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Abstract This study investigated transfer of improvements in stability recovery performance to novel perturbations. Thirty adults (20-53 yr) were assigned equally to three treadmill walking groups: groups exposed to eight trip perturbations of either low or high magnitude and a third control group that walked unperturbed. Following treadmill walking, participants were exposed to stability loss from a forward-inclined position (lean-and-release) and an overground trip. Lower limb joint kinematics for the swing phase of recovery steps was compared for the three tasks using statistical parametric mapping and recovery performance was analysed by margin of stability and base of support. The perturbation groups improved stability (greater margin of stability) over the eight gait perturbations. There was no group effect for stability recovery in lean-and-release. For the overground trip, both perturbation groups showed similar enhanced stability recovery (margin of stability and base of support) compared to controls. Differences in joint angle kinematics between treadmill-perturbation and lean-and-release were more prolonged and greater than between the two gait perturbation tasks. This study indicates that: (i) practising stability control enhances human resilience to novel perturbations; (ii) enhancement is not necessarily dependent on perturbation magnitude; (iii) differences in motor response patterns between tasks may limit transfer.

Abstract Background Early support for children with developmental disabilities is crucial but frequently unavailable in low-resource settings. We conducted a mixed-methods evaluation to assess the feasibility, acceptability, and impact of a programme of early detection and intervention for young children with developmental disabilities in Western Uganda. Methods Early child development training for healthcare workers (HCWs) was implemented in three rural districts, and attendance was tracked. HCW knowledge and confidence were assessed pre-/post-intervention, and referral numbers tracked to evaluate impact. Facilitators were trained and mentored to deliver a participatory, group, early intervention programme (EIP) for young children with developmental disabilities and their families. Facilitators were tracked as they were identified, trained, and delivered the intervention, and attendance of families was tracked. Pre−/post-intervention assessments evaluated changes in family quality of life (PedsQL 2.0, Family Impact Module), and child nutritional outcomes. Focus group discussions with stakeholders also assessed feasibility, acceptability and impact. Results Overall, 93 HCWs from 45 healthcare facilities received training. In the pre−/post-evaluation, median knowledge and confidence scores increased significantly (from 4.0 to 7.0 and from 2.7 to 4.7, respectively (p

Objectives: We examined HIV sero-positivity and risk factors in patients admitted with ischaemic stroke (IS) and haemorrhagic stroke (HS) in Kampala, Uganda. Study design: We conducted a matched case-control study between December 2016 and December 2018 ​at ​St Francis Hospital, Nsambya. Methods: The study population comprised of stroke cases (adults aged ≥18 years with IS or HS confirmed by neuroimaging) and controls (age- and sex-matched stroke-free adults aged ≥18 years who were recruited from the same hospital as the cases). A comprehensive assessment for sociodemographic, lifestyle and clinical factors was performed using the World Health Organization (WHO) STEP-wise approach to Surveillance (STEPS) for stroke risk factor surveillance. We used conditional logistic regression to identify risk factors associated with IS or HS. Results: We enrolled 137 matched case-control pairs; 48 (35%) were men, and the mean ages were 62.4 years (SD ​± ​14.8) for cases and 61.1 years (SD ​± ​14.1) for controls. Of stroke patients, 86 (63%) had IS and 51 (37%) had HS. Overall, HIV sero-positivity was 10% among stroke cases versus 7% among controls. HIV sero-positivity was not significantly associated with stroke (unadjusted odds ratio [uOR] ​= ​1.49, 95% confidence interval [CI] 0.59–3.78). A self-reported family history of diabetes mellitus was associated with an increased risk of all stroke (adjusted odds ratio [aOR] ​= ​4.41, 95% CI 1.47–13.2), as well as for IS and HS separately (aOR ​= ​3.66, 95% CI 1.09–12.4 and aOR ​= ​4.99, 95% CI 1.02–24.4, respectively). High blood pressure (≥140/90 ​mmHg) was associated with an increased risk of all stroke (aOR ​= ​12.3, 95% CI 42–44.1), and this was also true for IS and HS individually (aOR ​= ​6.48, 95% CI 1.15–36.7 and aOR ​= ​5.63, 95% CI 1.74–18.2, respectively). Conclusions: No association was found between HIV sero-positivity and stroke occurrence among Ugandan stroke patients. Hypertension and a self-reported family history of diabetes mellitus were significant risk factors for both IS and HS. Interventions to reduce hypertension and diabetes mellitus in the Ugandan population are urgently required. Much larger studies are required to demonstrate if any association exists between HIV and stroke.

Folate is a water-soluble vitamin that is essential to DNA synthesis and replication. Its deficiency is a leading cause of megaloblastic anemia, which is often asymptomatic but can present with nonspecific symptoms, such as fatigue and lightheadedness. Folate deficiency can rarely present with pancytopenia, which has been described in past case reports but even more scarcely in transplant recipients. We present a 74-year-old bilateral lung transplantee who presented with presyncope and was found to have severe pancytopenia with folate deficiency during the initial workup. Some medications, including mycophenolate mofetil, valganciclovir, and posaconazole were held. Peripheral blood smear showed blastoid cells, but follow-up imaging and flow cytometry negated any concern for a malignant process. Bone marrow biopsy showed an extremely hypocellular marrow with marked trilineage hypoplasia. He required blood product transfusions, but his admission was overall uneventful with no life-threatening sequelae. His blood counts improved with folate replacement and discontinuation of offending medications. He was discharged after nine days in stable condition. Two months later, he experienced a milder and self-limited recurrence of pancytopenia with normal folate and cobalamin levels., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Au-Yeung et al.)

Background: Gum arabic, a polysaccharide exudate from Acacia senegal (L.) Willdenow trees, has already been used by African native people in natural medicine., Methods: Using whole-blood samples from young (20-35 years) and older (>80 years) healthy volunteers (each group n = 10), the effect of an aqueous solution of GA on phagocytosis of Escherichia coli was examined with a gentamicin protection assay. Whole-blood samples of each volunteer were stimulated with GA and as a control with CpG oligodeoxynucleotides (Toll-like receptor -9 agonists) for 2 h, then co-incubated with E. coli for 30 min and thereafter treated with gentamicin for up to 240 min to kill extracellular bacteria. Then, whole-blood cells were lysed with distilled water, and colony-forming units were counted by quantitative plating. Cytokine enzyme-linked immunosorbent assay for the detection of TNF-α and IL-6 was performed using the blood supernatant., Results: The GA concentration tested (20 mg/mL) did not affect the viability of eukaryotic cells. Phagocytosis of E. coli by whole-blood leukocytes derived from young ( p = 0.008) and older ( p = 0.004) healthy volunteers was increased by 120.8% (young) and 39.2% (old) after stimulation with GA. In contrast, CpG only stimulated the bacterial phagocytosis by cells derived from young volunteers ( p = 0.004). Stimulation of whole blood with GA increased the intracellular killing of E. coli in young ( p = 0.045) and older volunteers ( p = 0.008) and induced a TNF-α release in whole blood collected from older volunteers but not from younger ones ( p = 0.008)., Conclusions: These data encourage the isolation of active compounds of GA and the initiation of clinical trials addressing the preventive effect of GA on bacterial infections.

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., (The Author(s). Published by S. Karger AG, Basel.)

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 β-lactam/β-lactamase inhibitor combinations have the principal problem that both compounds must achieve adequate CSF concentrations. In the commercially available combinations, the dose of the β-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.

Introduction: Patients suffering from a Clostridioides difficile infection have a higher overall mortality than patients with similar comorbidities., Methods: Whole blood samples of 15 patients with C. difficile enteritis and 15 control patients matched for age and sex were used to analyze the capacity of blood phagocytes to internalize and kill encapsulated Escherichia (E.) coli. The median age of C. difficile patients and control patients was 81 and 82 years, respectively. Blood samples were co-incubated with E. coli for 15 or 30 min. After 15 min of co-incubation, extracellular bacteria were killed by gentamicin for 15-45 min. Then eukaryotic cells were lysed with distilled water, and the number of intracellular bacteria per ml whole blood was determined by quantitative plating on agar plates. Both groups were compared by Mann-Whitney U test., Results: After 15 or 30 min of co-incubation, blood phagocytes from patients with C. difficile enteritis showed a reduced density of phagocytosed or adherent bacteria in comparison to blood phagocytes from control patients (15 min: p = 0.046, 30 min: p = 0.005). The density of intracellular bacteria decreased less rapidly over time in the blood from C. difficile patients (median Δlog CFU/mL × h [25th/75th percentile] -0.893 [-1.893/-0.554] vs. -1.483 [-2.509/-1.028]; p = 0.02). In line with these results, the percentage of intracellularly killed bacteria was decreased in phagocytes from C. difficile-infected patients compared to controls (median intracellular killing rate 64.3% for blood phagocytes from C. difficile patients vs. 81.9% for blood phagocytes from control patients within 30 min of co-incubation, p = 0.048)., Conclusion: Blood phagocytes from patients with C. difficile enteritis exhibited a reduced capacity to phagocytose and kill bacteria in comparison to blood phagocytes from age- and sex-matched control patients. Patients with C. difficile infection may have a higher disposition to develop infectious diseases than age- and sex-matched control patients., (© 2024 S. Karger AG, Basel.)

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-1β 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Eggers, Ballüer, Mohamed, Nau and Seele.)

We present measurements of the cross section and double-helicity asymmetry A&#95;{LL} of direct-photon production in p[over →]+p[over →] collisions at sqrt[s]=510  GeV. The measurements have been performed at midrapidity (|η|<0.25) with the PHENIX detector at the Relativistic Heavy Ion Collider. At relativistic energies, direct photons are dominantly produced from the initial quark-gluon hard scattering and do not interact via the strong force at leading order. Therefore, at sqrt[s]=510  GeV, where leading-order-effects dominate, these measurements provide clean and direct access to the gluon helicity in the polarized proton in the gluon-momentum-fraction range 0.02

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., (© 2023. The Author(s).)

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 Aβ 1-40 , Aβ 1-42 , 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., Competing Interests: The authors have no conflict of interest to report., (© 2022 – The authors. Published by IOS Press.)

Background: The crosstalk and reactivity of the cell type glia, especially microglia and astrocytes, have progressively gathered research attention in understanding proper brain function regulated by the innate immune response. Therefore, methods to isolate highly viable and pure glia for the analysis on a cell-specific level are indispensable., New Method: We modified previously established techniques: Animal numbers were reduced by multiple microglial harvests from the same mixed glial culture, thereby maximizing microglial yields following the principles of the 3Rs (replacement, reduction, and refinement). We optimized Magnetic-activated cell sorting (MACS®) of microglia and astrocytes by applying cultivated primary glial cell suspensions instead of directly sorting dissociated single cell suspension., Results: We generated highly viable and pure microglia and astrocytes derived from a single mixed culture with a purity of ~99%, as confirmed by FACS analysis. Field emission scanning electron microscopy (FESEM) demonstrated integrity of the MACS-purified glial cells. Tumor necrosis factor (TNF) and Interleukin-10 (IL-10) ELISA confirmed pro- and anti-inflammatory responses to be functional in purified glia, but significantly weakened compared to non-purified cells, further highlighting the importance of cellular crosstalk for proper immune activation., Comparison With Existing Method(s): Unlike previous studies that either isolated a single type of glia or displayed a substantial proportion of contamination with other cell types, we achieved isolation of both microglia and astrocytes at an increased purity (99-100%)., Conclusions: We have created an optimized protocol for the efficient purification of both primary microglia and astrocytes. Our results clearly demonstrate the importance of purity in glial cell cultivation in order to examine immune responses, which particularly holds true for astrocytes. We propose the novel protocol as a tool to investigate the cell type-specific crosstalk between microglia and astrocytes in the frame of CNS diseases., (Copyright © 2021. Published by Elsevier B.V.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)