significantly associated with one-year mortality (OR 4.81; 95% CI 2.77-8.33; P < 0.001). SIGNIFICANCE: Factors predicting one-year mortality were a high early simplified HOSPITAL score, not living at home, and a 30-day unplanned readmission.

[Internal differential diagnoses in acute back pain : An internal perspective on the possible causes of acute back pain]. / Internistische Differenzialdiagnosen bei akuten Rückenschmerzen : Eine internistische Perspektive zu den möglichen Ursachen von akuten Rückenschmerzen.

The majority of patients with acute back pain have no serious underlying disease; however, many internal diseases can be manifested as acute or chronic back pain. Therefore, in the assessment of patients with back pain the clinical history and clinical examination are important in order to detect indications for a possible underlying disease. Particularly red flags that indicate an acute or life-threatening disease should not be missed. In most cases where such red flags, risk factors or clinical indications are not present, no systematic search for internal underlying diseases is necessary. This article summarizes the most relevant differential diagnoses and clinical indications as well as warning symptoms.

Goal-Directed Mobility of Medical Inpatients-A Mini Review of the Literature.

Background: Inpatients spend most of their hospitalization in bed, which can lead to negative physical, social, and psychological outcomes, especially in the geriatric population. Goal-directed mobilization involves setting mobility goals with patients and care teams working together toward achieving these goals. Methods: Three different platforms (SCOPUS, Ovid Medline, PubMed) were searched. Search terms included "goal-directed," "goal-attainment" or "goal-setting," and "inpatient" or "hospitalization" and "mobility" or "mobilization." Articles were included if mobility goals were set in acutely hospitalized adults. Studies were excluded if only covering specific illness or surgery. Results: One Hundred Seventy three articles were screened for inclusion by two independent reviewers. In the final analysis, 13 articles (5 randomized controlled trials, 2 Post-hoc analyses, 3 quality-improvement projects, 1 pre-post two group analysis, 1 comment and 1 study protocol) were assessed. Goal-directed mobilization improved mobility-related outcomes, i.e., level of mobilization, activity, daily walking time and functional independence. Readmissions, quality of life, discharge disposition and muscle weakness were not significantly altered and there was conflicting evidence regarding length of stay and activities of daily living. Conclusion: There is a lack of evidence of goal-directed mobilization on relevant outcomes due to the low number of studies in the field and the study design used. Further research on goal-directed mobility should use standardized mobility protocols and measurements to assess mobility and the effects of goal-directed mobility more accurately and include broader patient populations.

Immune-Mediated Thrombotic Thrombocytopenic Purpura Following mRNA-Based COVID-19 Vaccine BNT162b2: Case Report and Mini-Review of the Literature.

Introduction: An increasing number of case reports have associated vaccinations against coronavirus disease 2019 (COVID-19) with immune-mediated thrombotic thrombocytopenic purpura (iTTP), a very rare but potentially life-threatening thrombotic microangiopathy, which leads to ischemic organ dysfunction. Thrombus formation in iTTP is related to a severe deficiency of the specific von Willebrand-factor-cleaving protease ADAMTS13 due to ADAMTS13 autoantibodies. Methods: We present a case of iTTP following exposure to the mRNA-based COVID-19 vaccine BNT162b2 (Comirnaty®, Pfizer-BioNTech). In addition, we review previously reported cases in the literature and assess current evidence. Results: Apart from our case, twenty cases of iTTP occurring after COVID-19 vaccination had been published until the end of November 2021. There were 11 male and 10 female cases; their median age at diagnosis was 50 years (range 14-84 years). Five patients (24%) had a preexisting history of iTTP. Recombinant adenoviral vector-based vaccines were involved in 19%, mRNA-based vaccines in 81%. The median onset of symptoms after vaccination was 12 days (range 5-37), with 20 cases presenting within 30 days. Treatment included therapeutic plasma exchange in all patients. Additional rituximab, caplacizumab, or both these treatments were given in 43% (9/21), 14% (3/21), and 24% (5/21) of cases, respectively. One patient died, despite a prolonged clinical course in one patient, all surviving patients were in clinical remission at the end of the observational period. Conclusion: Clinical features of iTTP following COVID-19 vaccination were in line with those of pre-pandemic iTTP. When timely initiated, an excellent response to standard treatment was seen in all cases. ADAMTS13 activity should be determined pre-vaccination in patients with a history of a previous iTTP episode. None of the reported cases met the WHO criteria for assessing an adverse event following immunization (AEFI) as a consistent causal association to immunization. Further surveillance of safety data and additional case-based assessment are needed.

Effect of goal-directed mobilisation intervention compared with standard care on physical activity among medical inpatients: protocol for the GoMob-in randomised controlled trial.

INTRODUCTION: Despite the fact that immobilisation is a major contributor to morbidity and mortality, patients hospitalised in general internal medicine (GIM) wards spend up to 50% of time in bed. Previous studies in selected patient populations showed increased mobility after implementation of goal-directed mobilisation (GDM). Due to the study design used so far, the degree of evidence is generally low. The effect of GDM on clinical outcomes and economically relevant indicators in patients hospitalised in GIM wards is currently unknown. This study aims to evaluate a GDM intervention compared to standard care on physical activity (de Morton Mobility Index, DEMMI) in medical inpatients. METHODS AND ANALYSIS: GoMob-in is a randomised, controlled, open-label study with blinded outcome assessment. We plan to enrol 160 inpatients with indication for physiotherapy on GIM wards of a tertiary hospital in Bern, Switzerland. Adult patients newly hospitalised on GIM wards will be included in the study. The primary outcome will be the change in the DEMMI score between baseline and 5 days. Secondary outcomes are change of DEMMI (inclusion to hospital discharge), mobilisation time (inclusion to day 5, inclusion to discharge), in-hospital delirium episodes, number of in-hospital falls, length of stay, number of falls within 3 months, number of re-hospitalisations and all-cause mortality within 3 months, change in independence during activities of daily living, concerns of falling, and quality of life within 3 months and destination after 3 months. Patients in the intervention group will be attributed a regularly updated individual mobility goal level made visible for all stakeholders and get a short educational intervention on GDM. ETHICS AND DISSEMINATION: This study has been approved by the responsible Ethics Board (Ethikkommission Bern/2020-02305). Written informed consent will be obtained from participants before study inclusion. Results will be published in open access policy peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04760392.

Cross-sectional Analysis of Recommendations for the Treatment of Hip and Knee Osteoarthritis in Clinical Guidelines.

OBJECTIVE: To compare guideline recommendations for hip and knee osteoarthritis (OA) and their level of evidence. DATA SOURCES: MEDLINE, Embase, the Cochrane Library, and websites of professional societies were searched in June 2020 using keywords such as knee or hip osteoarthritis, degenerative arthritis, guideline, and practice guideline. STUDY SELECTION: General treatment guidelines for OA of the hip or knee published in English. After 461 abstracts were screened, 31 publications (17 guidelines from 10 professional societies) were included for analysis. DATA EXTRACTION: Three reviewers assessed the quality of the guidelines according to the Appraisal of Guidelines for Research and Evaluation II tool. The rating of evidence and strength of recommendation was extracted and standardized into the Grading of Recommendations Assessment, Development, and Evaluation criteria. DATA SYNTHESIS: Of the 17 guidelines included, 6 (35%) were of high quality, 10 (59%) of moderate quality, and 1 (6%) of low quality. Guidelines published after 2017 were of good quality. Although guidelines generally agreed on a nonsurgical multimodal concept, including patient education, exercise, and weight loss in obese, some recommendations remained vague and the level of evidence varied widely. In pharmacologic treatment, oral nonsteroidal anti-inflammatory drugs were the mainstay for pain management. Guidelines published after 2017 were more cautious in their recommendation for the use of paracetamol and strong opioids. Disagreement was observed for chondroitin sulfate, glucosamine, and intra-articular hyaluronic acid injections. Recommendations were conflicting for the use of insoles, braces, and transcutaneous electrical stimulation. The main indications for hip/knee arthroplasty were severe, persisting pain and loss of function despite nonsurgical treatment. No guideline defined a minimum time of conservative treatment before surgery. CONCLUSIONS: We found a wide variation in evidence and strength of recommendations for OA treatment. Recommendations on when to refer patients for surgery remained unclear.

Development and validation of a score to assess complexity of general internal medicine patients at hospital discharge: a prospective cohort study.

OBJECTIVE: We aimed to develop and validate a score to assess inpatient complexity and compare its performance with two currently used but not validated tools to estimate complexity (ie, Charlson Comorbidity Index (CCI), patient clinical complexity level (PCCL)). METHODS: Consecutive patients discharged from the department of medicine of a tertiary care hospital were prospectively included into a derivation cohort from 1 October 2016 to 16 February 2017 (n=1407), and a temporal validation cohort from 17 February 2017 to 31 March 2017 (n=482). The physician in charge assessed complexity. Potential predictors comprised 52 parameters from the electronic health record such as health factors and hospital care usage. We fit a logistic regression model with backward selection to develop a prediction model and derive a score. We assessed and compared performance of model and score in internal and external validation using measures of discrimination and calibration. RESULTS: Overall, 447 of 1407 patients (32%) in the derivation cohort, and 116 of 482 patients (24%) in the validation cohort were identified as complex. Eleven variables independently associated with complexity were included in the score. Using a cut-off of ≥24 score points to define high-risk patients, specificity was 81% and sensitivity 57% in the validation cohort. The score's area under the receiver operating characteristic (AUROC) curve was 0.78 in both the derivation and validation cohort. In comparison, the CCI had an AUROC between 0.58 and 0.61, and the PCCL between 0.64 and 0.69, respectively. CONCLUSIONS: We derived and internally and externally validated a score that reflects patient complexity in the hospital setting, performed better than other tools and could help monitoring complex patients.

Bacterial meningitis: insights into pathogenesis and evaluation of new treatment options: a perspective from experimental studies.

Bacterial meningitis is associated with high mortality and morbidity rates. Bacterial components induce an overshooting inflammatory reaction, eventually leading to brain damage. Pathological correlates of neurofunctional deficits include cortical necrosis, damage of the inner ear and hippocampal apoptosis. The hippocampal dentate gyrus is important for memory acquisition and harbors a neuronal stem cell niche, thus being potentially well equipped for regeneration. Adjuvant therapies aimed at decreasing the inflammatory reaction, for example, dexamethasone, and those protecting the brain from injury have been evaluated in animal models of the disease. They include nonbacteriolytic antibiotics (e.g., daptomycin), metalloproteinase inhibitors and modulators of the immunological response, for example, granulocyte colony-stimulating factor. Increasing research interest has recently been focused on interventions aimed at supporting regenerative processes.

The matrix metalloproteinase inhibitor RS-130830 attenuates brain injury in experimental pneumococcal meningitis.

BACKGROUND: Pneumococcal meningitis (PM) is characterized by high mortality and morbidity including long-term neurofunctional deficits. Neuropathological correlates of these sequelae are apoptosis in the hippocampal dentate gyrus and necrosis in the cortex. Matrix metalloproteinases (MMPs) play a critical role in the pathophysiology of PM. RS-130830 (Ro-1130830, CTS-1027) is a potent partially selective inhibitor of MMPs of a second generation and has been evaluated in clinical trials as an anti-arthritis drug. It inhibits MMPs involved in acute inflammation but has low activity against MMP-1 (interstitial collagenase), MMP-7 (matrilysin) and tumour necrosis factor α converting enzyme (TACE). METHODS: A well-established infant rat model of PM was used where live Streptococcus pneumoniae were injected intracisternally and antibiotic treatment with ceftriaxone was initiated 18 h post infection (hpi). Treatment with RS-130830 (75 mg/kg bis in die (bid) i.p., n = 40) was started at 3 hpi while control littermates received the vehicle (succinylated gelatine, n = 42). RESULTS: Cortical necrosis was significantly attenuated in animals treated with RS-130830, while the extent of hippocampal apoptosis was not influenced. At 18 hpi, concentrations of interleukin (IL)-1ß and IL-10 were significantly lower in the cerebrospinal fluid of treated animals compared to controls. RS-130830 significantly reduced weight loss and leukocyte counts in the cerebrospinal fluid of survivors of PM. CONCLUSION: This study identifies MMP inhibition, specifically with RS-130830, as an efficient strategy to attenuate disease severity and cortical brain injury in PM.

The mood-stabilizer lithium prevents hippocampal apoptosis and improves spatial memory in experimental meningitis.

Pneumococcal meningitis is associated with high morbidity and mortality rates. Brain damage caused by this disease is characterized by apoptosis in the hippocampal dentate gyrus, a morphological correlate of learning deficits in experimental paradigms. The mood stabilizer lithium has previously been found to attenuate brain damage in ischemic and inflammatory diseases of the brain. An infant rat model of pneumococcal meningitis was used to investigate the neuroprotective and neuroregenerative potential of lithium. To assess an effect on the acute disease, LiCl was administered starting five days prior to intracisternal infection with live Streptococcus pneumoniae. Clinical parameters were recorded, cerebrospinal fluid (CSF) was sampled, and the animals were sacrificed 42 hours after infection to harvest the brain and serum. Cryosections of the brains were stained for Nissl substance to quantify brain injury. Hippocampal gene expression of Bcl-2, Bax, p53, and BDNF was analyzed. Lithium concentrations were measured in serum and CSF. The effect of chronic lithium treatment on spatial memory function and cell survival in the dentate gyrus was evaluated in a Morris water maze and by quantification of BrdU incorporation after LiCl treatment during 3 weeks following infection. In the hippocampus, LiCl significantly reduced apoptosis and gene expression of Bax and p53 while it increased expression of Bcl-2. IL-10, MCP-1, and TNF were significantly increased in animals treated with LiCl compared to NaCl. Chronic LiCl treatment improved spatial memory in infected animals. The mood stabilizer lithium may thus be a therapeutic alternative to attenuate neurofunctional deficits as a result of pneumococcal meningitis.

Endogenous and synthetic MMP inhibitors in CNS physiopathology.

Matrix metalloproteinases (MMPs, including the membrane-type MMPs (MT-MMPs)), a disintegrin and metalloproteinase (ADAM), and ADAM with thrombospondin motifs belong to the metzincins, a subclass of metalloproteinases that contain a Met residue and a Zn(2+) ion at the catalytic site necessary for enzymatic reaction. MMP proteolytic activity is mainly controlled by their natural tissue inhibitors of metalloproteinase (TIMP). A number of synthetic inhibitors have been developed to control deleterious MMP activity. The roles of MMPs and some of their ECM substrates in CNS physiology and pathology are covered by other chapters of the present volume and will thus not be addressed in depth. This chapter will focus (i) on the endogenous MMP inhibitors in the CNS, (ii) on MMP and TIMP regulations in three large classes of neuropathologic processes (inflammatory, neurodegenerative, and infectious), and (iii) on synthetic inhibitors of MMPs and the perspective of their use in different brain diseases.

Matrix metalloproteinase inhibition lowers mortality and brain injury in experimental pneumococcal meningitis.

Pneumococcal meningitis (PM) results in high mortality rates and long-lasting neurological deficits. Hippocampal apoptosis and cortical necrosis are histopathological correlates of neurofunctional sequelae in rodent models and are frequently observed in autopsy studies of patients who die of PM. In experimental PM, inhibition of matrix metalloproteinases (MMPs) and/or tumor necrosis factor (TNF)-converting enzyme (TACE) has been shown to reduce brain injury and the associated impairment of neurocognitive function. However, none of the compounds evaluated in these studies entered clinical development. Here, we evaluated two second-generation MMP and TACE inhibitors with higher selectivity and improved oral availability. Ro 32-3555 (Trocade, cipemastat) preferentially inhibits collagenases (MMP-1, -8, and -13) and gelatinase B (MMP-9), while Ro 32-7315 is an efficient inhibitor of TACE. PM was induced in infant rats by the intracisternal injection of live Streptococcus pneumoniae. Ro 32-3555 and Ro 32-7315 were injected intraperitoneally, starting at 3 h postinfection. Antibiotic (ceftriaxone) therapy was initiated at 18 h postinfection, and clinical parameters (weight, clinical score, mortality rate) were recorded. Myeloperoxidase activities, concentrations of cytokines and chemokines, concentrations of MMP-2 and MMP-9, and collagen concentrations were measured in the cerebrospinal fluid. Animals were sacrificed at 42 h postinfection, and their brains were assessed by histomorphometry for hippocampal apoptosis and cortical necrosis. Both compounds, while exhibiting disparate MMP and TACE inhibitory profiles, decreased hippocampal apoptosis and cortical injury. Ro 32-3555 reduced mortality rates and cerebrospinal fluid TNF, interleukin-1ß (IL-1ß) and collagen levels, while Ro 32-7315 reduced weight loss and cerebrospinal fluid TNF and IL-6 levels.