Mitochondrial DNA drives neuroinflammation through the cGAS-IFN signaling pathway in the spinal cord of neuropathic pain mice.

Neuroinflammation is pivotal in the development of neuropathic pain (NeP). While mitochondrial deoxyribonucleic acid (mtDNA) and cyclic GMP-AMP synthase (cGAS) are recognized for inducing inflammation in various neurological disorders, their involvement in NeP remains ambiguous. In this study, we examined: (1) the changes in mtDNA and cGAS in mice with NeP induced by chronic constriction injury (CCI) of the sciatic nerve, whether mtDNA triggers inflammation via the cGAS signaling; (2) the effects of RU.521, a cGAS antagonist, on CCI-induced nociception (allodynia and hyperalgesia) and relative inflammatory protein expression; (3) the activation of microglia and the cGAS-IFN pathway mediated by mtDNA in BV2 cell; (4) the effect of RU.521 on mtDNA-induced inflammatory response in BV2 cells. Results revealed reduced mtDNA levels in the sciatic nerve but increased levels in the spinal cord of CCI mice, along with elevated cGAS expression and inflammatory factors. RU.521 alleviated nociceptive behaviors in CCI mice, possibly by normalizing cGAS levels and suppressing inflammation. Neuron-derived mtDNA provoked cellular activation and upregulated cGAS signaling in BV2 cells. Additionally, RU.521 and DNase I effectively inhibited cGAS-induced inflammation. These findings underscore the critical role of mtDNA accumulation and mtDNA-mediated cGAS signaling in NeP development after peripheral nerve injury.

Assessment of Mendelian and risk-factor genes in Alzheimer disease: A prospective nationwide clinical utility study and recommendations for genetic screening.

PURPOSE: To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD). METHODS: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) ≤65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92). RESULTS: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees. CONCLUSION: We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure.

The Impact of the COVID-19 Pandemic on the Psychological Well-Being of Caregivers of People with Dementia or Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.

The aim of this systematic review was to investigate the effects of the COVID-19 lockdown on the psychological well-being of caregivers of people with dementia or mild cognitive impairment (PwD/MCI). Electronic databases were searched from inception to August 2022 for observational studies investigating the COVID-19 lockdown and psychological well-being of caregivers of PwD/MCI. Summary estimates of standardized mean differences (SMD) in psychological well-being scores pre- versus during COVID-19 were calculated using a random-effects model. Fifteen studies including 1702 caregivers (65.7% female, mean age 60.40 ± 12.9 years) with PwD/MCI were evaluated. Five studies found no change in psychological well-being parameters, including depression, anxiety, distress, caregiver burden, and quality of life. Ten studies found a worsening in at least one parameter: depression (six studies, n = 1368; SMD = 0.40; 95%CI: 0.09-0.71; p = 0.01, I2 = 86.8%), anxiety (seven studies, n = 1569; SMD = 1.35; 95%CI: 0.05-2.65; I2 = 99.2%), caregiver distress (six studies, n = 1320, SMD = 3.190; 95%CI: 1.42-4.95; p < 0.0001; I2 = 99.4%), and caregiver burden (four studies, n = 852, SMD = 0.34; 95%CI: 0.13-0.56; p = 0.001; I2 = 54.1%) (p < 0.05). There was an increase in depression, anxiety, caregiver burden, and distress in caregivers of PwD/MCI during the lockdown in the COVID pandemic. This could have longer term consequences, and it is essential that caregivers' psychological well-being is assessed and supported, to benefit both themselves and those for whom they care.

Experimental confirmation of driving pressure boosting and smoothing for hybrid-drive inertial fusion at the 100-kJ laser facility.

In laser-driven inertial confinement fusion, driving pressure boosting and smoothing are major challenges. A proposed hybrid-drive (HD) scheme can offer such ideal HD pressure performing stable implosion and nonstagnation ignition. Here we report that in the hemispherical and planar ablator targets installed in the semicylindrical hohlraum scaled down from the spherical hohlraum of the designed ignition target, under indirect-drive (ID) laser energies of ~43-50 kJ, the peak radiation temperature of 200 ± 6 eV is achieved. And using only direct-drive (DD) laser energies of 3.6-4.0 kJ at an intensity of 1.8 × 1015 W/cm2, in the hemispherical and planar targets the boosted HD pressures reach 3.8-4.0 and 3.5-3.6 times the radiation ablation pressure respectively. In all the above experiments, significant HD pressure smoothing and the important phenomenon of how a symmetric strong HD shock suppresses the asymmetric ID shock pre-compressed fuel are demonstrated. The backscattering and hot-electron energy fractions both of which are about one-third of that in the DD scheme are also measured.

A call for clinical trial globalization in Alzheimer's disease and related dementia.

BACKGROUND: The burden of Alzheimer's disease and related dementia (ADRD) is projected to disproportionally impact low-middle-income countries (LMICs). However, there is a systematic under-representation of LMICs in ADRD clinical trial platforms. METHODS: We aimed to determine the global distribution of ADRD clinical trials and identify existing barriers for conducting clinical trials in LMICs. Primary data sources to identify trial distribution in LMICs included ClinicalTrials.gov and the International Trials Registry Platform. An additional systematic review and expert consensus interviews were conducted to identify barriers for conducting clinical trials in LMICs. FINDINGS: Among 1237 disease-modifying therapies tested in ADRD clinical trials, only 11.6% have been or are conducted in emerging economies (upper-middle income [9.6%] and low-middle income [2.0%]). We identified several limitations for trial implementation including a lack of financial resources, low industry presence, regulatory obstacles, and operational barriers INTERPRETATION: Although LMICs bear the greatest burden of ADRD globally, substantial development of clinical trial platforms to address this inequity and health disparity is lacking.

The Nebulous Association between Cognitive Impairment and Falls in Older Adults: A Systematic Review of the Literature.

BACKGROUND: In older people, dementia is a well-established risk factor for falls. However, the association and the causal relationship between falls and the earlier stages of cognitive impairment remains unclear. The purpose of the study was to review the literature data on the association between falls and cognitive impairment, no dementia, including Mild Cognitive Impairment. METHODS: According to PRISMA guidelines, we searched five electronic databases (EMBASE, Web of Science, Medline, CINAHL, and PsychINFO) for articles published between January 2011 and August 2022 on observational studies of older people with a cognitive assessment and/or cognitive impairment diagnosis and a recording of falls. Their quality was reviewed according to the STROBE checklist. RESULTS: We selected 42 of the 4934 initially retrieved publications. In 24 retrospective studies, a statistically significant association between falls and cognitive status was found in only 15 of the 32 comparisons (47%). Of the 27 cross-sectional analyses in prospective studies, only eight (30%) were positive and significant. We counted four longitudinal analyses, half of which suggested a causal relationship between falls and cognitive impairment. The investigational methods varied markedly from one study to another. CONCLUSION: It is still not clear whether falls are associated with cognitive impairment, no dementia. Data in favor of a causal relationship are scarce. Further studies are needed to clarify their relationship.

Impact of COVID-19 Pandemic on Caregivers of People with an Intellectual Disability, in Comparison to Carers of Those with Other Disabilities and with Mental Health Issues: A Multicountry Study.

Carers supporting people with an intellectual disability often rely on others to manage the burden of care. This research aims to compare the differences between carer groups and understand the predictors of loneliness changes and burden for carers of people with an intellectual disability. Data from the international CLIC study were analysed. In total, 3930 carers responded from four groups; people who care for those with mental health difficulties (n = 491), dementia (n = 1888), physical disabilities (n = 1147), and Intellectual disabilities (n = 404). Cross tabulation and the chi-squared test were used to compare group compositions and binary logistic regression to model predictors within the intellectual disability group. A total of 65% of those caring for people with an intellectual disability experienced increased burden, and 35% of carers of people with an intellectual disability and another condition experienced more severe loneliness. Becoming severely lonely was predicted by feeling burdened by caring (AOR, 15.89) and worsening mental health (AOR, 2.13) Feeling burden was predicted by being aged between 35 and 44 (AOR, 4.24), poor mental health (AOR, 3.51), and feelings of severe loneliness prior to the pandemic (AOR, 2.45). These findings demonstrate that those who were already struggling with caring experienced the greatest difficulties during the COVID-19 lockdowns.

Genetic polymorphisms of PRKAA1 (AMPKα1) and postherpetic pain susceptibility: Multicenter, randomized control, and haplotype analysis study.

Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is a pivotal regulatory protein in energy metabolism. In a pilot study, we found that AMPK-associated energy metabolism imbalance in neurons contributes to the occurrence and maintenance of neuropathic pain (NeP). This study aimed to explore the relationship between genetic polymorphisms of AMPK gene (Rs13361707, rs3792822, and rs10074991) in PRKAA1 and postherpetic neuralgia (PHN) in Chinese individuals. Hundred and thirty two patients with PHN and 118 control individuals were enrolled in this study. All blood samples were shuffled and blinded to the person performing the haplotype analysis. Rs13361707, rs3792822, and rs10074991 PRKAA1 genotypes were identified in all participants. Dominant and recessive models were used for evaluating the association between these nucleotide polymorphisms and PHN susceptibility. A haplotype analysis of PHN patients and healthy controls was performed. Clinical characteristics between the two groups were not significantly different (p > 0.05) except that the ages in control subjects were younger than the PHN patients (p < 0.05). Genotypes and allele frequencies are significantly different between the PHN patients and control subjects for the rs13361707 and rs10074991 polymorphisms (p < 0.05), but not for rs3792822 (p > 0.05). In addition, the CCG haplotype of rs13361707-rs3792822-rs10074991 correlated negatively with PHN occurrence, but TCA was positively correlated with PHN (p < 0.05). Our results indicate that PRKAA1 gene polymorphisms rs13361707 and rs10074991 were associated with a risk of PHN, and that the CCG haplotype of rs13361707-rs3792822-rs10074991 correlated negatively with PHN occurrence in haplotype analysis. TCA was positively associated with PHN in Chinese individuals.

What Tools Can We Use to Screen for Fall Risk in Older Patients with Mild Cognitive Impairment? Findings from the MEMENTO Cohort.

OBJECTIVES: Identifying risk factors for falls can improve outcomes in older patients without cognitive decline. Yet this has not been demonstrated in older people with mild cognitive impairment (MCI). We therefore sought to better identify risk factors for falls in this particular group. DESIGN: The analysis was conducted on the MEMENTO cohort, which is a large, French, prospective cohort. SETTING AND PARTICIPANTS: We included older people (>65 years old) with MCI (defined from neuropsychological scores) and a Short Physical Performance Battery (SPPB) score at baseline. METHODS: Fallers were defined as participants having fallen at least once during the study's 2-year follow-up period. We compared clinical, neuropsychological, and biological data at baseline in fallers vs nonfallers. Additional analyses were performed on the following subgroups: women, men, people aged ≥75 years. RESULTS: Of the 1416 people included in our study, 194 (13.5%) fell at least once. A bivariate analysis showed that fallers were older, predominantly women, less independent in activities of daily living, and more apathetic. Fallers performed less well in executive function, balance, and gait tests. In a multivariable analysis, only age, gender, the number of limitations in instrumental activities of daily living, and living alone were significantly associated with falls. In a multivariable analysis of the subgroup of oldest patients and of the subgroup of men, executive function was significantly worse in fallers than in nonfallers. CONCLUSION AND IMPLICATIONS: Our results demonstrate that easily attainable risk factors can be used to identify individuals with MCI with a higher risk of falls and for whom prevention could be beneficial. Future studies are needed to further evaluate the role of mild executive dysfunction in certain subgroups, such as men and oldest patients.

Sex differences: From preclinical pharmacology to clinical pharmacology.

Sex is a crucial variable to take into account in medical research. In this review, we attempted to present its importance at all stages of research and even during drug's post-marketing surveillance. Most preclinical research studies do not take sex into account while many diseases are known to present sexual dimorphism. However, a shift in thinking occurred since the January 2016 implementation of the US Institutes of Health recommendations to take sex into account in research. Nevertheless, in preclinical studies, the lack of sex-based statistical analyses persists. Moreover, in humans, women are often under-represented in some clinical trials, despite well-identified sexual dimorphism. In addition, some pathologies are subject to social representations of diseases considered "male" or "female" which can also lead to a delay in diagnosis and management for both sexes. Finally, many drug classes may be subject to sex differences in efficacy and safety. For example, women present more adverse events than men, mainly because of different pharmacokinetic parameters. Accounting sex as a variable from the preclinical phase is essential to improve the transposition of observed results and move towards personalized medicine.

Does the LHPP gene share a common biological function in pancancer progression?

Although emerging evidence has revealed that LHPP, a histidine phosphatase protein, suppresses the progression of different cancers, a pan-cancer analysis still remains unavailable. Therefore, we first utilized different bioinformatics tools to explore the tumor inhibitory role of LHPP protein across 33 tumor types based on the TCGA project. Additionally, HGC-27 gastric cancer cells were used to evaluate the biological functions of LHPP after stable transfection with lentiviruses. Consequently, LHPP mRNA and protein expression were down-regulated in the most cancer tissues corresponding to normal tissues. The data showed that patients with higher LHPP performance had a better prognosis of overall survival (OS) and disease-free survival (DFS) in brain glioma and renal carcinoma. In addition, we found that enhancement of LHPP expression attenuated the proliferation, migration and invasion of gastric cancer cells. The expression levels of cell-cycle-related and EMT-related molecules, such as CDK4, CyclinD1, Vimentin and Snail, were clearly reduced. Moreover, a genetic alteration analysis showed that the most frequent mutation types in LHPP protein was amplification. The patients without LHPP mutation showed a better tendency of prognosis in UCEC, STAD and COAD. Cancer-associated fibroblast infiltration was also observed in head and neck squamous cell carcinoma, stomach adenocarcinoma and testicular germ cell tumors. In summary, our pancancer analysis among various tumor types could provide a comprehensive understanding of LHPP biological function in the progression of malignant diseases and promote the development of novel therapeutic targets.

Dexmedetomidine alleviates pain in MPTP-treated mice by activating the AMPK/mTOR/NF-κB pathways in astrocytes.

Pain is a major non-motor symptom that contributes to impaired quality of life in Parkinson's disease (PD). However, the mechanisms and treatment of pain in PD have not been well studied. Dexmedetomidine (Dex) is used for analgesia and sedation during deep brain stimulation (DBS) and may reverse the progression of PD. Here, we explored the effect of Dex on Parkinson's pain and the underlying mechanism. C57BL/6 mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg) to establish a PD model. Then, the mice were treated with Dex (50 µg/kg) or Compound C (CC, 10 mg/kg, AMPK inhibitor). A motor behavioral test was used to validate the PD model, and a plantar test was conducted to assess mechanical and thermal stimulation thresholds. Immunofluorescence and western blotting were used to analyze the level of tyrosine hydroxylase (TH) in the substantia nigra (SN) and the expression of c-Fos, GFAP, p-AMPK, mTOR, NF-κB, TNFα, and IL-6 in the dorsal horn of the spinal cord (DHSC). We found that mice exhibited motor dysfunction and mechanical allodynia and thermal hyperalgesia after MPTP injection, and these changes were partially reversed by Dex. Dex also reduced MPTP-induced astrocyte activation and TNFα and IL-6 expression, increased p-AMPK and reduced mTOR and NF-κB expression in DHSC. Moreover, the effects of Dex were partially reversed by the AMPK inhibitor Compound C. Conclusions: These findings reveal that Dex protects dopaminergic neurons in PD and alleviates pain by reducing the activation of DHSC astrocytes through the AMPK/mTOR/NF-κB pathway. Therefore, Dex may be a potential drug for treating Parkinson's pain.

The challenges of mental health of staff working with people with intellectual disabilities during COVID-19--A systematic review.

BACKGROUND: The COVID-19 pandemic has posed a great risk to the mental health of health workers (HWs). There are likely to be particular concerns for staff working with adults with an intellectual disability, where infection control may be more challenging. METHOD: We conducted a systematic review of original research examining the mental health of HWs working with people with intellectual disability, published between March 2020 and July 2021. RESULTS: Five original research studies were included. A high proportion of HWs working with people with intellectual disability reported having had poor mental health including stress, anxiety, and depression. This manifested in similar patterns as for other HWs and also some specific patterns seen as the need to manage increased rates of mental health issues of the people they support. Sources of support and resilience were also identified. CONCLUSION: The support system should target risk factors, answer unmet needs, and build resilience. More research is also required on the ongoing and long-term effects.

Effect of AMPK Subunit Alpha 2 Polymorphisms on Postherpetic Pain Susceptibility in Southwestern Han Chinese.

Introduction: Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) can influence energy metabolism. Energy metabolism imbalance is closely associated with the occurrence of neuropathic pain (NeP). Rs10789038 and rs2796498 are genetic polymorphisms of PRKAA2, the gene encoding AMPK, which is closely related to energy metabolism imbalance. This study aimed to explore the relationship between PRKAA2 and postherpetic neuralgia (PHN) in the southwestern Chinese Han population. Methods: This study enrolled 132 PHN patients and 118 healthy subjects. The rs10789038 and rs2796498 PRKAA2 genotypes were identified in all participants. The association between these single nucleotide polymorphisms and PHN susceptibility was evaluated in the dominant and recessive models. Haplotype analysis of patients with PHN and healthy controls was performed. Results: The PHN patients were older than the healthy subjects (P < 0.05); however, the other clinical characteristics between two groups were not significantly different (all P >0.05). Genotypes and allele frequencies differed significantly between PHN patients and healthy subjects in the rs10789038 polymorphism (P < 0.05), but not in rs2796498 (P > 0.05). In addition, the GG haplotype of rs10789038-rs2796498 correlated negatively with PHN occurrence in haplotype analysis (P < 0.05). Conclusion: PHN occurrence may be related to the PRKAA2 rs10789038 A>G genetic polymorphism in the southwestern Chinese Han population.

CXCR4/CX43 Regulate Diabetic Neuropathic Pain via Intercellular Interactions between Activated Neurons and Dysfunctional Astrocytes during Late Phase of Diabetes in Rats and the Effects of Antioxidant N-Acetyl-L-Cysteine.

Growing evidence suggests that the interactions between astrocytes and neurons exert important functions in the central sensitization of the spinal cord dorsal horn in rodents with diabetes and neuropathic pain (DNP). However, it still remains unclear how signal transmission occurs in the spinal cord dorsal horn between astrocytes and neurons, especially in subjects with DNP. Chemokine CXC receptor 4 (CXCR4) plays critical roles in DNP, and connexin 43 (CX43), which is also primarily expressed by astrocytes, contributes to the development of neuropathy. We thus postulated that astrocytic and neuronal CXCR4 induces and produces inflammatory factors under persistent peripheral noxious stimulation in DNP, while intercellular CX43 can transmit inflammatory stimulation signals. The results showed that streptozotocin-induced type 1 diabetic rats developed heat hyperalgesia and mechanical allodynia. Diabetes led to persistent neuropathic pain. Diabetic rats developed peripheral sensitization at the early phase (2 weeks) and central sensitization at the late phase (5 weeks) after diabetes induction. Both CXCR4 and CX43, which are localized and coexpressed in neurons and astrocytes, were enhanced significantly in the dorsal horn of spinal cord in rats undergoing DNP during late phase of diabetes, and the CXCR4 antagonist AMD3100 reduced the expression of CX43. The nociceptive behavior was reversed, respectively, by AMD3100 at the early phase and by the antioxidant N-acetyl-L-cysteine (NAC) at the late phase. Furthermore, rats with DNP demonstrated downregulation of glial fibrillary acidic protein (GFAP) as well as upregulation of c-fos in the spinal cord dorsal horn at the late phase compared to the controls, and upregulation of GFAP and downregulation of c-fos were observed upon treatment with NAC. Given that GFAP and c-fos are, respectively, makers of astrocyte and neuronal activation, our findings suggest that CXCR4 as an inflammatory stimulation protein and CX43 as an intercellular signal transmission protein both may induce neurons excitability and astrocytes dysfunction in developing DNP.

Care partner needs of people with neurodegenerative disorders: What are the needs, and how well do the current assessment tools capture these needs? A systematic meta-review.

OBJECTIVES: The burden on care partners, particularly once dementia emerges, is among the greatest of all caregiving groups. This meta-review aimed to (1) synthesis evidence on the self-reported needs of care partners supporting people living with neurodegenerative disorders; (2) compare the needs according to care partner and care recipient characteristics; and (3) determine the face validity of existing care partner needs assessment tools. METHODS: We conducted a systematic review of reviews involving a thematic synthesis of care partner needs and differences in needs according to demographic and other characteristics. We then conducted a gap analysis by identifying the themes of needs from existing needs assessment tools specific to dementia and cross-matching them with the needs derived from the thematic synthesis. RESULTS: Drawing on 17 published reviews, the identified range of needs fell into four key themes: (1) knowledge and information, (2) physical, social and emotional support, (3) care partner self-care, and (4) care recipient needs. Needs may differ according to disease trajectory, relationship to the care recipient, and the demographic characteristics of the care partner and recipient. The 'captured needs' range between 8% and 66% across all the included needs assessment tools. CONCLUSIONS: Current tools do not fully or adequately capture the self-identified needs of care partners of people living with neurodegenerative disorders. Given the high burden on care partners, which has been further exacerbated by the COVID-19 (SARS CoV-2) pandemic, the needs assessment tools should align with the self-reported needs of care partners throughout the caregiving trajectory to better understand unmet needs and target supportive interventions.

Perisciatic Nerve Dexmedetomidine Alleviates Spinal Oxidative Stress and Improves Peripheral Mitochondrial Dynamic Equilibrium in a Neuropathic Pain Mouse Model in an AMPK-Dependent Manner.

Neuropathic pain (NPP) is a debilitating clinical condition that presently has few effective treatments. NPP is caused by uncontrolled central oxidative stress and inflammation. Preliminary studies indicate that dexmedetomidine (DEX), an agonist of the alpha-2 adrenergic receptor, is beneficial for treating NPP. In this paper, the effects of administering DEX around injured nerves in a chronic constriction injury- (CCI-) induced neuropathic pain mouse model are investigated. According to the results, the perineural DEX significantly reversed the decline in the mechanical threshold and thermal latency in CCI mice (p < 0.001). In the peripherally affected ischiadic nerve, the perineuronal DEX upregulated the expressions of pAMPK, OPA1, and SNPH but not Drp1 or KIF5B. The aforementioned effects of administering DEX can be partially reversed by compound C, a selective and reversible inhibitor of AMP-activated protein kinase (AMPK). Furthermore, it was found that perineural DEX significantly inhibited the CCI-induced upregulation of the immediate early gene c-Fos, overexpression of the inflammatory factors tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), attenuation of the NADH dehydrogenase complexes I, II, III, and IV, and the repression of ATP, SOD, and GSH in the dorsal horn of the spinal cord (DHSC) (p < 0.01). These findings indicate that perineuronal DEX protected the injured ischiadic nerves and attenuated neuropathic pain via AMPK activation to improve energy supply in the peripheral injured nerves, alleviate the inflammatory factor release, and inhibit oxidative stress in the DHSC.

Care burden, loneliness, and social isolation in caregivers of people with physical and brain health conditions in English-speaking regions: Before and during the COVID-19 pandemic.

BACKGROUND: Public health restrictions due to the COVID-19 (SARS CoV-2) pandemic have disproportionately affected informal caregivers of people living with long term health conditions. We aimed to explore levels of care burden, loneliness, and social isolation among caregivers of people with enduring physical and brain health conditions in English-speaking regions worldwide, by investigating outcomes before and during the COVID-19 pandemic. METHODS: A cross-sectional anonymous online survey data from 2287 English-speaking caregivers of people with long term health conditions from four English-speaking regions (UK, Ireland, USA, New Zealand) included measures of care burden, loneliness, and social isolation, reported before and during the COVID-19 pandemic. Analyses were descriptive, followed by an ordinal regression model for predictors of burden. RESULTS: Compared to pre-pandemic levels, all caregivers experienced a significant increase in burden, loneliness, and isolation. Caregivers of people with both brain health and physical conditions were the most burdened and had the highest levels of loneliness and isolation compared to caregivers of people with either a brain health or physical condition only. The increase in care burden among caregivers of people with brain health challenges was associated with caregiver's gender, moderate and severe emotional loneliness, magnitude and frequency of isolation during the pandemic, and care circumstances (cohabitation with the care recipient, restrictions on the ability to provide care). CONCLUSIONS: Health and social care interventions should target caregivers' care circumstances and psychological outcomes, particularly in women, accounting for the significant additional burden of care, loneliness, and isolation resulting from pandemic-related restrictions.

Staff mental health while providing care to people with intellectual disability during the COVID-19 pandemic.

Background: The COVID-19 pandemic has placed enormous strain on health systems around the world, undermining the mental health and wellbeing of healthcare workers. Supporting people with intellectual disabilities may be particularly challenging for workers, as some people with intellectual disabilities may have a limited understanding of the pandemic, and find it challenging to adhere to the restrictions imposed by public health guidelines such as social distancing, lockdowns and change in usual routine and activities. In addition, many people with intellectual disabilities have increased vulnerability to more negative effects of COVID-19, with significantly higher mortality rates. Although there is emerging research on the mental health of healthcare staff during this time, there has been little specific work on the mental health of staff working with people with intellectual disability, particularly a lack of qualitative research. Methods: The current study employed semi-structured interviews with 13 healthcare workers (12 women and 1 man) who were working with people with intellectual disability during the COVID-19 pandemic. The interview data were analysed using thematic content analysis. Findings: The participants spoke in depth about the challenges of the working environment, the impact of providing care during the pandemic on staff mental health, supporting staff mental health and wellbeing and learning for the future. Conclusions: Systematic efforts are required to protect the mental health of this staff cohort, as well as encouraging resilience and successful coping among staff themselves.

Dexmedetomidine Can Enhance PINK1/Parkin-Mediated Mitophagy in MPTP-Induced PD Mice Model by Activating AMPK.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra (SN). Our previous study has shown that dexmedetomidine (Dex) can protect mitochondrial function and reduce apoptosis in MPP+-induced SH-SY5Y cells. Evidences have shown that mitophagy is related to the development of PD. In this study, we investigated whether Dex can enhance mitophagy in MPTP-induced mice to play a neuroprotective effect. In our experiment, mice were injected with MPTP 30 mg/kg intraperitoneally for 5 consecutive days to establish a PD subacute model. Dex (30, 50, and 100 µg/kg) was injected intraperitoneally 30 minutes before each injection of MPTP, respectively. Our results showed that Dex (50 µg/kg) most significantly attenuated MPTP-induced motor dysfunction and restored TH-positive neurons in the SN, increased the expression of the antiapoptotic protein Bcl-2, and decreased the expression of apoptotic proteins cleaved casepase3, cleaved casepase9, and Bax. Moreover, Dex increased the activity of mitochondrial Complexes I-IV and decreased the level of oxidative stress, manifesting as decreased MDA levels and increased SOD and GSH-PX levels. Besides, under transmission electron microscopy, Dex increased the mitophagosome which is an autophagosome with a mitochondrion-like structure inside under the electron microscope. In addition, Dex could also increase the expression of mitophagy-related proteins p-AMPK, LC3II/I, PINK1, and Parkin and decrease P62. However, after using Compound C (CC, 10 mg/kg, AMPK inhibitor), the effects of Dex on increasing PINK1/Parkin-induced mitophagy and neuroprotection were attenuated. In conclusion, Dex may improve mitochondrial function by activating AMPK to enhance PINK1/Parkin-induced mitophagy, thereby protecting dopaminergic neurons.