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Objective: To evaluate the effects of uncoupling protein (UCP) 1, UCP2 and UCP3 gene variants on body composition and metabolic changes in response to chronic overfeeding and the recovery after the period of overfeeding. Subjects and design: Twenty-four normal weight men (21±2 y), who constituted 12 pairs of identical twins, ate a 4.2 MJ/day energy surplus, 6 days a week, during a period of 100 days. The subjects were asked to return to the laboratory for testing at 4 months and for a final examination 5 y after completion of the overfeeding protocol. Methods: Resting metabolic rate (RMR) measurements were performed before and after overfeeding. A 4.2 MJ test meal was consumed, after which calorimetric measurements were continued for 240 min. Total body fat was assessed by hydrodensitometry and total subcutaneous fat by the sum of eight skinfolds. Polymorphisms were typed by PCR and PCR-RFLP-techniques. Thyroid stimulating hormone (TSH) concentrations after a thyrotropin releasing hormone (TRH) injection were measured by radioimmunoassay (RIA). Results: The changes in body weight and adiposity were not different between UCP1 Bcl I, UCP2 alanine to valine (A55V), UCP2 insertion/deletion (I/D) or UCP3 Rsa I genotypes. However, the recovery from overfeeding was worse among G-allele carriers of the UCP1 Bcl I, I allele non-carriers of the UCP2 I/D, AV heterozygote subjects of the UCP2 A55V and CC subjects of the UCP3 Rsa I polymorphisms. RMR was lower both before (P=0.01) and after (P=0.001) overfeeding in subjects with the CC genotype of the UCP3 Rsa I polymorphism. Moreover, after overfeeding, the UCP2 A55V heterozygote and UCP3 Rsa I CC homozygote subjects had significantly higher respiratory quotient (RQ) values at rest (P

Objective: To demonstrate sexual dimorphism in serum leptin levels not only during puberty, but also in childhood in Japan. Design: Cross-sectional study. Setting: Hamamatsu-Hokuen study in Japan. Subjects: Body weight and height were measured in normal-weight Japanese children and adolescents (143 boys, 178 girls), and 161 boys and 129 girls whose percentage of overweight for the standard (%Wt) was more than+25%. Serum leptin levels were compared with %Wt. Subjects were divided into group 1 (6–10 y of age) and group 2 (11–15 y of age) according to their age. Results: In overweight subjects, leptin was more highly correlated with %Wt in boys of group 2 (r=0.67, P

Cells respond to perturbations such as inflammation by sensing changes in metabolite levels. Especially prominent is arginine, which has long known connections to the inflammatory response. Here we show that depletion of arginine during inflammation decreased levels of arginyl-tRNA synthetase (ArgRS) in the nucleus. We found that nuclear ArgRS interacted with serine/arginine repetitive matrix protein 2 (SRRM2) in membrane-less, condensate-like, SRRM2-dependent nuclear speckles. This interaction impeded SRRM2 speckle trafficking and resulted in changes in alternative mRNA splicing. Splice site usage was regulated in opposite directions by ArgRS and SRRM2. These ArgRS- and SRRM2-dependent splicing changes cumulated in synthesis of different protein isoforms that altered cellular metabolism and peptide presentation to immune cells. Our findings delineate a novel mechanism whereby a tRNA synthetase responds to a metabolic change and modulates the splicing machinery via condensate trafficking for cellular responses to inflammatory injury.

Heart rate variability is a robust biomarker of emotional well-being, consistent with the shared brain networks regulating emotion regulation and heart rate. While high heart rate oscillatory activity clearly indicates healthy regulatory brain systems, can increasing this oscillatory activity also affect brain function? To test this possibility, we randomly assigned 106 young adult participants to one of two 5-week interventions involving daily biofeedback that either increased heart rate oscillations (Osc+ condition) or had little effect on heart rate oscillations (Osc- condition) and examined effects on brain activity during rest and during regulating emotion. While there were no significant changes in the right amygdala-medial prefrontal cortex (MPFC) functional connectivity (our primary outcome), the Osc+ intervention increased left amygdala-MPFC functional connectivity and functional connectivity in emotion-related resting-state networks during rest. It also increased down-regulation of activity in somatosensory brain regions during an emotion regulation task. The Osc- intervention did not have these effects. In this healthy cohort, the two conditions did not differentially affect anxiety, depression or mood. These findings indicate that heart rate oscillatory activity not only provides a measure of the current state of regulatory brain systems but also changes emotion network coordination in the brain.Significance StatementPeople whose breathing makes their heart rate oscillate more (leading to higher heart rate variability or HRV) generally have better regulated emotion. Thus, HRV may indicate functioning of brain networks regulating emotion and internal body states. But heart rate oscillations may not only reflect brain regulatory networks but also help shape these networks. We randomly assigned participants to practice either increasing heart rate oscillations using slow-paced breathing or decreasing them using personalized strategies. Daily practice increasing heart rate oscillations affected brain activity in emotion-related networks even during times when participants breathed no differently than the comparison group. Thus, HRV is more than just an outcome measure--it can help shape the subsequent functioning of emotion-related brain networks.

Urban forests are valuable spaces for species conservation, protection of local biodiversity and provision of ecosystem services. However, they are also vulnerable to the impact of extreme climate events like hurricanes. Understanding how urban forests are responding to hurricane disturbances is crucial to improve their design, management, and resilience. Here we analyzed pre-and post-hurricane surveys in 52 residential yards in San Juan to assess urban forests responses after Hurricanes Irma and Maria impacted Puerto Rico in 2017. We used these surveys to compare vegetation structure and composition (including species-specific mortality and damage rates) and to quantify changes in the ecosystem services provided by these yards. We found that hurricane disturbances significantly altered the structure but not the composition of yard vegetation. We detected a 27% reduction and 31% mortality of standing stems, and a significant reduction in plants health. Yard species composition was dominated by non-native species and this trend did not change with hurricane disturbance. Changes in vegetation structure translated into substantial reductions in ecosystem services. Food provision, an important service provided by a large proportion of yards before the hurricane, reported the highest reduction (41.9%) while carbon storage was the service that changed the least (9%). Our combined results emphasize the key role played by residential yards providing ecosystem services in tropical cities and call for further efforts to manage private and public urban forests in ways that may ensure their resilience to mitigate extreme climate events, provide multiple ecosystem services, and promote long-term urban sustainability.

Anxiety disorders are highly prevalent among individuals with a history of prenatal alcohol exposure (PAE), and adolescent rodents demonstrate anxiety-like behavior following moderate PAE on Gestational Day (G) 12. A likely systemic target of PAE is the stress peptide corticotrophin-releasing factor (CRF), as activation of CRF receptor 1 (CRFR1) in the medial nucleus of the central amygdala (CeM) is known to increase anxiety-like behavior in adults. To determine if CRF-CRFR1 interactions underly PAE-induced anxiety, functional changes in CRF system activity were investigated in adolescent male and female Sprague Dawley rats following G12 PAE. Compared to air-exposed controls, PAE increased basal spontaneous (s) inhibitory post-synaptic current (IPSC) frequency in the CeM of males, but not females. Furthermore, PAE blunted CRFR1-regulated miniature (m) IPSCs in a sex- and dose-specific manner, and only PAE males demonstrated tonic CRFR1 activity in the CeM. It was further determined that G12 PAE decreased CRFR1 mRNA in the CeM of males while increasing regional expression in females. Finally, infusion of a CRFR1 agonist into the CeM of adolescents produced a blunted expression of CRFR1-induced anxiety-like behavior exclusively in PAE males, mirroring the blunted physiology demonstrated by PAE males. Cumulatively, these data suggest that CRFR1 function within the CeM is age- and sex-specific, and PAE not only increases the expression of anxiety-like behavior, but may reduce the efficacy of treatment for PAE-induced anxiety through CRFR1-associated mechanisms. Therefore, future research will be necessary to develop targeted treatment of anxiety disorders in individuals with a history of PAE.

Fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance that results from an impaired collagen turnover. Peptidase D (PEPD) plays a vital role in collagen turnover by degrading proline-containing dipeptides. Nevertheless, its specific function and importance in AT is unknown. GWAS identified the rs731839 variant in the locus near PEPD that uncouples obesity from insulin resistance and dyslipidaemia, thus indicating that defective PEPD might impair AT remodelling and exacerbate metabolic complications. Here we show that in human and murine obesity, PEPD expression and activity decrease in AT, coupled to the release of PEPD systemically. Both events, in turn, are associated with the accumulation of fibrosis in AT and insulin resistance. Using pharmacologic and genetic animal models of PEPD down-regulation, we show that whereas dysfunctional PEPD activity provokes AT fibrosis, it is the PEPD secreted by AT the main contributor to inflammation, insulin resistance and metabolic dysfunction. Also, PEPD originated in inflammatory macrophages (Mɸ), plays an essential role promoting fibro-inflammatory responses via activation of EGFR in Mɸ and preadipocytes. Using genetic ablation of pepd in Mɸ that prevents obesity-induced PEPD release, also averts AT fibro-inflammation and obesity-associated metabolic dysfunctions. Taking advantage of factor analysis, we have identified the coupling of prolidase decreased activity and increased systemic levels of PEPD as the essential pathogenic triggers of AT fibrosis and insulin resistance. Thus, PEPD produced by Mɸ qualifies as a biomarker of AT fibro-inflammation and a therapeutic target for AT fibrosis and obesity-associated insulin resistance and type 2 diabetes.

Rationale There is growing interest in the therapeutic potential of cannabidiol (CBD) across a range of psychiatric disorders. CBD has been found to reduce anxiety during experimentally induced stress in anxious individuals and healthy controls. However, the mechanisms underlying the putative anxiolytic effects of CBD are unknown. Objectives We sought to investigate the behavioural and neural effects of a single dose of CBD vs. placebo on a range of emotion-related measures to test cognitive-mechanistic models of its effects on anxiety. Methods We conducted a randomised, double-blind, placebo-controlled, crossover, acute oral challenge of 600 mg of CBD in 24 healthy participants on emotional processing, with neuroimaging (viewing emotional faces during functional magnetic resonance imaging) and cognitive (emotional appraisal) measures as well as subjective response to experimentally induced anxiety. Results CBD did not produce effects on brain responses to emotional faces and cognitive measures of emotional processing, or modulate experimentally induced anxiety, relative to placebo. Conclusions Given the rising popularity of CBD for its putative medical benefits, these findings question whether further research is warranted to investigate the clinical potential of CBD for the treatment of anxiety disorders.

BackgroundChild-rearing isolation may increase the risk of child abuse and negatively affect child development owing to increased urbanization and decline in family and community support systems.PurposeThis study aimed to identify the prevalence of child-rearing isolation and the related sociodemographic factors among mothers in Japan using data from the Final Survey of Healthy Parents and Children 21.ParticipantsMothers of young children attending their health checkups.MethodsMultivariate logistic regression models assessed the association between child-rearing isolation and socio-demographic variables. Data from 69,337 women were analyzed.ResultsMothers who experienced child-rearing isolation comprised 0.2% of all participants. Mothers who were 35- to 39-years-old at childbirth (OR = 1.6, CI[1.0, 2.4], p = .036), unemployed (OR = 1.7, CI[1.3, 2.4], p = .001), experienced financial difficulty (OR = 1.8, CI[1.3, 2.5], p < .001), had husbands with limited participation in child-rearing (OR = 5.7, CI[4.2, 7.9], p < .001), lived in special wards in Tokyo Metropolis (OR = 4.2, CI[2.2, 8.3], p < .001), had child abuse concerns (OR = 2.1, CI [1.5, 2.9], p < .001), and had no time to relax with their child (OR = 4.5, CI [3.1-6.7], p < .001) exhibited higher odds ratio for child-rearing isolation, compared to those who did not.ConclusionsFindings showed the impact of urban living on maternal health, the influence of isolation on mothers’ anxiety about child-rearing and their potential for child maltreatment. The importance of fathers’ involvement in child-rearing for preventing maternal child-rearing isolation was highlighted.SignificancePrevious studies have shown that social isolation is significantly associated with morbidity and mortality. One of the most pressing issues in Japan is child-rearing isolation of mothers with infants. Child-rearing isolation is considered a risk factor for abuse and disruption of healthy parent-child relationships. However, no studies have examined the associated factors of child-rearing isolation among mothers, adjusting for confounding factors. Our results provide evidence that child-rearing isolation is a risk factor for maltreatment. In addition, we found new evidence that maternal child-rearing isolation is significantly associated with age at birth, lack of spousal participation in parenting, and urban living.

Hereditary ataxias are a group of devastating neurological disorders that affect coordination of gait and are often associated with poor coordination of hands, speech, and eye movements. Ataxia with Ocular Apraxia type 1 (AOA1) (OMIM: 606350.0006) is characterized by slowly progressive symptoms of childhood-onset and pathogenic mutations in APTX; the only known cause underpinning AOA1. APTX encodes the protein Aprataxin, composed of three domains sharing homology with proteins involved in DNA damage, signaling, and repair. We present four siblings from an endogamic family in a rural, isolated town of Colombia with ataxia and ocular apraxia of childhood-onset and confirmed molecular diagnosis of AOA1, homozygous for the W279* p.Trp279Ter mutation. We predicted the mutated APTX with Alpha Fold to demonstrate the effects of this stop-gain mutation that deletes three beta helices encoded by amino acid 270 to 339 rescinding the C2H2-type zinc fingers (Znf) (C2H2 Znf) DNA-binding and DNA-repair domain and the whole tridimensional structure of the APTX. All siblings exhibited different ages of onset (4, 6, 8, and 11 y/o) and heterogeneous patterns of dysarthria (ranging from absence to mild-moderate dysarthria). Neuropsychological evaluation showed no neurocognitive impairment in three siblings, but one sibling showed temporospatial disorientation, semantic and phonologic fluency impairment, episodic memory affection, constructional apraxia, moderate anomia, low executive function, and symptoms of depression. This heterogeneous phenotype suggests genetic interactions can shape the natural history of AOA1. To our knowledge, this report represents the most extensive series of siblings affected with AOA1 in Latin America, and the genetic analysis completed adds important knowledge to outline this family’s disease and general complex phenotype of hereditary ataxias.

Acute decompensation in patients with liver cirrhosis is characterized by the development of ascites, gastrointestinal bleeding, hepatic encephalopathy, or bacterial infection and is often accompanied by further extrahepatic organ dysfunction. Since critically ill patients with decompensated cirrhosis have a high mortality risk, rapid identification and treatment of the triggering event of decompensation (e.g., infection, hemorrhage, drugs) as well as specific measures for the treatment of concomitant extrahepatic organ dysfunctions are essential in order to improve the patient's prognosis and to prevent the development of acute-on-chronic liver failure (ACLF).

Purpose: Theta Burst Stimulation can influence adult neuro-visual response in imbalanced visual pathways, possibly by influencing cortical excitability. Our objective was to compare suppressive imbalance (SI) and visual acuity (VA) after applying repetitive Transcranial Magnetic Stimulation (TMS) between groups of subjects with normal binocular vision, visual asymmetry and amblyopia. Methods: Thirty – five volunteers between 19 and 51 years of age, were split into three groups: 6 volunteers with asymmetric VA (group A); 19 amblyopes (group B); and 10 subjects with normal binocular vision (group C). VA and SI of all groups were evaluated before and after a single session of continuous theta-burst stimulation (cTBS) or placebo stimulation over the right occipital cortex. Results: In both groups A and B we found a significant VA improvement in the non-dominant eye after cTBS (p=0.04 and p=0.01, respectively). In SI evaluation, group A and group B also revealed a significant improvement after the cTBS session (p=0.03 and p=0.01, respectively).Finally, in the group of volunteers with normal binocular vision and for placebo groups A and B, there were no significant differences in VA and SI after cTBS. Conclusions: Amblyopic and visually asymmetric individuals improved VA and SI of the non-dominant eye after cTBS when compared to baseline and to placebo stimulation. These enhancements were not found in the group of volunteers with normal binocular vision. We can therefore reasonably assume that cTBS may interfere with the visual system of subjects that present some kind of asymmetry, possibly by improving neuronal imbalances.

ObjectivesThis study had three objectives: first, to investigate the relative importance of the five mindfulness facets to negative affect (NA) among patients with chronic musculoskeletal pain; second, to test the hypothesis that observing is associated with lower NA only if occurs in an accepting manner; and third, to investigate the relation between mindfulness and obsessive–compulsive symptoms (OCS).MethodsOne hundred and nineteen patients with chronic musculoskeletal pain filled the Five-Facets Mindfulness Questionnaire (FFMQ), the Depression, Anxiety, Stress Scale (DASS), and the Obsessive– compulsive Inventory-Revised (OCI-R). A latent variable was constructed to represent NA. Multiple regression analysis was conducted, and several indices of relative importance were calculated.ResultsExcept for Observing, all mindfulness facets had significant bivariate and unique relation with NA. Acting with Awareness was the most important predictor, followed by Nonjudging and Describing. The contribution of Nonreactivity was small. Regarding the second objective, the Observing × Nonjudging and Observing × Nonreactivity interactions were not significant. Finally, the five facets of mindfulness explained about one-half of the variance in obsession and one-fifth of the variance in compulsion. After excluding the shared variance between obsession and compulsion, mindfulness was only related to obsession.ConclusionsExcept for Observing, all mindfulness facets seem to have unique contributions to psychological symptoms; among them, Acting with Awareness seems most important. Current evidence is inconsistent in supporting the moderating role of acceptance in the influence of observing. Finally, in the context of OCS, it seems that mindfulness is more related to obsession than compulsion.

Contemporary cognitive theories of anxiety and attention processing propose that heightened levels of anxiety vulnerability are associated with a decreasing ability to inhibit the allocation of attention towards task-irrelevant information. Existing performance-based research has most often used eye-movement assessment variants of the antisaccade paradigm to demonstrate such effects. Critically, however, eye-movement assessment methods are limited by expense, the need for expert training in administration, and limited mobility and scalability. These barriers have likely led to researchers’ use of suboptimal methods of assessing the relationship between attentional control and anxiety vulnerability. The present study examined the capacity for a non-eye-movement-based variant of the antisaccade task, the masked-target antisaccade task (Guitton et al., 1985), to detect anxiety-linked differences in attentional control. Participants (N = 342) completed an assessment of anxiety vulnerability and performed the masked-target antisaccade task in an online assessment session. Greater levels of anxiety vulnerability predicted poorer performance on the task, consistent with findings observed from eye-movement methods and with cognitive theories of anxiety and attention processing. Results also revealed the task to have high internal reliability. Our findings indicate that the masked-target antisaccade task provides a psychometrically reliable, low-cost, mobile, and scalable assessment of anxiety-linked differences in attentional control.

Implant-related bone infections are a major complication in orthopedic surgery that lead to inflammation and bone destruction. Bacterial biofilm formation on the implant is discussed to polarize the immune response towards tolerance and to facilitate bacterial persistence. In addition to their role in the early immune response, macrophages are osteoclast precursor cells. Therefore, macrophages can link inflammation and RANKL-mediated osteoclastogenic bone destruction. We investigated the influence of Staphylococcus aureus (SA) and epidermidis (SE) biofilm formation on immune function and osteoclastogenesis using RAW264.7 cells and conditioned media (CM) of planktonic and biofilm cultures in the presence and absence of the osteoclastogenic transcription factor RANKL. Analysis of immune cell activation, metabolic activity and osteoclast formation revealed that a planktonic environment causes a pro-inflammatory response. This was also partially induced by biofilm CM. Simultaneous stimulation with CM and RANKL suppressed osteoclast formation in favor of a long-term immune activation. While the early macrophage response towards CM was dominated by glycolysis, the CM and RANKL approach shifted metabolism towards increased mitochondrial biomass and activity. This was most evident in biofilm CM. We further showed that planktonic CM effects are mediated through activation of TLR signaling and induction of IFN-β production. In biofilm CM, high lactate levels seem to significantly contribute to the modulation of macrophages. Our results can contribute to find targets for therapeutic intervention that restore an effective pro-inflammatory immune response, which could help to control implant-related bone infections. Importance The number of endoprosthetic and bone reconstructive surgeries is rising and accordingly incidences of implant-related bone infections increase. Biofilm formation on the implant surface protects bacteria against most antibiotics and the host’s immune response. Thus, novel therapeutic strategies for prevention or treatment of biofilm formation are needed. Furthermore, bone infections are associated with osteoclast-mediated bone destruction, which promotes infection progression and ultimately leads to implant loosening. We investigated the effect of staphylococci-mediated biofilm formation on macrophage immune activation and osteoclastogenic differentiation, respectively. In planktonic and biofilm environments, immune cell activation dominated over osteoclastogenesis. The effects of planktonic environments were mainly mediated through activation of TLR signaling and resulted in a pronounced pro-inflammatory and IFN-β macrophage immune response. In biofilm environments, high lactate levels impaired osteoclast formation but also prevented an effective long-term immune activation. Therefore, targeting biofilm-derived metabolites but also IFN-β signaling might be promising novel treatment strategies.

Acknowledgements: Not applicable., Funder: Fisher and Paykal Healthcare, BACKGROUND: Minimally invasive surgery is becoming more common and transfemoral transcatheter aortic valve replacement is offered to older patients with multiple comorbidities. Sternotomy is not required but patients must lie flat and still for up to 2-3 h. This procedure is increasingly being performed under conscious sedation with supplementary oxygen, but hypoxia and agitation are commonly observed. METHODS: In this randomised controlled trial, we hypothesised that high-flow nasal oxygen would provide superior oxygenation as compared with our standard practice, 2 l min-1 oxygen by dry nasal specs. This was administered using the Optiflow THRIVE Nasal High Flow delivery system (Fisher and Paykel, Auckland, New Zealand) at a flow rate of 50 l min-1 and FiO2 0.3. The primary endpoint was the change in arterial partial pressure of oxygen (pO2) during the procedure. Secondary outcomes included the incidence of oxygen desaturation, airway interventions, the number of times the patient reached for the oxygen delivery device, incidence of cerebral desaturation, peri-operative oxygen therapy duration, hospital length of stay and patient satisfaction scores. RESULTS: A total of 72 patients were recruited. There was no difference in change in pO2 from baseline using high-flow compared with standard oxygen therapy: median [IQR] increase from 12.10 (10.05-15.22 [7.2-29.8]) to 13.69 (10.85-18.38 [8.5-32.3]) kPa vs. decrease from 15.45 (12.17-19.33 [9.2-22.8]) to 14.20 (11.80-19.40 [9.7-35.1]) kPa, respectively. The percentage change in pO2 after 30 min was also not significantly different between the two groups (p = 0.171). There was a lower incidence of oxygen desaturation in the high-flow group (p = 0.027). Patients in the high-flow group assigned a significantly higher comfort score to their treatment (p ≤ 0.001). CONCLUSION: This study has demonstrated that high flow, compared with standard oxygen therapy, does not improve arterial oxygenation over the course of the procedure. There are suggestions that it may improve the secondary outcomes studied. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) 13,804,861. Registered on 15 April 2019. https://doi.org/10.1186/ISRCTN13804861.

Background: Althoughpre-emptive therapy with oral tetracycline, moisturizer, sunscreen and topical corticosteroid isuseful for preventing acneiform eruption (AfE) due to epidermal growth factor receptor (EGFR) inhibitors, no studies have examinedthe efficacy of topical corticosteroids themselves, or investigated the optimal strength of the corticosteroid for treating facial AfE (FAfE).Patients and Methods: Screened patients with RAS wild-typecolorectal cancerstarted pre-emptive therapy with oral minocycline and moisturizeron initiation of cetuximab or panitumumab therapy. Patients who developed grade 1 or 2 FAfEwere randomly allocated to two groups:a ranking-down (RD) group,started with a very strong corticosteroid, and serially ranked down every 2 weeks unless FAfE exacerbated, and a ranking-up (RU) group, started with a weak corticosteroid and serially ranked up at exacerbation. FAfE grade, patient quality of life, and adverse events (AEs) with topical corticosteroid were evaluated every 2 weeks.The primary endpoint was the total number of times grade 2 or higher FAfEidentified in thecentral review of the 8-weektreatment period.Results: No significant differences in total numbers of grade 2 or higher FAfE and inAEs caused by topical corticosteroids were observedbetweengroups during the 8-week. Incidence of grade 2 or higher FAfEwas tended to lower inthe RD group during the first 2 weeks.Conclusion: Considering long-term care of FAfE, the RU regimen appears suitableand should be considered the standard treatment for FAfEdue to EGFR inhibitor therapy. Trial registration: UMIN Clinical Trials Registry (UMIN000024113)

Hybrid necrosis of wheat is caused by two dominant complementary genes Ne1 and Ne2 present in normal phenotype parents and is regarded as a barrier to gene flow between crop species. However, the necrosis alleles still occur at high frequency in modern wheat varieties. In this study, we constructed two high-density genetic maps of Ne1 and Ne2 in winter wheat. In these cultivars, Ne1 was found to be located in a span interval of 0.50 centimorgan (cM) on chromosome 5BL delimited by markers Nwu_5B_4137 and Nwu_5B_5114, while Ne2 co-segregated with markers Lseq102 and TC67744 on 2BS. Statistical analysis confirmed that the dosage effect of Ne alleles also existed in moderate and severe hybrid necrosis systems, and the symptoms of necrosis can also be affected by the genetic background. Furthermore, we clarified the discrete distribution and proportion of the Ne1 and Ne2 in China’s major wheat regions, and concluded that introduced modern cultivars directly affect the frequencies of necrosis genes in modern Chinese cultivars (lines), especially that of Ne2. Taking investigations in spring wheat together, we proposed that hybrid necrosis alleles could positively affect breeding owing to their linked excellent genes. Additionally, based on the pedigree, we speculated that the Ne1 and Ne2 in winter wheat may directly originate from wild emmer and introduced cultivars or hexaploid triticale, respectively.

Objective: the optimal management of asymptomatic, skull-based meningiomas is not well defined. The aim of this study is to compare the imaging and clinical outcomes of patients with asymptomatic, skull-based meningiomas managed either with upfront stereotactic radiosurgery (SRS) or active surveillance. Methods: this retrospective, multicenter study involved patients with asymptomatic, skull-based meningiomas. The study end-points included local tumor control and the development of new neurological deficits attributable to the tumor. Factors associated with tumor progression and neurological morbidity were also analyzed. Results: the combined unmatched cohort included 417 patients. Following propensity score matching for age, tumor volume, and follow-up 110 patients remained in each cohort. Tumor control was achieved in 98.2% and 61.8% of the SRS and active surveillance cohorts, respectively. SRS was associated with superior local tumor control (p < 0.001, HR = 0.01, 95% CI = 0.002-0.13) compared to active surveillance. Three patients (2.7%) in the SRS cohort and six (5.5%) in the active surveillance cohort exhibited neurological deterioration. One (0.9%) patient in the SRS-treated and 11 (10%) patients in the active surveillance cohort required surgical management of their meningioma during follow-up. Conclusions: SRS is associated with superior local control of asymptomatic, skull-based meningiomas as compared to active surveillance and does so with low morbidity rates. SRS should be offered as an alternative to active surveillance as the initial management of asymptomatic skull base meningiomas. Active surveillance policies do not currently specify the optimal time to intervention when meningioma growth is noted. Our results indicate that if active surveillance is the initial management of choice, SRS should be recommended when radiologic tumor progression is noted and prior to clinical progression., NA

Aggressiveness is one of the most basic behaviors, characterized by targeted intentional actions oriented to cause harm. The reactive type of aggression is regulated mostly by the brain’s prefrontal cortex; however, the molecular changes underlying aggressiveness in adults have not been fully characterized. Here we used an RNA-seq approach to investigate differential gene expression in the prefrontal cortex of bovines from the aggressive Lidia breed at different age stages: young three-year old and adult four-year-old bulls. A total of 50 up and 193 down-regulated genes in the adult group were identified. Furthermore, a cross-species comparative analysis retrieved 29 genes in common with previous studies on aggressive behaviors, representing an above-chance overlap with the differentially expressed genes in adult bulls.Particularly, we detected changes in the regulation of networks such as synaptogenesis, involved in maintenance and refinement of synapses, and the glutamate receptor pathway, which acts as excitatory driver in aggressive responses. Our results provide insights into candidate genes and networks involved in the molecular mechanisms leading to the maturation of the brain. The reduced reactive aggression typical of domestication has been proposed to form part of a retention of juvenile traits as adults (neoteny). The significant age-associated differential expression of genes implicated in aggressive behaviors and concomitant increase in Lidia cattle aggression validates this species as a novel model comparator to explore the impact of behavioral neoteny under domestication.

INTRODUCTION: The animal studies raise concerns about the possible ototoxicity of phenolic chemicals. Therefore, we conducted an epidemiologic study to examine the associations of phenols and parabens with hearing impairment. MATERIALS AND METHODS: Bisphenol A (BPA), benzophenone-3 (BP-3), and triclosan (TCS) were measured in urine samples in the National Health and Nutrition Examination Survey (NHANES) 2003–06 and 2009–12. Methyl paraben (MPB) and propyl paraben (PPB) were measured in urine samples in NHANES 2005–06 and 2009–12. Hearing impairment was defined as a hearing threshold of more than 25 dB at each hearing frequency in the better ear. Tests for linear trend were conducted using the median concentrations of urinary phenols or parabens in each quartile as a continuous variable. RESULTS: A total of 1809 participants (women = 52.0%) aged 20 and above were included in the final analysis (For MPB and PPB, the sample size was 1188). After adjusting for potential confounders, we found positive associations between BPA and hearing impairment at 3 K (p-trend = 0.04); between TCS and hearing impairment at 6 K (p-trend = 0.03); However, the odds ratio (OR) for the highest compared with the lowest quartile of both BPA and TCS did not reach statistical significance. In contrast, we found unexpected negative associations between BP-3 and hearing impairment at 0.5 K (p-trend = 0.04), 1 K (p-trend = 0.02), 2 K (p-trend

BackgroundSince the description of bilateral ligation of internal iliac arteries (BLIIA) and preperitoneal pelvic packing (PPP) for haemorrhage control in pelvic injury patients, multiple reports have been published advocating its use with acceptable outcomes. We analyzed our experience with this technique in a setting where the facility of hybrid Operating room for simultaneous angioembolisation is not available.Material and MethodsWe prospectively analysed data of sixty-six patients who presented in a state of unresponsive shock with pelvic fracture between January 2014 and September 2019. After initial resuscitation, they all underwent BLIIA with PPP as part of damage control surgery.ResultsOut of 66 patients, 55 were male. The mean age was 36.12 years. All patients sustained blunt trauma, with road traffic injuries being the most common mechanism involving 65 % of the patients followed by fall from height. The mean systolic blood pressure at the time of surgery was 77 ±34.46mm Hg. Median packed red blood cell transfusion in the first 24 hours was 8.5 units with IQR of 6-12. The hemorrhage related mortality was 48%.ConclusionBLIIA with PPP may be considered as a viable treatment option in hemodynamically unstable patients with pelvic injuries in resource constraint facilities.

Purpose Back pain is a major problem worldwide and is linked to intervertebral disc degeneration and Modic change. Several studies report growth of bacteria following extraction of degenerate discs at spine surgery. A pathophysiological role for infection in back pain has been proposed. Method We conducted a PRISMA systematic review. MEDLINE, PubMed, Scopus and Web of Science were searched with the terms Modic change, intervertebral dis*, bacteria, microb*, and infect*. Date limits of 2001–2021 were set. Human studies investigating the role of bacteria in disc degeneration or Modic change in vertebrae were included. Results Thirty-six articles from 34 research investigations relating to bacteria in human degenerate discs were found. Cutibacterium acnes was identified in pathological disc material. A ‘candidate bacterium’ approach has been repeatedly adopted which may have biased results to find species a priori, with disc microbial evidence heavily weighted to find C. acnes. Conclusion Evidence to date implicates C. acnes identified through culture, microscopy and sequencing, with some suggestion of diverse bacterial colonisation in the disc. This review found studies which used culture methods and conventional PCR for bacterial detection. Further agnostic investigation using newer methods should be undertaken.

Purpose This study aims to assess the results, rebubbling rate, and graft survival after Descemet membrane endothelial keratoplasty (DMEK) with regard to the number and type of previous glaucoma surgeries. Methods This is a clinical retrospective review of 1845 consecutive DMEK surgeries between 07/2011 and 08/2017 at the Department of Ophthalmology, University of Cologne. Sixty-six eyes were included: group 1 (eyes with previous glaucoma drainage devices (GDD); n = 27) and group 2 (eyes with previous trabeculectomy (TE); n = 39). Endothelial cell loss (ECL), central corneal thickness, graft failure, rebubbling rate, and best spectacle-corrected visual acuity (BSCVA) up to 3 years after DMEK were compared between subgroups of patients with different numbers of and the two most common types of glaucoma surgeries either GDD or TE or both. Results Re-DMEK rate due to secondary graft failure was 55.6% (15/27) in group 1 and 35.9% in group 2. The mean graft survival time in group 1 was 25 ± 11 months and 31.3 ± 8.6 months in group 2 (p = 0.009). ECL in surviving grafts in group 1 was 35% (n = 13) at 6 months, 36% at 12 months (n = 8), and 27% (n = 4) at 2 years postoperatively. In group 2, ECL in surviving grafts was 41% (n = 10) at 6 months, 36% (n = 9) at 12 months, and 38% (n = 8) at 2 years postoperatively. Rebubbling rate in group 1 was 18.5% (5/27) and 35.9% (14/39) in group 2 (p = 0.079). Conclusion Eyes with previous GDD had no higher risk for an increased rebubbling rate but a higher risk for a re-DMEK due to secondary graft failure with a mean transplant survival time of about 2 years. Compared to eyes with preexisting glaucoma drainage device, eyes after trabeculectomy had less secondary graft failures and a longer mean graft survival rate.

INTRODUCTION The ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE study in Japan (OVERCOME [Japan]) assessed the impact and burden of migraine in Japan. METHODS OVERCOME (Japan) was a cross-sectional, observational, population-based web survey of Japanese people with migraine conducted between July and September 2020. The burden and impact of migraine were assessed using the Migraine Disability Assessment (MIDAS), Migraine-Specific Quality-of-Life Questionnaire (MSQ), Migraine Interictal Burden Scale (MIBS-4), and Work Productivity and Activity Impairment-Migraine scale. Results were stratified by average number of monthly headache days (0-3, 4-7, 8-14, ≥ 15). RESULTS In total, 17,071 Japanese people with migraine completed the survey. Of these, 14,033 (82.2%) met International Classification of Headache Disorders, 3rd edition criteria for migraine and 9667 (56.6%) reported a physician diagnosis of migraine. Overall, 20.7% of respondents experienced moderate-to-severe disability (MIDAS). Moderate-to-severe interictal burden (MIBS-4) was experienced by 41.5% of respondents. MSQ scores in all domains were lowest in respondents with the most frequent headaches (≥ 15 monthly headache days) and highest in those with the lowest frequency headaches (≤ 3 monthly headache days), indicating poorer quality of life in those with more frequent headaches. Work time missed due to migraine (absenteeism) increased with increasing headache frequency, from 3.8 to 6.2%; presenteeism affected 29.8-49.9% of work time. Although migraine burden was greatest in people with the most frequent headaches, those with the lowest headache frequency still experienced substantial disability, interictal burden, and impacts on productivity and quality of life. There was also substantial unmet need for migraine care: 36.5% of respondents had ever hesitated to seek medical care for their headaches, and 89.8% had never used preventive medication. CONCLUSION In Japan, the burden of migraine and barriers to migraine care are substantial. Improving patient awareness and healthcare provider vigilance may help improve patient outcomes.

PURPOSE To examine plasma retinol status and its determinants in Chinese pregnant or lactating women. METHODS A cross-sectional study involving 1211 healthy women in mid-pregnancy, late pregnancy, or lactation was conducted in northern, central, and southern China. Plasma retinol concentration was determined by high-performance liquid chromatography. Multivariate quantile regression or modified Poisson regression was used to estimate adjusted medians, or to examine the associations of suboptimal retinol concentration (

PURPOSE To describe the outcomes of surgical bleb revisions from a tertiary glaucoma service in Singapore. METHODS One hundred and thirty-one eyes of 129 patients who underwent surgical bleb revisions at the Singapore National Eye Centre between 2007 and 2014 were included in the study. The indications for bleb revision were: bleb-related infection (BRI), early and late bleb leak, early and late overfiltration, and bleb dysesthesia. Regression analysis was applied to elucidate risk factors. RESULTS The mean age of the patients was 66 years, 62.6% were male, and 88.5% were Chinese. The majority of the eyes had primary glaucoma (79.4%). The mean interval from the initial trabeculectomy or phaco-trabeculectomy to the bleb revision was 58.8 months. The overall success rate was 69.5%. By Kaplan-Meier survival analysis, the overall cumulative success range fell from 78.6% to 49.1% over 10 years. Eyes with early bleb leak had lower surgical success compared to eyes with late bleb leak, early overfiltration and late overfiltration (P = 0.026, log-rank test). The IOP improved significantly post-operatively for eyes with BRI, early bleb leak, late bleb leak, early overfiltration and overfiltration (P

While exercise and physical activity have been suggested to reduce mortality and symptoms in cancer, knowledge on these associations in patients with childhood cancer (CCPs) is sparse. Anti-inflammatory properties of exercise might mediate these beneficial effects. We investigated the influence of exercise on the inflammation markers neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and systemic-immune-inflammation index (SII) and associations to patient-reported-outcomes in CCPs in a randomized-controlled trial. Results show associations between inflammation markers and patient-reported outcomes. Compared to the control group, SII was significantly reduced following exercise (p=0.036). Anti-inflammatory effects of exercise are also present in CCPs and may underlie exercise-induced benefits on symptoms. Clinical Trial Registration Number: NCT02612025, Supportive care in cancer;Bd 30. 2021, Heft 4, S. 2905-2908

Objectives This study investigated the 10-year trends of weight and prevalence of underweight, overweight and obesity according to disability grade and types compared with those without disabilities. Methods This serial cross-sectional analysis was conducted using national disability registration data with national general health checkup data from 2008 to 2017. Age-standardized prevalence of underweight and obesity were analyzed for each year, according to the presence, type, and severity of disabilities. Odds of underweight, overweight, obesity, and severe obesity were examined by multinomial logistic regression after adjusting for socio-demographic and clinical variables using data in 2017. Results Over 10 million subjects in each year were included in the analysis. In 2017, 14,246,785 people with age between 19 and 110 years were included and 53.1% was men. For 10 years, age-standardized prevalence of obesity and severe obesity showed significant increases regardless of sex and presence of disability. However, age-standardized underweight prevalence in people without disability tended to decrease whereas it was an increase in 2012 and the prevalence has remained steady since in people with disability. People with disabilities had higher odds of underweight compared to those without disability (OR 1.41, 95% CI 1.38–1.44 in male and OR 1.31, 95% CI 1.28–1.34 in female), especially in those with severe disabilities (OR 2.00, 95% CI 1.94–2.06 in male and OR 1.83, 95% CI 1.77–1.89 in female). Women with disabilities are more likely to be obese than those without disabilities regardless of disability severity (OR 1.40, 95% CI 1.38–1.41). Participants with mental disorder showed the highest prevalence of obesity, followed by epilepsy and developmental disability. Conclusions Having a disability was associated with higher odds/probability of both obesity and underweight. The intersection of female, severe disability, and mental/developmental disabilities was associated with probability of severe obesity. Simultaneous efforts are needed to develop health policy to reduce both the prevalence of obesity and underweight.

Summary Background The relationship between acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) and levels of certain inflammatory factors remains controversial. The purpose of this meta-analysis was to summarize the available studies evaluating the association between levels of inflammatory factors and ARDS/ALI incidence. Methods We searched the PubMed, EmBase, and Cochrane databases for studies published up to July 2017. For each inflammatory factor, a random effects model was employed to pool results from different studies. Results We identified 63 studies that included 6243 patients in our meta-analysis. Overall, the results indicated that the levels of angiopoietin (ANG)-2 (standard mean difference, SMD: 1.34; P P = 0.012), IL‑6 (SMD: 0.66; P = 0.005), and tumor necrosis factor (TNF)-α (SMD: 0.98; P = 0.001) were significantly higher in patients with ARDS/ALI than in unaffected individuals. No significant differences were observed between patients with ARDS/ALI and unaffected individuals in terms of the levels of IL‑8 (SMD: 0.61; P = 0.159), IL-10 (SMD: 1.10; P = 0.231), and plasminogen activator inhibitor (PAI)-1 (SMD: 0.70; P = 0.060). Conclusions ARDS/ALI is associated with a significantly elevated levels of ANG‑2, IL-1β, IL‑6, and TNF‑α, but not with IL‑8, IL-10, and PAI‑1 levels.

Over the past decades, virtual reality (VR) has found its way into biofeedback (BF) therapy programs. Using VR promises to overcome challenges encountered in traditional BF such as low treatment motivation, low attentional focus and the difficulty of transferring learnt abilities to everyday life. Yet, a comprehensive research synthesis is still missing. Hence, this scoping review aims to provide an overview over empirical studies on VR based BF regarding key outcomes, included samples, used soft- and hardware, BF parameters, mode of application and potential limitations. We systematically searched Medline, PsycINFO, Scopus, CINAHL, Google Scholar and Open Grey for empirical research. Eighteen articles met the inclusion criteria. Samples mostly consisted of healthy (44.4%) and/or adult (77.7%) participants. Outcomes were mainly anxiety (44.4%), stress (44.4%) or pain reduction (11.1%), which were reduced by the VR-BF interventions at least as much as by classical BF. Participants in VR-BF interventions showed higher motivation and involvement as well as a better user experience. Heart rate or heart rate variability were the most frequently used BF parameters (50.0%), and most VR-BF interventions (72.2%) employed a natural environment (e.g., island). Currently, there is no clear evidence that VR-BF is more effective than traditional BF. Yet, results indicate that VR-BF may have advantages regarding motivation, user experience, involvement and attentional focus. Further research is needed to assess the specific impact of VR and gamification. Also, testing a broader range of clinical and younger samples would allow more far-reaching conclusions.

Intrauterine infections are an urgent problem of modern neonatology. One of the causes of intrauterine infective foetal lesions is physiological immunosuppression. The purpose of this study is to investigate the cytokine status in newborns infected with perinatal infections, depending on their body weight. The study examined 145 newborns. Taking into account their body weight, they were divided into 2 groups: main and secondary. The study was conducted in the immunological laboratory of the Medical Centre of Marat Ospanov West Kazakhstan Medical University in the city of Aktobe, with the determination of the level of IgM and IgG to the herpes simplex virus (HSV) types 1, 2, cytomegalovirus (CMV), and chlamydia using the MULTISKANASCENT analyser with the "Chemo" T system. The main results of this study are the predominance of the anti-inflammatory component in both normal weight and underweight infants, which is evidence of the Th-cell-mediated immune response prevalence. The applied value of this study lies in the possibility of applying its results in practice to obtain effective methods to counteract the occurrence and development of intrauterine infections.

Sodium bicarbonate (NaHCOsub3/sub) is no longer recommended by the Neonatal Resuscitation Program (NRP), but is still being used by some neonatologists. The effects of NaHCOsub3/subon cerebral hemodynamics are unclear. Therefore, we investigated the effects of NaHCOsub3/subon cerebral blood flow (CBF) and cerebrovascular function using a newborn piglet model.Newborn pigs were anesthetized, intubated, and ventilated. Cranial windows were implanted to evaluate changes in pial arteriolar diameters (PADs) as a surrogate for CBF during a 4-h intravenous infusion of 3% NaHCOsub3/sub. Cerebrovascular reactivity to vasodilators and vasoconstrictors was investigated during vehicle control and during NaHCOsub3/subinfusion.NaHCOsub3/subinfusion caused significant and progressive pial arteriolar vasoconstrictions. During NaHCOsub3/subinfusion, cerebrovascular reactivity was preserved. Adding vasodilators decreased cerebral vasoconstriction, while adding vasoconstrictors exaggerated cerebral vasoconstriction.Intravenous infusion of NaHCOsub3/subover 4 h caused progressive vasoconstriction of pial arterioles. Cerebrovascular function evaluated by the responses of pial arterioles to physiologically relevant vasoconstrictors and vasodilators was preserved during NaHCOsub3/subinfusion. A notable additional reduction of PADs was observed during NaHCOsub3/subinfusion in the presence of vasoconstrictors. Extrapolating our findings to human neonates should alarm the clinicians that using NaHCOsub3/subin neonates may cause cerebral hypoperfusion.Cerebral vasoconstriction occurs during slow infusion of 3% diluted NaHCOsub3/sub. Cerebral vasoconstriction is exaggerated when another vasoconstrictor is added during NaHCOsub3/subinfusion. Cerebrovascular function is preserved during NaHCOsub3/subinfusion. Clinicians should be aware of the risk of cerebral hypoperfusion with NaHCOsub3/subinfusion in vulnerable neonates.

OBJECTIVE The purpose of this paper was to examine changes in situational temptations to smoke among women in early to late pregnancy enrolled in a texting trial to help them quit smoking. We compared changes between (1) intervention arms, (2) those who quit, (3) those who reduced by 50% or more, and (4) those who reduced by less than 50%. We also examined cravings overtime in the intervention arm and the relationship between real-time cravings assessed via text message and situational temptations. METHODS This was a secondary analysis of the Baby Steps trial, a randomized controlled trial testing the efficacy of a text-based scheduled gradual reduction (SGR) intervention on cessation. We used t-tests to examine changes across intervention arms and repeated measured proc mixed to explore changes in situational temptations and cravings. RESULTS Among all women, situational temptations decreased from early to late pregnancy for the positive, negative, and habitual subscales, (ps

Angina is a significant contributor to disability and impairment in quality of life in patients with chronic coronary syndromes (CCS). An elevated heart rate (HR) may trigger myocardial ischemia by increasing oxygen consumption and decreasing the diastolic time, compromising the coronary flow. HR-lowering strategies offer symptom control and prevent cardiovascular events in subgroups of patients with CCS. However, the best therapeutic approach to achieve the desired HR in patients with CCS can be challenging based on efficacy and tolerability. Guidelines usually propose β-blockers and/or non-dihydropyridine calcium channel blockers (CCB) for angina patients with elevated HR. Nonetheless, there is no clear evidence of greater antianginal efficacy of this strategy versus an alternative HR-lowering agent. Ivabradine reduces the HR by blocking the If current in the sinoatrial node without affecting myocardial contractility or vascular tone. The magnitude of the HR reduction by ivabradine is proportional to the initial HR, which decreases the risk of significant bradycardia. Ivabradine increases the diastolic time and the coronary flow reserve to a greater extent than β-blockers and favors collateralization, improving the regional blood flow. We present two clinical cases of patients with symptomatic CCS in whom HR control with ivabradine was fundamental for symptom control and improvement in left ventricular (LV) function. An earlier combination of ivabradine plus β-blockers would have provided more rapid symptom control and improved LV function in the first case. In the second case, the primary mechanism responsible for angina was most likely a coronary vasomotor abnormality, in which the use of β-blockers aggravated the discomfort. The combination of a dihydropyridine CCB plus ivabradine was highly influential in symptom control. Due to its effects beyond HR reduction and good tolerability, ivabradine should be considered an essential ally in managing patients with angina and high HR with or without LV dysfunction.

Achromatopsia (ACHM), also known as rod monochromatism or total color blindness, is an autosomal recessively inherited retinal disorder that affects the cones of the retina, the type of photoreceptors responsible for high-acuity daylight vision. ACHM is caused by pathogenic variants in one of six cone photoreceptor-expressed genes. These mutations result in a functional loss and a slow progressive degeneration of cone photoreceptors. The loss of cone photoreceptor function manifests at birth or early in childhood and results in decreased visual acuity, lack of color discrimination, abnormal intolerance to light (photophobia), and rapid involuntary eye movement (nystagmus). Up to 90% of patients with ACHM carry mutations in CNGA3 or CNGB3, which are the genes encoding the alpha and beta subunits of the cone cyclic nucleotide-gated (CNG) channel, respectively. No authorized therapy for ACHM exists, but research activities have intensified over the past decade and have led to several preclinical gene therapy studies that have shown functional and morphological improvements in animal models of ACHM. These encouraging preclinical data helped advance multiple gene therapy programs for CNGA3- and CNGB3-linked ACHM into the clinical phase. Here, we provide an overview of the genetic and molecular basis of ACHM, summarize the gene therapy-related research activities, and provide an outlook for their clinical application.

Zusammenfassung Hintergrund Eine adäquate Anpassung der Glukokortikoidsubstitution an unterschiedliche Situationen ist essenziell für Leistungsfähigkeit und Lebensqualität von Patienten mit Nebennierenrindeninsuffizienz (NNRI). Sie dient darüber hinaus der Vermeidung lebensbedrohlicher adrenaler Krisen. Ziel der Arbeit Verbesserung der Versorgung von Patienten mit Nebennierenrindeninsuffizienz. Material und Methoden Selektive Literaturrecherche unter besonderer Berücksichtigung neuerer Studien. Ergebnisse Eine optimale Glukokortikoidsubstitution hat das Ziel, die physiologischen Kortisolschwankungen möglichst genau nachzuahmen. Hier haben in den letzten Jahren Präparate mit veränderter Pharmakokinetik das Therapiespektrum erweitert. Im Vordergrund stehen eine adäquate Anpassung der Substitution in Stresssituationen sowie die Vermeidung und adäquate Behandlung adrenaler Krisen, die mit einer Inzidenz von 4,8 bis 8,3 Krisen pro 100 Patientenjahre auftreten und mit einer Mortalität von etwa 0,5 pro 100 Patientenjahre weiterhin eine tödliche Bedrohung darstellen. Schlussfolgerung Zur Verhinderung lebensbedrohlicher Nebennierenkrisen ist eine Schulung von Patienten, Angehörigen und insbesondere auch medizinischem Personal notwendig.

Long-term exercise training has been considered as an effective strategy to counteract age-related hormonal declines and minimise muscle atrophy. However, human data relating circulating hormone levels with motor nerve function are scant. The aims of the study were to explore associations between circulating sex hormone levels and motor unit (MU) characteristics in older men, including masters athletes competing in endurance and power events. Forty-three older men (mean ± SD age: 69.9 ± 4.6 years) were studied based on competitive status. The serum concentrations of dehydroepiandrosterone (DHEA), total testosterone (T) and estradiol were quantified using liquid chromatography mass spectrometry. Intramuscular electromyographic signals were recorded from vastus lateralis (VL) during 25% of maximum voluntary isometric contractions and processed to extract MU firing rate (FR), and motor unit potential (MUP) features. After adjusting for athletic status, MU FR was positively associated with DHEA levels (p = 0.019). Higher testosterone and estradiol were associated with lower MUP complexity; these relationships remained significant after adjusting for athletic status (p = 0.006 and p = 0.019, respectively). Circulating DHEA was positively associated with MU firing rate in these older men. Higher testosterone levels were associated with reduced MUP complexity, indicating reduced electrophysiological temporal dispersion, which is related to decreased differences in conduction times along axonal branches and/or MU fibres. Although evident in males only, this work highlights the potential of hormone administration as a therapeutic interventional strategy specifically targeting human motor units in older age.

Numerous studies in the literature are concerned with proposing new constitutive models for sands to simulate cyclic loading. Despite considerable progress in this area, there are various limitations on their simulation capabilities that are either overlooked or not communicated clearly by the developers. A number of these limitations are rather crucial for the end users, and therefore, providing discussion and analysis of them would be of great value for both applications and future developments. The present work is devoted to discussing seven characteristic limitations, which are frequently observed in cyclic loading simulations. Four advanced constitutive models are considered in this study: two bounding surface elastoplasticity and two hypoplasticity models—with the models in each category following a hierarchical order of complexity. Relevant cyclic loading experimental test data on Toyoura and Karlsruhe fine sands support the analysis. The key issues discussed include stress overshooting, one-way ratcheting in cyclic strain accumulation, liquefaction strength curves, stress attractor in strain-controlled shearing, hypoelasticity, cyclic oedometer stiffness, and effect of drained preloading. The presented results elaborate on the specific limitations and capabilities of these rather advanced models in simulating several essential aspects of cyclic loading of sands.

PURPOSE Evaluation of the impact of catheter ablation for ventricular extrasystoles (VES) in structurally normal hearts on quality of life (QOL) and symptomatology. METHODS Symptom analysis assessed with a disease-specific questionnaire, EHRA score for AF, and QOL analysis at baseline and 1 year after ablation. RESULTS The study enrolled 39 patients between April 2016 and November 2019. Two patients were excluded from further analysis. At baseline, palpitations were reported in 31/37 (84%); syncope in 12/37 (32%); other cardiac symptoms in 33/37 (89%) of patients. The EHRA score was 3 or 4 in 13 patients (35%). With the modified arrhythmia-specific questionnaire (MASQ) psychological and physical scores were 46 and 39%. The overall perception of health in the SF-36 was 56 ± 16%. Ablation was performed in 35/37 (95%). At regular follow-up, symptoms were reported in 14/37 (38%) patients. ECG suggested a good procedural outcome in 65% with VES burden on Holter

This paper provides a commentary on "Vascular amputees: A study in disappointment" (Little et al. 1974) and its significance in the development of the disability rights movement, as well as the movements for values-based medicine and person-centred health and social care.

Background To examine published data and assess evidence relating to safety and efficacy of surgical management of symptomatic pineal cysts without hydrocephalus (nhSPC), we performed a systematic review of the literature and meta-analysis. Methods Following the PRISMA guidelines, we searched Pubmed and SCOPUS for all reports with the query ‘Pineal Cyst’ AND ‘Surgery’ as of March 2021, without constraints on study design, publication year or status (PROSPERO_CRD:42,021,242,517). Assessment of 1537 hits identified 26 reports that met inclusion and exclusion criteria. Results All 26 input studies were either case reports or single-centre retrospective cohorts. The majority of outcome data were derived from routine physician-recorded notes. A total of 294 patients with surgically managed nhSPC were identified. Demographics: Mean age was 29 (range: 4–63) with 77% females. Mean cyst size was 15 mm (5–35). Supracerebellar-infratentorial approach was adopted in 90% of cases, occipital-transtentorial in 9%, and was not reported in 1%. Most patients were managed by cyst resection (96%), and the remainder by fenestration. Mean post-operative follow-up was 35 months (0–228). Presentation: Headache was the commonest symptom (87%), followed by visual (54%), nausea/vomit (34%) and vertigo/dizziness (31%). Other symptoms included focal neurology (25%), sleep disturbance (17%), cognitive impairment (16%), loss of consciousness (11%), gait disturbance (11%), fatigue (10%), ‘psychiatric’ (2%) and seizures (1%). Mean number of symptoms reported at presentation was 3 (0–9). Outcomes: Improvement rate was 93% (to minimise reporting bias only consecutive cases from cohort studies were considered, N = 280) and was independent of presentation. Predictors of better outcomes were large cyst size (OR = 5.76; 95% CI: 1.74–19.02) and resection over fenestration (OR = 12.64; 3.07–52.01). Age predicted worse outcomes (OR = 0.95; 0.91–0.99). Overall complication rate was 17% and this was independent of any patient characteristics. Complications with long-term consequences occurred in 10 cases (3.6%): visual disturbance (3), chronic incisional pain (2), sensory disturbance (1), fatigue (1), cervicalgia (1), cerebellar stroke (1) and mortality due to myocardial infarction (1). Conclusions Although the results support the role of surgery in the management of nhSPCs, they have to be interpreted with a great deal of caution as the current evidence is limited, consisting only of case reports and retrospective surgical series. Inherent to such studies are inhomogeneity and incompleteness of data, selection bias and bias related to assessment of outcome carried out by the treating surgeon in the majority of cases. Prospective studies with patient-reported and objective outcome assessment are needed to provide higher level of evidence.

Acute coronary syndrome (ACS) may lead to adverse remodelling and impaired cardiac function. Limited data exists on the effect of culprit coronary artery lesion site and impact on longitudinal cardiac remodelling. The present study included a total of 299 patients suffering from ACS treated with percutaneous coronary intervention (PCI). All patients had two echocardiographic examinations. The first echocardiography was median 2(IQR: 1;3) days following PCI, while the follow-up echocardiography (FUE) was median 257(IQR: 96;942) days following the first. Patients were grouped based on coronary artery PCI location; left anterior descending artery (LAD), right coronary artery (RCA) or circumflex artery (Cx). Patients with multiple lesions were excluded. Mean age was 63 ± 11 years and 77% were male. At FUE, mean left ventricular ejection fraction was 42 ± 9% and global longitudinal strain (GLS) was - 13 ± 4%. PCI treatment was allocated as 168 LAD lesions, 95 RCA lesions, and 36 Cx lesions. Linear regression analysis showed that patients with a LAD lesion displayed worsening in E/A (mean ∆ = 0.05, β = - 0.196, p = 0.001) and a larger increase in LVEDV (mean ∆ = 33.18 mL, β = 0.135, p = 0.012). Meanwhile patients with Cx lesion were significantly associated with a larger decrease in E/e' (mean ∆ = 2.6, β = - 0.120, p = 0.028). Patients with Cx lesion were observed to have elevated E/e' at baseline, which normalized at FUE. The present study suggests that culprit coronary artery lesion has a differential impact on myocardial remodelling. This information may potentially aid in understanding the pathophysiological differences in cardiac structure and function amongst patients with ACS.

PURPOSE SharpSense™ technology is an upgradable software enhancement introduced to the Abbott Confirm Rx™ insertable cardiac monitor (ICM). This study aims to characterize the real-world performance of SharpSense algorithms by comparing device detected pause and bradycardia episodes before and after the SharpSense upgrade. METHODS Confirm Rx devices with at least 90 days monitoring each before and after SharpSense upgrade were included in the study. Bradycardia and pause detections and subcutaneous electrocardiograms (SECGs) within 90 days before and after the upgrade were extracted from Merlin.net™ patient care network for evaluation and adjudicated by expert adjudicators. RESULTS A total of 197 devices were included in the analysis. Devices were implanted for syncope (35.0%), atrial fibrillation (32.5%), cryptogenic stroke (16.8%), and other indications including palpitations (15.7%). The SharpSense upgrade significantly reduced the number of bradycardia detections by 86.8% and pause detections by 93.1%. In adjudicated SECGs, the upgrade significantly reduced false positive (FP) bradycardia episodes by 91.5% and FP pause episodes by 82.8%. The percentage of devices with at least one FP episode was reduced from 39 to 20% for bradycardia and from 52 to 35% for pause. The number of devices with FP rate greater than 1 episode per week was reduced from 23 to 8% for bradycardia and from 39 to 20% for pause. CONCLUSIONS In this real-world performance evaluation, the algorithms incorporated in SharpSense software upgrade in Confirm Rx ICMs substantially reduced false positive bradycardia and pause detections and the number of transmitted SECGs for clinic review.

PURPOSE Otitis media with effusion (OME), recurrent acute otitis media and conductive hearing loss (CHL) are significantly prevalent in children with cleft palate (CP) and cleft lip and palate (CLP). Rapid Maxillary Expansion (RME) appears to have a positive effect also on middle ear disorders in these patients. The study aims to offer a prospective evaluation of RME effects in a group of patients with CP/CLP in terms of OME, CHL. METHODS A prospective observational study was conducted. Thirty-four CP, CLP and submucosa cleft patients who received orthodontic indication to RME treatment for OME or conductive hearing loss in a tertiary institutional Care Unit of San Paolo Hospital, Milan (IT), were included. Twenty-two patients matched for age and with analogous inclusion criteria except for indication to RME treatment were enrolled in the control group. Clinical otolaryngological evaluation, pure tone audiometry and tympanogram were performed at the beginning of treatment (T0), at the end of the expansion (T1) and at 6-month follow-up (T2). MAIN OUTCOME MEASURES Air-bone gaps and tympanogram results at each time interval. RESULTS In the main group, RME allowed a statistically significant improvement of air-bone gaps (according to frequency, p

Initial research suggests stepped-care approaches to therapy for youth anxiety is associated with reduced therapy time with similar therapeutic outcomes to treatment-as-usual in real-world settings. Research on the acceptability and feasibility of stepped-care approaches in routine practice is very limited. In a secondary analysis of a pilot randomised controlled trial that compared stepped-care to treatment-as-usual in adolescent mental health services, we examine acceptability and feasibility from consumer and clinician perspectives. Fifteen adolescents and ten clinicians provided brief quantitative and qualitative feedback. Some benefits were noted and these related to improved access to treatment; however, major barriers were also noted. Concerns related to the lack of consumer and clinician choice and flexibility in delivery of stepped interventions, challenges engaging adolescents with internet interventions and associated guided telephone calls, and workplace issues. Systemic changes to facilitate consumer preferences, clinician flexibility and staffing are needed for stepped-care to be feasible in routine care.

Purpose It is suggested that non-specific low back pain (LBP) can be related to nerve ingrowth along granulation tissue in disc fissures, extending into the outer layers of the annulus fibrosus. Present study aimed to investigate if machine-learning modelling of magnetic resonance imaging (MRI) data can classify such fissures as well as pain, provoked by discography, with plausible accuracy and precision. Methods The study was based on previously collected data from 30 LBP patients (age = 26–64 years, 11 males). Pressure-controlled discography was performed in 86 discs with pain-positive discograms, categorized as concordant pain-response at a pressure ≤ 50 psi and for each patient one negative control disc. The CT-discograms were used for categorization of fissures. MRI values and standard deviations were extracted from the midsagittal part and from 5 different sub-regions of the discs. Machine-learning algorithms were trained on the extracted MRI markers to classify discs with fissures extending into the outer annulus or not, as well as to classify discs as painful or non-painful. Results Discs with outer annular fissures were classified in MRI with very high precision (mean of 10 repeated testings: 99%) and accuracy (mean: 97%) using machine-learning modelling, but the pain model only demonstrated moderate diagnostic accuracy (mean accuracy: 69%; precision: 71%). Conclusion The present study showed that machine-learning modelling based on MRI can classify outer annular fissures with very high diagnostic accuracy and, hence, enable individualized diagnostics. However, the model only demonstrated moderate diagnostic accuracy regarding pain that could be assigned to either a non-sufficient model or the used pain reference.

BACKGROUND The aim of our study was to assess the efficacy of sinus laser therapy (SiLaT) for the treatment of pilonidal disease. METHODS All adult patients treated with SiLaT in our department between June 1, 2018, and August 23, 2019, were included in the study. Success was defined as the closure of cutaneous orifices and the absence of discharge or abscesses. RESULTS We included 29 consecutive patients (22 males) with a median age of 32.5 ± 10.5 years. Eight patients had already undergone prior surgery for pilonidal disease. The procedure was performed under spinal (55%) or general (45%) anesthesia. The mean follow-up was 370.3 days (± 165.8 days). We observed 2 primary failures (6.9%) and 7 recurrences (24.1%). Ultimately, 20 patients were considered to have been cured (69%). The mean time to healing was 25 days (± 8.1 days). No serious complications were reported. Usual activities were resumed within a mean of 4.9 days (± 7.2), and 86% of patients reported being "very satisfied" with the treatment. The body mass index was lower for patients who were cured (24.0 ± 3.6) than for those who experienced treatment failure (27.6 ± 3.4; p = 0.018). The cured patients were less likely to have one or more secondary openings (35.0 versus 88.9%, p = 0.014). CONCLUSIONS Almost 70% of our patients were cured by SiLaT. Complications were rare and mild. The technique appeared to be less effective for overweight patients and those with one or more secondary openings associated with pilonidal pits.

Background Due to rising costs in health care delivery, reimbursement decisions have progressively been based on quality measures. Such quality indicators have been developed for neurosurgical procedures, collectively. We aimed to evaluate their applicability in patients that underwent surgery for vestibular schwannoma and to identify potential new disease-specific quality indicators. Methods One hundred and three patients operated due to vestibular schwannoma were subject to analysis. The primary outcomes of interest were 30-day and 90-day reoperation, readmission, mortality, nosocomial infection and surgical site infection (SSI) rates, postoperative cerebral spinal fluid (CSF) leak, facial, and hearing function. The secondary aim was the identification of prognostic factors for the mentioned primary outcomes. Results Thirty-day (90-days) outcomes in terms of reoperation were 10.7% (14.6%), readmission 9.7% (13.6%), mortality 1% (1%), nosocomial infection 5.8%, and SSI 1% (1%). A 30- versus 90-day outcome in terms of CSF leak were 6.8% vs. 10.7%, new facial nerve palsy 16.5% vs. 6.1%. Hearing impairment from serviceable to non-serviceable hearing was 6.8% at both 30- and 90-day outcome. The degree of tumor extension has a significant impact on reoperation (p p = 0.015), postoperative hemorrhage (p p = 0.026). Conclusions Our data demonstrate the importance of entity-specific quality measurements being applied even after 30 days. We identified the occurrence of a CSF leak within 90 days postoperatively, new persistent facial nerve palsy still present 90 days postoperatively, and persisting postoperative hearing impairment to non-serviceable hearing as potential new quality measurement variables for patients undergoing surgery for vestibular schwannoma.

Background and objective Excessive daytime sleepiness (EDS) and fatigue are major complaints in patients with obstructive sleep apnoea (OSA) syndrome. Pitolisant is an orally active selective histamine H3 receptor (H3R) antagonist/inverse agonist, which enhances histaminergic transmissions in the brain and thereby elicits strong wake-promoting effects. This article assesses the efficacy and safety of pitolisant 20 mg in patients with OSA, based on existing randomised controlled studies. Methods An individual patient data (IPD) meta-analytical two-level (study-patient) hierarchical model was used assuming a random treatment effect. The Epworth Sleepiness Scale (ESS) and Oxford Sleep Resistance (OSleR) tests were co-primary endpoints. Results A total of 512 patients, including 384 treated with pitolisant and 128 with placebo, were included in the analysis. Compared with placebo, pitolisant reduced mean ESS by − 3.1 (95% CI [− 4.1; − 2.1]; p < 0.001) and improved OSleR by 1.18 (1.02; 1.35, p = 0.022); 30% more patients had reduced fatigue (risk ratio [RR] = 1.3, [1.11; 1.53]), p = 0.001) and 46% more patients had improved Clinical Global Impression (CGI) (RR = 1.46 [1.12; 1.89], p = 0.005). No significant differences in safety endpoints were found. These results proved homogeneous across studies and subgroups of the population. Conclusion The results provide evidence of a significant benefit of pitolisant in improving EDS and fatigue, irrespective of baseline conditions. Supplementary Information The online version contains supplementary material available at 10.1007/s40261-021-01104-8.