Reconstruction and Simulation of Neocortical Microcircuitry.

We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm(3) containing ~31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ~8 million connections with ~37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies. PAPERCLIP: VIDEO ABSTRACT.

Influence of Pathophysiological Patterns of Coronary Artery Disease on Immediate Percutaneous Coronary Intervention Outcomes.

BACKGROUND: Diffuse coronary artery disease (CAD) impacts the safety and efficacy of percutaneous coronary intervention (PCI). Pathophysiological CAD patterns can be quantified using fractional flow reserve (FFR) pullbacks incorporating the pullback pressure gradient (PPG) calculation. This study aimed to establish the capacity of PPG to predict optimal revascularisation and procedural outcomes. METHODS: This prospective, investigator-initiated, single-arm, multicentre study enrolled patients with at least one epicardial lesion with an FFR ≤ 0.80 scheduled for PCI. Manual FFR pullbacks were employed to calculate PPG. The primary outcome of optimal revascularisation was defined as a post-PCI FFR ≥ 0.88. RESULTS: 993 patients with 1044 vessels were included. The mean FFR was 0.68 ± 0.12, PPG 0.62 ± 0.17, and post-PCI FFR 0.87 ± 0.07. PPG was significantly correlated with the change in FFR after PCI (r=0.65, 95% CI 0.61-0.69, p<0.001) and demonstrated excellent predicted capacity for optimal revascularisation (AUC 0.82, 95% CI 0.79-0.84, p<0.001). Conversely, FFR alone did not predict revascularisation outcomes (AUC 0.54, 95% CI 0.50-0.57). PPG influenced treatment decisions in 14% of patients, redirecting them from PCI to alternative treatment modalities. Periprocedural myocardial infarction occurred more frequently in patients with low PPG (<0.62) compared to those with focal disease (OR 1.71, 95% CI: 1.00-2.97). CONCLUSIONS: Pathophysiological CAD patterns distinctly affect the safety and effectiveness of PCI. The PPG showed an excellent predictive capacity for optimal revascularisation and demonstrated added value compared to a FFR measurement.

Role of endogenous GLP-1 on arterial stiffness and renal haemodynamics following bariatric surgery.

BACKGROUND: Cardiovascular trials have revealed the positive impact of GLP-1 receptor agonists (GLP-1 RAs) on cardiovascular outcomes in type 2 diabetes (T2D). However, the specific effects of endogenous GLP-1 on arterial stiffness and renal function remain understudied. This study aimed to explore the influence of endogenous GLP-1 response post-bariatric surgery on arterial stiffness and renal haemodynamic. METHODS: Thirty individuals with morbid obesity and without T2D, scheduled for Roux-en-Y Gastric Bypass (RYGB), were included. Clinical parameters, 3-hour oral glucose tolerance test (OGTT) with serial sampling for glycaemia, GLP-1 and insulin, carotid-femoral pulse wave velocity (cf-PWV), carotid distensibility coefficient (carotid-DC) and renal resistive index (RRI) measurements were conducted pre-surgery and 1-year post-surgery. Participants were categorized into high-response and low-response groups based on their post-surgery increase in GLP-1 (median increase of 104% and 1%, respectively, pre- vs. post-surgery). RESULTS: Post-surgery, high-response group demonstrated a greater reduction in cf-PWV (p = .033) and a greater increase (p = .043) in carotid DC compared to low-response group. These enhancements were observed independently of weight loss or blood pressure changes. High-response group exhibited a reduction in RRI (p = .034), although this association was influenced by improvement in pulse pressure. Finally, a multivariate stepwise regression analysis indicated that the percentage increase of GLP1, Δ-GLP1(AUC)%, was the best predictor of percentage decrease in cf-PWV (p = .014). CONCLUSIONS: Elevated endogenous GLP-1 response following RYGB was associated with improved arterial stiffness and renal resistances, suggesting potential cardio-renal benefits. The findings underscore the potential role of endogenous GLP-1 in influencing vascular and renal haemodynamics independent of traditional weight loss.

Plant-Based Milk Consumption and Growth in Children 1-10 Years of Age.

BACKGROUND: The effects of plant-based milk consumption on the growth of children are unclear. OBJECTIVES: We aimed to evaluate the relationship between plant-based milk consumption and BMI in childhood. Secondary objectives were to examine the association with height and whether these relationships are mediated by dairy milk intake and modified by age or the type of plant-based milk consumed. METHODS: A prospective cohort study was conducted in healthy children aged 1-10 y through the TARGet Kids! primary care research network in Toronto, Canada. Linear mixed-effect modeling and logistic generalized estimating equations were used to evaluate the association between plant-based milk consumption (number of 250 mL cups/d) and BMI. A mediation analysis was conducted to examine whether dairy milk intake mediated these relationships. Effect modification by age and type of plant-based milk was explored. RESULTS: Among 7195 children (mean age: 3.1 y; 52.3% male), higher plant-based milk consumption was associated with lower BMI (P = 0.0002) and height (P = 0.005). No association was found with BMI categories. Lower dairy milk intake partially mediated these relationships. A child aged 5 y who consumed 3 cups of plant-based milk compared with 3 cups of dairy milk had a lower weight of 0.5 kg and lower height of 0.8 cm. Associations did not change over time and were similar for children who consumed soy milk compared with other plant-based milks. CONCLUSIONS: Plant-based milk consumption was associated with lower BMI and height, but both were within the normal range on average. Future longitudinal studies are needed to determine whether these associations persist over time.

Factors Associated With Loss to Follow-Up in Surgical Trials: A Systematic Review and Meta-Analysis.

INTRODUCTION: Loss to follow-up (LTFU) distorts results of randomized controlled trials (RCTs). Understanding trial characteristics that contribute to LTFU may enable investigators to anticipate the extent of LTFU and plan retention strategies. The objective of this systematic review and meta-analysis was to investigate the extent of LTFU in surgical RCTs and evaluate associations between trial characteristics and LTFU. METHODS: MEDLINE, Embase, and PubMed Central were searched for surgical RCTs published between January 2002 and December 2021 in the 30 highest impact factor surgical journals. Two-hundred eligible RCTs were randomly selected. The pooled LTFU rate was estimated using random intercept Poisson regression. Associations between trial characteristics and LTFU were assessed using metaregression. RESULTS: The 200 RCTs included 37,914 participants and 1307 LTFU events. The pooled LTFU rate was 3.10 participants per 100 patient-years (95% confidence interval [CI] 1.85-5.17). Trial characteristics associated with reduced LTFU were standard-of-care outcome assessments (rate ratio [RR] 0.17; 95% CI 0.06-0.48), surgery for transplantation (RR 0.08; 95% CI 0.01-0.43), and surgery for cancer (RR 0.10; 95% CI 0.02-0.53). Increased LTFU was associated with patient-reported outcomes (RR 14.21; 95% CI 4.82-41.91) and follow-up duration ≥ three months (odds ratio 10.09; 95% CI 4.79-21.28). CONCLUSIONS: LTFU in surgical RCTs is uncommon. Participants may be at increased risk of LTFU in trials with outcomes assessed beyond the standard of care, surgical indications other than cancer or transplant, patient-reported outcomes, and longer follow-up. Investigators should consider the impact of design on LTFU and plan retention strategies accordingly.

Treatment outcomes of regenerative endodontic therapy in immature permanent teeth with pulpal necrosis: A systematic review and network meta-analysis.

AIM: The aim of this study was to assess which treatment modality regarding scaffold selection for immature permanent teeth with pulpal necrosis will be the most successful for regenerative endodontic treatment (RET). METHODOLOGY: PubMed, Cochrane, Web of Science and Embase, and additional records until August 2022 were searched providing a total of 3021 articles, and nine of these articles were included for quantitative synthesis. The reviewers selected eligible randomized controlled trials and extracted pertinent data. Network meta-analysis was conducted to estimate treatment effects for primary outcomes (clinical and radiographic healing) and secondary outcomes (apical closure, root length and root wall thickness increase) following RET [mean difference (MD); 95% credible interval (CrI) and surface under the cumulative ranking curve (SUCRA)]. The quality of the included studies was appraised by the revised Cochrane risk of bias tool, and the quality of evidence was assessed using the GRADE approach. RESULTS: Six interventions from nine included studies were identified: blood clot scaffold (BC), blood clot scaffold with basic fibroblast growth factor, blood clot scaffold with collagen, platelet pellet, platelet-rich plasma (PRP) and platelet-rich fibrin (PRF). The PRP scaffold showed the greatest increase in root lengthening at 6-12 months (MD = 4.2; 95% CrI, 1.2 to 6.8; SUCRA = 89.0%, very low confidence). PRP or PRF achieved the highest level of success for primary and secondary outcomes at 1-6 and 6-12 months. Blood clot scaffold (with collagen or combined with basic fibroblast growth factor (bFGF)) achieved the highest level of success for secondary outcomes beyond 12 months follow-up. A very low to low quality of evidence suggests that both PRP and PRF exhibit the greatest success evaluating primary and secondary outcomes within 12 months postoperatively compared to the traditional blood clot scaffold protocol. CONCLUSION: Limited evidence suggests both PRP and PRF exhibit success in the short-term, not long-term. The value of this information stems in its recommendation for future randomized trials prioritizing both of these materials in their protocol.

Vagal dysautonomia in patients with Chagas disease and mortality: 14-year results of a population cohort of the elderly.

INTRODUCTION: Great part of Chagas disease (ChD) mortality occurs due to ventricular arrhythmias, and autonomic function (AF) may predict unfavorable outcomes. We aimed to evaluate the predictive value of AF indexes in ChD patients. METHODS: The Bambuí Study of Aging is a prospective cohort of residents ≥60 years at study onset (1997), in the southeastern Brazilian city of Bambuí (15,000 inhabitants). Consented participants underwent annual follow-up visits, and death certificates were tracked. AF was assessed by the maximum expiration on minimum inspiration (E:I) ratio during ECG acquisition and by heart rate variability indices: SDRR (standard deviation of adjacent RR intervals) and RMSSD (square root of the mean of the sum of squares of the differences between adjacent RR intervals)), calculated using a computer algorithm. Cox proportional hazards regression was performed to access the prognostic value of AF indexes, expressed as terciles, for all-cause mortality, after adjustment for demographic, clinical and ECG variables. RESULTS: From 1742 qualifying residents, 1000 had valid AF tests, being 321 with ChD. Among these, median age was 68 (64-74) years, and 32.5% were men. In Cox survival analyses, only SDRR was associated with all-cause mortality in non-adjusted models: SDRR (hazard ratio (HR): 1.26 (95% CI 1.08-1.47), p < 0.001), E:I ratio (HR: 1.13 (95% CI 0,98-1.31), p = 0.10) and RMSSD (HR: 0.99 (0.86-1.16), p = 0.95). After adjustment for sex and age, none of the indexes remained as independent predictors. CONCLUSION: Among elderly patients with ChD, AF indexes available in this cohort were not independent predictors of 14-year mortality.

Characterizing the spike timing of a chaotic laser by using ordinal analysis and machine learning.

Semiconductor lasers with optical feedback are well-known nonlinear dynamical systems. Under appropriate feedback conditions, these lasers emit optical pulses that resemble neural spikes. Influenced by feedback delay and various noise sources, including quantum spontaneous emission noise, the dynamics are highly stochastic. A good understanding of the spike timing statistics is needed to develop photonic systems capable of using the fast-spiking laser output for novel applications, such as information processing or random number generation. Here we analyze experimental sequences of inter-spike intervals (ISIs) recorded when a sinusoidal signal was applied to the laser current. Different combinations of the DC value and frequency of the signal applied to the laser lead to ISI sequences with distinct statistical properties. This variability prompts an investigation into the relationship between experimental parameters and ISI sequence statistics, aiming to uncover potential encoding methods for optical spikes, since this can open a new way of encoding and decoding information in sequences of optical spikes. By using ordinal analysis and machine learning, we show that the ISI sequences have statistical ordinal properties that are similar to Flicker noise signals, characterized by a parameter α that varies with the signal that was applied to the laser current when the ISIs were recorded. We also show that for this dataset, the (α, permutation entropy) plane is more informative than the (complexity, permutation entropy) plane because it allows better differentiation of ISI sequences recorded under different experimental conditions, as well as better differentiation of original and surrogate ISI sequences.

Survival of fixed prosthetic restorations on vital and nonvital teeth: A systematic review.

PURPOSE: To evaluate the survival rate of full-coverage tooth-supported fixed prosthetic restorations, single crowns (SCs), and fixed dental prostheses (FDPs), taking into consideration the potential influence of tooth-vitality, presence and type of post, and type of prosthetic restoration material. MATERIALS AND METHODS: In October 2022, two authors independently conducted a search in PubMed, Web of Science, and Scopus electronic databases as well as a hand search to identify clinical human studies on full-coverage SCs and FDPs supported by vital and/or non-vital abutments and/or a combination of both, with a minimum observation period of 24 months. RESULTS: Out of 4198 studies identified through the database search and 22 through hand searching, 26 studies fulfilled the inclusion criteria and were included in the analysis of the present systematic review. Included studies scored six points and more according to Newcastle-Ottawa Scale (NOS). The highest estimated 5-year survival rate was observed for (metal-ceramic and all-ceramic) SCs on vital teeth (98.3%; 95% CI [98.1, 98.6%]) and all ceramic SCs on non-vital teeth with fiber post (95.0%; 95% CI [94.5-95.4%]). Metal-ceramic SCs on vital teeth (97.1%; 95% CI [95.6-98.7%]) showed a statistically significant higher estimated 5-year survival rate compared to metal-ceramic SCs with cast metal post (90.7%; 95% CI [87.4-94.0%], P < 0.001), fiber post (91.3%; 95% CI [90.9-91.6%], P < 0.001) and without post (85.7%; 95% CI [80.7, 90.6%], P < 0.032). All-ceramic SCs with fiber post had a statistically significant higher estimated 5-year survival rate (95.0%; 95% CI [94.5-95.4%]) compared to metal-ceramic SCs on non-vital teeth with fiber post (91.3%; 95% CI [90.9-91.6%], P < 0.001). SCs (all-ceramic and metal-ceramic) with fiber post had a statistically significantly higher estimated 5-year survival rate of (92.7%; 95% CI [92.4-92.9%]) than SCs made of metal-ceramic and retained by cast metal post (90.7%; 95% CI [87.4-94.0%], P < 0.001). For FDPs, the 5-year survival rate was significantly higher for FDPs on vital abutments (84.9%; 95% CI [75.9, 93.9%]) compared to FDPs retained by non-vital abutment/s (81.3%; 95% CI [80.3, 82.2%], P = 0.049) irrespective to presence, type of post, and FDPs material. The results are limited by the limited number of studies and the presence of uncontrolled confounding clinical variables. CONCLUSIONS: Within the limitations of the study, tooth vitality is suggested to contribute positively to the survival of SCs and FDPs.

Timing of Initiation of Renal-Replacement Therapy in Acute Kidney Injury.

BACKGROUND: Acute kidney injury is common in critically ill patients, many of whom receive renal-replacement therapy. However, the most effective timing for the initiation of such therapy remains uncertain. METHODS: We conducted a multinational, randomized, controlled trial involving critically ill patients with severe acute kidney injury. Patients were randomly assigned to receive an accelerated strategy of renal-replacement therapy (in which therapy was initiated within 12 hours after the patient had met eligibility criteria) or a standard strategy (in which renal-replacement therapy was discouraged unless conventional indications developed or acute kidney injury persisted for >72 hours). The primary outcome was death from any cause at 90 days. RESULTS: Of the 3019 patients who had undergone randomization, 2927 (97.0%) were included in the modified intention-to-treat analysis (1465 in the accelerated-strategy group and 1462 in the standard-strategy group). Of these patients, renal-replacement therapy was performed in 1418 (96.8%) in the accelerated-strategy group and in 903 (61.8%) in the standard-strategy group. At 90 days, death had occurred in 643 patients (43.9%) in the accelerated-strategy group and in 639 (43.7%) in the standard-strategy group (relative risk, 1.00; 95% confidence interval [CI], 0.93 to 1.09; P = 0.92). Among survivors at 90 days, continued dependence on renal-replacement therapy was confirmed in 85 of 814 patients (10.4%) in the accelerated-strategy group and in 49 of 815 patients (6.0%) in the standard-strategy group (relative risk, 1.74; 95% CI, 1.24 to 2.43). Adverse events occurred in 346 of 1503 patients (23.0%) in the accelerated-strategy group and in 245 of 1489 patients (16.5%) in the standard-strategy group (P<0.001). CONCLUSIONS: Among critically ill patients with acute kidney injury, an accelerated renal-replacement strategy was not associated with a lower risk of death at 90 days than a standard strategy. (Funded by the Canadian Institutes of Health Research and others; STARRT-AKI ClinicalTrials.gov number, NCT02568722.).

Rationale and design of the pullback pressure gradient (PPG) global registry.

INTRODUCTION: Diffuse disease has been identified as one of the main reasons leading to low post-PCI fractional flow reserve (FFR) and residual angina after PCI. Coronary pressure pullbacks allow for the evaluation of hemodynamic coronary artery disease (CAD) patterns. The pullback pressure gradient (PPG) is a novel metric that quantifies the distribution and magnitude of pressure losses along the coronary artery in a focal-to-diffuse continuum. AIM: The primary objective is to determine the predictive capacity of the PPG for post-PCI FFR. METHODS: This prospective, large-scale, controlled, investigator-initiated, multicenter study is enrolling patients with at least 1 lesion in a major epicardial vessel with a distal FFR ≤ 0.80 intended to be treated by PCI. The study will include 982 subjects. A standardized physiological assessment will be performed pre-PCI, including the online calculation of PPG from FFR pullbacks performed manually. PPG quantifies the CAD pattern by combining several parameters from the FFR pullback curve. Post-PCI physiology will be recorded using a standardized protocol with FFR pullbacks. We hypothesize that PPG will predict optimal PCI results (post-PCI FFR ≥ 0.88) with an area under the ROC curve (AUC) ≥ 0.80. Secondary objectives include patient-reported and clinical outcomes in patients with focal vs. diffuse CAD defined by the PPG. Clinical follow-up will be collected for up to 36 months, and an independent clinical event committee will adjudicate events. RESULTS: Recruitment is ongoing and is expected to be completed in the second half of 2023. CONCLUSION: This international, large-scale, prospective study with pre-specified powered hypotheses will determine the ability of the preprocedural PPG index to predict optimal revascularization assessed by post-PCI FFR. In addition, it will evaluate the impact of PPG on treatment decisions and the predictive performance of PPG for angina relief and clinical outcomes.

Intracluster correlation coefficients in osteoarthritis cluster randomized trials: A systematic review.

OBJECTIVES: The design, analysis, and interpretation of cluster randomized clinical trials (RCTs) require accounting for potential correlation of observations on individuals within the same cluster. Reporting of observed intracluster correlation coefficients (ICCs) in cluster RCTs, as recommended by Consolidated Standards of Reporting Trials (CONSORT), facilitates sample size calculation of future cluster RCTs and understanding of the trial statistical power. Our objective was to summarize observed ICCs in osteoarthritis (OA) cluster RCTs. DESIGN: Systematic review of knee/hip OA cluster RCTs. We searched Cochrane Central Register of Controlled Trials for trials published from 2012, when CONSORT cluster RCTs extension was published, to September 2022. We calculated the proportion of cluster RCTs that reported observed ICCs. Of those that did, we extracted observed ICCs. PROSPERO: CRD42022365660. RESULTS: We screened 1121 references and included 20 cluster RCTs. Only 5 trials (25%) reported the observed ICC for at least one outcome variable. ICC values for pain outcomes were: 0, 0.01, 0.18; for physical function outcomes were: 0, 0.06, 0.13 (knee)/0.27 (hip); Western Ontario and McMaster Universities Arthritis Index (WOMAC) total: 0.02, 0.02; symptoms of anxiety/depression: 0.22; disability: 0; and global change: 0. One out of four (25%) trials reported an ICC that was larger than the ICC used for sample size calculation and thus was underpowered. CONCLUSIONS: Despite CONSORT statement recommendations for reporting cluster RCTs, few OA trials reported the observed ICC. Given the importance of the ICC to interpretation of trial results and future trial design, this reporting gap warrants attention.

Human land-uses homogenize stream assemblages and reduce animal biomass production.

Human land-use change is a major threat to natural ecosystems worldwide. Nonetheless, the effects of human land-uses on the structure of plant and animal assemblages and their functional characteristics need to be better understood. Furthermore, the pathways by which human land uses affect ecosystem functions, such as biomass production, still need to be clarified. We compiled a unique dataset of fish, arthropod and macrophyte assemblages from 61 stream ecosystems in two Neotropical biomes: Amazonian rainforest and Uruguayan grasslands. We then tested how the cover of agriculture, pasture, urbanization and afforestation affected the taxonomic richness and functional diversity of those three species assemblages, and the consequences of these effects for animal biomass production. Single trait categories and functional diversity were evaluated, combining recruitment and life-history, resource and habitat-use, and body size. The effects of intensive human land-uses on taxonomic and functional diversities were as strong as other drivers known to affect biodiversity, such as local climate and environmental factors. In both biomes, the taxonomic richness and functional diversity of animal and macrophyte assemblages decreased with increasing cover of agriculture, pasture, and urbanization. Human land-uses were associated with functional homogenization of both animal and macrophyte assemblages. Human land-uses reduced animal biomass through direct and indirect pathways mediated by declines in taxonomic and functional diversities. Our findings indicate that converting natural ecosystems to supply human demands results in species loss and trait homogenization across multiple biotic assemblages, ultimately reducing animal biomass production in streams.

Parthenolide inhibits proliferation and invasion, promotes apoptosis, and reverts the cell-cell adhesion loss through downregulation of NF-κB pathway TNF-α-activated in colorectal cancer cells.

The activation of the nuclear factor-κB (NF-κB) pathway has been associated with the development and progression of colorectal cancer (CRC). Parthenolide (PTL), a well-known inhibitor of the NF-κB pathway, has emerged as an alternative treatment. However, whether PTL activity is tumor cell-specific and dependent on the mutational background has not been defined. This study investigated the antitumor role of PTL after tumor necrosis factor-α (TNF-α) stimulation in various CRC cell lines with different mutational statuses of TP53. We observed that CRC cells displayed different patterns of basal p-IκBα levels; PTL reduced cell viability according to p-IκBα levels and p-IκBα levels varied among the cell lines according to the time of TNF-α stimulation. High concentrations of PTL reduced more effectively p-IκBα levels than low doses of PTL. However, PTL increased total IκBα levels in Caco-2 and HT-29 cells. In addition, PTL treatment downregulated p-p65 levels in HT-29 and HCT-116 cells stimulated by TNF-α in a dose-dependent manner. Moreover, PTL induced cell death via apoptosis and reduced the proliferation rate of TNF-α-treated HT-29 cells. Finally, PTL downregulated the messenger RNA levels of interleukin-1ß, a downstream cytokine of NF-κB, reverted the E-cadherin-mediated disorganization of cell-cell contacts, and decreased the invasion of HT-29 cells. Together, these results suggest a differential antitumoral activity of PTL on CRC cells with different mutational statuses of TP53, modulating cell death, survival, and proliferation underlying the NF-κB pathway TNF-α-induced. Therefore, PTL has emerged as a potential treatment for CRC in an inflammatory NF-κB-dependent manner.

Delayed onset Bickerstaff brainstem encephalitis overlapping Miller-Fisher Syndrome during SARS-CoV-2 infection.

Bickerstaff brainstem encephalitis (BBE) is a neuroimmunologic disease characterized by the acute onset of external ophthalmoplegia, ataxia, and consciousness disturbance, mostly subsequent to an infection. BBE is considered to be a variant of Miller-Fisher syndrome (MFS), which also exhibits external ophthalmoplegia and ataxia but not presenting consciousness alterations. Therefore, these two medical conditions are included in the clinical spectrum of the "Fisher-Bickerstaff syndrome" ( Shahrizaila and Yuki in J Neurol Neurosurg Psychiatry 84(5):576-583) [1]. With regard to the etiopathogenesis, increasing evidence worldwide suggests that SARS-CoV-2 infection-enhanced immune response is involved in a wide range of neurological complications such as Guillain-Barré syndrome (GBS), MFS, acute necrotizing encephalitis (ANE), myelitis, acute disseminated encephalomyelitis (ADEM), and, although very rarely, BBE either (Hosseini et al. in Rev Neurosci 32:671-691) [2]. We report a case of a patient affected by delayed onset BBE overlapping MFS during a mild SARS-CoV-2 infection. To the best of our knowledge, similar cases have never been reported.

Repositioning of Benzodiazepine Drugs and Synergistic Effect with Ciprofloxacin Against ESKAPE Pathogens.

Infectious diseases are among the leading causes of morbidity and mortality worldwide. Combating them becomes more complex when caused by the pathogens of the ESKAPE group, which are Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. The purpose of this study was to investigate the repositioning potential of the benzodiazepines clonazepam and diazepam individually and in combination with the antibacterial ciprofloxacin against ESKAPE. The minimum inhibitory concentration and minimum bactericidal concentration against seven American Type Culture Collection (ATCC) reference standard strains and 64 ESKAPE clinical isolates were determined. In addition, the interaction with ciprofloxacin was determined by the checkerboard method and fractional inhibitory concentration index (FICI) of clonazepam against 11 ESKAPE and diazepam against five ESKAPE. We also list the results found and their clinical significance. Benzodiazepines showed similar antibacterial activity against Gram-positive and Gram-negative. The checkerboard and FICI results showed a synergistic effect of these drugs when associated with ciprofloxacin against almost all tested isolates. Viewing the clinical cases studied, benzodiazepines have potential as treatment alternatives. The results allow us to conclude that clonazepam and diazepam, when in combination with ciprofloxacin, have promising activity against ESKAPE, therefore, assuming the position of candidates for repositioning.

Phase synchronization in a sparse network of randomly connected neurons under the effect of Poissonian spike inputs.

This article investigates the emergence of phase synchronization in a network of randomly connected neurons by chemical synapses. The study uses the classic Hodgkin-Huxley model to simulate the neuronal dynamics under the action of a train of Poissonian spikes. In such a scenario, we observed the emergence of irregular spikes for a specific range of conductances and also that the phase synchronization of the neurons is reached when the external current is strong enough to induce spiking activity but without overcoming the coupling current. Conversely, if the external current assumes very high values, then an opposite effect is observed, i.e., the prevention of the network synchronization. We explain such behaviors considering different mechanisms involved in the system, such as incoherence, minimization of currents, and stochastic effects from the Poissonian spikes. Furthermore, we present some numerical simulations where the stimulation of only a fraction of neurons, for instance, can induce phase synchronization in the non-stimulated fraction of the network, besides cases in which for larger coupling values, it is possible to propagate the spiking activity in the network when considering stimulation over only one neuron.

Parent and physician beliefs, perceptions and knowledge of plant milks for children.

Background: Parent and physician perceptions of plant milk are unclear. Aim: To explore parent and physician perceptions of plant milk for children and to gain a better understanding of why parents and physicians might choose plant milk for children. Methods: A mixed methods study was conducted using a questionnaire and interviews with parents and physicians participating in the TARGet Kids! cohort study. Questionnaire data were analyzed using descriptive statistics. Interview transcripts were analyzed using thematic analysis. Results: Parents reported a variety of reasons for choosing plant milk for their children including concerns around allergies, the environment, animal welfare, plant-based diet, health benefits, taste and hormones in cow's milk. Parents gave their children various types of plant milks and physicians provided various recommendations to parents of children not consuming cow's milk. Our study identified that 79% of parents and 51% of physicians were unaware that soy milk is the recommended cow's milk substitute for children. Additionally, 26% of parents did not know some plant milks are not fortified and can contain added sugar. Three main themes were identified from interviews about why parents and physicians may choose plant milk for children: (i) healthiness of plant milk; (ii) concerns about hormones; and (iii) environmental impacts. Conclusions: Parents and physicians choose the milk that they believe is healthiest for their child or patient. However, a lack of clarity on the effects of plant milk consumption on children's health resulted in conflicting views on whether plant milk or cow's milk is healthier for children.

Clinical and Urodynamic results of the Argus T® sling in moderate and severe male stress urinary incontinence after radical prostatectomy - a 5 year prospective study.

PURPOSE: Sling as a therapeutic option for male stress urinary incontinence (SUI) has been reviewed in the last two decades, as it is a relatively simpliest surgery compared to artificial urinary sphincter and has the ability to modulate urethral compression. This study aims to evaluate the efficacy, rate of complications, quality of life and the effects on bladder emptying of the Argus T® compressive and ajustable sling in moderate and severe male SUI treatment. MATERIALS AND METHODS: Men eligible for stress urinary incontinence treatment after radical prostatectomy were recruited and prospectively evaluated, from March 2010 to November 2016. It was selected outpatient men with moderate and severe SUI, after 12 months of radical prostatectomy, who have failed conservative treatment. All patients had a complete clinical and urodynamic pre and post treatment evaluation, by means of clinical history, physical examination, urine culture, 1-hour pad test and ICIq-SF questionnaire. The UDS was performed after 12, 18 and 24 months postoperatively. RESULTS: Thirty-seven men underwent sling surgery, 19 patients (51.4%) with moderate and 18 (48.6%) with severe SUI. The minimum follow-up time was 5 years. Overall, we had a success rate of 56.7% at 60 months follow-up. After surgery, we did not observe significant changes in the urodynamic parameters evaluated during the follow-up. No patient had urodynamic bladder outlet obstruction (BOO) after sling implantation. Readjustment of the Argus T® sling was performed in 16 (41%) of the patients and 51% of the patients reported some adverse event. CONCLUSION: We demonstrate a long-term efficacy and safety of Sling Argus T® as an alternative to moderate and severe male SUI treatment. Furthermore, in our study bulbar urethra compression does not lead to bladder outlet obstruction.

Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy.

BACKGROUND: B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition. METHODS: We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed. RESULTS: A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], -9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06). CONCLUSIONS: Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.).