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ABSTRACT The interferon (IFN) system protects mammals from diseases caused by virus infections. IFN synthesis is induced by pattern recognition receptor signaling pathways activated by virus infection. IFN is secreted from the infected cells and acts upon neighboring cells by binding cell surface receptors and triggering induction of hundreds of IFN-stimulated genes and proteins, many of which block different steps of virus replication. The IFN-induced tetratricopeptide repeat proteins (IFIT) are a family of RNA-binding proteins. We and others have previously reported that IFIT2 protects mice from many neurotropic RNA viruses; indeed, Ifit2−/− mice are very susceptible to intranasal or subcutaneous infections with vesicular stomatitis virus (VSV). Here, using a newly generated conditional knockout mouse, we report that ablation of Ifit2 expression only in neuronal cells was sufficient to render mice susceptible to neuropathogenesis caused by intranasal, but not subcutaneous, infection of VSV. Another genetically modified mouse line, expressing a mutant IFIT2 that cannot bind RNA, was as susceptible to VSV infection as Ifit2−/− mice. These results demonstrated that IFIT2 RNA-binding activity is essential for protecting mice against neurological diseases caused by intranasal infection of VSV.IMPORTANCEInterferon’s (IFN’s) antiviral effects are mediated by the proteins encoded by the interferon-stimulated genes. IFN-stimulated genes (IFIT2) is one such protein, which inhibits replication of many RNA viruses in the mouse brain and the resultant neuropathology. Our study sheds light on how IFIT2 works. By ablating Ifit2 expression only in neuronal cells, using a newly generated conditional knockout mouse line, we showed that Ifit2 induction in the neurons of the infected mouse was necessary for antiviral function of interferon. IFIT2 has no known enzyme activity; instead, it functions by binding to cellular or viral proteins or RNAs. We engineered a new mouse line that expressed a mutant IFIT2 that cannot bind RNA. These mice were very susceptible to infection with vesicular stomatitis virus indicating that the RNA-binding property of IFIT2 was essential for its antiviral function in vivo.

Objective: To describe the characteristics of COVID-19 patients with pneumothorax and pneumomediastinum (PTX/PM) and their association with patient outcomes. Patients and methods: Adults admitted to five Mayo Clinic hospitals with COVID-19 between 03/2020–01/2022 were evaluated. PTX/PM was defined by imaging. Descriptive analyses and a matched (age, sex, admission month, COVID-19 severity) cohort comparison was performed. Hospital mortality, length of stay (LOS), and predisposing factors were assessed. Results: Among 6663 patients, 197 had PTX/PM (3 %) (75 PM, 40 PTX, 82 both). The median age was 59, with 71 % males. Exposure to invasive and non-invasive mechanical ventilation and high-flow nasal cannula before PTX/PM were 42 %, 17 %, and 20 %, respectively. Among isolated PTX and PM/PTX patients 70 % and 53.7 % underwent an intervention, respectively, while 96 % of the PM-only group was followed conservatively.A total of 171 patients with PTX/PM were compared to 171 matched controls. PTX/PM patients had more underlying lung disease (40.9 vs. 23.4 %, p

Abstract Water discharge and sediment flux variations are important parameters controlling the morphodynamic behaviour of rivers. Although quantitative estimates for water discharge and sediment flux variability are well‐constrained for modern rivers, far fewer assessments of flow and sediment flux intermittency in ancient fluvial systems from the rock record are available. In this study, a relationship between water discharge, sediment flux variability and patterns of changing fluvial stratigraphic architecture in the Middle Eocene Escanilla Formation, Spain, is explored. Water discharge intermittency factor (IWF), calculated as a ratio of the total water discharge (over the averaging time period) to the instantaneous channel‐forming water discharge if sustained for the same period, ranges from 0.03 to 0.11 in the high amalgamation intervals and from 0.10 to 0.32 in the low amalgamation intervals. Similarly, the sediment flux intermittency factor (ISF) is estimated to be in the range of 0.008 to 0.01 in the high amalgamation intervals and of 0.01 to 0.03 in the low amalgamation intervals. Consequently, high amalgamation intervals were most probably deposited under more intermittent and short‐lived intense precipitation events while low amalgamation intervals were the result of less intermittent flows spread throughout the year. Overall, these estimates are consistent with values from modern ephemeral rivers typically found in arid to semi‐arid climate and is in agreement with available proxy data for the Middle Eocene climatic context of the studied alluvial system. This highlights an important connection between hydroclimate, river morphodynamics and landscape evolution, and has implications to predict river flow and sediment transport across the Earth's surface in the geological past.

In the realm of supply chains, the necessity of a robust reverse logistics network is paramount. While substantial efforts have been directed towards enhancing forward logistics, the domain of reverse logistics remains underdeveloped. This article presents an approach that centers on the formulation of a reverse logistics network for an Indian e-commerce company specializing in apparel sales. Through the construction of single and multi-objective integer programs, the aim is to simultaneously mitigate economic costs and environmental repercussions. To tactfully address environmental concerns while maintaining cost efficiency, different network designs are proposed via the utilization of multi-objective Integer programs, solved using IBM ILOG CPLEX Optimization Studio an optimization software based upon simplex algorithm. The Environmental-Cost-Efficiency (ECE) framework is used to evaluate the multiple network designs. Scrutinizing the intricate equilibrium between costs and ecological implications, the study ultimately identifies an optimized reverse logistics network that yields maximal returns on investment in terms of environmental impact reduction. This comprehensive exploration of the cost-environment trade-off offers valuable guidance to similar organizations aiming to prudently minimize ecological footprints without compromising financial viability. Just as the reverse logistics network is vital within supply chains, this article underscores the potential of its strategic enhancement in driving eco-friendly and economically efficient practices.

Background: With no unified system for tumor associated macrophages (TAMs) density assessment, limited information is available on their relationship with β-catenin expression. Aim: To evaluate the density of CD68+ TAMs in gastric adenocarcinoma samples by immunohistochemistry and correlate it with grade, stage, invasion, and beta-catenin. Designs and Settings: Formalin fixed paraffin embedded (FFPE) blocks from gastrectomy specimens of proven gastric adenocarcinoma were prospectively and retrospectively were studied over a period of two years. Materials and Methods: Immunohistochemistry with CD68 and β-catenin was performed. TAM density was qualitatively compared in “tumor” versus “stroma” and “tumor” versus “non-tumor” regions. Quantitative CD68+ TAM density was assessed using different methods and compared. Cases were classified as high and low TAM based on the median value and correlated with histologic type, location, grade, stage and β-catenin expression pattern. Statistical Analysis: Spearman's rank correlation test was used to compare the different methods of TAM density evaluation. The categorical variables were studied using Pearson's Chi-square or Fisher's exact test. CD68+ TAM density and β-catenin expression were correlated by analysis of variance. A P value ≤ 0.05 was taken as statistically significant. Results: The CD68+ TAMs in the “tumor” versus “non-tumor” area (p = 0.34) and “tumor” versus “stroma distribution” (p = 0.81) did not show any statistical significance. All methods of TAM density were found to be comparable. High TAM group is significantly associated with lymphovascular invasion, tumor depth, lymph node metastasis, and abnormal β-catenin expression. Conclusion: TAMs density plays an important role in the tumor stage. Macrophages may possibly induce gastric cancer invasiveness by activating β-catenin pathway.

In this paper, a modified method is used to approximate the solution to the time-fractional n-dimensional Navier–Stokes equation. The modified method is the Variational Iteration Transform Method, which is implemented in the equation whose fractional order derivative is described in the Caputo sense. The proposed method's findings are presented and examined using figures. It is demonstrated that the proposed method is efficient, dependable, and simple to apply to various science and engineering applications.

Summary:. Demand for gender-affirming facial surgery is growing rapidly. Frontal sinus setback, one of the key procedures used in gender-affirming facial surgery, has a particularly high impact on gender perception. Mixed reality (MR) allows a user to view and virtually overlay three-dimensional imaging on the patient and interact with it in real time. We used the Medivis’s SurgicalAR system in conjunction with the Microsoft HoloLens Lucille2 (Microsoft). Computed tomography imaging was uploaded to SurgicalAR, and a three-dimensional (3D) hologram was projected onto the display of the HoloLens. The hologram was registered and matched to the patient, allowing the surgeon to view bony anatomy and underlying structures in real time on the patient. The surgeon was able to outline the patient’s frontal sinuses using the hologram as guidance. A 3D printed cutting guide was used for comparison. Negligible difference between the mixed reality-based outline and 3D-printed outline was seen. The process of loading the hologram and marking the frontal sinus outline lasted less than 10 minutes. The workflow and usage described here demonstrate significant promise for the use of mixed reality as imaging and surgical guidance technology in gender-affirming facial surgery.

Abstract To improve lithium-ion battery technology, it is essential to probe and comprehend the microscopic dynamic processes that occur in a real-world composite electrode under operating conditions. The primary and secondary particles are the structural building blocks of battery cathode electrodes. Their dynamic inconsistency has profound but not well-understood impacts. In this research, we combine operando coherent multi-crystal diffraction and optical microscopy to examine the chemical dynamics in local domains of layered oxide cathode. Our results not only pinpoint the asynchronicity of the lithium (de)intercalation at the sub-particle level, but also reveal sophisticated diffusion kinetics and reaction patterns, involving various localized processes, e.g., chemical onset, reaction front propagation, domains equilibration, particle deformation and motion. These observations shed new lights onto the activation and degradation mechanisms of state-of-the-art battery cathode materials.

The effectiveness of the local fractional reduced differential transformation method (LFRDTM) for the approximation of the solution related to the extended n-term local fractional Klein-Gordon equation is the main aim of this paper in which fractional complex transform and local fractional derivative have been employed to analyze the n-term Klein-Gordon equations, and Cantor sets. The proposed method, along with the existence of the solutions demonstrated through some examples, provides a powerful mathematical means in solving fractional linear differential equations. Considering these points, the paper also provides an accurate and effective method to solve complex physical systems that display fractal or self-similar behavior across various scales. In conclusion, the fractional complex transform with the local fractional differential transform method has been proven to be a robust and flexible approach towards obtaining effective approximate solutions of local fractional partial differential equations.

Pediatric high-grade glioma (pHGG) including pediatric glioblastoma (pGBM) are highly aggressive pediatric central nervous system (CNS) malignancies. pGBM comprises approximately 3% of all pediatric CNS malignancies and has a 5-year survival rate of approximately 20%. Surgical resection and chemoradiation are often the standard of care for pGBM and pHGG, however, even with these interventions, survival for children diagnosed with pGBM and pHGG remains poor. Due to shortcomings associated with the standard of care, many efforts have been made to create novel immunotherapeutic approaches targeted to these malignancies. These efforts include the use of vaccines, cell-based therapies, and immune-checkpoint inhibitors. However, it is believed that in many pediatric glioma patients an immunosuppressive tumor microenvironment (TME) possess barriers that limit the efficacy of immune-based therapies. One of these barriers includes the presence of immunosuppressive myeloid cells. In this review we will discuss the various types of myeloid cells present in the glioma TME, including macrophages and microglia, myeloid-derived suppressor cells, and dendritic cells, as well as the specific mechanisms these cells can employ to enable immunosuppression. Finally, we will highlight therapeutic strategies targeted to these cells that are aimed at impeding myeloid-cell derived immunosuppression.

Abstract Ancient fluvial deposits typically display repetitive changes in their depositional architecture such as alternating intervals of coarse-grained highly amalgamated (HA), laterally-stacked, channel bodies, and finer-grained less amalgamated (LA), vertically-stacked, channels encased in floodplain deposits. Such patterns are usually ascribed to slower, respectively higher, rates of base level rise (accommodation). However, “upstream” factors such as water discharge and sediment flux also play a potential role in determining stratigraphic architecture, yet this possibility has never been tested despite the recent advances in the field of palaeohydraulic reconstructions from fluvial accumulations. Here, we chronicle riverbed gradient evolution within three Middle Eocene (~ 40 Ma) fluvial HA-LA sequences in the Escanilla Formation in the south-Pyrenean foreland basin. This work documents, for the first time in a fossil fluvial system, how the ancient riverbed systematically evolved from lower slopes in coarser-grained HA intervals, and higher slopes in finer-grained LA intervals, suggesting that bed slope changes were determined primarily by climate-controlled water discharge variations rather than base level changes as often hypothesized. This highlights the important connection between climate and landscape evolution and has fundamental implications for our ability to reconstruct ancient hydroclimates from the interpretation of fluvial sedimentary sequences.

BackgroundThe gold standard for gathering data from electronic health records (EHR) has been manual data extraction; however, this requires vast resources and personnel. Automation of this process reduces resource burdens and expands research opportunities.ObjectiveThis study aimed to determine the feasibility and reliability of automated data extraction in a large registry of adult COVID-19 patients.Materials and methodsThis observational study included data from sites participating in the SCCM Discovery VIRUS COVID-19 registry. Important demographic, comorbidity, and outcome variables were chosen for manual and automated extraction for the feasibility dataset. We quantified the degree of agreement with Cohen’s kappa statistics for categorical variables. The sensitivity and specificity were also assessed. Correlations for continuous variables were assessed with Pearson’s correlation coefficient and Bland–Altman plots. The strength of agreement was defined as almost perfect (0.81–1.00), substantial (0.61–0.80), and moderate (0.41–0.60) based on kappa statistics. Pearson correlations were classified as trivial (0.00–0.30), low (0.30–0.50), moderate (0.50–0.70), high (0.70–0.90), and extremely high (0.90–1.00).Measurements and main resultsThe cohort included 652 patients from 11 sites. The agreement between manual and automated extraction for categorical variables was almost perfect in 13 (72.2%) variables (Race, Ethnicity, Sex, Coronary Artery Disease, Hypertension, Congestive Heart Failure, Asthma, Diabetes Mellitus, ICU admission rate, IMV rate, HFNC rate, ICU and Hospital Discharge Status), and substantial in five (27.8%) (COPD, CKD, Dyslipidemia/Hyperlipidemia, NIMV, and ECMO rate). The correlations were extremely high in three (42.9%) variables (age, weight, and hospital LOS) and high in four (57.1%) of the continuous variables (Height, Days to ICU admission, ICU LOS, and IMV days). The average sensitivity and specificity for the categorical data were 90.7 and 96.9%.Conclusion and relevanceOur study confirms the feasibility and validity of an automated process to gather data from the EHR.

Introduction: With evolving pandemic, a substantial proportion of patients are presenting with liver dysfunction as an extra-pulmonary manifestation of COVID-19 illness. We planned this study to evaluate the incidence of liver dysfunction in COVID-19 pneumonia and find an association between abnormal liver function and the severity of the disease. Method: We retrospectively analysed the hospital records of 344 patients with moderate to severe COVID-19 illness admitted to a Dedicated COVID Hospital in North India. Results: Out of 344 patients included in the study, 59.9% were males. The abnormal liver functions were present in 78.49% of patients at admission. Mean age of the patient with liver dysfunction was 53.41 ± 15.71 years. The incidence of elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and hypoalbuminemia was 82.96%, 74.91%, and 69.7%, respectively, in patients with COVID-19 at admission. A positive correlation was found between the levels of AST, ALT and hypoalbuminemia with severity of disease. Mortality was 33% in patients with liver dysfunction in comparison to 18.9% in patients with normal liver functions. Conclusion: More than 75% of the patient had abnormal liver functions at admission, and mortality was also high in this group. Mortality can be effectively reduced if laboratory parameters such as elevated AST and ALT and hypoalbuminemia are closely monitored at admission and during hospital stay in patients with risk factors like male, age

Evolutionary dynamics in spatially structured populations has been studied for a long time. More recently, the focus has been to construct structures that amplify selection by fixing beneficial mutations with higher probability than the well-mixed population and lower probability of fixation for deleterious mutations. It has been shown that for a structure to substantially amplify selection, self-loops are necessary when mutants appear predominately in nodes that change often. As a result, for low mutation rates, self-looped amplifiers attain higher steady-state average fitness in the mutation-selection balance than well-mixed populations. But what happens when the mutation rate increases such that fixation probabilities alone no longer describe the dynamics? We show that self-loops effects are detrimental outside the low mutation rate regime. In the intermediate and high mutation rate regime, amplifiers of selection attain lower steady-state average fitness than the complete graph and suppressors of selection. We also provide an estimate of the mutation rate beyond which the mutation-selection dynamics on a graph deviates from the weak mutation rate approximation. It involves computing average fixation time scaling with respect to the population sizes for several graphs.

In the reproductive age group among all ovarian germ cell tumors mature cystic teratoma (MCT) is the most common one. Rarely there is malignant transformation (MT) of MCT with an incidence of 1-3 %. The MT of MCT is mostly in the postmenopausal age group. It is extremely rare in women less than 40 years of age. Here we report a case of 35- year old young female who presented with lower abdominal mass and pain abdomen for the last 4 months radiating to back and left thigh. In ultrasonography there was suspicion of left adnexal mass. Contrast enhanced CT scan (CECT) revealed left adnexal mass possibly malignant transformation of teratoma. All the tumor markers were within normal limits except CA19-9 which was elevated (80U/ml). Extensive surgery was done and samples of hysterectomy, bilateral salpingo-oophorectomy, omentectomy along pelvic and paraaortic lymph nodes were sent for histopathology. Histopathology correlated with radiology and revealed extensive areas of necrosis, the predominant component of squamous cell carcinomatous component along with focal areas showing footprints of benign MCT in the form of clusters of fat cells, few hair shafts intermingled with malignant cells. So the final diagnosis of malignant transformation of mature cystic teratoma in form of squamous cell carcinoma was made. The patient was followed up and was showing partial response to ongoing chemotherapy.

Abstract Background Persistent sinus tachycardia (ST) is frequently encountered during pregnancy and peripartum period and its etiology often remains elusive. We sought to examine the possible association between unexplained persistent ST and obstetric outcomes. Methods A case control study was conducted using chart review of women admitted in labor to one of 7 hospitals of Northwell Health between January 2015 to June 2021. After excluding women with structurally abnormal hearts, we identified patients with persistent ST during the peripartum period, defined as a heart rate of more than 100 bpm for more than 48 h. A control group was created by randomly subsampling those who did not meet the inclusion criteria for sinus tachycardia. Obstetric outcomes were measured as mother’s length of stay (LOS), pre-term labor (PTL), admission to the neonatal ICU (NICU), and whether she received cesarean-section (CS). Results Seventy-eight patients with persistent ST were identified, out of 141,769 women admitted for labor throughout the Northwell Health system. 23 patients with ST attributable to infection or hypovolemia from anemia requiring transfusion and 55 with unclear etiology were identified. After adjusting for age and parity, pregnant mothers with ST were 2.35 times more likely to have a CS than those without (95% CI: 1.46–3.81, p = 0.0005) and had 1.38 times the LOS (1.21- 1.56, p

Crop rotation, a sustainable agricultural technique, has been at humanity’s disposal since time immemorial and is practised globally. Switching between cover crops and cash crops helps avoid the adverse effects of intensive farming. Determining the optimum cash-cover rotation schedule for maximizing yield has been tackled on multiple fronts by agricultural scientists, economists, biologists and computer scientists, to name a few. However, considering the uncertainty due to diseases, pests, droughts, floods and impending effects of climate change is essential when designing rotation strategies. Analysing this time-tested technique of crop rotations with a new lens of Parrondo’s paradox allows us to optimally use the rotation technique in synchrony with uncertainty. While previous approaches are reactive to the diversity of crop types and environmental uncertainties, we make use of the said uncertainties to enhance crop rotation schedules. We calculate optimum switching probabilities in a randomized cropping sequence and suggest optimum deterministic sequences and judicious use of fertilizers. Our methods demonstrate strategies to enhance crop yield and the eventual profit margins for farmers. Conforming to translational biology, we extend Parrondo’s paradox, where two losing situations can be combined eventually into a winning scenario, to agriculture.

A majority of people living with motor neuron disease (MND) experience weakness of the neck and as a result, experience head drop. This exacerbates problems with everyday activities (eating, talking, breathing, etc). Neck collars are often used to support head drop; however, these are typically designed for prehospitalization settings to manage and brace the cervical region of the spine. As a result, it has been recorded that people living with MND often reject these collars for a variety of reasons but most notably because they are too restricting. The current standardized outcome measures (most notably restricting cervical range of motion) used for neck collars are summarized herein along with whether they are suitable for a bespoke neck collar specifically designed for people living with MND.

BackgroundA diagnosis of MND takes an average 10-16 months from symptom onset. Early diagnosis is important to access supportive measures to maximise quality of life. The COVID-19 pandemic has caused significant delays in NHS pathways; the majority of GP appointments now occur online with subsequent delays in secondary care assessment. Given the rapid progression of MND, patients may be disproportionately affected resulting in late stage new presentations. We used Monte Carlo simulation to model the pre-COVID-19 diagnostic pathway and then introduced plausible COVID-19 delays.MethodsThe diagnostic pathway was modelled using gamma distributions of time taken: 1) from symptom onset to GP presentation, 2) for specialist referral, and 3) for diagnosis reached after neurology appointment. We incorporated branches to simulate delays: when patients did not attend their GP and when the GP consultation did not result in referral. An emergency presentation was triggered when diagnostic pathway time was within 30 days of projected median survival. Total time-to-diagnosis was calculated over 100,000 iterations. The pre-COVID-19 model was estimated using published data and the Improving MND Care Survey 2019. We estimated COVID-19 delays using published statistics.ResultsThe pre-COVID model reproduced known features of the MND diagnostic pathway, with a median time to diagnosis of 399 days and predicting 5.2% of MND patients present as undiagnosed emergencies. COVID-19 resulted in diagnostic delays from 558 days when only primary care was 25% delayed, to 915 days when both primary and secondary care were 75%. The model predicted an increase in emergency presentations ranging from 15.4%-44.5%.InterpretationsThe model suggests the COVID-19 pandemic will result in later-stage diagnoses and more emergency presentations of undiagnosed MND. Late-stage presentations may require rapid escalation to multidisciplinary care. Proactive recognition of acute and late-stage disease with altered service provision will optimise care for people with MND.

Context: The use of human-derived amniotic barrier membranes in regenerative procedures along with allograft like demineralized freeze-dried bone allograft (DFDBA) has displayed promising outcomes. Aims: The objective of the current research was to clinically and radiographically evaluate and compare amniotic membrane (AM) and collagen membrane (CM) in combination with open flap debridement (OFD) along with DFDBA in the management of human periodontal intrabony defects. Settings and Design: The present research-based study was a randomized controlled clinical trial of 6 months duration. Materials and Methods: A total of twenty chronic periodontitis patients with intrabony defects were randomly divided into two groups: Group 1 treated with OFD + DFDBA + AM and Group 2 with OFD + DFDBA + CM. Clinical parameters such as plaque index (PI), gingival index (GI), pocket probing depth (PPD), and relative attachment level were recorded and evaluated at baseline, 3 months, and 6 months. The relative intrabony defect component level (rIBD) was recorded at baseline and after 6 months employing a millimeter X-ray grid. Statistical Analysis Used: For comparison of clinical parameters and radiographic parameters at various intervals unpaired t-test, repeated measures ANOVA test, and paired t-test were used. The P value was taken statistically significant when less than 0.05 (P < 0.05). Results: A statistically significant difference in PI, GI, PPD, and RAL for both the groups were found on intragroup comparison between baseline, 3 months, and 6 months (P < 0.05). On intragroup comparison, the difference in mean rIBD was statistically significant from baseline to 6 months. However, for all the clinical and radiographic parameters, no statistically significant difference was noted between both the groups (P > 0.05). Conclusions: In the treatment of intrabony defects AM being an allograft can be considered an alternative novel membrane for regenerative procedures.

Summary: Antisense locked nucleic acid (LNA) technology has been widely used for silencing microRNAs with enhanced specificity and efficiency. In this protocol, we first describe the procedure for targeted intracranial delivery of LNAs to silence microRNAs specifically in the mouse brain. We then detail the steps to isolate RNA and protein from mouse brain, followed by using RT-PCR and Western blotting to confirm microRNA silencing. This noninvasive approach can only be applied to mouse brain to specifically target silencing of microRNAs.For complete details on the use and execution of this protocol, please refer to Sharma et al. (2021).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Objectives Examine the association between arrhythmias and adverse maternal outcomes in women with structurally normal hearts.Methods This was a case–control study of women admitted in labour to one of eight hospitals of Northwell Health from January 2015 to June 2021. After excluding women with structurally abnormal hearts, we identified women with an arrhythmic event and randomly subsampled the rest of the cohort to create a control group of 1025 patients. Multivariate analysis was performed to examine the association between arrhythmias and the incidence of caesarean section (CS), preterm labour (PTL), admission to the neonatal intensive care unit and longer length of stay (LOS).Results Of 1 41 769 women admitted in labour with a structurally normal heart, 137 had at least one arrhythmic event (0.097%). Supraventricular tachycardia (SVT), atrial fibrillation/flutter (AF) and frequent premature ventricular complexes or non-sustained ventricular tachycardia (VA) were present in 65 (0.046%), 22 (0.016%) and 46 (0.032%) women, respectively. Arrhythmia was previously diagnosed in 58.0% SVT cases but only in 9.7% AF and 8.1% VA cases. After adjusting for age, parity and comorbidities, the presence of any arrhythmia was an independent predictor of CS (OR 1.7 95% CI 1.2 to 2.5), PTL (OR 1.8, CI 1.1 to 3.0) and LOS (mean ratio 1.6, CI 1.4 to 1.8). This association was driven by presence of SVT and AF, whereas VAs were not associated with adverse outcomes.Conclusions Arrhythmias, specifically SVT and AF, during labour in women with structurally normal heart are independently associated with adverse obstetrical outcomes.

The human gut microbiome interacts with many diseases, with recent small studies suggesting a link with COVID-19 severity. Exploring this association at the population-level may provide novel insights and help to explain differences in COVID-19 severity between countries. We explore whether there is an association between the gut microbiome of people within different countries and the severity of COVID-19, measured as hospitalisation rate. We use data from the large (n = 3,055) open-access gut microbiome repository curatedMetagenomicData, as well as demographic and country-level metadata. Twelve countries were placed into two groups (high/low) according to COVID-19 hospitalisation rate before December 2020 (ourworldindata.com). We use an unsupervised machine learning method, Topological Data Analysis (TDA). This method analyses both the local geometry and global topology of a high-dimensional dataset, making it particularly suitable for population-level microbiome data. We report an association of distinct baseline population-level gut microbiome signatures with COVID-19 severity. This was found both with a PERMANOVA, as well as with TDA. Specifically, it suggests an association of anti-inflammatory bacteria, including Bifidobacteria species and Eubacterium rectale, with lower severity, and pro-inflammatory bacteria such as Prevotella copri with higher severity. This study also reports a significant impact of country-level confounders, specifically of the proportion of over 70-year-olds in the population, GDP, and human development index. Further interventional studies should examine whether these relationships are causal, as well as considering the contribution of other variables such as genetics, lifestyle, policy, and healthcare system. The results of this study support the value of a population-level association design in microbiome research in general and for the microbiome-COVID-19 relationship, in particular. Finally, this research underscores the potential of TDA for microbiome studies, and in identifying novel associations.

BackgroundObesity affects the course of critical illnesses. We aimed to estimate the association of obesity with the severity and mortality in coronavirus disease 2019 (COVID-19) patients.Data SourcesA systematic search was conducted from the inception of the COVID-19 pandemic through to 13 October 2021, on databases including Medline (PubMed), Embase, Science Web, and Cochrane Central Controlled Trials Registry. Preprint servers such as BioRxiv, MedRxiv, ChemRxiv, and SSRN were also scanned.Study Selection and Data ExtractionFull-length articles focusing on the association of obesity and outcome in COVID-19 patients were included. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were used for study selection and data extraction. Our Population of interest were COVID-19 positive patients, obesity is our Intervention/Exposure point, Comparators are Non-obese vs obese patients The chief outcome of the study was the severity of the confirmed COVID-19 positive hospitalized patients in terms of admission to the intensive care unit (ICU) or the requirement of invasive mechanical ventilation/intubation with obesity. All-cause mortality in COVID-19 positive hospitalized patients with obesity was the secondary outcome of the study.ResultsIn total, 3,140,413 patients from 167 studies were included in the study. Obesity was associated with an increased risk of severe disease (RR=1.52, 95% CI 1.41-1.63, p

Gingival recession on the lingual aspect of teeth may cause dentinal hypersensitivity problems in patients. Treatment of such recessions is not a regular procedure owing to its anatomical restraints, difficulty in isolation as well as lack of esthetic importance. The present case describes the use of connective tissue graft (CTG) in the treatment of isolated lingual recession on mandibular lateral incisor using minimally invasive tunneling technique. Six-month posttreatment follow-up showed a root coverage of 3.5 mm with enhanced width of keratinized tissue. This report encourages the application of CTG along with tunneling technique in the treatment of lingual recession to achieve root coverage as well as alleviate patient's dentinal hypersensitivity issues.

Background: Periodontitis is a chronic inflammatory disease that is mainly initiated by plaque biofilm which may require treatment using periodontal flap surgery. Recently, diode lasers have become popular in the field of periodontology owing to advantages such as antibacterial effect, promoting angiogenesis, and providing hemostasis. However, scientific data on application of diode laser in periodontal flap surgery and its benefits are limited. Hence, the aim of the study was to investigate the adjunctive effect of removal of remnant pocket epithelium by 980 nm diode laser and biostimulation in modified Widman flap (MWF) surgery for the treatment of chronic periodontitis. Materials and Methods: A total of 20 patients with generalized chronic periodontitis with pocket probing depth (PPD) ≥5mm post Phase I therapy were selected for this split-mouth study. MWF surgery was performed in Group 1, and in Group 2, MWF surgery with adjunctive diode laser de-epithelization and biostimulation was done. Clinical parameters including PPD, clinical attachment level, plaque index, and gingival index were recorded at baseline and 3 months following treatment, and postprocedural pain (Visual Analog Scale [VAS] score) was assessed 1-week posttreatment. In addition, colony-forming units/milliliter (CFU/ml) of anaerobic bacteria at baseline and 3 months were microbiologically examined. Results: MWF surgery along with diode laser led to a significant improvement in Group 2 compared to Group 1 in clinical parameters such as PPD, relative clinical attachment level, VAS score as well as microbial parameter CFU/ml after 3 months. Conclusion: Diode laser as an adjunct to MWF in chronic periodontitis can provide enhanced clinical attachment gain with little postoperative discomfort.

Objective: Photobiomodulation (PBM) using diode laser is regarded an effective modality for the repair of tissues and control of pain. Ozone, owing to its biocompatibility, healing, and antimicrobial properties, is used in dentistry as well. This study was carried to clinically compare and evaluate the healing of gingival depigmented wounds using ozonated oil and PBM. Materials and Methods: A laser depigmentation procedure was conducted on seven patients exhibiting bilateral upper and lower gingival melanin hyperpigmentation, followed by the application of ozonated oil (Group 1) and laser PBM (Group 2). The clinical parameters are taken namely Visual Analog Scale and Healing Index (HI), were evaluated on the 3rd, 7th, and 15th day. Results: Statistical analysis showed better HI in Group I as compared to Group II on the 3rd day, but it was comparable in both groups on the 7th and 15th day. Conclusion: The application of ozonated oil was found to be more efficacious in promoting the initial healing of wound in comparison to PBM. Both ozonated oil and PBM also showed the same capabilities in reduction of the postoperative pain.

Aim: The study aimed to assess the minimally invasive Vestibular Incision Subperiosteal Tunnel Access (VISTA) technique for treatment of Millers Class I or Class II buccal gingival recession defects and to compare the effectiveness of a bioresorbable collagen membrane or advanced platelet rich fibrin (A-PRF). Methods and Material: 20 sites with Millers Class I or II gingival recession were recruited and allocated into 2 groups with 10 sites each. Group 1: VISTA with A-PRF, Group 2: VISTA with with bioresorbable collagen membrane (Healiguide)®. Standardized Clinical Parameters: Plaque Index (PI), Gingival Index (GI), Clinical attachment level (CAL )Pocket Probing Depth (PPD) Recession Height (RH ) and width of keratinized gingiva (WKG) were measured at baseline 3 months and 6 months. Results: Both groups showed significant improvement in clinical parameters. However reduction in recession height and mean root coverage percentage was greater in A-PRF group after 6 months. Conclusions: VISTA with both A-PRF and Healiguide showed good clinical outcomes but better results were obtained when A-PRF was used.

Background: Platelet-rich fibrin (PRF) has emerged as one of the promising regenerative materials in the field of periodontics. Hence, this study evaluated the efficacy of subepithelial connective tissue graft (SCTG) and PRF in surgical reconstruction of interdental papillae using Han and Takei technique. Materials and Methods: A total of 20 sites with Class I and Class II interdental papilla defects were assigned to two groups (Group 1 – Han and Takie technique + SCTG and Group 2 – Han and Takie technique + PRF). Parameters such as papillary height (PH), distance from the contact point to the tip of papillae (CPTP), papilla presence index (PPI), pocket probing depth (PPD), relative clinical attachment level (RCAL), plaque index (PI), gingival index (GI), and distance from contact point to alveolar crest (CP-BC) were measured at baseline and after 3 months. The significance of difference within and between the groups was evaluated with paired and unpaired t-tests. Results: The mean PI, GI, PPD, RCAL, PPI, and CPTP distance decreased significantly, whereas the mean PH increased significantly in Group 1 as well as in Group 2. After 3 months, mean reduction in CPTP distance and mean gain in PH were statistically significant in Group 1 as compared to Group 2. However, there was no significant difference in mean CPBC distance between baseline and 3 months in Group 1 as well as in Group 2. Conclusion: Both the techniques were effective in the treatment of papillary recession defects; however, more significant clinical papillary enhancement was achieved after the surgical reconstruction with SCTG.

Context: RJ is a natural bee product and is known to have remarkable health benefits. The objective was to evaluate its antimicrobial potential against periodontopathic bacteria and compare the same with chlorhexidine. Aims: The aim was to evaluate and compare the antimicrobial activity of royal jelly (RJ) with chlorhexidine against the periodontopathic bacteria (aerobic and anaerobic) in subgingival plaque. Materials and Methods: Subgingival plaque samples of 15 chronic periodontitis patients were taken, and clinical parameters were evaluated. Inhibitory effect of RJ and chlorhexidine was investigated “in vitro” on the growth of aerobic and anaerobic bacteria by colony count, minimum inhibitory concentration, and minimum bactericidal concentration (MBC) by the method of serial broth dilution. Statistical Analysis Used: ANOVA statistical analysis was used in this study. Results: Subgingival anaerobic bacteria predominate (colony-forming unit). Chlorhexidine is more sensitive in inhibiting aerobic and anaerobic bacteria (at concentration 50 μg/100 μl). A higher concentration of RJ is required to have an inhibitory effect. MBC of chlorhexidine shows no growth on blood agar plates, whereas minimum bacterial growth is seen around the RJ. Conclusions: Chlorhexidine (gold standard) has a higher inhibitory effect in the case of chronic periodontitis; however, RJ can also be used as an alternative but at higher concentration and lesser dilution. Evaluation of the quality, quantity and the biological activity of RJ is a necessity and must be done before its “in vivo” application.

ABSTRACT The nature and the intensity of innate immune response to virus infection determine the course of pathogenesis in the host. Among the many pathogen-associated molecular pattern recognition receptors, STING, an endoplasmic reticulum (ER)-associated protein, plays a pivotal role in triggering responses to microbial or cellular cytoplasmic DNA. Herpes simplex virus 1 (HSV-1), a common human pathogen, activates STING signaling, and the resultant induction of type I interferon causes inhibition of virus replication. In this context, we have observed that phosphorylation of Tyr245 of STING by epidermal growth factor receptor kinase is necessary for interferon induction. Here, we report that phosphorylation of Tyr240 by the tyrosine kinase Syk is essential for all signaling activities of STING. Our analysis showed that upon ligand-binding, STING dimerizes and interacts with membrane-bound EGFR, which autophosphorylates and provides the platform for the recruitment of cytoplasmic Syk to the signaling complex and its activation. Activated Syk phosphorylates Tyr240 of STING, followed by phosphorylation of Tyr245 by epidermal growth factor receptor (EGFR). Pharmacological or genetic ablation of Syk activity resulted in an arrest of STING in the ER compartment and a complete block of gene induction. Consequently, in the absence of Syk, HSV-1 could not induce interferon, and it replicated more robustly. IMPORTANCE The innate immune response to virus infection leads to interferon production and inhibition of viral replication. STING, an ER-bound protein, mediates such a response to cytoplasmic cellular or microbial DNA. HSV-1, a DNA virus, activates STING, and it replicates more efficiently in the absence of STING signaling. We demonstrate that phosphorylation of Tyr240 of STING by the protein tyrosine kinase Syk is essential for STING-mediated gene induction. To signal, ligand-activated STING recruits two kinases, Syk and EGFR, which phosphorylate Tyr240 and Tyr245, respectively. The dependence of STING signaling on Syk has broad significance, because STING plays a major role in many microbial, mitochondrial, and autoimmune diseases as well as in cancer development and therapy.

Since its emergence in Wuhan, China, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread very rapidly around the world, resulting in a global pandemic. Though the vaccination process has started, the number of COVID-affected patients is still quite large. Hence, an analysis of hotspot mutations of the different evolving virus strains needs to be carried out. In this regard, multiple sequence alignment of 71,038 SARS-CoV-2 genomes of 98 countries over the period from January 2020 to June 2021 is performed using MAFFT followed by phylogenetic analysis in order to visualize the virus evolution. These steps resulted in the identification of hotspot mutations as deletions and substitutions in the coding regions based on entropy greater than or equal to 0.3, leading to a total of 45 unique hotspot mutations. Moreover, 10,286 Indian sequences are considered from 71,038 global SARS-CoV-2 sequences as a demonstrative example that gives 52 unique hotspot mutations. Furthermore, the evolution of the hotspot mutations along with the mutations in variants of concern is visualized, and their characteristics are discussed as well. Also, for all the non-synonymous substitutions (missense mutations), the functional consequences of amino acid changes in the respective protein structures are calculated using PolyPhen-2 and I-Mutant 2.0. In addition to this, SSIPe is used to report the binding affinity between the receptor-binding domain of Spike protein and human ACE2 protein by considering L452R, T478K, E484Q, and N501Y hotspot mutations in that region.

Dorsal arachnoid webs are rare, and there is a lack of understanding regarding which patients are predisposed to forming them. A 52-year-old female, with an extensive spinal operative history and intrathecal opioid pain pump, presented to the emergency department with thoracic spine pain. Imaging revealed an arachnoid web at the T3 level. The patient was taken to the operating room for resection of the arachnoid web and had resolution of her neurological signs and symptoms postoperatively. Our experience suggests that the presence of an intrathecal pain pump may be a risk factor for the development of arachnoid web.

STING is a nodal point for cellular innate immune response to microbial infections, autoimmunity and cancer; it triggers the synthesis of the antiviral proteins, type I interferons. Many DNA viruses, including Herpes Simplex Virus 1 (HSV1), trigger STING signaling causing inhibition of virus replication. Here, we report that HSV1 evades this antiviral immune response by inducing a cellular microRNA, miR-24, which binds to the 3' untranslated region of STING mRNA and inhibits its translation. Expression of the gene encoding miR-24 is induced by the transcription factor AP1 and activated by MAP kinases in HSV1-infected cells. Introduction of exogenous miR-24 or prior activation of MAPKs, causes further enhancement of HSV1 replication in STING-expressing cells. Conversely, transfection of antimiR-24 inhibits virus replication in those cells. HSV1 infection of mice causes neuropathy and death; using two routes of infection, we demonstrated that intracranial injection of antimiR-24 alleviates both morbidity and mortality of the infected mice. Our studies reveal a new immune evasion strategy adopted by HSV1 through the regulation of STING and demonstrates that it can be exploited to enhance STING's antiviral action.

Background: There is growing interest in the connection between the gut microbiome and human health and disease. Conventional approaches to analyse microbiome data typically entail dimensionality reduction and assume linearity of the observed relationships, however, the microbiome is a highly complex ecosystem marked by non-linear relationships. In this study, we use topological data analysis (TDA) to explore differences and similarities between the gut microbiome across several countries.Methods: We used curated adult microbiome data at the genus level from the GMrepo database. The dataset contains OTU and demographical data of over 4,400 samples from 19 studies, spanning 12 countries. We analysed the data with tmap, an integrative framework for TDA specifically designed for stratification and enrichment analysis of population-based gut microbiome datasets.Results: We find associations between specific microbial genera and groups of countries. Specifically, both the USA and UK were significantly co-enriched with the proinflammatory genera Lachnoclostridium and Ruminiclostridium, while France and New Zealand were co-enriched with other, butyrate-producing, taxa of the order Clostridiales.Conclusion: The TDA approach demonstrates the overlap and distinctions of microbiome composition between and within countries. This yields unique insights into complex associations in the dataset, a finding not possible with conventional approaches. It highlights the potential utility of TDA as a complementary tool in microbiome research, particularly for large population-scale datasets, and suggests further analysis on the effects of diet and other regionally varying factors.

In this paper, we investigate the performance of the proposed oceanic monitoring system that connects the oceanic life with the terrestrial life. For continuous real-time monitoring and ubiquitous coverage, the communication system is aided with a satellite link. Multiple sensor nodes (SN) are deployed at different water levels that collect sensor data and transmit it to underwater vehicles (UV) using underwater visible light communication (UVLC). The UVLC system provides higher data rates at lower latency as compared to existing radio frequency (RF) and acoustic wave alternative for underwater communication (UWC). The UWC system comprises of horizontal haul (HH) and vertical haul (VH) UVLC links modelled using turbulence induced fading. The vertical haul links are modelled as the concatenation of successive non-mixing turbulent links to take into account the change of turbulence with the change of water level. The UVs and submarines communicate with the floating vessels (FVs) using vertical haul UVLC link. The UVs collect the data from the low power sensor nodes and offloads it to the FVs, which further beams it to the satellite on the RF carriers. The novel expressions of performance metrics such as outage probability and average bit error rate are derived. Further, the performance of the system is analysed for various system and channel parameters to prove the feasibility of the proposed communication system.

Introduction: Postthrombotic syndrome (PTS) occurs in 20%–60% of patients after acute deep-vein thrombosis (DVT) treated with anticoagulation alone. Residual thrombus after DVT leads to ambulatory venous hypertension which consequently causes PTS. Thus, evacuating the clot during DVT itself might prevent PTS – the “Open Vein Hypothesis.” Pharmacomechanical catheter-directed thrombolysis (PCDT) evacuates the thrombus working on this very hypothesis. PCDT is usually performed using specialized devices which are expensive and not easily available in our country. In this study, we describe a method to perform PCDT using a commonly available and inexpensive guiding catheter in an aim to prevent PTS after DVT. Aims and Objectives: This study aimed to evaluate if in acute DVT, our method of PCDT reduces the occurrence of PTS, as compared to anticoagulation alone. Design: This is a prospective, randomized, comparative, cohort study. Study Period: The study was conducted from June 2016 to May 2017 with 1-year follow-up. Materials and Methods: Patients presenting with acute DVT of

The coronavirus (COVID-19) pandemic has disrupted clinical trials globally, with unique implications for research into the human gut microbiome. In this mini-review, we explore the direct and indirect influences of the pandemic on the gut microbiome and how these can affect research and clinical trials. We explore the direct bidirectional relationships between the COVID-19 virus and the gut and lung microbiomes. We then consider the significant indirect effects of the pandemic, such as repeated lockdowns, increased hand hygiene, and changes to mood and diet, that could all lead to longstanding changes to the gut microbiome at an individual and a population level. Together, these changes may affect long term microbiome research, both in observational as well as in population studies, requiring urgent attention. Finally, we explore the unique implications for clinical trials using faecal microbiota transplants (FMT), which are increasingly investigated as potential treatments for a range of diseases. The pandemic introduces new barriers to participation in trials, while the direct and indirect effects laid out above can present a confounding factor. This affects recruitment and sample size, as well as study design and statistical analyses. Therefore, the potential impact of the pandemic on gut microbiome research is significant and needs to be specifically addressed by the research community and funders.

The interferon-induced tetratricopeptide repeat protein (Ifit2) protects mice from lethal neurotropic viruses. Neurotropic coronavirus MHV-RSA59 infection of Ifit2-/- mice caused pronounced morbidity and mortality accompanied by rampant virus replication and spread throughout the brain. In spite of the higher virus load, induction of many cytokines and chemokines in the brains of infected Ifit2-/- mice were similar to that in wild-type mice. In contrast, infected Ifit2-/- mice revealed significantly impaired microglial activation as well as reduced recruitment of NK1.1 T cells and CD4 T cells to the brain, possibly contributing to the lack of viral clearance. These two deficiencies were associated with a lower level of microglial expression of CX3CR1, the receptor of the CX3CL1 (Fractalkine) chemokine, which plays a critical role in both microglial activation and leukocyte recruitment. The above results uncovered a new potential role of an interferon-induced protein in immune protection.

Neurodegenerative diseases are a collection of disorders that result in the progressive degeneration and death of neurons. They are clinically heterogenous and can present as deficits in movement, cognition, executive function, memory, visuospatial awareness and language. Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation tool that allows for the assessment of cortical function in vivo. We review how TMS has been used for the investigation of three neurodegenerative diseases that differ in their neuroanatomical axes: (1) Motor cortex—corticospinal tract (motor neuron diseases), (2) Non-motor cortical areas (dementias), and (3) Subcortical structures (parkinsonisms). We also make four recommendations that we hope will benefit the use of TMS in neurodegenerative diseases. Firstly, TMS has traditionally been limited by the lack of an objective output and so has been confined to stimulation of the motor cortex; this limitation can be overcome by the use of concurrent neuroimaging methods such as EEG. Given that neurodegenerative diseases progress over time, TMS measures should aim to track longitudinal changes, especially when the aim of the study is to look at disease progression and symptomatology. The lack of gold-standard diagnostic confirmation undermines the validity of findings in clinical populations. Consequently, diagnostic certainty should be maximized through a variety of methods including multiple, independent clinical assessments, imaging and fluids biomarkers, and post-mortem pathological confirmation where possible. There is great interest in understanding the mechanisms by which symptoms arise in neurodegenerative disorders. However, TMS assessments in patients are usually carried out during resting conditions, when the brain network engaged during these symptoms is not expressed. Rather, a context-appropriate form of TMS would be more suitable in probing the physiology driving clinical symptoms. In all, we hope that the recommendations made here will help to further understand the pathophysiology of neurodegenerative diseases.

Introduction: Acupressure works to stimulate (tonify or sedate) specific reflex points located along the lines of energy. In needleless or laser acupuncture, low-intensity lasers are used to stimulate the trigger points, thereby curing many medical conditions. The use of this is called low-level laser therapy (LLLT). The aim of this article is to give a brief overview on needleless acupuncture using LLLT. Methodology: A literature search using keywords such as “laser acupuncture,” “needleless acupuncture,” and “low-level laser therapy” was made on Google Scholar, PubMed, PubMed Central, Science Direct, and Scopus. Results: Needleless acupuncture or laser acupuncture is one of the most popular methods for treating pain in the world. It has proved to be an effective option for various existing treatments and as a supplement to many current treatments as well. Conclusion: Acupressure with lasers is a proven, natural, and cost-effective professional and self-care system of treatment that can improve the quality life of patients.

Congenital mesoblasticnephroma (CMN) is a benign and very rare renal tumor, typically occurring in utero or during infancy. We are reporting a very young case of left sided classical congenital mesoblasticnephroma in a full term, small for gestational age, male neonate; who was detected with left sided flank mass immediately after birth. The patient was managed successfully by total nephrectomy. The diagnosis of CMN-classical type was confirmed on histopathological examination.

Abstract The objective was to examine whether: (1) statin use was associated with muscle related outcomes at age 60–64, (2) these associations were modified by 25-hydroxyvitamin D (25(OH)D) status and explained by inflammation, body-size or lifestyle in a British birth cohort. Markers of myalgia (intrusive body pain) and myopathy (self-reported and performance-based measures) were examined in 734 men and 822 women (MRC National Survey of Health and Development). Statin use was associated with intrusive body pain, difficulty climbing stairs and slower chair rise speed. Some associations were modified by 25(OH)D e.g. the association with intrusive body pain was evident in the insufficient (13–20 ng/l) and deficient (20 ng/l (OR = 0.8,95% CI 0.5–1.4) (p = 0.003 for interaction). Associations were maintained in fully adjusted models of intrusive body pain and difficulty climbing stairs, but for chair rise speed they were fully accounted for by inflammation, body-size and lifestyle. In a nationally representative British population in early old age, statin use was associated with lower limb muscle-related outcomes, and some were only apparent in those with 25(OH)D status below 20 ng/l. Given 25(OH)D is modifiable in clinical practice, future studies should consider the links between 25(OH)D status and muscle related outcomes.

Abstract Background Increasing age is the biggest risk factor for dementia, of which Alzheimer’s disease is the commonest cause. The pathological changes underpinning Alzheimer’s disease are thought to develop at least a decade prior to the onset of symptoms. Molecular positron emission tomography and multi-modal magnetic resonance imaging allow key pathological processes underpinning cognitive impairment – including β-amyloid depostion, vascular disease, network breakdown and atrophy – to be assessed repeatedly and non-invasively. This enables potential determinants of dementia to be delineated earlier, and therefore opens a pre-symptomatic window where intervention may prevent the onset of cognitive symptoms. Methods/design This paper outlines the clinical, cognitive and imaging protocol of “Insight 46”, a neuroscience sub-study of the MRC National Survey of Health and Development. This is one of the oldest British birth cohort studies and has followed 5362 individuals since their birth in England, Scotland and Wales during one week in March 1946. These individuals have been tracked in 24 waves of data collection incorporating a wide range of health and functional measures, including repeat measures of cognitive function. Now aged 71 years, a small fraction have overt dementia, but estimates suggest that ~1/3 of individuals in this age group may be in the preclinical stages of Alzheimer’s disease. Insight 46 is recruiting 500 study members selected at random from those who attended a clinical visit at 60–64 years and on whom relevant lifecourse data are available. We describe the sub-study design and protocol which involves a prospective two time-point (0, 24 month) data collection covering clinical, neuropsychological, β-amyloid positron emission tomography and magnetic resonance imaging, biomarker and genetic information. Data collection started in 2015 (age 69) and aims to be completed in 2019 (age 73). Discussion Through the integration of data on the socioeconomic environment and on physical, psychological and cognitive function from 0 to 69 years, coupled with genetics, structural and molecular imaging, and intensive cognitive and neurological phenotyping, Insight 46 aims to identify lifetime factors which influence brain health and cognitive ageing, with particular focus on Alzheimer’s disease and cerebrovascular disease. This will provide an evidence base for the rational design of disease-modifying trials.

Background: The aim of the present study was to compare the root coverage of localized gingival recession (GR) using modified coronally advanced flap (CAF) (Sanctis and Zucchelli's technique) and root conditioning 24% ethylenediaminetetraacetic acid (EDTA) when done under magnification and without magnification. Materials and Methods: A total of 20 sites were taken with Miller's Class I GR (10 in test and 10 in control). All clinical parameters were recorded at baseline, 1 month, and 3 months. CAF and root conditioning were done with 24% EDTA. Surgical procedure at test site was carried under magnification ×3.5 and at control site was done without magnification. Results: Plaque index, gingival index, clinical attachment level, probing depth, width of keratinized tissue (WKT), recession depth (RD), and recession width (RW) at baseline and 3 months were compared using Student's t- test. Mean WKT at baseline in control and test group was 4.22 ± 2.05 and 3.22 ± 1.09 which increased to 4.56 ± 1.59 and 4.50 ± 0.94, respectively, at 3 months. RD at baseline in control and test groups was 2.56 ± 0.53 and 2.67 ± 0.87 which reduced to 1.83 ± 0.71 and 1.22 ± 1.20, respectively. RW at baseline in control and test group was 3.56 ± 1.13 and 3.67 ± 0.50 which decreased to 3.06 ± 1.01 and 1.72 ± 1.39, respectively. All the clinical parameters were statistically not significant between control and test groups. Mean visual analog scale (VAS) at 7 days postoperatively in control and test groups was 1.78 ± 0.97 and 0.22 ± 0.44, respectively. The VAS scores were found to be significantly lower in the test group at both 3rd and 7th day postoperatively showing less pain in test group. Conclusion: Microsurgery offers less pain and enhanced outcomes when compared to traditional macrosurgery.

Context: Dentinal hypersensitivity (DH) is a chronic disorder in which patients report sharp and acute pain to a variety of stimuli. Till date, a standardized procedure to treat DH is missing, though several alternative treatment strategies have been designed, including laser therapies. Aim: The aim of the study was to treat DH with minimum chemical concentration and least laser energy level with longer follow-up period. Materials and Methods: One hundred and twenty patients were randomly divided into four groups: (i) Group 1-5% potassium nitrate (KNO3); (ii) Group 2 - gallium-aluminum-arsenide diode laser (62.2 J/cm2, wavelength - 980 nm, noncontact pulse mode, and power wattage - 0.5 W); (iii) Group 3 - combined 5% KNO3and the diode laser; and (iv) Group 4 - placebo (control). The visual analog scale (VAS) scores were recorded, analyzed, and compared to tactile stimuli, cold water, and air blast tests at different intervals for 6 weeks. Results: Synergistic use of 5% KNO3and diode laser (Group 3) significantly reduced the DH pain, which was almost negligible after 6th week (97%–99% of the pain was reported to be relieved) and showed promising results than any other studied groups. Further, the diode laser (Group 2) showed better results than 5% KNO3 (Group 1). One-way ANOVA and Bonferroni correction post hoc test revealed the combination of groups with significant differences in the mean VAS scores at the different interval of time (P < 0.01). Conclusions: Convincingly, the combined application of 5% KNO3with the diode laser can be recommended for treating DH patients.

Summary: Loss-of-function mutations in CNTNAP2 cause a syndromic form of autism spectrum disorder in humans and produce social deficits, repetitive behaviors, and seizures in mice. However, the functional effects of these mutations at cellular and circuit levels remain elusive. Using laser-scanning photostimulation, whole-cell recordings, and electron microscopy, we found a dramatic decrease in excitatory and inhibitory synaptic inputs onto L2/3 pyramidal neurons of the medial prefrontal cortex (mPFC) of Cntnap2 knockout (KO) mice, concurrent with reduced spines and synapses, despite normal dendritic complexity and intrinsic excitability. Moreover, recording of mPFC local field potentials (LFPs) and unit spiking in vivo revealed increased activity in inhibitory neurons, reduced phase-locking to delta and theta oscillations, and delayed phase preference during locomotion. Excitatory neurons showed similar phase modulation changes at delta frequencies. Finally, pairwise correlations increased during immobility in KO mice. Thus, reduced synaptic inputs can yield perturbed temporal coordination of neuronal firing in cortical ensembles. : Lazaro et al. demonstrate a decrease in synaptic inputs onto mPFC L2/3 pyramidal neurons of Cntnap2 KO mice, concurrent with reduced spines and synapses. These lead to perturbed network activity, with mPFC cells exhibiting reduced phase locking and altered preferred phases to slow LFP oscillations, which may underlie autism-related phenotypes. Keywords: oscillation, delta, theta, phase-locking, inhibition, brain state, connectivity, functional, biomarker, EEG

Motor cortex (M1) paired-pulse TMS (ppTMS) probes excitatory and inhibitory intracortical dynamics by measurement of motor-evoked potentials (MEPs). However, MEPs reflect cortical and spinal excitabilities and therefore cannot isolate cortical function. Concurrent TMS-EEG has the ability to measure cortical function, while limiting peripheral confounds; TMS stimulates M1, whilst EEG acts as the readout: the TMS-evoked potential (TEP). Whilst varying preconditioning stimulus intensity influences intracortical inhibition measured by MEPs, the effects on TEPs is undefined. TMS was delivered to the left M1 using single-pulse and three, ppTMS paradigms, each using a different preconditioning stimulus: 70%, 80% or 90% of resting motor threshold. Corticospinal inhibition was present in all three ppTMS conditions. ppTMS TEP peaks were reduced predominantly under the ppTMS 70 protocol but less so for ppTMS 80 and not at all for ppTMS 90. There was a significant negative correlation between MEPs and N45 TEP peak for ppTMS 70 reaching statistical trends for ppTMS 80 and 90. Whilst ppTMS MEPs show inhibition across a range of preconditioning stimulus intensities, ppTMS TEPs do not. TEPs after M1 ppTMS vary as a function of preconditioning stimulus intensity: smaller preconditioning stimulus intensities result in better discriminability between conditioned and unconditioned TEPs. We recommend that preconditioning stimulus intensity should be minimized when using ppTMS to probe intracortical inhibition.