CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8+ T Cells.

The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8+ TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226hi TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226+CD8+ T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.

Assessing the outcomes of parasacral transcutaneous electrical nerve stimulation (PTENS) in the treatment of enuresis in children: A systematic review and meta-analysis of randomized control trials.

INTRODUCTION: Nocturnal enuresis (NE) is a common pathology in children that can have significant behavioral, emotional, and social impacts on a child's life. Recent studies have assessed PTENS as a potential treatment method for NE, particularly in those who do not respond to initial first-line treatments. Literature has shown varying results with regard to its success. There has been no systematic review and meta-analysis to date assessing outcomes following this treatment. OBJECTIVES: Despite multiple studies showing the potential benefits of PTENS in NE, there has been no consensus regarding its efficacy. The aim of this study was to systematically analyze the effects of PTENS on children with NE. STUDY DESIGN: In September 2021, a search of PubMed, Embase and the Cochrane Library was carried out for studies relating to outcomes following PTENS in children with NE. Studies included were original publication English language randomized controlled trial (RCT's) with at least ten children receiving parasacral transcutaneous electrical nerve stimulation (PTENS). After assessing for relevant studies, data were collated and analyzed from the included studies. Risk of bias was assessed using the Cochrane seven domain assessment. Our primary outcome was response and nonresponse to treatment. These results were combined in a fixed effects meta-analysis model to obtain an overall estimate of the success rate. Information regarding demographics was also collected. There was no external funding for this review. RESULTS: Of 145 studies found initially, four RCT's (208 children) were included. The weighted mean rate of full response to active PTENS was 10.8% (0%-19%). All studies considered, meta-analysis showed no difference between PTENS and controls (RR: 0.70, 95% confidence interval [CI: 0.37-1.32]). Subgroup analysis of monosymptomatic enuresis showed no effect of PTENS compared to controls (RR = 0.58, 95% CI: [0.24-1.42]). When grouped, studies comparing PTENS to sham/behavioral treatment showed no benefit compared to controls (RR = 0.81, 95% CI: [0.05-12.53]) and those comparing PTENS to biofeedback/interferential current (IFC) showed no difference to controls (RR = 0.69, 95% CI: [0.36-1.33]). There was no evidence of a difference between cases and controls between these latter subgroups (RR = 0.70, 95% CI: [0.37-1.32]). DISCUSSION/CONCLUSION: Our results suggest that PTENS has no clear benefit in the management of children with NE compared to controls. Subgroup analysis showed that its use in monosymptomatic NE has no clear advantage. However, this review has highlighted the need for further high quality studies. Limitations to this review included a relatively small sample size and the use of prior or concomitant therapies.

A multinational survey on the management of the urinary tract in newborns with spina bifida: Are we following current EAU/ESPU guidelines?

AIMS: In August 2019, the European Association of Urology (EAU) and European Society for Paediatric Urology (ESPU) published updated guidelines on the management of neurogenic bladder in children and adolescents. Our study aimed to establish whether members of the ESPU are adhering to these guidelines. METHODS: We designed a survey comprising 26 questions using SurveyMonkey®. Respondents were asked about management of neurogenic bladder at birth in newborns with spina bifida (SB), urological investigations, as well as short and long-term follow-up in their institutions. RESULTS: There were 103 respondents to the survey (754 recipients, giving a response rate of 14%) spanning 36 countries. 100% of respondents carry out a renal/bladder ultrasound at birth. Only 53% routinely commence clean intermittent catheterization soon after birth as recommended by the guidelines. Only 56% recommend anticholinergic medications after abnormal videourodynamics (VUDs). The guidelines recommend the use of continued antibiotic prophylaxis if there is evidence of vesicoureteral reflux and hostile bladder/non-conclusive results on VUDs which is followed by only 30% of providers. 63% of respondents carry out baseline VUDs at the recommended time. Seeing larger volumes of SB patients, having a formal SB protocol, having formal SB multidisciplinary clinics and working in a tertiary referral center did not make respondents more likely to adhere to guidelines. CONCLUSIONS: Our survey demonstrated that large variations from the EAU/ESPU guidelines exist in practice. The study confirms that further work is required across institutions and countries to implement these evidence-based recommendations for standardized practice.

A SARS-CoV-2 targeted siRNA-nanoparticle therapy for COVID-19.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in humans. Despite several emerging vaccines, there remains no verifiable therapeutic targeted specifically to the virus. Here we present a highly effective small interfering RNA (siRNA) therapeutic against SARS-CoV-2 infection using a novel lipid nanoparticle (LNP) delivery system. Multiple siRNAs targeting highly conserved regions of the SARS-CoV-2 virus were screened, and three candidate siRNAs emerged that effectively inhibit the virus by greater than 90% either alone or in combination with one another. We simultaneously developed and screened two novel LNP formulations for the delivery of these candidate siRNA therapeutics to the lungs, an organ that incurs immense damage during SARS-CoV-2 infection. Encapsulation of siRNAs in these LNPs followed by in vivo injection demonstrated robust repression of virus in the lungs and a pronounced survival advantage to the treated mice. Our LNP-siRNA approaches are scalable and can be administered upon the first sign of SARS-CoV-2 infection in humans. We suggest that an siRNA-LNP therapeutic approach could prove highly useful in treating COVID-19 disease as an adjunctive therapy to current vaccine strategies.

Intraoperative autologous transfusion and oncologic outcomes in liver transplantation for hepatocellular carcinoma: a propensity matched analysis.

BACKGROUND: Intraoperative autologous transfusion (IAT) of salvaged blood is a common method of resuscitation during liver transplantation (LT), however concern for recurrence in recipients with hepatocellular carcinoma (HCC) has limited widespread adoption. METHODS: A review of patients undergoing LT for HCC between 2008 and 2018 was performed. Clinicopathologic and intraoperative characteristics associated with inferior recurrence-free (RFS) and overall survival (OS) were identified using Kaplan-Meier analysis and uni-/multi-variable Cox proportional hazards modeling. Propensity matching was utilized to derive clinicopathologically similar groups for subgroup analysis. RESULTS: One-hundred-eighty-six patients were identified with a median follow up of 65 months. Transplant recipients receiving IAT (n = 131, 70%) also had higher allogenic transfusions (median 5 versus 0 units, P < 0.001). There were 14 recurrences and 46 deaths, yielding an estimated 10-year RFS and OS of 89% and 67%, respectively. IAT was not associated with RFS (HR 0.89/liter, P = 0.60), or OS (HR 0.98/liter, P = 0.83) pre-matching, or with RFS (HR 0.97/liter, P = 0.92) or OS (HR 1.04/liter, P = 0.77) in the matched cohort (n = 49 per group). CONCLUSION: IAT during LT for HCC is not associated with adverse oncologic outcomes. Use of IAT should be encouraged to minimize the volume of allogenic transfusion in patients undergoing LT for HCC.

Covid-19, non-Covid-19 and excess mortality rates not comparable across countries.

Evidence that more people in some countries and fewer in others are dying because of the pandemic, than is reflected by reported coronavirus disease 2019 (Covid-19) mortality rates, is derived from mortality data. Using publicly available databases, deaths attributed to Covid-19 in 2020 and all deaths for the years 2015-2020 were tabulated for 35 countries together with economic, health, demographic and government response stringency index variables. Residual mortality rates (RMR) in 2020 were calculated as excess mortality minus reported mortality rates due to Covid-19 where excess deaths were observed deaths in 2020 minus the average for 2015-2019. Differences in RMR are differences not attributed to reported Covid-19. For about half the countries, RMR's were negative and for half, positive. The absolute rates in some countries were double those in others. In a regression analysis, population density and proportion of female smokers were positively associated with both Covid-19 and excess mortality while the human development index and proportion of male smokers were negatively associated with both. RMR was not associated with any of the investigated variables. The results show that published data on mortality from Covid-19 cannot be directly comparable across countries. This may be due to differences in Covid-19 death reporting and in addition, the unprecedented public health measures implemented to control the pandemic may have produced either increased or reduced excess deaths due to other diseases. Further data on cause-specific mortality is required to determine the extent to which residual mortality represents non-Covid-19 deaths and to explain differences between countries.

Comparing the outcomes of parasacral transcutaneous electrical nerve stimulation for the treatment of lower urinary tract dysfunction in children: A systematic review and meta-analysis of randomized controlled trials.

AIMS: Despite published evidence in recent decades suggesting improvement in lower urinary tract symptoms (LUTS) with the use of parasacral transcutaneous electrical nerve stimulation (PTENS), no consensus guidelines for therapy exist. This study systematically reviews the literature to assess the effect of PTENS in children with LUTS. METHODS: A database search conducted up to December 2019 included Medline, EMBASE, and the Cochrane Library. From the literature review, 6 randomized controlled studies (234 participants) comparing PTENS and standard treatment (urotherapy/anticholinergics) were considered. From each study, the success rates were available for PTENS and the control group. The ratio of success rates was computed-that is, the risk ratio (RR) and the risk difference (RD). RESULTS: The overall success rate with PTENS was 1.92 times that of children undergoing standard urotherapy alone (RR: 1.92, 95% confidence interval [CI: 1.02, 3.61]) and 1.56 for those undergoing either urotherapy alone or with pharmacotherapy (anticholinergics; RR: 1.56, 95% CI [1.04, 2.40]). No difference in the success rate was found when PTENS was used in patients failing previous treatment (urotherapy and pharmacological therapy; RR: 0.175, 95% CI [0.02, 1.45]). CONCLUSIONS: Current evidence suggests that PTENS is beneficial in children with LUTS. The chance of success is 1.92 times that of children undergoing standard urotherapy. However, in children who have failed urotherapy and pharmacological therapy, PTENS monotherapy has a limited role and should be an adjunct. Literature shortcomings included small numbers of patients, differing inclusion criteria, and PTENS protocols. A need exists for quality multicenter randomized controlled trials to prove the efficacy of PTENS in children with LUTS.

"Establishing the criterion validity of the interRAI Check-Up Self-Report instrument".

BACKGROUND: Low and middle-income countries have growing older populations and could benefit from the use of multi-domain geriatric assessments in overcoming the challenge of providing quality health services to older persons. This paper reports on the outcomes of a study carried out in Cape Town, South Africa on the validity of the interRAI Check-Up Self-Report instrument, a multi-domain assessment instrument designed to screen older persons in primary health settings. This is the first criterion validity study of the instrument. The instrument is designed to identify specific health problems and needs, including psychosocial or cognition problems and issues related to functional decline. The interRAI Check-Up Self-Report is designed to be compatible with the clinician administered instruments in the interRAI suite of assessments, but the validity of the instrument against clinician ratings has not yet been established. We therefore sought to establish whether community health workers, rather than trained healthcare professionals could reliably administer the self-report instrument to older persons. METHODS: We evaluated the criterion validity of the self-report instrument through comparison to assessments completed by a clinician assessor. A total of 112 participants, aged 60 or older were recruited from 7 seniors clubs in Khayelitsha, Cape Town. Each participant was assessed by one of two previously untrained, non-healthcare personnel using the Check-Up Self-report version and again by a trained assessor using the clinician version of the interRAI Check-Up within 48 h. Our analyses focused on the degree of agreement between the self-reported and clinician-rated versions of the Check-Up based on the simple or weighted kappa values for the two types of ratings. Binary variables used simple kappas, and ordinal variables with three or more levels were examined using weighted kappas with Fleiss-Cohen weights. RESULTS: Based on Cohen's Kappa values, we were able to establish that high levels of agreement existed between clinical assessors and lay interviewers, indicating that the instrument can be validly administered by community health workers without formal healthcare training. 13% of items had kappa values ranging between 0.10 and 0.39; 51% of items had kappa values between 0.4 and 0.69; and 36% of items had values of between 0.70 and 1.00. CONCLUSION: Our findings indicate that there is potential for the Check-Up Self-Report instrument to be implemented in under-resourced health systems such as South Africa's.

A qualitative examination of policy and structural factors driving care workers' adverse experiences in long-term residential care facilities for the older adults in Cape Town.

BACKGROUND: There is lack of adequate training and policy support for employed care workers (CWs) employed in the South African (SA) older persons' sector. Existing literature neglects the influence of training and policy support on CWs' experiences in long-term care (LTC) for older adults in residential care facilities (RCFs). We investigated the ways in which CWs' experiences are rooted in the lack of adequate training and policy support. METHODS: Qualitative data was collected through focus group (FG) interviews with 32 CWs employed in RCFs in the City of Cape Town. Data was also collected using semi-structured interviews with representatives of five RCFs for older adults and four training organisations providing CW training in the City of Cape Town, South Africa. RESULTS: Despite some positive caregiving experiences, CWs face role ambiguity and experience care work as a 'career-less job'. They also face poor employment conditions, negative interpersonal relations at work, and role overload. They are not coping with the demands of LTC due to role overload, and lack of basic caregiving skills, coping skills and socio-emotional support. Their motivation to cope and provide quality care is hamstrung by their experiences of role ambiguity, poor employment conditions, negative interpersonal relations at work, and lack of career growth opportunities. CONCLUSIONS: Findings suggest that CWs' experiences derive from the policy and structural context of caregiving. Policy inadequacies and lack of structural support create conditions for adverse conditions which negatively impact on CWs motivation and ability to cope with the demands of LTC. Lack of policy implementation presents structural barriers to quality LTC in the older persons' sector. Implementation of policies and systems for professionalising care work is long overdue.

"They don't care about us": older people's experiences of primary healthcare in Cape Town, South Africa.

BACKGROUND: As older people age, they have different health needs compared to younger people. South African elder care policy places a strong emphasis on ageing in community rather than institutional settings, but the primary healthcare system is not geared to address the health needs of older people living in community settings. METHODS: This paper presents findings of nine focus groups conducted with community-dwelling older adults in three areas (high, medium and low-income) in Cape Town, South Africa over 2 months in 2017. These discussions addressed primary health services available to older persons, their ability to access these services and their expectations and experiences of care. RESULTS: Findings showed that while participants in the high-income area had few challenges accessing quality care or support services, services available in lower-income areas were much less responsive and participants displayed low trust in the healthcare system, feeling that their needs were overlooked. Participants who experienced poor doctor-patient communication often failed to comply with treatment, while those who experienced patient-centered communication, either through the private sector or NGO-public sector partnerships had better perceptions of care. CONCLUSIONS: Older persons' complex health needs cannot be adequately addressed by a process-driven approach to care. Supporting patient-centered communication and care may help health workers to understand older persons health needs and improve patient understanding, trust and co-operation. This paper suggests the importance of community support services in enhancing health access and developing systems that enable healthcare providers to better understand and respond to older persons' needs in resource-constrained settings.

Peer-to-peer support model to improve quality of life among highly vulnerable, low-income older adults in Cape Town, South Africa.

BACKGROUND: Developing countries are experiencing rapid population ageing. Many do not have the resources or formal structures available to support the health and wellbeing of people as they age. In other contexts, the use of peer support programmes have shown favourable outcomes in terms of reducing loneliness, increasing physical activity and managing chronic disease. Such programmes have not been previously developed or tested in African countries. We piloted a peer-to-peer support model among vulnerable community-dwelling adults in a developing country (South Africa) to examine the program's effect on wellbeing and social engagement. METHODS: A pre-post, pilot design was used to evaluate targeted outcomes, including wellbeing, social support, social interaction, mood, loneliness and physical activity. A total of 212 persons, aged 60+ years and living independently in a low-income area in Cape Town were recruited and screened for eligibility by trained assessors. Participants were assessed using the interRAI CheckUp, WHO-5 Wellbeing index, and the MOS-SS 8 instruments before and after the 5-month intervention, during which they received regular visits and phone calls from trained peer volunteers. During visits volunteers administered a wellness screening, made referrals to health and social services; built friendships with clients; encouraged social engagement; promoted healthy living; and provided emotional and informational support. RESULTS: Volunteer visits with clients significantly increased levels of self-reported wellbeing by 58%; improved emotional and informational support by 50%; decreased reports of reduced social interaction by 91%; reduced loneliness by 70%; improved mood scores represented as anxiety, depression, lack of interest or pleasure in activities, and withdrawal from activities of interest; and increased levels of physical activity from 49 to 66%. DISCUSSION: The intervention led to demonstrable improvement in client wellbeing. Policymakers should consider integrating peer-support models into existing health programs to better address the needs of the elderly population and promote healthy ageing in resource-poor community settings. Longer-term and more rigorous studies with a control group are needed to support these findings and to investigate the potential impact of such interventions on health outcomes longitudinally.

The Value of Isosulfan Blue Dye in Addition to Isotope Scanning in the Identification of the Sentinel Lymph Node in Breast Cancer Patients With a Positive Lymphoscintigraphy: A Randomized Controlled Trial (ISRCTN98849733).

BACKGROUND: Sentinel lymph node biopsy (SLNB) has become the gold standard for axillary staging. Debate remains as to the optimal method of SLN detection. OBJECTIVES: Determine whether patients undergoing an SLNB required the addition of isosulfan blue dye to radioisotope when an SLN was identified on a preoperative lymphoscintigram. METHODS: A prospective randomized controlled trial comparing the combination of radioisotope and blue dye versus radioisotope alone was performed between March 2010 and September 2012. The trial protocol was registered with Current Controlled Trials. Women with clinically and radiologically node-negative breast cancer with a positive preoperative lymphoscintigram were eligible for inclusion. RESULTS: A total of 667 patients were included in the analysis with 342 patients receiving the combination (blue dye and radioisotope) and 325 patients receiving radioisotope alone. The groups were evenly matched both demographically and pathologically. The mean age was 48 years (48.3 vs 47.7 years; P = 0.47), the mean tumour size was 24.2 mm (24.3 mm vs 24.1 mm; P = 0.7) and there was no statistically significant difference in the grade of the tumors between the 2 groups (P = 0.58). There was no difference in the identification rate, nor was that in the number of nodes retrieved between the 2 groups (P = 0.30). There was no difference in the number of positive lymph nodes that were identified between the 2 groups (23.8% vs 22.1%; P = 0.64). CONCLUSIONS: This study failed to demonstrate an advantage with the addition of isosulfan blue dye to radioisotope in the identification of the SLN in the presence of a positive preoperative lymphoscintigram.

The effect of acetabular inclination on metal ion levels following metal-on-metal hip arthroplasty.

Acetabular inclination angles have been suggested as a principal determinant of circulating metal ion levels in metal-on-metal hip arthroplasties. We aimed to determine whether inclination angle correlates with ion levels in arthroplasties using the Articular Surface Replacement (ASR) system. Patients undergoing ASR arthroplasties had blood metal ion levels and radiograph analysis performed a mean of 3.2 years after surgery. Inclination angle showed only a weak correlation with cobalt (r=0.21) and chromium (r=0.15) levels. The correlation between inclination angle and cobalt levels was significant only with small femoral components, although it was still weak. Multiple regression showed a complex interaction of factors influencing ion levels but inclination angle accounted for little of this variation. We conclude that the acetabular inclination angle is not a meaningful determinant of metal ion levels in ASR arthroplasties.

MRI findings following metal on metal hip arthroplasty and their relationship with metal ion levels and acetabular inclination angles.

Following the global recall of all ASR metal on metal hip products, our aim was to correlate MRI findings with acetabular inclination angles and metal ion levels in patients with these implants. Both cobalt and chromium levels were significantly higher in the presence of a periprosthetic fluid collection. There was no association between the presence of a periprosthetic mass, bone marrow oedema, trochanteric bursitis or greater levels of abductor muscle destruction for cobalt or chromium. There was no association between the level of periprosthetic tissue reaction and the acetabular inclination angle with any of the pathologies identified on MRI. The relationship between MRI pathology, metal ion levels and acetabular inclination angles in patients with ASR implants remains unclear adding to the complexity of managing patients.

Outcomes of detrusorectomy in neurogenic bladders: A systematic review and meta-analysis.

INTRODUCTION: This systematic review and meta-analysis aims to assess the outcomes of detrusorectomy in children with neurogenic bladder (NB). MATERIALS AND METHODS: A search was performed in PUBMED, EMBASE and the Cochrane Library database in August 2023. The following search terms were used: "detrusorectomy", "detrusorotomy", "auto-augmentation". The two main primary outcomes were improvement in bladder capacity and bladder compliance after intervention. Outcomes were dichotomized into favorable and unfavorable. The secondary outcomes were the effect of postoperative bladder cycling on bladder compliance and bladder capacity and complications. RESULTS: 258 references were screened for inclusion, of these 242 were excluded. 8 of the remaining 16 studies were included for the qualitative and quantitative analysis. All studies were retrospective case series studies (165 patients). Median follow-up time varied between studies (1.75-11.1 years), while two studies reported a mean follow-up time of 8.1 years. Using a random effects meta-analysis, the overall rate for unchanged or improved bladder capacity was 95% (Proportion[CI]: 0.95 [0.61; 1.00]). The overall rate for improved bladder compliance after detrusorectomy was 67% (Proportion[CI]: 0.67 [0.26; 0.92)) (Summary Fig). In the bladder cycling group improved compliance was found in 89% of patients (Proportion[CI]: 0.89 [0.41; 0.99]), whereas it was 21% in the non-cycling group (Proportion[CI]: 0.21 [0.04; 0.61]) (p = 0.0552). Bladder cycling did not affect bladder capacity as the overall rate for unchanged or improved bladder capacity was 98% (Proportion[CI]: 0.98 [0.35; 0.92]) in the cycling and 73% (Proportion[CI]: 0.73 [0.46; 0.90]) in the non-cycling group (p > 0.05). Overall complications were encountered in 16 (9.7%) patients, with major complications (stones, bladder perforations) detected only in 5(3%) patients. DISCUSSION: Detrusorectomy leads to an improved bladder compliance in 67% of children. As such, detrusorectomy proves to be a viable procedure to enhance bladder compliance or to cure overactivity. Importantly, the beneficial effect of detrusorectomy on bladder compliance seems to be long-lasting. Bladder capacity remained unchanged or improved in almost all patients undergoing detrusorectomy. Postoperative bladder cycling was effective in improving bladder compliance outcome compared to the non-cycling group. Proper patient selection is the key to good postoperative outcomes. CONCLUSIONS: Detrusorectomy enhances bladder compliance in pediatric neurogenic bladders. Postoperative bladder cycling improves bladder compliance and the overall complication rate of the procedure is low. Therefore, detrusorectomy should be considered a valuable therapeutic option in the comprehensive management of neurogenic bladders in children.

An intranasally delivered ultra-conserved siRNA prophylactically represses SARS-CoV-2 infection in the lung and nasal cavity.

There remains a striking overall mortality burden of COVID-19 worldwide. Given the waning effectiveness of current SARS-CoV-2 antivirals due to the rapid emergence of new variants of concern (VOC), we employed a direct-acting molecular therapy approach using gene silencing RNA interference (RNAi) technology. In this study, we developed and screened several ultra-conserved small-interfering RNAs (siRNAs) before selecting one potent siRNA candidate for pre-clinical in vivo testing. This non-immunostimulatory, anti-SARS-CoV-2 siRNA candidate maintains its antiviral activity against all tested SARS-CoV-2 VOC and works effectively as a single agent. For the first time, significant antiviral effects in both the lungs and nasal cavities of SARS-CoV-2 infected mice were observed when this siRNA candidate was delivered intranasally (IN) as a prophylactic agent with the aid of lipid nanoparticles (LNPs). Importantly, a pre-exposure prophylactic IN-delivered anti-SARS-CoV-2 siRNA antiviral that can ameliorate viral replication in the nasal cavity could potentially prevent aerosol spread of respiratory viruses. An IN delivery approach would allow for the development of a direct-acting nasal spray approach that could be self-administered prophylactically.

Epidemiological transition: a historical analysis of immigration patterns by country of origin (1861-1986) related to circulatory system diseases and all-cause mortality in twentieth-century Australia.

BACKGROUND AND OBJECTIVES: Circulatory system disease (CSD) patterns vary over time and between countries, related to lifestyle risk factors, associated in turn with socioeconomic circumstances. Current global CSD epidemics in developing economies are similar in scale to those observed previously in the USA and Australasia. Australia exhibits an important macroeconomic phenomenon as a rapidly transitioning economy with high immigration throughout the nineteenth and twentieth centuries. We wished to examine how that historical immigration related to CSD patterns subsequently. METHODS AND SETTING: We provide a novel empirical analysis employing census-derived place of birth by age bracket and sex from 1891 to 1986, in order to map patterns of immigration against CSD mortality rates from 1907 onwards. Age-specific generalised additive models for both CSD mortality in the general population, and all-cause mortality for the foreign-born (FB) only, from 1910 to 1980 were also devised for both males and females. RESULTS: The percentage of FB fell from 32% in 1891 to 9.8% in 1947. Rates of CSD rose consistently, particularly from the 1940s onwards, peaked in the 1960s, then declined sharply in the 1980s and showed a strong period effect across age groups and genders. The main effects of age and census year and their interaction were highly statistically significant for CSD mortality for males (p<0.001, each term) and for females (p<0.001, each term). The main effect of age and year were statistically significant for all-cause mortality minus net migration rates for the FB females (each p<0.001), and for FB males, age (p<0.001) was significant. CONCLUSIONS: We argue our empirical calculations, supported by historical and socioepidemiological evidence, employing immigration patterns as a proxy for epidemiological transition, affirm the life course hypothesis that both early life circumstances and later life lifestyle drive CSD patterns.

Prophylactic intranasal administration of lipid nanoparticle formulated siRNAs reduce SARS-CoV-2 and RSV lung infection.

RNA interference (RNAi) is an emerging and promising therapy for a wide range of respiratory viral infections. This highly specific suppression can be achieved by the introduction of short-interfering RNA (siRNA) into mammalian systems, resulting in the effective reduction of viral load. Unfortunately, this has been hindered by the lack of a good delivery system, especially via the intranasal (IN) route. Here, we have developed an IN siRNA encapsulated lipid nanoparticle (LNP) in vivo delivery system that is highly efficient at targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory syncytial virus (RSV) lung infection in vivo. Importantly, IN siRNA delivery without the aid of LNPs abolishes anti-SARS-CoV-2 activity in vivo. Our approach using LNPs as the delivery vehicle overcomes the significant barriers seen with IN delivery of siRNA therapeutics and is a significant advancement in our ability to delivery siRNAs. The study presented here demonstrates an attractive alternate delivery strategy for the prophylactic treatment of both future and emerging respiratory viral diseases.

Body mass index and height over three generations: evidence from the Lifeways cross-generational cohort study.

BACKGROUND: Obesity and its measure of body mass index are strongly determined by parental body size. Debate continues as to whether both parents contribute equally to offspring body mass which is key to understanding the aetiology of the disease. The aim of this study was to use cohort data from three generations of one family to examine the relative maternal and paternal associations with offspring body mass index and how these associations compare with family height to demonstrate evidence of genetic or environmental cross-generational transmission. METHODS: 669 of 1082 families were followed up in 2007/8 as part of the Lifeways study, a prospective observational cross-generation linkage cohort. Height and weight were measured in 529 Irish children aged 5 to 7 years and were self-reported by parents and grandparents. All adults provided information on self-rated health, education status, and indicators of income, diet and physical activity. Associations between the weight, height, and body mass index of family members were examined with mixed models and heritability estimates computed using linear regression analysis. RESULTS: Self-rated health was associated with lower BMI for all family members, as was age for children. When these effects were accounted for evidence of familial associations of BMI from one generation to the next was more apparent in the maternal line. Heritability estimates were higher (h2 = 0.40) for mother-offspring pairs compared to father-offspring pairs (h2 = 0.22). In the previous generation, estimates were higher between mothers-parents (h2 = 0.54-0.60) but not between fathers-parents (h2 = -0.04-0.17). Correlations between mother and offspring across two generations remained significant when modelled with fixed variables of socioeconomic status, health, and lifestyle. A similar analysis of height showed strong familial associations from maternal and paternal lines across each generation. CONCLUSIONS: This is the first family cohort study to report an enduring association between mother and offspring BMI over three generations. The evidence of BMI transmission over three generations through the maternal line in an observational study corroborates the findings of animal studies. A more detailed analysis of geno and phenotypic data over three generations is warranted to understand the nature of this maternal-offspring relationship.

Prepubertal methylphenidate leads to sex-dependent differences in probabilistic discounting.

Prescription psychostimulants, such as methylphenidate (MPH), have served as a first line treatment for ADHD and associated developmental disorders since 1961. Psychostimulants has been shown to improve attention, response inhibition, and reduce hyperactivity in patients with ADHD, as well as in non-clinical human populations and animals. While there is a considerable amount of preclinical research investigating the effects of stimulant medications on reward sensitivity and basic learning in male rats, less is understood about their effects in females. Further, there are competing theories on the long-term cognitive impact of MPH, specifically in children who do not have ADHD. To this end, Long-Evans female and male rats were exposed to methylphenidate (0, 2.5, 5 mg/kg, BID, IP) for 20 days during early development (PD10-29). After discontinuation of MPH into adulthood, rats (beginning PD 60) were trained and tested for risk-preference using a 2-choice probabilistic discounting task. For this task, rats were given an option between a 'large-risky' choice (3 sugar pellets delivered on a probabilistic VR schedule) and 'small-certain' choice (1 sugar pellet delivered on a FR schedule). Rats were subsequently tested on an open field conflict test. The results demonstrate that prepubertal exposure to MPH can have lasting effects on decision-making. Specifically, female rats treated with 2.5 mg/kg MPH displayed a decrease in preference for the risky option, whereas male rats treated with the same dose showed an overall increase in preference compared to sex-matched controls. Irrespective of sex, rats treated with 2.5 mg/kg MPH also demonstrated a decrease in anxiety/inhibitory behavior on the modified open field test compared to controls. These results were not due to differences in locomotor behavior. Overall, the study contributes to the growing body of evidence to suggest that MPH exposure early in development can have a sex-dependent impact on decision-making in adulthood.