A fortunate bitten tongue-Hypothyroidism despite repeatedly normal plasma thyrotropin levels.

Key Clinical Message: Hypophyseal dysfunction may be overlooked by the currently generally accepted laboratory routine for the differential diagnosis in patients suffering from symptoms of depression or dementia. Abstract: Hypothyroidism is an important cause of depression and potentially reversible cognitive impairment. Whereas the determination of the plasma concentration of thyrotropin (TSH) is generally considered part of the laboratory screening tests for dementia, the measurement of total or free triiodothyronine (T3, FT3), thyroxine (T4, FT4) and cortisol in plasma does not belong to the routine diagnostic workup in patients with depression or suspected dementia. In an 87-year-old lady suffering from increasingly poor general health, decreased fluid and food intake, mood depression and lack of energy, three measurements of plasma TSH produced normal values. A cranial computed tomography (cCT) 2 days prior to hospital admission had been assessed as apparently normal. A second cCT performed following a loss of consciousness complicated by tongue bite showed a hypophyseal tumor. Then, low plasma levels of FT3, FT4 and cortisol were found. Following hormone replacement and transsphenoidal tumor resection, the patient recovered rapidly. The present case report illustrates the pitfalls of measuring merely the TSH level in the detection of thyroid and hypophyseal dysfunction.

Hydrogen peroxide is responsible for the cytotoxic effects of Streptococcus pneumoniae on primary microglia in the absence of pneumolysin.

INTRODUCTION: Streptococcus pneumoniae is the most common cause of bacterial meningitis and meningoencephalitis in humans. The bacterium produces numerous virulence determinants, among them hydrogen peroxide (H2O2) and pneumolysin (Ply), which contribute to bacterial cytotoxicity. Microglia, the resident phagocytes in the brain, are distinct from other macrophages, and we thus compared their susceptibility to pneumococcal toxicity and their ability to phagocytose pneumococci with those of bone marrow-derived macrophages (BMDM). METHODS: Microglia and BMDM were co-incubated with S. pneumoniae D39 to analyze survival of phagocytes by fluorescence microscopy, bacterial growth by quantitative plating, and phagocytosis by an antibiotic protection assay. Ply was detected by hemolysis assay and Western blot analysis. RESULTS: We found that microglia were killed during pneumococcal infection with a wild-type and an isogenic ply-deficient mutant, whereas viability of BMDM was not affected by pneumococci. Treatment with recombinant Ply showed a dose-dependent cytotoxic effect on microglia and BMDM. However, high concentrations of recombinant Ply were required and under the chosen experimental conditions, Ply was not detectable in the supernatant during infection of microglia. Inactivation of H2O2 by exogenously added catalase abolished its cytotoxic effect. Consequently, infection of microglia with pneumococci deficient for the pyruvate oxidase SpxB, primarily producing H2O2, resulted in reduced killing of microglia. CONCLUSION: Taken together, in the absence of Ply, H2O2 caused cell death in primary phagocytes in concentrations produced by pneumococci.

New Antibiotics for the Treatment of Nosocomial Central Nervous System Infections.

Nosocomial central nervous system (CNS) infections with carbapenem- and colistin-resistant Gram-negative and vancomycin-resistant Gram-positive bacteria are an increasing therapeutic challenge. Here, we review pharmacokinetic and pharmacodynamic data and clinical experiences with new antibiotics administered intravenously for the treatment of CNS infections by multi-resistant bacteria. Cefiderocol, a new siderophore extended-spectrum cephalosporin, pharmacokinetically behaves similar to established cephalosporins and at high doses will probably be a valuable addition in our therapeutic armamentarium for CNS infections. The new glycopeptides dalbavancin, telavancin, and oritavancin are highly bound to plasma proteins. Although effective in animal models of meningitis, it is unlikely that they reach effective cerebrospinal fluid (CSF) concentrations after intravenous administration alone. The ß-lactam/ß-lactamase inhibitor combinations have the principal problem that both compounds must achieve adequate CSF concentrations. In the commercially available combinations, the dose of the ß-lactamase inhibitor tends to be too low to achieve adequate CSF concentrations. The oxazolidinone tedizolid has a broader spectrum but a less suitable pharmacokinetic profile than linezolid. The halogenated tetracycline eravacycline does not reach CSF concentrations sufficient to treat colistin-resistant Gram-negative bacteria with usual intravenous dosing. Generally, treatment of CNS infections should be intravenous, whenever possible, to avoid adverse effects of intraventricular therapy (IVT). An additional IVT can overcome the limited penetration of many new antibiotics into CSF. It should be considered for patients in which the CNS infection responds poorly to systemic antimicrobial therapy alone.

[Congenital malformations of the brain misinterpreted as sequelae of poliomyelitis]. / Angeborene Fehlbildungen des Gehirns als Folgezustände der Poliomyelitis verkannt.

BACKGROUND: Poliomyelitis is an infectious disease of the peripheral motor neurons, which predominantly affects children and causes residual palsies. Because of the oral poliomyelitis vaccination started in Germany in 1960 and 1962 and the following rapid decline of the incidence of this infection, the postpolio syndrome in Germany is a disease of older people. METHODS: Since 2008, we have offered a poliomyelitis outpatient consultation at the Center of Geriatrics, Protestant Hospital Göttingen-Weende and have treated 33 patients. RESULTS: The spectrum of persistent deficits after poliomyelitis ranges from palsy of single extremities to severe disability with (temporary) ventilator dependence. Many patients suffer from scoliosis or shortening of limbs of different degrees, which promotes degenerative diseases of the spinal cord and joints with secondary myelopathy, injury of spinal nerve roots or peripheral nerves or respiratory failure. The postpolio syndrome is characterized by an increase of the functional deficits after decades of compensation. The palsies of 2 of the 33 patients were not caused by poliomyelitis but by myelomeningocele and schizencephaly, respectively. CONCLUSION: The motor deficits acquired in childhood enable the majority of the patients to successfully master their lives. Because of the limited compensatory capacities of postpolio patients, even small increases in the severity of the palsy can cause a severe decline of the functional status and an impairment of the ability to live an independent life. In a substantial proportion of patients with the diagnosis poliomyelitis the symptoms are caused by other diseases.

Treatment of septic encephalopathy and encephalitis - a critical appraisal.

INTRODUCTION: The central nervous system is frequently involved during severe sepsis. Patients either develop septic encephalopathy characterized by delirium and coma or focal neurological signs as a consequence of septic-embolic or septic-metastatic encephalitis. AREAS COVERED: In this review, a summary of currently available literature on established and some promising experimental treatment options for septic encephalopathy and encephalitis is provided, with a focus on the clinical utility of published studies. EXPERT OPINION: Treatment relies on proper identification of the causative pathogen and rapidly initiated adequate empirical or (after identification of the pathogen) tailored antibiotic therapy, fluid and electrolyte management. In the presence of brain abscess(es) or mycotic aneurysm(s), surgery or interventional neuroradiology must be considered. Pharmacological approaches to prevent delirium of different etiology include the use of dexmedetomidine and (with limitations) of melatonin and its derivatives. In the absence of a specific pharmacological treatment, non-pharmacological bundles of interventions (e.g. promotion of sleep, cognitive stimulation, early mobilization and adequate therapy of pain) are of proven efficacy to prevent delirium of different etiology including sepsis. Experimental promising therapies include the use of non-bacteriolytic antibiotics and the reduction of the toxic effects of microglial activation.

Septic encephalopathy in the elderly - biomarkers of potential clinical utility.

Next to acute sickness behavior, septic encephalopathy is the most frequent involvement of the brain during infection. It is characterized by a cross-talk of pro-inflammatory cells across the blood-brain barrier, by microglial activation and leukocyte migration, but not by the entry of infecting organisms into the brain tissue. Septic encephalopathy is very frequent in older persons because of their limited cognitive reserve. The predominant clinical manifestation is delirium, whereas focal neurological signs and symptoms are absent. Electroencephalography is a very sensitive method to detect functional abnormalities, but these abnormalities are not specific for septic encephalopathy and of limited prognostic value. Routine cerebral imaging by computer tomography usually fails to visualize the subtle abnormalities produced by septic involvement of the brain. Magnetic resonance imaging is by far more sensitive to detect vasogenic edema, diffuse axonal injury or small ischemic lesions. Routine laboratory parameters most suitable to monitor sepsis, but not specific for septic encephalopathy, are C-reactive protein and procalcitonin. The additional measurement of interleukin (IL)-6, IL-8, IL-10 and tumor necrosis factor-α increases the accuracy to predict delirium and an unfavorable outcome. The most promising laboratory parameters to quantify neuronal and axonal injury caused by septic encephalopathy are neurofilament light chains (NfL) and S100B protein. Neuron-specific enolase (NSE) plasma concentrations are strongly influenced by hemolysis. We propose to determine NSE only in non-hemolytic plasma or serum samples for the estimation of outcome in septic encephalopathy.

A suspension of inactivated bacteria used for vaccination against recurrent urinary tract infections increases the phagocytic activity of murine macrophages.

Background: Urinary tract infections are a major cause of the consumption of antibiotics in humans. Methods: We studied the effect of a vaccine (StroVac®, containing inactivated bacteria and used to prevent recurrent urinary tract infections) licensed in Germany on the release of pro-inflammatory cytokines and the phagocytosis of Escherichia (E.) coli in primary murine macrophages and the macrophage cell line J774A.1. Results: StroVac® increased the release of the cytokines TNF-α, IL-6, IL-12/23 p40, and IL-1ß and stimulated the phagocytosis of E. coli in a dose-dependent manner. This effect was independent of LPS as shown by the use of macrophages isolated from LPS-resistant C3H/HeJ mice. At concentrations up to 30 mg/l it was not toxic to bacteria or eukaryotic cells. Conclusion: StroVac® does not only act via the adaptive but also by stimulating the innate immune system. This stimulation may help to build trained innate immunity against bacterial pathogens involved in recurrent urinary tract infections.

German guidelines on community-acquired acute bacterial meningitis in adults.

INTRODUCTION: The incidence of community-acquired acute bacterial meningitis has decreased during the last decades. However, outcome remains poor with a significant proportion of patients not surviving and up to 50% of survivors suffering from long-term sequelae. These guidelines were developed by the Deutsche Gesellschaft für Neurologie (DGN) under guidance of the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) to guide physicians through diagnostics and treatment of adult patients with acute bacterial meningitis. RECOMMENDATIONS: The most important recommendations are: (i) In patients with suspected acute bacterial meningitis, we recommend that lumbar cerebrospinal fluid (with simultaneous collection of serum to determine the cerebrospinal fluid-serum glucose index and blood cultures) is obtained immediately after the clinical examination (in the absence of severely impaired consciousness, focal neurological deficits, and/or new epileptic seizures). (ii) Next, we recommend application of dexamethasone and empiric antibiotics intravenously. (iii) The recommended initial empiric antibiotic regimen consists of ampicillin and a group 3a cephalosporin (e.g., ceftriaxone). (iv) In patients with severely impaired consciousness, new onset focal neurological deficits (e.g. hemiparesis) and/or patients with newly occurring epileptic seizures, we recommend that dexamethasone and antibiotics are started immediately after the collection of blood; we further recommend that -if the imaging findings do not indicate otherwise -a lumbar CSF sample is taken directly after imaging. (v) Due to the frequent occurrence of intracranial and systemic complications, we suggest that patients with acute bacterial meningitis are treated at an intensive care unit in the initial phase of the disease. In the case of impaired consciousness, we suggest that this is done at an intensive care unit with experience in the treatment of patients with severe CNS diseases. CONCLUSIONS: The German S2k-guidelines give up to date recommendations for workup, diagnostics and treatment in adult patients with acute bacterial meningitis.

Multiple Triplet Metal-Centered Jahn-Teller Isomers Determine Temperature-Dependent Luminescence Lifetimes in [Ru(bpy)3 ]2.

Understanding the factors that determine the luminescence lifetime of transition metal compounds is key for applications in photocatalysis and photodynamic therapy. Here we show that for [ Ru ( bpy ) 3 ] 2 + ${[{\rm{Ru}}({\rm{bpy}})_{\rm{3}} ]^{{\rm{2 + }}} }$ (bpy = 2,2'-bipyridine), the generally accepted idea that emission lifetimes can be controlled optimizing the energy barrier from the emissive triplet metal-to-ligand charge-transfer (3 MLCT) state to the thermally-activated triplet metal-centered (3 MC) state or the energy gap between both states is a misconception. Further, we demonstrate that considering a single relaxation pathway determined from the minimum that is lowest in energy leads to wrong temperature-dependent emission lifetimes predictions. Instead, we obtain excellent agreement with experimental temperature-dependent lifetimes when an extended kinetic model that includes all the pathways related to multiple Jahn-Teller isomers and their effective reaction barriers is employed. These concepts are essential to correctly design other luminescent transition metal complexes with tailored emission lifetimes based on theoretical predictions.

[Geriatric traumatological rounds in a primary care hospital]. / Die alterstraumatologische Visite in einem Krankenhaus der Regelversorgung.

Geriatric traumatological rounds (GTR) with representatives of several disciplines are a challenge in the setting of primary care hospitals with limited resources. The GTR were started with only an experienced traumatologist and a geriatrician in 2019. Routine quality control data showed a reduction of the frequency of cardiac failure and mortality after the start of the GTR. Therefore, even the minimum variant of GTR with the focus on the differential diagnosis of falls and adequate drug treatment appears to be beneficial for the patient. Special attention is given to the medical treatment of cardiac failure, pulmonary diseases, osteoporosis, psychiatric disorders and anemia. Vitamin B12 and folate deficiency are substituted. When anticoagulants or platelet aggregation inhibitors are indicated, they are resumed early. Potentially inadequate drugs for older patients are avoided. Doses of many drugs used in geriatric patients must be adjusted to a reduced renal function often present in old age. Frequent electrolyte abnormalities are diagnosed and adequately treated.

Ceftriaxone-induced neutropenia successfully overcome by a switch to penicillin G in Cardiobacterium hominis endocarditis.

Leukopenia, including agranulocytosis, is a severe complication of treatment with all ß-lactam antibiotics. Its incidence increases with age. Cardiobacterium hominis endocarditis after implantation of an aortic valve bio-prosthesis in a 77-year-old woman was treated with ceftriaxone 2 g/day plus gentamicin 160 mg/day intravenously. On Day 25 of treatment, blood leukocytes had decreased to 1800/µl (neutrophils 370/µl). Antibiotic therapy was switched to penicillin G 20 million international units (IU)/day. Thereafter, blood leukocytes including neutrophils normalized suggesting that penicillin G was less bone marrow-toxic than ceftriaxone. High-dose ciprofloxacin, the alternative to penicillin G, was avoided because of the risk of cognitive and behavioral side effects. The present case suggests that with close laboratory monitoring a ß-lactam with differing side chains should not be considered contraindicated after ß-lactam antibiotic-induced neutropenia.

Serological testing for syphilis in the differential diagnosis of cognitive decline and polyneuropathy in geriatric patients.

BACKGROUND: In the 19th century, neurosyphilis was the most frequent cause of dementia in Western Europe. Now dementia caused by syphilis has become rare in Germany. We studied whether routine testing of patients with cognitive abnormalities or neuropathy for antibodies against Treponema pallidum has therapeutic consequences in geriatric patients. METHODS: A Treponema pallidum electrochemiluminescence immunoassay (TP-ECLIA) is routinely performed in all in-patients treated at our institution with cognitve decline or neuropathy and no or insufficient previous diagnostic workup. Patients with a positive TP-ECLIA treated from October 2015 to January 2022 (76 months) were retrospectively evaluated. In cases of positive TP-ECLIA, further specific laboratory investigations were performed to assess whether antibiotic therapy was indicated. RESULTS: In 42 of 4116 patients (1.0%), TP-ECLIA detected antibodies directed against Treponema in serum. Specifity of these antibodies was ensured by immunoblot in 22 patients (11 × positiv, 11 × borderline values). Treponema-specific IgM was detectable in the serum of one patient, in 3 patients the Rapid Plasma Reagin (RPR) test, a modified Venereal Disease Research Laboratory test (VDRL), in serum was positiv. CSF analysis was performed in 10 patients. One patient had CSF pleocytosis. In 2 other patients, the Treponema-specific IgG antibody index was elevated. 5 patients received antibiotic therapy (4 × ceftriaxone 2 g/d i.v., 1 × doxycycline 300 mg/d p.o.). CONCLUSION: In approx. 1‰ of patients with previously undiagnosed or not sufficiently diagnosed cognitive decline or neuropathy, the diagnostic workup for active syphilis resulted in a course of antibiotic treatment.

Spatial and temporal variation of routine parameters: pitfalls in the cerebrospinal fluid analysis in central nervous system infections.

The cerebrospinal fluid (CSF) space is convoluted. CSF flow oscillates with a net flow from the ventricles towards the cerebral and spinal subarachnoid space. This flow is influenced by heartbeats, breath, head or body movements as well as the activity of the ciliated epithelium of the plexus and ventricular ependyma. The shape of the CSF space and the CSF flow preclude rapid equilibration of cells, proteins and smaller compounds between the different parts of the compartment. In this review including reinterpretation of previously published data we illustrate, how anatomical and (patho)physiological conditions can influence routine CSF analysis. Equilibration of the components of the CSF depends on the size of the molecule or particle, e.g., lactate is distributed in the CSF more homogeneously than proteins or cells. The concentrations of blood-derived compounds usually increase from the ventricles to the lumbar CSF space, whereas the concentrations of brain-derived compounds usually decrease. Under special conditions, in particular when distribution is impaired, the rostro-caudal gradient of blood-derived compounds can be reversed. In the last century, several researchers attempted to define typical CSF findings for the diagnosis of several inflammatory diseases based on routine parameters. Because of the high spatial and temporal variations, findings considered typical of certain CNS diseases often are absent in parts of or even in the entire CSF compartment. In CNS infections, identification of the pathogen by culture, antigen detection or molecular methods is essential for diagnosis.

Reducing the use of sleep-inducing drugs during hospitalisation by a multi-faceted intervention: a pilot study.

OBJECTIVES: Many patients receive benzodiazepines or Z-drugs during hospitalisation due to sleeping problems. In a pilot study, we aimed to find out whether, and to what degree, a multi-faceted intervention can reduce the use of these drugs, especially in older patients and those without a psychiatric or neurological disorder. The results of this pilot study should inform the design of a randomised controlled trial (RCT). METHODS: In a quasi-experimental design, we implemented the intervention in a German hospital with the support of the hospital director, medical and nursing staff and employee representatives. We compared prescription data for sleep-inducing drugs before and after the intervention by Fisher's exact test and used odds ratios (ORs) with their 95% CIs as a measure of effect size. RESULTS: The data from 960 patients aged ≥65 years before intervention and 1049 patients after intervention were analysed. Before intervention, 483 (50.3%) of the patients received sleep-inducing drugs at some time during their hospital stay. After the intervention, 381 (36.3%) patients received a sleep-inducing drug, resulting in an OR of 0.56 (95% CI 0.47 to 0.68) (p<0.001). The reduction was particularly pronounced in patients without a psychiatric or neurological disorder (from 45.0% to 28.8%). In particular, the consumption of benzodiazepines declined from 24.3% to 8.5% (OR 0.31; 95% CI 0.23 to 0.4) (p<0.001). CONCLUSIONS: A multi-faceted intervention to change the practice of the use of sleep-inducing drugs in one hospital was successful in terms of drug reduction, particularly for benzodiazepines. The intervention was effective especially for target persons-that is, those without a psychiatric or neurological disease. Awareness of the magnitude of the change and the role of important stakeholders could help researchers and hospital staff to design a large RCT, including control hospitals, to evaluate the success of a multi-faceted intervention on a scientifically sound basis.

Intracerebral Infection with E. coli Impairs Spatial Learning and Induces Necrosis of Hippocampal Neurons in the Tg2576 Mouse Model of Alzheimer's Disease.

Background: In patients with Alzheimer's disease (AD), bacterial infections are often associated with a cognitive decline. Animal models of genuine acute infections with viable bacteria which induce deterioration of neurodegenerative diseases are missing. Objective: We assessed the effect of an intracerebral infection with E. coli in a mouse model of AD. Methods: 13-month-old Tg2576 +/- mice and transgene negative littermates (Tg2576 -/-) received an intracerebral injection with E. coli K1 or saline followed by treatment with ceftriaxone starting 41 h post infection (p.i.) for 5 days. For 4 weeks, mice were monitored for clinical status, weight, motor functions, and neuropsychological status using the Morris water maze. ELISAs, stainings, and immunohistochemistry in brains were performed at the end of the experiment. Results: Mortality of the infection was approximately 20%. After 4 weeks, spatial learning of infected Tg2576 +/- mice was compromised compared to non-infected Tg2576 +/- mice (p < 0.05). E. coli infection did not influence spatial learning in Tg2576 -/- mice, or spatial memory in both Tg2576 +/- and -/- mice within 4 weeks p.i.. Necrosis of hippocampal neurons was induced in infected compared to non-infected Tg2576 +/- mice 4 weeks p.i., whereas brain concentrations of Aß1-40, Aß1-42, and phosphoTau as well as axonal damage and microglia density were not altered. Conclusion: Here, we proved in principle that a genuine acute bacterial infection can worsen cognitive functions of AD mice. Mouse models of subacute systemic infections are needed to develop new strategies for the treatment of bacterial infections in patients with AD in order to minimize their cognitive decline.

Chronic Candida albicans meningitis misdiagnosed as polymyalgia rheumatica and successfully treated with voriconazole.

The outcome of chronic meningitis depends to a large degree on the causative pathogen and the interval between onset of symptoms and diagnosis. We present a patient with a delayed diagnosis and several complications, for whom adequate therapy resulted in a favorable outcome. In a 76-year-old male patient, Candida albicans meningitis was diagnosed 4 months after the onset of symptoms. CSF findings (protein >1000 mg/L, predominance of intrathecal immunoglobulin A synthesis, lactate concentrations of approx. 10 mmol/L, leukocyte counts around 1000/µl, variable differential leukocyte counts) resembled tuberculous meningitis. In spite of the long interval without treatment, voriconazole 200 mg every 12 h for 7 weeks followed by fluconazole 300 mg/day maintenance therapy for 7 months led to a recovery with only mild deficits. The case illustrates that 1. C. albicans can cause chronic meningitis in patients without severe immune defects, 2. patients can survive C. albicans meningitis with mild long-term sequelae even when diagnosis and adequate treatment are delayed, and 3. voriconazole as a sole agent may be suitable for treatment of C. albicans meningitis.

Interferon-gamma impairs phagocytosis of Escherichia coli by primary murine peritoneal macrophages stimulated with LPS and differentially modulates proinflammatory cytokine release.

INTRODUCTION: Interferon-γ levels are increased upon viral infections and during inflamm-aging. Resistance to infections due to Escherichia coli (E. coli), a major cause of bacteriaemia and sepsis, is impaired in aged individuals, partly due to altered phagocytic capacity and cytokine release of immune cells. Here, we analyzed the effect of IFN-γ on phagocytosis of E. coli K1 and release of proinflammatory cytokines by macrophages in resting condition and upon stimulation with different bacterial Toll-like receptor (TLR) agonists. METHODS: Primary peritoneal macrophages from C57BL/6 mice were exposed to medium or stimulated with agonists of TLR4 (LPS), 1/2 (Pam3CSK4), and 9 (CpG-DNA) in the presence and absence of IFN-γ (100 U/ml) for 24 h. TNF-α, IL-6, and KC were measured in the cell culture supernatant by ELISA. Macrophages were exposed to viable E. coli K1. After 90 min, intracellular phagozytosed bacteria were quantified by quantitative plating. RESULTS: Macrophages treated with LPS 1 µg/ml in the presence of IFN-γ ingested more than 10-fold lower numbers of E. coli than macrophages treated with LPS alone. Phagocytosis of E. coli by macrophages in resting condition or upon stimulation with Pam3CSK4 or CpG was not significantly affected by IFN-γ. Cytokine release was differentially modulated by IFN-γ, with reduced KC release by TLR-stimulated macrophages in the presence of IFN-γ being the most striking effect. CONCLUSIONS: In vitro, IFN-γ reduces the phagocytosis of E. coli by LPS-stimulated macrophages and differentially modulates cytokine release of macrophages activated by different bacterial TLR agonists. Elevated levels of IFN-γ might lead to reduced bacterial clearance and worse outcome of bacterial infections, e.g., in aged individuals and after viral infections and other inflammatory events.

Neural Injury and Repair in a Novel Neonatal Mouse Model of Listeria Monocytogenes Meningoencephalitis.

To improve the therapy of neonatal central nervous system infections, well-characterized animal models are urgently needed. The present study analyzes neuropathological alterations with particular focus on neural injury and repair in brains of neonatal mice with Listeria monocytogenes (LM) meningitis/meningoencephalitis using a novel nasal infection model. The hippocampal formation and frontal cortex of 14 neonatal mice with LM meningitis/meningoencephalitis and 14 uninfected controls were analyzed by histology, immunohistochemistry, and in situ tailing for morphological alterations. In the dentate gyrus of the hippocampal formation of mice with LM meningitis/meningoencephalitis, an increased density of apoptotic neurons visualized by in situ tailing (p = 0.04) and in situ tailing plus immunohistochemistry for activated Caspase-3 (p < 0.0001) was found. A decreased density of dividing cells stained with an anti-PCNA-antibody (p < 0.0001) and less neurogenesis visualized by anti-calretinin (p < 0.0001) and anti-calbindin (p = 0.01) antibodies were detected compared to uninfected controls. The density of microglia was higher in LM meningitis (p < 0.0001), while the density of astrocytes remained unchanged. Infiltrating monocytes and neutrophilic granulocytes likely contributed to tissue damage. In conclusion, in the brains of LM-infected mice a strong immune response was observed which led to neuronal apoptosis and an impaired neural regeneration. This model appears very suitable to study therapies against long-term sequelae of neonatal LM meningitis.

Reduced Clostridioides difficile infections in hospitalised older people through multiple quality improvement strategies.

OBJECTIVES: To reduce infections with Clostridioides difficile (CDI) in geriatric patients by interventions easily implementable in standard clinical care. METHODS: Prevalence and incidence of CDI between January 2015 and February 2020 were analysed (n = 25,311 patients). Pre-intervention status was assessed from April 2016 to March 2017 (n = 4,922). Between May 2017 and August 2019, a monocentric interventional crossover study (n = 4,655) was conducted including standard care and three interventions: (A) sporicidal cleaning of hospital wards, (B) probiotics and (C) improvement in personal hygiene for CDI patients. This was followed by a multicentric comparison of the interventional bundle (A + B + C) between September 2019 and February 2020 (n = 2,593) with the pre-intervention phase. In 98 CDI cases and matched controls individual risk factors for the development of CDI were compared. RESULTS: Time series analyses of CDI cases revealed a reduction in the prevalence of CDI in all three participating centres prior to the multicentric intervention phase. In the monocentric phase, no effect of individual interventions on CDI prevalence was identified. However, an aggregated analysis of CDI cases comparing the pre-intervention and the multicentric phase revealed a significant reduction in CDI prevalence. Risk factors for the development of CDI included use of antibiotics, anticoagulants, previous stay in long-term care facilities, prior hospital admissions, cardiac and renal failure, malnutrition and anaemia. CONCLUSIONS: The observed reduction in CDI may be attributed to heightened awareness of the study objectives and specific staff training. Individual interventions did not appear to reduce CDI prevalence. A further randomised trial would be necessary to confirm whether the bundle of interventions is truly effective.