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Purpose of Review Neurodevelopmental disorders disproportionately affect males. The mechanisms underlying male vulnerability or female protection are not known and remain understudied. Determining the processes involved is crucial to understanding the etiology and advancing treatment of neurodevelopmental disorders. Here, we review current findings and theories that contribute to male preponderance of neurodevelopmental disorders, with a focus on autism. Recent Findings Recent work on the biological basis of the male preponderance of autism and other neurodevelopmental disorders includes discussion of a higher genetic burden in females and sex-specific gene mutations or epigenetic changes that differentially confer risk to males or protection to females. Other mechanisms discussed are sex chromosome and sex hormone involvement. Specifically, fetal testosterone is involved in many aspects of development and may interact with neurotransmitter, neuropeptide, or immune pathways to contribute to male vulnerability. Finally, the possibilities of female underdiagnosis and a multi-hit hypothesis are discussed. Summary This review highlights current theories of male bias in developmental disorders. Topics include environmental, genetic, and epigenetic mechanisms; theories of sex chromosomes, hormones, neuroendocrine, and immune function; underdiagnosis of females; and a multi-hit hypothesis.

Background Resistance to osimertinib in advanced EGFR- mutated non-small cell lung cancer (NSCLC) constitutes a significant challenge for clinicians either in terms of molecular diagnosis and subsequent therapeutic implications. Methods This is a prospective single-centre study with the primary objective of characterising resistance mechanisms to osimertinib in advanced EGFR- mutated NSCLC patients treated both in first- and in second-line. Next-Generation Sequencing analysis was conducted on paired tissue biopsies and plasma samples. A concordance analysis between tissue and plasma was performed. Results Sixty-five advanced EGFR -mutated NSCLC patients treated with osimertinib in first- ( n  = 56) or in second-line ( n  = 9) were included. We managed to perform tissue and liquid biopsies in 65.5% and 89.7% of patients who experienced osimertinib progression, respectively. Acquired resistance mechanisms were identified in 80% of 25 patients with post-progression samples, with MET amplification ( n  = 8), EGFR C797S ( n  = 3), and SCLC transformation ( n  = 2) the most frequently identified. The mean concordance rates between tissue and plasma for the EGFR activating mutation and for the molecular resistance mechanisms were 87.5% and 22.7%, respectively. Conclusions Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.

Biological sex shapes the manifestation and progression of neurodevelopmental disorders (NDDs), however, the underlying mechanisms remains unclear. Hemideletion of the 16p11.2 region (16p11.2 del/+) is associated with NDDs, and 16p11.2 del/+ mice exhibit sex-specific, striatum-related phenotypes relevant to NDDs. In this study, using snRNA-seq, we identify cell type- and sex-specific transcriptomic changes in D1- and D2-spiny projection neurons (SPNs), with greater impact in males. Fiber photometry recordings reveal reduced neuronal activity in the dorsal striatum of 16p11.2 del/+ males, but not females, with D2-SPNs identified as the primary contributors to this reduction. Behaviorally, we utilize conditional genetic approaches and find that selective hemideletion in D2-SPNs, but not D1-SPNs, induces male-specific hyperactivity, whereas cortical hemideletion increases hyperactivity in both sexes. Thus, a locus linked to NDDs acts in distinct striatal circuits, selectively impacting behavior in a sex- and cell type-specific manner. This study demonstrates that 16p11.2 hemideletion, a genetic deletion linked to neurodevelopmental disorders, affects male and female mice differently, altering specific striatal neuronal circuits and driving sex-specific behavioral changes.

Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity have been proposed as a substrate of memory storage. Here, we examine the impact of brief periods of sleep deprivation on dendritic structure. In mice, we find that five hours of sleep deprivation decreases dendritic spine numbers selectively in hippocampal area CA1 and increased activity of the filamentous actin severing protein cofilin. Recovery sleep normalizes these structural alterations. Suppression of cofilin function prevents spine loss, deficits in hippocampal synaptic plasticity, and impairments in long-term memory caused by sleep deprivation. The elevated cofilin activity is caused by cAMP-degrading phosphodiesterase-4A5 (PDE4A5), which hampers cAMP-PKA-LIMK signaling. Attenuating PDE4A5 function prevents changes in cAMP-PKA-LIMK-cofilin signaling and cognitive deficits associated with sleep deprivation. Our work demonstrates the necessity of an intact cAMP-PDE4-PKA-LIMK-cofilin activation-signaling pathway for sleep deprivation-induced memory disruption and reduction in hippocampal spine density. The demands of modern society means that millions of people do not get sufficient sleep on a daily basis. Sleep deprivation, even if only for brief periods, can impair learning and memory. In many cases, this impairment appears to be related to changes in the activity of a brain region called the hippocampus. However, the exact processes responsible for producing the effects of sleep deprivation remain unclear. During learning or forming a new memory, the connections between the relevant neurons in the brain change. Havekes et al. found that depriving mice of sleep for just five hours dramatically reduced the connectivity between neurons in the hippocampus. This reduction is caused by the increased activity of cofilin, a protein that breaks down the actin filaments that shape the connections between neurons. Havekes et al. then used a virus to introduce an inactive version of cofilin into hippocampal neurons to suppress the activity of the naturally present cofilin. This manipulation prevented both the loss of the connections between neurons and the memory deficits normally associated with sleep deprivation. Havekes et al. also found that recovery sleep leads to the re-wiring of neurons in the hippocampus. Future studies are now needed to determine how the neurons are able to re-wire themselves during recovery sleep.

BackgroundsDue to a lack of randomized and large studies, the optimal surgical approach for Siewert 2 gastroesophageal junctional (GEJ) adenocarcinoma remains unknown. This population-based cohort study aimed to compare survival between esophagectomy and total gastrectomy for the treatment of Siewert 2 GEJ adenocarcinoma.MethodsData from the National Cancer Database (NCDB) from 2010 to 2016 was used to identify patients with non-metastatic Siewert 2 GEJ adenocarcinoma who received either esophagectomy (n = 999) or total gastrectomy (n = 8595). Propensity score-matching (PSM) and multivariable analyses were used to account for treatment selection bias.ResultsComparison of the unmatched cohort’s baseline demographics showed that the patients who received esophagectomy were younger, had a lower burden of medical comorbidities, and had fewer clinical positive lymph nodes. The patients in the unmatched cohort who received gastrectomy had a significantly shorter overall survival than those who received esophagectomy (median, 47 vs. 68 months [p < 0.001]; 5-year survival, 45 % vs. 53 %). After matching, gastrectomy was associated with significantly reduced survival compared with esophagectomy (median, 51 vs. 68 months [p < 0.001]; 5-year survival, 47 % vs. 53 %), which remained in the adjusted analyses (hazard ratio [HR], 1.22; 95 % confidence interval [CI], 1.09–1.35; p < 0.001).ConclusionsIn this large-scale population study with propensity-matching to adjust for confounders, esophagectomy was prognostically superior to gastrectomy for the treatment of Siewert 2 GEJ adenocarcinoma despite comparable lymph node harvest, length of stay, and 90-day mortality. Adequately powered randomized controlled trials with robust surgical quality assurance are the next step in evaluating the prognostic outcomes of these surgical strategies for GEJ cancer.

Acoustic emission is a well-known noninvasive methodology for the study of defects in materials but still rarely applied in the field of cultural heritage diagnostic. How alteration products and degradation processes affect the acoustic emission signal still is an open issue. The proposed study concerns the utilization of such techniques to investigate the relations existing between the moisture content and the typology and amount of crystallized salts with the acoustic emission features. This work focuses on spruce wood logs belonging to an historical warehouse in Trondheim, Norway, since no strictly scientific studies exist on the conservation conditions of these big wooden structures. The methodology, also involving the moisture content measurement of structures and the samplings of portions analyzed through vacuum microbalance, allowed identifying a clear relationship between the amount of water in logs as a function of their distance from the ground and variations in the amplitude of the acoustic emission signals.

Bruton’s tyrosine kinase (BTK) is essential for B-cell proliferation/differentiation and it is generally believed that its expression and function are limited to bone marrow-derived cells. Here, we report the identification and characterization of p65BTK, a novel isoform abundantly expressed in colon carcinoma cell lines and tumour tissue samples. p65BTK protein is expressed, through heterogeneous nuclear ribonucleoprotein K (hnRNPK)-dependent and internal ribosome entry site-driven translation, from a transcript containing an alternative first exon in the 5′-untranslated region, and is post-transcriptionally regulated, via hnRNPK, by the mitogen-activated protein kinase (MAPK) pathway. p65BTK is endowed with strong transforming activity that depends on active signal-regulated protein kinases-1/2 (ERK1/2) and its inhibition abolishes RAS transforming activity. Accordingly, p65BTK overexpression in colon cancer tissues correlates with ERK1/2 activation. Moreover, p65BTK inhibition affects growth and survival of colon cancer cells. Our data reveal that BTK, via p65BTK expression, is a novel and powerful oncogene acting downstream of the RAS/MAPK pathway and suggest that its targeting may be a promising therapeutic approach.

We report our single-center experience on the neurological manifestations of long COVID. This is a retrospective observational study. All consecutive patients referred to the neurological long COVID outpatient clinic of our institute from January 21 2021 to December 9 2021 underwent a general neurological objective examination. Treatments and investigations (brain MRI, neuropsychological evaluation, or others) were prescribed on an individual basis as per standard clinical practice. A follow-up visit was performed when appropriate. Descriptive statistics were presented as absolute and relative frequencies for categorical variables and as means, median, and ranges for continuous variables. One hundred and three patients were visited (mean age 50.5 ±36 years, 62 females). The average time from acute COVID-19 infection to the first visit to our outpatient clinic was 243 days. Most patients presented with a mild form of acute COVID-19, with only 24 cases requiring hospitalization. The neurological symptoms mostly (n=70/103, 68%) started during the acute phase (before a negative swab for SARS-CoV-2). The most frequent acute manifestations reported, which lately became persistent, were fatigue (n=58/103, 56%), olfactory/taste dysfunction (n=58/103, 56%), headache (n=47/103, 46%), cognitive disorders (n=46/103, 45%), sleep disorders (n=30/103, 29%), sensitivity alterations (n=29/103, 28%), and dizziness (n=7/103, 7%). Tremor was also reported (n=8/103, 7%). Neuropsychological evaluation was performed in 30 patients and revealed alterations in executive functions (n=6/30, 20%), memory (n=11/30, 37%), with pathological depressive (n=9/30, 30%) and anxiety (n=8/30, 27%) scores. Brain MRIs have been performed in 41 cases, revealing nonspecific abnormal findings only in 4 cases. Thirty-six patients underwent a follow-up, where a general improvement was observed but rarely (n=2/36) a complete recovery. The majority of patients presenting persistent neurological symptoms (most frequently fatigue, cognitive disorders, and olfactory dysfunctions) developed a previous mild form of COVID-19. Further studies are required to develop therapeutic strategies.

BackgroundThe risk of cardiovascular morbidities is higher in patients (pts) with RA and is exacerbated with type 2 diabetes (T2D).1 Recent analysis showed that abatacept (ABA), a biologic (b)DMARD, has a lower incidence of T2D in pts with RA in clinical practice.2 ObjectivesTo compare baseline characteristics of pts with RA on DMARDs and evaluate incidence of T2D among these pts based on DMARD exposure.MethodsAdministrative claims data (2006–2016) from Optum Clinformatics (database A), QuintilesIMS PharMetrics Plus (database B) and Truven MarketScan® (database C). Inclusion criteria were: 2 RA diagnosis codes+1 DMARD prescription; age ≥18 years;≥3 months baseline (pre-index date); and 3 months of follow-up (post-index date). Mutually exclusive treatment groups (grp) were created based on the first prescription (index date) using a hierarchy of ABA, non-ABA bDMARDs (TNF inhibitors [TNFi] and non-TNFi [excluding ABA]) and conventional DMARDs (cDMARD; MTX or hydroxychloroquine [HCQ]). Also, an RA grp without DMARD use (NoDMARD) was identified. The index date for NoDMARD was first diagnosis date. Incident T2D was identified as those without T2D prior to index using one International Classification of Disease (ICD)−9 or ICD-10 diagnosis code for T2D. Assessment of T2D risk between treatment grps was based on regression and disease risk score (DRS) models. Adjusted incidence rate for T2D was based on a Cox model (stratified by DRS grps and categorised into 4 equal grps using quartile scores) with treatment as the independent variable.ResultsIn databases A, B and C, 84,875, 2 07 811 and 1 94 819 pts with RA were identified, respectively (table 1). The combined proportions of pts in each treatment grp were: 3%–4% ABA; 12%–16% non-ABA bDMARD; and 41%–45% cDMARDs. Pts treated with ABA were older compared with those on non-ABA bDMARDs and a greater proportion had T2D risk factors of obesity, hypertension, dyslipidaemia and heart failure (table 1). The adjusted hazard ratios for T2D were significantly higher for non-bDMARD grps of TNFi and other bDMARDs vs ABA (figure 1).Abstract THU0688 – Table 1Baseline Risk Factors for T2D in Pts With RA by DMARD GrpsABATNFiNon-TNFiMTX onlyHCQcDMARD – othersNoDMARD Database A (N)2825956963212 67618 233436836 572Age≥55 years52.538.860.363.353.462.661.3Smoking11.39.88.711.211.211.714.1Obesity9.77.16.27.47.98.210.0Hypertension39.930.536.244.140.746.754.8Dyslipidaemia35.928.429.141.239.943.952.2Database B (N)649730 329166429 82149 65210 35879 490Age≥55 years45.534.139.649.741.748.945.0Smoking9.48.48.09.38.99.311.7Obesity8.46.45.16.57.57.19.3Hypertension36.125.227.234.431.935.842.4Dyslipidaemia31.224.423.133.632.636.742.0Database C (N)885329 671171430 66947 85010 89165 171Age≥55 years50.736.043.354.946.154.553.1Smoking4.75.05.55.45.25.36.8Obesity5.44.65.04.85.24.86.4Hypertension37.726.229.236.133.537.843.8Dyslipidaemia28.923.423.131.130.233.738.4All data are% unless indicated otherwiseAbstract THU0688 – Figure 1Hazard Ratios for Incidence of T2D in Pts With RA on Different DMARDs.(HR>1 favours abatacept, HR<1 favours other therapies)ConclusionsPts with RA treated with abatacept had greater risk factors for T2D at baseline. However, the adjusted risk of new-onset T2D was lower among abatacept pts versus other bDMARDs.References[1] Solomon DH, et al. Arthritis Rheum2004;50:3444–9.[2] Ozen G, et al. Ann Rheum Dis2017;76:848–54.Disclosure of InterestE. Alemao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Z. Guo Employee of: Bristol-Myers Squibb, L. Ferri Employee of: Bristol-Myers Squibb, L. Burns Employee of: Bristol-Myers Squibb

Midbrain dopaminergic (DA) axons make long longitudinal projections towards the striatum. Despite the importance of DA striatal innervation, processes involved in establishment of DA axonal connectivity remain largely unknown. Here we demonstrate a striatal-specific requirement of transcriptional regulator Nolz1 in establishing DA circuitry formation. DA projections are misguided and fail to innervate the striatum in both constitutive and striatal-specific Nolz1 mutant embryos. The lack of striatal Nolz1 expression results in nigral to pallidal lineage conversion of striatal projection neuron subtypes. This lineage switch alters the composition of secreted factors influencing DA axonal tract formation and renders the striatum non-permissive for dopaminergic and other forebrain tracts. Furthermore, transcriptomic analysis of wild-type and Nolz1 −/− mutant striatal tissue led to the identification of several secreted factors that underlie the observed guidance defects and proteins that promote DA axonal outgrowth. Together, our data demonstrate the involvement of the striatum in orchestrating dopaminergic circuitry formation. The mechanisms regulating midbrain dopaminergic innervation during development are unclear. Here, the authors showed that Nolz1 is required for axonal guidance of dopaminergic neurons during embryonic development of the mouse brain.