The effectiveness of nitrofurantoin, fosfomycin and trimethoprim for the treatment of cystitis in relation to renal function

Objectives: We evaluated the effect of renal function on clinical failure rates of nitrofurantoin, fosfomycin and trimethoprim for the treatment of cystitis in primary care. Methods: Data were retrospectively obtained from 78 Dutch general practitioner (GP) practices between 2013 and 2019. Eligible episodes in patients (>11 years) were those requiring 5 days of nitrofurantoin (NF5), single-dose fosfomycin–trometamol (FT1), 3 days of trimethoprim (TMP3) for uncomplicated cystitis, or 7 days of nitrofurantoin (NF7) or trimethoprim (TMP7) for complicated cystitis. Clinical failure was defined as second antibiotic prescription for cystitis or pyelonephritis within 28 days post-prescription. Mixed effects regression analysis was used, with patient and GP practice as random effects and demography, comorbidity, and cystitis history as fixed effects. Results: Adjusted odds ratios (aORs) for clinical failure per 10mL/min decrease in estimated glomerular filtration rate (eGFR) were 1.05 (95% CI: 1.01–1.09) for NF5 (n = 24,591), 0.96 (95% CI: 0.92–1.01) for FT1 (n = 5359), 0.98 (95% CI: 0.89–1.08) for TMP3 (n = 1064), 1.05 (95% CI: 1.02–1.09) for NF7 (n = 10,628) and 1.02 (95% CI: 0.93–1.14) for TMP7 (n = 831). In uncomplicated cystitis and eGFR ≥60 mL/min, clinical failures occurred in 14.6% (1895/12 980) of NF5-treated, 20.7% (266/1283) of FT1-treated (aOR versus NF5 1.37, 95% CI 1.18–1.59) and 20.8% (66/318) of TMP3-treated patients (aOR 1.42, 95% CI 1.07–1.87 versus NF5). In uncomplicated cystitis and eGFR <60 mL/min, FT1 resulted in 16.0% (39/244) and NF5 in 23.3% clinical failures (110/472), aOR: 0.61, 95% CI: 0.39–0.95). Conclusions: In eGFR ≥60 mL/min treatment with fosfomycin or trimethoprim for uncomplicated cystitis was associated with more clinical failure than treatment with nitrofurantoin, while in eGFR <60 mL/min nitrofurantoin was associated with more clinical failure than fosfomycin–trometamol. Renal function, if known, should be considered in the clinical decision-making for cystitis treatment

Fluid resuscitation in sepsis: the great 30 mL per kg hoax

Large volume fluid resuscitation is currently viewed as the cornerstone of the treatment of septic shock. The surviving sepsis campaign (SSC) guidelines provide a strong recommendation to rapidly administer a minimum of 30 mL/kg crystalloid solution intravenously in all patients with septic shock and those with elevated blood lactate levels. However, there is no credible evidence to support this recommendation. In fact, recent findings from experimental, observational and randomized clinical trials demonstrate improved outcomes with a more restrictive approach to fluid resuscitation. Accumulating evidence suggests that aggressive fluid resuscitation is harmful. Paradoxically, excess fluid administration may worsen shock. In this review, we critically evaluate the scientific evidence for a weight-based fluid resuscitation approach. Furthermore, the potential mechanisms and consequences of harm associated with fluid resuscitation are discussed. Finally, we recommend an individualized, conservative and physiologic guided approach to fluid resuscitation

Observation of the screening signature in the lateral photovoltage of electrons in the Quantum Hall regime

The lateral photovoltage generated in the plane of a two-dimensional electron system (2DES) by a focused light spot, exhibits a fine-structure in the quantum oscillations in a magnetic field near the Quantum Hall conductivity minima. A double peak structure occurs near the minima of the longitudinal conductivity oscillations. This is the characteristic signature of the interplay between screening and Landau quantization.Comment: 4 pages, 4 figures, to be published in Phys. Rev.

The effects of aerobic exercise and transcranial direct current stimulation on cognitive function in older adults with and without cognitive impairment:A systematic review and meta-analysis

Background: Aerobic exercise (AE) may slow age-related cognitive decline. However, such cognition-sparing effects are not uniform across cognitive domains and studies. Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation and is also emerging as a potential alternative to pharmaceutical therapies. Like AE, the effectiveness of tDCS is also inconsistent for reducing cognitive impairment in ageing. The unexplored possibility exists that pairing AE and tDCS could produce synergistic effects and reciprocally augment cognition-improving effects in older individuals with and without cognitive impairments. Previous research found such synergistic effects on cognition when cognitive training is paired with tDCS in older individuals with and without mild cognitive impairment (MCI) or dementia. Aim: The purpose of this systematic review with meta-analysis was to explore if pairing AE with tDCS could augment singular effects of AE and tDCS on global cognition (GC), working memory (WM) and executive function (EF) in older individuals with or without MCI and dementia. Methods: Using a PRISMA-based systematic review, we compiled studies that examined the effects of AE alone, tDCS alone, and AE and tDCS combined on cognitive function in older individuals with and without mild cognitive impairment (MCI) or dementia. Using a PICOS approach, we systematically searched PubMed, Scopus and Web of Science searches up to December 2021, we focused on ‘MoCA’, ‘MMSE’, ‘Mini-Cog’ (measures) and ‘cognition’, ‘cognitive function’, ‘cognitive’, ‘cognitive performance’, ‘executive function’, ‘executive process’, ‘attention’, ‘memory’, ‘memory performance’ (outcome terms). We included only randomized controlled trials (RTC) in humans if available in English full text over the past 20 years, with participants’ age over 60. We assessed the methodological quality of the included studies (RTC) by the Physiotherapy Evidence Database (PEDro) scale. Results: Overall, 68 studies were included in the meta-analyses. AE (ES = 0.56 [95% CI: 0.28–0.83], p = 0.01) and tDCS (ES = 0.69 [95% CI: 0.12–1.26], p = 0.02) improved GC in all three groups of older adults combined (healthy, MCI, demented). In healthy population, AE improved GC (ES = 0.46 [95% CI: 0.22–0.69], p = 0.01) and EF (ES = 0.27 [95% CI: 0.05–0.49], p = 0.02). AE improved GC in older adults with MCI (ES = 0.76 [95% CI: 0.21–1.32], p = 0.01). tDCS improved GC (ES = 0.69 [90% CI: 0.12–1.26], p = 0.02), all three cognitive function (GC, WM and EF) combined in older adults with dementia (ES = 1.12 [95% CI: 0.04–2.19], p = 0.04) and improved cognitive function in older adults overall (ES = 0.69 [95% CI: 0.20–1,18], p = 0.01). Conclusion: Our systematic review with meta-analysis provided evidence that beyond the cardiovascular and fitness benefits of AE, pairing AE with tDCS may have the potential to slow symptom progression of cognitive decline in MCI and dementia. Future studies will examine the hypothesis of this present review that a potentiating effect would incrementally improve cognition with increasing severity of cognitive impairment

Dynamic Interactive Social Cognition Training in Virtual Reality (DiSCoVR) for adults with Autism Spectrum Disorder:A feasibility study

Background: Social cognitive difficulties in Autism Spectrum Disorder (ASD) can affect the daily lives of people with ASD profoundly, impacting the development and maintenance of meaningful social relations. Social cognition training (SCT) is commonly used for improving social functioning, but lacks ecological validity and the ability to effectively mimic social situations. Development of virtual reality (VR) interventions, focusing on enhancing social cognition, could add to the effectiveness of SCT within ASD care, by offering a safe, interactive and practical training setting, where generalization of knowledge and skills to the real-world are promoted. In this paper, our primary aim is to evaluate the feasibility and acceptance by participants and therapists of the Dynamic Interactive Social Cognition Method: Training in Virtual Reality (DiSCoVR) protocol as developed for adults with schizophrenic spectrum disorder (SSD), adapted for ASD (DiSCoVR-A). 26 participants, aged 18-63, took part in a pilot study. 22 participants completed baseline and post-assessment, including primary outcome evaluation assessment through a semi-structured interview. Secondary measures focused on social cognition, emotion recognition, mental flexibility, social anxiety, empathy and social responsiveness and were assessed at baseline (T0), post-treatment (T1), and at follow-up (T2) sixteen weeks after completion of the intervention. Results: Our results show that the majority of participant and therapists found the VR intervention acceptable and feasible, as reported in evaluation questionnaires and interviews. Conclusion: These preliminary findings are promising; however, controlled research is needed to further investigate the effectiveness of VR within social cognition training for adults with ASD

Meaningful outcomes for children and their caregivers attending a paediatric brain centre

Aim: To identify meaningful outcomes of children and their caregivers attending a paediatric brain centre. Method: We compiled a long list of outcomes of health and functioning of children with brain-related disorders such as cerebral palsy, spina bifida, (genetic) neurodevelopmental disorders, and acquired brain injury. We incorporated three perspectives: patients, health care professionals, and published outcome sets. An aggregated list was categorized using the International Classification of Functioning, Disability, and Health: Children and Youth version in a patient validation survey for children and parent-caregivers to prioritize outcomes. Outcomes were considered meaningful when ranked ‘very important’ by 70% or more of the participants. Results: We identified 104 outcomes from the three perspectives. After categorizing, 59 outcomes were included in the survey. Thirty-three surveys were completed by children (n = 4), caregivers (n = 24), and parent-caregivers together with their child (n = 5). Respondents prioritized 27 meaningful outcomes covering various aspects of health and functioning: emotional well-being, quality of life, mental and sensory functions, pain, physical health, and activities (communication, mobility, self-care, interpersonal relationships). Parent-caregiver concerns and environmental factors were newly identified outcomes. Interpretation: Children and parent-caregivers identified meaningful outcomes covering various aspects of health and functioning, including caregiver concerns and environmental factors. We propose including those in future outcome sets for children with neurodisability. What this paper adds: Outcomes that children with brain-related disorders and their parent-caregivers consider to be the most meaningful cover a wide range of aspects of functioning. Involving these children and their parent-caregivers resulted in the identification of important outcomes that were not covered by professionals and the literature. Parent-caregiver-related factors (coping, burden of care) and environmental factors (support, attitudes, and [health care] services) were identified as meaningful.</p

De-identification procedures for magnetic resonance images and the impact on structural brain measures at different ages

Surface rendering of MRI brain scans may lead to identification of the participant through facial characteristics. In this study, we evaluate three methods that overwrite voxels containing privacy-sensitive information: Face Masking, FreeSurfer defacing, and FSL defacing. We included structural T1-weighted MRI scans of children, young adults and older adults. For the young adults, test-retest data were included with a 1-week interval. The effects of the de-identification methods were quantified using different statistics to capture random variation and systematic noise in measures obtained through the FreeSurfer processing pipeline. Face Masking and FSL defacing impacted brain voxels in some scans especially in younger participants. FreeSurfer defacing left brain tissue intact in all cases. FSL defacing and FreeSurfer defacing preserved identifiable characteristics around the eyes or mouth in some scans. For all de-identification methods regional brain measures of subcortical volume, cortical volume, cortical surface area, and cortical thickness were on average highly replicable when derived from original versus de-identified scans with average regional correlations \u3e.90 for children, young adults, and older adults. Small systematic biases were found that incidentally resulted in significantly different brain measures after de-identification, depending on the studied subsample, de-identification method, and brain metric. In young adults, test-retest intraclass correlation coefficients (ICCs) were comparable for original scans and de-identified scans with average regional ICCs \u3e.90 for (sub)cortical volume and cortical surface area and ICCs \u3e.80 for cortical thickness. We conclude that apparent visual differences between de-identification methods minimally impact reliability of brain measures, although small systematic biases can occur

Knockdown of nicotinamide N-methyltransferase suppresses proliferation, migration and chemoresistance of Merkel cell carcinoma cells in vitro

Merkel cell carcinoma (MCC) is an aggressive skin cancer, with a propensity for early metastasis. Therefore, early diagnosis and the identification of novel targets become fundamental. The enzyme nicotinamide N-methyltransferase (NNMT) catalyzes the reaction of N-methylation of nicotinamide and other analogous compounds. Although NNMT overexpression was reported in many malignancies, the significance of its dysregulation in cancer cell phenotype was partly clarified. Several works demonstrated that NNMT promotes cancer cell proliferation, migration, and chemoresistance. In this study, we investigated the possible involvement of this enzyme in MCC. Preliminary immunohistochemical analyses were performed to evaluate NNMT expression in MCC tissue specimens. To explore the enzyme function in tumor cell metabolism, MCC cell lines have been transfected with plasmids encoding for short hairpin RNAs (shRNAs) targeting NNMT mRNA. Preliminary immunohistochemical analyses showed elevated NNMT expression in MCC tissue specimens. The effect of enzyme downregulation on cell proliferation, migration, and chemosensitivity was then evaluated through MTT, trypan blue, and wound healing assays. Data obtained clearly demonstrated that NNMT knockdown is associated with a decrease of cell proliferation, viability, and migration, as well as with enhanced sensitivity to treatment with chemotherapeutic drugs. Taken together, these results suggest that NNMT could represent an interesting MCC biomarker and a promising target for targeted anti-cancer therapy

Brain structure, IQ, and psychopathology in young offspring of patients with schizophrenia or bipolar disorder

BACKGROUND.: Studying offspring of schizophrenia (SZo) and bipolar disorder patients (BDo) provides important information on the putative neurodevelopmental trajectories underlying development toward severe mental illnesses. We compared intracranial volume (ICV), as a marker for neurodevelopment, and global and local brain measures between SZo or BDo and control offspring (Co) in relation to IQ and psychopathology. METHODS.: T1-weighted magnetic resonance imaging (MRI) brain scans were obtained from 146 participants (8-19 years; 40 SZo, 66 BDo, 40 Co). Linear mixed models were applied to compare ICV, global, and local brain measures between groups. To investigate the effect of ICV, IQ (four subtests Wechsler Intelligence Scale for Children/Wechsler Adult Intelligence Scale-III) or presence of psychopathology these variables were each added to the model. RESULTS.: SZo and BDo had significantly lower IQ and more often met criteria for a lifetime psychiatric disorder than Co. ICV was significantly smaller in SZo than in BDo (d = -0.56) and Co (d = -0.59), which was largely independent of IQ (respectively, d = -0.54 and d = -0.35). After ICV correction, the cortex was significantly thinner in SZo than in BDo (d = -0.42) and Co (d = -0.75) and lateral ventricles were larger in BDo than in Co (d = 0.55). Correction for IQ or lifetime psychiatric diagnosis did not change these findings. CONCLUSIONS.: Despite sharing a lower IQ and a higher prevalence of psychiatric disorders, brain abnormalities in BDo appear less pronounced (but are not absent) than in SZo. Lower ICV in SZo implies that familial risk for schizophrenia has a stronger association with stunted early brain development than familial risk for bipolar disorder