Publications by authors named "T McHugh"

581 Publications

Brain-specific heterozygous loss-of-function of ATP2A2, endoplasmic reticulum Ca2+ pump responsible for Darier's disease, causes behavioral abnormalities and a hyper-dopaminergic state.

Hum Mol Genet 2021 Jun 8. Epub 2021 Jun 8.

Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan.

A report of a family of Darier's disease with mood disorders drew attention when the causative gene was identified as ATP2A2 (or SERCA2), which encodes a Ca2+ pump on the ER membrane and is important for intracellular Ca2+ signaling. Recently, it was found that loss-of-function mutations of ATP2A2 confer a risk of neuropsychiatric disorders including depression, bipolar disorder, and schizophrenia. In addition, a genome-wide association study found an association between ATP2A2 and schizophrenia. However, the mechanism of how ATP2A2 contributes to vulnerability to these mental disorders is unknown. Here, we analyzed Atp2a2 heterozygous brain-specific conditional knockout (hetero cKO) mice. The ER membranes prepared from the hetero cKO mouse brain showed decreased Ca2+ uptake activity. In Atp2a2 heterozygous neurons, decays of cytosolic Ca2+ level were slower than control neurons after depolarization. The hetero cKO mice showed altered behavioral responses to novel environments and impairments in fear memory, suggestive of enhanced dopamine signaling. In vivo dialysis demonstrated that extracellular dopamine levels in the NAc were indeed higher in the hetero cKO mice. These results altogether indicate that the haploinsufficiency of Atp2a2 in the brain causes prolonged cytosolic Ca2+ transients which possibly results in enhanced dopamine signaling, a common feature of mood disorders and schizophrenia. These findings elucidate how ATP2A2 mutations causing a dermatological disease may exert their pleiotropic effects on the brain and confer a risk for mental disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddab137DOI Listing
June 2021

New hepatitis C virus infection, re-infection and associated risk behaviour in male Irish prisoners: a cohort study, 2019.

Arch Public Health 2021 Jun 8;79(1):97. Epub 2021 Jun 8.

School of Medicine, University College Dublin, Dublin, Ireland.

Background: Prisoners are recognised as a high-risk population and prisons as high-risk locations for the transmission of hepatitis c virus (HCV) infection. Injecting drug use (IDU) is the main driver of HCV infection in prisoners and harm reduction services are often suboptimal in prison settings. HCV prevalence and incident data in prisoners is incomplete which impacts the public health opportunity that incarceration provides in identifying, treating and preventing HCV infection. The aim of this study is to identify new HCV infection and associated risk factors in an Irish male prison.

Methods: We conducted a follow up (18-month) cohort study on prisoners who had previously tested negative, self-cleared or had been successfully treated for HCV infection. We conducted the study in a male medium security prison located in Dublin Ireland (Mountjoy Prison) using HCV serology, a review of medical records and a researcher-administered questionnaire.

Results: 99 prisoners with a mean age of 33.2 yrs. participated in the study and 82(82.8%) completed a research-administered questionnaire. Over half (51%) had a history of drug use from a young age (14.8 yrs.), 49.9% a history of heroin use and 39% a history of IDU. The prevalence of HIV and hepatitis B virus core antibody was 3% and HCV antibody was 22.2%. No new HCV infections were identified in those who had never been infected (n = 77), had self-cleared (n = 9) or achieved sustained virological response (n = 12). Small numbers of prisoners continued to engage in risk-behaviour including, IDU both in the prison (n = 2) and the community (n = 3), sharing syringes (n = 1) and drug taking paraphernalia (n = 6) and receiving non-sterile tattoos (n = 3).

Conclusion: Despite the high numbers of Irish prisoners with a history of IDU and HCV infection, new HCV infection is low or non-existent in this population. Small numbers of prisoners continue to engage in risk behaviour and larger studies are required to further understand HCV transmission in this cohort in an Irish and international context.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13690-021-00623-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186141PMC
June 2021

Calcitonin receptor signaling in the medial preoptic area enables risk-taking maternal care.

Cell Rep 2021 Jun;35(9):109204

Laboratory for Affiliative Social Behavior, RIKEN Center for Brain Science, Saitama 351-0198, Japan. Electronic address:

Maternal mammals exhibit heightened motivation to care for offspring, but the underlying neuromolecular mechanisms have yet to be clarified. Here, we report that the calcitonin receptor (Calcr) and its ligand amylin are expressed in distinct neuronal populations in the medial preoptic area (MPOA) and are upregulated in mothers. Calcr+ MPOA neurons activated by parental care project to somatomotor and monoaminergic brainstem nuclei. Retrograde monosynaptic tracing reveals that significant modification of afferents to Calcr+ neurons occurs in mothers. Knockdown of either Calcr or amylin gene expression hampers risk-taking maternal care, and specific silencing of Calcr+ MPOA neurons inhibits nurturing behaviors, while pharmacogenetic activation prevents infanticide in virgin males. These data indicate that Calcr+ MPOA neurons are required for both maternal and allomaternal nurturing behaviors and that upregulation of amylin-Calcr signaling in the MPOA at least partially mediates risk-taking maternal care, possibly via modified connectomics of Calcr+ neurons postpartum.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2021.109204DOI Listing
June 2021

Association of Tracheostomy With Outcomes in Patients With COVID-19 and SARS-CoV-2 Transmission Among Health Care Professionals: A Systematic Review and Meta-analysis.

JAMA Otolaryngol Head Neck Surg 2021 May 27. Epub 2021 May 27.

Department of Surgery, Otolaryngology-Head and Neck Division, McMaster University, Hamilton, Ontario, Canada.

Importance: Approximately 5% to 15% of patients with COVID-19 require invasive mechanical ventilation (IMV) and, at times, tracheostomy. Details regarding the safety and use of tracheostomy in treating COVID-19 continue to evolve.

Objective: To evaluate the association of tracheostomy with COVID-19 patient outcomes and the risk of SARS-CoV-2 transmission among health care professionals (HCPs).

Data Sources: EMBASE (Ovid), Medline (Ovid), and Web of Science from January 1, 2020, to March 4, 2021.

Study Selection: English-language studies investigating patients with COVID-19 who were receiving IMV and undergoing tracheostomy. Observational and randomized clinical trials were eligible (no randomized clinical trials were found in the search). All screening was performed by 2 reviewers (P.S. and M.L.). Overall, 156 studies underwent full-text review.

Data Extraction And Synthesis: We performed data extraction in accordance with Meta-analysis of Observational Studies in Epidemiology guidelines. We used a random-effects model, and ROBINS-I was used for the risk-of-bias analysis.

Main Outcomes And Measures: SARS-CoV-2 transmission between HCPs and levels of personal protective equipment, in addition to complications, time to decannulation, ventilation weaning, and intensive care unit (ICU) discharge in patients with COVID-19 who underwent tracheostomy.

Results: Of the 156 studies that underwent full-text review, only 69 were included in the qualitative synthesis, and 14 of these 69 studies (20.3%) were included in the meta-analysis. A total of 4669 patients were included in the 69 studies, and the mean (range) patient age across studies was 60.7 (49.1-68.8) years (43 studies [62.3%] with 1856 patients). We found that in all studies, 1854 patients (73.8%) were men and 658 (26.2%) were women. We found that 28 studies (40.6%) investigated either surgical tracheostomy or percutaneous dilatational tracheostomy. Overall, 3 of 58 studies (5.17%) identified a small subset of HCPs who developed COVID-19 that was associated with tracheostomy. Studies did not consistently report the number of HCPs involved in tracheostomy. Among the patients, early tracheostomy was associated with faster ICU discharge (mean difference, 6.17 days; 95% CI, -11.30 to -1.30), but no change in IMV weaning (mean difference, -2.99 days; 95% CI, -8.32 to 2.33) or decannulation (mean difference, -3.12 days; 95% CI, -7.35 to 1.12). There was no association between mortality or perioperative complications and type of tracheostomy. A risk-of-bias evaluation that used ROBINS-I demonstrated notable bias in the confounder and patient selection domains because of a lack of randomization and cohort matching. There was notable heterogeneity in study reporting.

Conclusions And Relevance: The findings of this systematic review and meta-analysis indicate that enhanced personal protective equipment is associated with low rates of SARS-CoV-2 transmission during tracheostomy. Early tracheostomy in patients with COVID-19 may reduce ICU stay, but this finding is limited by the observational nature of the included studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoto.2021.0930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160928PMC
May 2021

Indigenous Youth Mentorship Program: essential characteristics of a Canadian multi-site community-university partnership with Indigenous communities.

Health Promot Int 2021 May 19. Epub 2021 May 19.

Faculty of Kinesiology, Sport, and Recreation, University of Alberta, 4-378 Edmonton Clinic Health Academy, Mailbox #54, 11405 87 Avenue, Edmonton, AB T6G 2P5, Canada.

The Indigenous Youth Mentorship Program (IYMP) is a peer-led health promotion program grounded in the teachings of Indigenous scholars. IYMP is delivered as a multi-sited community-university partnership (CUP) with Indigenous communities across Canada for elementary students. A local young adult health leader and high school youth mentors offer students healthy snacks, physical activity games, relationship building activities and traditional cultural teachings. IYMP aims to improve children's health and wellbeing and empower Indigenous youth and communities. The purpose of this descriptive qualitative study was to describe the essential characteristics of this multi-sited CUP as perceived by the IYMP principal investigators (PIs). Key informant interviews were conducted with 5 IYMP PIs (2 Indigenous) and analysed using content analysis. The overarching theme was forming a community of practice (CoP), where people with a common interest share best practices as they interact regularly. Four sub-themes were shared interest for Indigenous health/wellbeing and social justice, relationships, mentorship and taking a decolonizing research approach. The IYMP CoP allowed mentorship to occur across regions. The essential characteristics that made the IYMP CUPs successful could be used to inform other multi-sited CUPs with Indigenous communities. Those with mutual interests in Indigenous health and partnership with Indigenous communities could consider forming a CoP. Within a newly formed CoP, relationships and mentorship can be developed through discussion and activities. It is imperative within the CoP to take a decolonizing approach to research and acknowledge the impact that colonial policies and practices have had on generations of Indigenous peoples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/heapro/daab039DOI Listing
May 2021