Protein network analysis links the NSL complex to Parkinson's disease via mitochondrial and nuclear biology.

Whilst the majority of Parkinson's Disease (PD) cases are sporadic, much of our understanding of the pathophysiological basis of the disease can be traced back to the study of rare, monogenic forms of PD. In the past decade, the availability of genome-wide association studies (GWAS) has facilitated a shift in focus, toward identifying common risk variants conferring increased risk of developing PD across the population. A recent mitophagy screening assay of GWAS candidates has functionally implicated the non-specific lethal (NSL) complex in the regulation of PINK1-mitophagy. Here, a bioinformatics approach has been taken to investigate the proteome of the NSL complex, to unpick its relevance to PD pathogenesis. The NSL interactome has been built, using 3 online tools: PINOT, HIPPIE and MIST, to mine curated, literature-derived protein-protein interaction (PPI) data. We built (i) the 'mitochondrial' NSL interactome exploring its relevance to PD genetics and (ii) the PD-oriented NSL interactome to uncover biological pathways underpinning the NSL/PD association. In this study, we find the mitochondrial NSL interactome to be significantly enriched for the protein products of PD-associated genes, including the Mendelian PD genes LRRK2 and VPS35. In addition, we find nuclear processes to be amongst those most significantly enriched within the PD-associated NSL interactome. These findings strengthen the role of the NSL complex in sporadic and familial PD, mediated by both its mitochondrial and nuclear functions.

Respect for the journey: a survivor-led investigation of undergoing psychotherapy assessment.

PURPOSE: Psychotherapy assessments are key decision points for both clients and services, carrying considerable weight on both sides. Limited research indicates that assessments have immediate and long-term impacts on clients, particularly where trauma has been experienced, affecting engagement with therapy. Understanding assessments from clients' perspectives can inform service development and improve client experience. METHODS: This is a survivor-led exploration of clients' experiences of undergoing assessment for talking therapies. Interviews were conducted with seven people who had undergone assessment for psychological therapies in third sector and NHS services. Interviews were recorded, transcribed and analysed thematically. RESULTS: The core theme was 'respect for the journey' reflecting the need expressed by participants for their life experiences prior to the assessment to be given full respect and consideration. Six sub-themes were identified: trauma and desperation, fear of judgement, search for trust and safety, sharing and withholding (a balancing act), feeling deconstructed, and finding hope. CONCLUSIONS: The findings highlight the heightened emotional power surrounding psychotherapy assessments, reflecting the journey participants had undertaken to reach this point. The dilemma facing clients at the heart of an assessment-how much to share and how much to withhold-demonstrates the importance for services and assessors of treating the journey a client has made to the assessment with care and respect. Findings indicate the value of services and practitioners undertaking a trauma-informed approach to assessment encounters.

Survivor-led guidelines for conducting trauma-informed psychological therapy assessments: Development and modified Delphi study.

BACKGROUND: Psychological therapy assessments are a key point at which a person is accepted into a service or referred on. There is evidence of service users experiencing harm, dropping out of services and potentially experiencing poor outcomes because of inadequate assessment practices. Approaches to assessment tend to be developed by individual services, with a lack of research identifying what makes a good assessment. METHODS: This survivor-led study, based in England, aimed to generate guidelines for conducting trauma-informed psychological therapy assessments. The study was guided by a Service User Advisory Group and a Clinician Advisory Group. The study was conducted in three key stages: (i) identifying, modelling and drafting guideline content (ii) modified Delphi study and (iii) guideline finalization. Stage 1 was informed by literature reviews, qualitative research, data workshops with Advisory Groups and an expert consultation. Fifty-nine people with relevant experiences then participated in a single-stage modified Delphi (Stage 2). The guidelines were finalized through an analysis of Delphi open comments and a final expert consultation (Stage 3). RESULTS: The guidelines evolved through each stage of the process, and all items were deemed important by >90% of Delphi participants. The final trauma-informed guidelines contain eight principles, including 'focus on relationships', 'from systems to people' and 'healing environments'. CONCLUSIONS: Experiential knowledge was key in generating the guidelines and conceptualizing content, with a consequent focus on areas, such as recognizing power differentials, understanding oppression as trauma and the relational aspects of assessments. Future research should focus on guideline implementation and investigate whether this impacts service user dropout, engagement with therapy, and outcomes. PATIENT OR PUBLIC CONTRIBUTION: This study is an example of survivor research, with several authors, including the study lead, identifying as survivors. We consider the ways in which our identities as survivor researchers impacted the study findings.

Anxiety and Anticipated Pain Levels of Women With Self-Reported Penetration-Related Genito-Pelvic Pain are Elevated in Response to Pain-related Images.

BACKGROUND: Genito-pelvic pain (GPP) affects a sizable minority of women and results of existing treatments can be variable. A method of general pain treatment that has not yet been extended to penetration-related GPP is Explicit Motor Imagery (EMI), which uses pain-related images to help individuals with pain alter their responses to pain, resulting in reduced pain, less pain-related anxiety, and improved function. AIM: As a first step toward determining if EMI is a feasible method for treating penetration-related GPP, this study examined whether images that potentially signal genital pain are sufficient to induce an anxiety or anticipated pain response in women. METHODS: Participants were 113 women (62 with genital pain, 51 pain-free) recruited to complete an online study. Participants viewed randomized images of women engaging in various activities that potentially cause pain for people with penetration-related GPP (sitting, walking, running, lifting, inserting a tampon, implied penetrative sex, actual penetrative sex, implied gynecological exam, actual gynecological exam). Participants then rated each image on how much anxiety they experienced viewing the picture (viewing anxiety), and how much anxiety (anticipated anxiety) and pain (anticipated pain) they expected to experience doing the activity in the picture. OUTCOMES: Outcomes were the self-reported viewing anxiety, anticipated anxiety, and anticipated pain of women with and without self-reported penetration-related GPP in response to the pain-related images. RESULTS: Women who experienced self-reported penetration-related GPP reported significantly higher levels of viewing anxiety, anticipated anxiety, and anticipated pain in almost all categories of images, compared to women who were free of pain. The key exception was that women with and without self-reported penetration-related GPP reported similar levels of viewing anxiety when looking at images of implied and actual penetrative sex. CLINICAL TRANSLATION: These results support that pelvic and genital imagery serve as a sufficient stimulus to generate anxiety and anticipated pain in our study sample. EMI, which targets desensitization of heightened anxiety warrants further research as a potential novel treatment option. STRENGTHS & LIMITATIONS: This study was the first to assess responses to a wide array of pain-eliciting images in women with and without self-reported penetration-related GPP. A key limitation was that the pain sample was self-reported and not clinically diagnosed. CONCLUSION: Images of pain-related stimuli were sufficient to induce anxiety and anticipated pain in women with self-reported penetration-related GPP. This first step suggests that EMI may be a useful treatment option for women with penetration-related GPP. Kelly KJM, Fisher BL, Rosen NO, et al. Anxiety and Anticipated Pain Levels of Women With Self-Reported Penetration-Related Genito-Pelvic Pain are Elevated in Response to Pain-related Images. J Sex Med 2022;19:1281-1289.

The impact of glutaraldehyde based footbaths on Dichelobacter nodosus prevalence and the antimicrobial resistant community of the ovine interdigital skin.

Ovine footrot, is a highly contagious polymicrobial bacterial infection, primarily caused by Dichelobacter nodosus. Preventative bactericidal footbaths are commonly used in the sheep industry to reduce the spread of bacteria. However, their effect on the bacterial community is poorly understood. This is the first study to investigate the impact of 2% Digicur (ProGiene,UK) footbath on the bacterial community of the ovine interdigital skin following a common UK footbathing routine. Swab samples were analysed by qPCR to determine prevalence and load of D. nodosus and numerated on MacConkey agar in the presence or absence of tetracycline and ampicillin to determine phenotypic antimicrobial resistance. Metagenomics were used to determine the impact of a single footbath on the bacterial community and genotypic antimicrobial resistance. The results suggest 2% Digicur is ineffective at reducing the load of D. nodosus when applied as a one off or weekly footbath, however sheep may act as a reservoir for multi-drug resistant bacteria creating opportunities to spread antimicrobial resistance to other sheep and their environment.

Chelation Crosslinking of Biodegradable Elastomers.

Widely present in nature and in manufactured goods, elastomers are network polymers typically crosslinked by strong covalent bonds. Elastomers crosslinked by weak bonds usually exhibit more plastic deformation. Here, chelation as a mechanism to produce biodegradable elastomers is reported. Polycondensation of sebacic acid, 1,3-propanediol, and a Schiff-base (2-[[(2-hydroxyphenyl) methylene]amino]-1,3-propanediol) forms a block copolymer that binds several biologically relevant metal ions. Chelation offers a unique advantage unseen in conventional elastomer design because one ligand binds multiple metal ions, yielding bonds of different strengths. Therefore, one polymeric ligand coordinated with different metal ions produces elastomers with vastly different characteristics. Mixing different metal ions in one polymer offers another degree of control on material properties. The density of the ligands in the block copolymer further regulates the mechanical properties. Moreover, a murine model reveals that Fe3+ crosslinked foam displays higher compatibility with subcutaneous tissues than the widely used biomaterial-polycaprolactone. The implantation sites restore to their normal architecture with little fibrosis upon degradation of the implants. The versatility of chelation-based design has already shown promise in hydrogels and highly stretchy nondegradable polymers. The biodegradable elastomers reported here would enable new materials and new possibilities in biomedicine and beyond.

TGR5 Protects Against Colitis in Mice, but Vertical Sleeve Gastrectomy Increases Colitis Severity.

BACKGROUND AND AIMS: Bariatric surgery, such as vertical sleeve gastrectomy (VSG), is the most effective long-term treatment for obesity. However, there are conflicting reports on the effect of bariatric surgery on inflammatory bowel disease (IBD). Bariatric surgery increases bile acid concentrations, which can decrease inflammation by signaling through the bile acid receptor, TGR5. TGR5 signaling protects against chemically induced colitis in mice. VSG increases circulating bile acid concentrations to increase TGR5 signaling, which contributes to improved metabolic regulation after VSG. Therefore, we investigated the effect of VSG on chemically induced colitis development and the role of TGR5 in this context. METHODS: VSG or sham surgery was performed in high fat diet-fed male Tgr5+/+ and Tgr5-/- littermates. Sham-operated mice were food restricted to match their body weight to VSG-operated mice. Colitis was induced with 2.5% dextran sodium sulfate (DSS) in water post-operatively. Body weight, energy intake, fecal scoring, colon histopathology, colonic markers of inflammation, goblet cell counts, and colonic microRNA-21 levels were assessed. RESULTS: VSG decreased body weight independently of genotype. Consistent with previous work, genetic ablation of TGR5 increased the severity of DSS-induced colitis. Notably, despite the effect of VSG to decrease body weight and increase TGR5 signaling, VSG increased the severity of DSS-induced colitis. VSG-induced increases in colitis were associated with increased colonic expression of TNF-α, IL-6, MCP-1, and microRNA-21. CONCLUSIONS: While our data demonstrate that TGR5 protects against colitis, they also demonstrate that VSG potentiates chemically induced colitis in mice. These data suggest that individuals undergoing VSG may be at increased risk for developing colitis; however, further study is needed.

Sellar Masses that Present with Severe Hyponatremia.

OBJECTIVE: Hyponatremia is a known but underrecognized presentation of sellar lesions. Herein, we present a series of patients who presented with single or multiple episodes of hyponatremia. METHODS: Over 5 years, patients undergoing endonasal surgery for a de novo sellar mass with hyponatremia as an initial presentation were included. Pathology, sodium levels, pituitary hormonal status, and treatment course were documented. RESULTS: Of 282 patients, 16 (5.7%) (9 males, 7 females, age 32 to 84 years) presented with severe hyponatremia, with a mean serum sodium level of 115 ± 6 mmol/L (range, 101 to 125 mmol/L), and 3 patients had 2 or more episodes. Severe hyponatremia was a presenting sign in 0, 4.1, 14.3, and 37.5% of patients with craniopharyngiomas (n = 10), pituitary adenomas (n = 243), Rathke's cleft cysts (RCCs) (n = 21), and sellar arachnoid cysts (n = 8), respectively (P<.01). Half of the patients presenting with hyponatremia, including 6 of 10 patients with adenomas and 2 of 3 patients with RCCs, had pituitary apoplexy or cyst rupture. All patients had anterior pituitary gland dysfunction, including 81% with hypoadrenalism and 69% with hypothyroidism. Following surgery, hormonal status was unchanged or improved in 15 patients (median follow-up, 14 months). No patient had tumor/cyst recurrence or recurrent hyponatremia. CONCLUSION: Severe hyponatremia was a presenting sign in 5.7% of patients with sellar pathology, most frequently in patients with arachnoid cysts, RCCs, and pituitary apoplexy. Patients with new-onset severe hyponatremia and no obvious pharmacologic or systemic cause should undergo pituitary hormonal evaluation and brain imaging. Surgical resection and correction of hormonal deficiencies are associated with resolution of recurrent hyponatremic episodes.

Predictive value of hearing assessment by the auditory brainstem response following universal newborn hearing screening.

OBJECTIVE: This study set out to determine the accuracy with which tone pip ABR and click ABR, carried out in babies referred from universal newborn hearing screening, is able to predict the hearing outcome as determined by follow-up hearing tests. STUDY SAMPLE: The cohort of babies studied were all babies referred for hearing assessment from the universal newborn hearing screen in Sheffield, UK for the period January 2002 to September 2007, who were found to have a significant hearing impairment. DESIGN: The results of hearing assessment following referral from the newborn hearing screen were collected together with those of follow-up tests carried out up to an age when behavioural testing had established ear- and frequency-specific thresholds at 0.5, 1, 2 and 4 kHz. RESULTS: The standard deviation of the difference between the follow up and the tone pip ABR thresholds was 10.5 dB for the 4-kHz tone pip, 16.8 dB for the 1-kHz tone pip, and ranged between 21.7 and 24.7 dB for click ABR. CONCLUSIONS: The results of the study show that tone pip ABR following referral from newborn hearing screening has a similar accuracy to that reported in older subjects, and is a much better predictor compared to click ABR.

Failure to confirm genetic association between schizophrenia and markers on chromosome 1q23.3 in the region of the gene encoding the regulator of G-protein signaling 4 protein (RGS4).

The chromosome 1q23.3 region, which includes the RGS4 gene has been implicated in genetic susceptibility to schizophrenia by two linkage studies with lod scores of 6.35 and 3.20 and with positive lod between 2.00 and 3.00 scores in several other studies. Reduced post mortem RGS4 gene expression in the brain of schizophrenics was reported as well as positive allelic association between markers at the RGS4 gene locus and schizophrenia. We have attempted to replicate the finding of allelic association with schizophrenia in a UK based sample of 450 subjects with schizophrenia and 450 supernormal controls. We genotyped the same SNP marker alleles investigated in the earlier studies and also a di-nucleotide (GT)14 repeat microsatellite marker, which was 7 kb distal to RGS4. In the new UK sample there was no evidence for allelic or haplotypic association between RGS4 markers and schizophrenia. This might reflect genetic heterogeneity between the population samples, genotyping or other methodological problems. The finding weakens the evidence that mutations or variation in the RGS4 gene have an effect on schizophrenia susceptibility.

Failure to confirm allelic association between markers at the CAPON gene locus and schizophrenia in a British sample.

BACKGROUND: Linkage studies have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. It was then claimed that markers at the carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) gene showed allelic association with schizophrenia in Canadian families. A second Chinese study found a base pair polymorphism at the CAPON gene also associated with schizophrenia. METHODS: We attempted replication using eight markers from the Canadian study in a UK based sample of 450 cases and 450 supernormal controls. RESULTS: We found no evidence for allelic or haplotypic association with schizophrenia for any of the markers found to be associated in the Canadian sample. CONCLUSIONS: The negative results might reflect genetic heterogeneity between the Canadian, Chinese and UK samples or be due to methodological problems. The present finding weakens the evidence that mutations or variation in the CAPON gene are causing genetic susceptibility to schizophrenia in European populations.

The Epsin 4 gene on chromosome 5q, which encodes the clathrin-associated protein enthoprotin, is involved in the genetic susceptibility to schizophrenia.

Chromosome 5q33 is a region that has previously shown good evidence of linkage to schizophrenia, with four LOD scores >3.00 in independent linkage studies. We studied 450 unrelated white English, Irish, Welsh, and Scottish research subjects with schizophrenia and 450 ancestrally matched supernormal controls. Four adjacent markers at the 5' end of the Epsin 4 gene showed significant evidence of linkage disequilibrium with schizophrenia. These included two microsatellite markers, D5S1403 (P=.01) and AAAT11 (P=.009), and two single-nucleotide-polymorphism markers within the Epsin 4 gene, rs10046055 (P=.007) and rs254664 (P=.01). A series of different two- and three-marker haplotypes were also significantly associated with schizophrenia, as confirmed with a permutation test (HapA, P=.004; HapB, P=.0005; HapC, P=.007; and HapD, P=.01). The Epsin 4 gene encodes the clathrin-associated protein enthoprotin, which has a role in transport and stability of neurotransmitter vesicles at the synapses and within neurons. A genetically determined abnormality in the structure, function, or expression of enthoprotin is likely to be responsible for genetic susceptibility to a subtype of schizophrenia on chromosome 5q33.3.