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While diatoms are promising synthetic biology platforms, there currently exists a limited number of validated genetic regulatory parts available for genetic engineering. The standard method for diatom transformation, nonspecific introduction of DNA into chromosomes via biolistic particle bombardment, is low throughput and suffers from clonal variability and epigenetic effects. Recent developments in diatom engineering have demonstrated that autonomously replicating episomal plasmids serve as stable expression platforms for diverse gene expression technologies. These plasmids are delivered via bacterial conjugation and, when combined with modular DNA assembly technologies, provide a flexibility and speed not possible with biolistic-mediated strain generation. In order to expand the current toolbox for plasmid-based engineering in the diatom Phaeodactylum tricornutum, a conjugation-based forward genetics screen for promoter discovery was developed, and application to a diatom genomic DNA library defined 252 P. tricornutum promoter elements. From this library, 40 promoter/terminator pairs were delivered via conjugation on episomal plasmids, characterized in vivo, and ranked across 4 orders of magnitude difference in reporter gene expression levels.

Abstract The Rey Auditory Verbal Learning Test (RAVLT) is a commonly used tool for evaluating verbal learning and memory in neuropsychological assessments. In recent years, we developed a Virtual Reality (VR) adaptation of the RAVLT (VR-RVLT), aiming for increased ecological validity compared to the traditional pen and paper gold standard (GS-RAVLT). Following validation in healthy cohorts, the VR-RAVLT was validated with thirty individuals with Parkinson's Disease (PD) that completed both the GS-RAVLT and the VR- RAVLT. Validity of the VR-RAVLT was evaluated by assessing its construct and discriminant validity, and test–retest reliability, in comparison to the GS-RAVLT. Results of the PD participants were compared to those of 46 previously recruited healthy participants with comparable age and level of education. Main outcome measures derived from the remembered items on the test lists, exhibited significant and comparable correlations between VR-RAVLT and GS-RAVLT, both among healthy participants and PD participants. Likewise, serial position effects were similar for both formats amog the PD participants. Additionally, both formats showed similar discriminatory ability between healthy controls and PD participants, as well as comparable test–retest reliability measures. Taken together, the results suggest that the VR-based RAVLT is equally effective in measuring verbal memory capabilities in individuals with PD as compared to the GS-RAVLT. Certain results indicate that the virtual reality version has the capability to encompass additional factors that might impact memory performance, thereby suggesting an enhanced ecological validity.

Abstract Pediatric rehabilitation is fundamentally different from that of adults. Child physiology differs significantly from that of adults, necessitating specialized rehabilitation approaches. Unique injuries and varying metabolic rates underscore the need for tailored care, which changes over the years as the child grows and develops. Waiserberg’s paper, “When Everyone is Responsible, No One Takes Responsibility”: Exploring Pediatric Physiotherapy Services in Israel,” sheds light on a critical issue. While senior practitioners oversee policy implementation and service delivery, practical physiotherapy treatment lacks continuous monitoring. This is a critical issue. Ideally, every child who requires long-term clinical therapeutic interventions to keep up with peers in mobility, communication and cognitive skills should be assessed by specialists several times throughout the school years, and their personalized rehabilitation plan discussed, reviewed, and adjusted according to their progress. The absence of a standardized protocol for overseeing and directing comprehensive rehabilitation plans leaves therapists feeling alone and adrift, whether working in schools or medical settings. Such an assessment would be an opportunity to create a registry, which is currently nonexistent. The collected data would be a priceless resource in policy decision-making and service planning.

The survival rate for patients with head and neck cancer (HNC) diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts, and a novel HRASmut syngeneic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vascular angiogenesis in the primary tumor. Tipifarnib treatment also regulated AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.SignificanceMutant HRAS drives metastasis of head and neck cancer by switching off the Hippo pathway to activate the YAP1-AXL axis and to stimulate lymphovascular angiogenesis.

Abstract Introduction Depression and its components significantly impact dementia prediction and severity, necessitating reliable objective measures for quantification. Methods We investigated associations between emotion‐based speech measures (valence, arousal, and dominance) during picture descriptions and depression dimensions derived from the geriatric depression scale (GDS, dysphoria, withdrawal‐apathy‐vigor (WAV), anxiety, hopelessness, and subjective memory complaint). Results Higher WAV was associated with more negative valence (estimate = ‐0.133, p = 0.030). While interactions of apolipoprotein E (APOE) 4 status with depression dimensions on emotional valence did not reach significance, there was a trend for more negative valence with higher dysphoria in those with at least one APOE4 allele (estimate = –0.404, p = 0.0846). Associations were similar irrespective of dementia severity. Discussion Our study underscores the potential utility of speech biomarkers in characterizing depression dimensions. In future research, using emotionally charged stimuli may enhance emotional measure elicitation. The role of APOE on the interaction of speech markers and depression dimensions warrants further exploration with greater sample sizes. Highlights Participants reporting higher apathy used more negative words to describe a neutral picture. Those with higher dysphoria and at least one APOE4 allele also tended to use more negative words. Our results suggest the potential use of speech biomarkers in characterizing depression dimensions.

Abstract Diabetes is associated with cognitive decline, but the underlying mechanisms are complex and their relationship with Alzheimer’s Disease biomarkers is not fully understood. We assessed the association of small vessel disease (SVD) and amyloid burden with cognitive functioning in 47 non-demented older adults with type-2 diabetes from the Israel Diabetes and Cognitive Decline Study (mean age 78Y, 64% females). FLAIR-MRI, Vizamyl amyloid-PET, and T1W-MRI quantified white matter hyperintensities as a measure of SVD, amyloid burden, and gray matter (GM) volume, respectively. Mean hemoglobin A1c levels and duration of type-2 diabetes were used as measures of diabetic control. Cholesterol level and blood pressure were used as measures of cardiovascular risk. A broad neuropsychological battery assessed cognition. Linear regression models revealed that both higher SVD and amyloid burden were associated with lower cognitive functioning. Additional adjustments for type-2 diabetes-related characteristics, GM volume, and cardiovascular risk did not alter the results. The association of amyloid with cognition remained unchanged after further adjustment for SVD, and the association of SVD with cognition remained unchanged after further adjustment for amyloid burden. Our findings suggest that SVD and amyloid pathology may independently contribute to lower cognitive functioning in non-demented older adults with type-2 diabetes, supporting a multimodal approach for diagnosing, preventing, and treating cognitive decline in this population.

Abstract The IGF2BP family of RNA binding proteins consists of three paralogs that regulate intracellular RNA localization, RNA stability, and translational control. Although IGF2BP1 and 3 are oncofetal proteins, IGF2BP2 expression is maintained in many tissues, including the heart, into adulthood. IGF2BP2 is upregulated in cardiomyocytes during cardiac stress and remodeling and returns to normal levels in recovering hearts. We wondered whether IGF2BP2 might play an adaptive role during cardiac stress and recovery. Enhanced expression of an IGF2BP2 transgene in a conditional, inducible mouse line leads to dilated cardiomyopathy (DCM) and death within 3-4 weeks in newborn or adult hearts. Downregulation of the transgene after 2 weeks, however, rescues these mice, with complete recovery by 12 weeks. Hearts overexpressing IGF2BP2 downregulate sarcomeric and mitochondrial proteins and have fragmented mitochondria and elongated, thinner sarcomeres. IGF2BP2 is also upregulated in DCM or myocardial infarction patients. These results suggest that IGF2BP2 may be an attractive target for therapeutic intervention in cardiomyopathies.

IntroductionThe incidence of both type 1 diabetes (T1D) and type 2 diabetes (T2D) is increasing. Life expectancy is improving in T1D, resulting in a growing population of elderly adults with diabetes. While it is well established that older adults with T2D are at increased risk of cognitive impairment, little is known regarding cognitive aging in T1D and how their cognitive profiles may differ from T2D.Research design and methodsWe compared baseline cognitive function and low cognitive function by diabetes status (n=734 T1D, n=232 T2D, n=247 without diabetes) among individuals from the Study of Longevity in Diabetes (mean age=68). We used factor analysis to group cognition into five domains and a composite measure of total cognition. Using linear and logistic regression models, we examined the associations between diabetes type and cognitive function, adjusting for demographics, comorbidities, depression, and sleep quality.ResultsT1D was associated with lower scores on total cognition, language, executive function/psychomotor processing speed, and verbal episodic memory, and greater odds of low executive function/psychomotor processing speed (OR=2.99, 95% CI 1.66 to 5.37) and verbal episodic memory (OR=1.92, 95% CI 1.07 to 3.46), compared with those without diabetes. T2D was associated with lower scores on visual episodic memory. Compared with T2D, T1D was associated with lower scores on verbal episodic memory and executive function/psychomotor processing speed and greater odds of low executive function/psychomotor processing speed (OR=1.74, 95% CI 1.03 to 2.92).ConclusionsOlder adults with T1D had significantly poorer cognition compared with those with T2D and those without diabetes even after accounting for a range of comorbidities. Future studies should delineate how to reduce risk in this vulnerable population who are newly surviving to old age.

Abstract Background Transcatheter edge to edge repair (TEER) improves prognosis in patients with functional mitral regurgitation (FMR) receiving guideline directed medical therapy (GDMT). Many patients with FMR do not receive GDMT and the utility of TEER in this population remains unclear. Methods We retrospectively studied patients undergoing TEER. Clinical, echocardiographic and procedural variables were recorded. GDMT was defined as use of RAAS inhibitors and MRAs unless GFR was under 30 as well as beta blockers. The primary endpoint of the study was one year mortality. Results 168 patients (mean age 71.3 ± 9.3; 66% males) with FMR who underwent TEER were included of whom 116 (69%) received GDMT at the time of TEER and 52 (31%) did not. There were no significant demographic or clinical differences between the groups. There were no significant differences in procedural success and complications between groups. One year mortality was identical in the two groups (15% vs. 15%; RR 1.06, CI 0.43–2.63, P = 0.90). Conclusions Our findings suggest that procedural success and one year mortality following TEER was not significantly different in HFREF patients with FMR with or without GDMT. Larger, prospective studies are necessary to define the benefit of TEER in this population.

IntroductionWomen comprise two-thirds of people with dementia, making female sex a significant dementia risk factor. Both type 1 diabetes (T1D) and type 2 diabetes (T2D) are known dementia risk factors with an increasing global incidence. Understanding whether subtle sex differences persist in cognitive function prior to dementia in the context of diabetes may help elucidate the magnitude of sex effects on dementia risk.Research design and methodsWe examined cross-sectional data from the Study of Longevity in Diabetes (SOLID), a prospective cohort study of members of Kaiser Permanente Northern California aged 60 years and older with T1D (n=758), T2D (n=232) and without either T1D or T2D (n=247). We used factor analysis to generate summary scores of cognitive domains and used regression analyses to examine the associations between sex and cognition adjusting for sociodemographic and cardiovascular confounders.ResultsWe included 1237 participants (630 women and 607 men) with mean age 68 years. By design, the distribution of men and women in T1D, T2D and no diabetes was similar. Women had better cognitive performance than men in global cognition (β=0.21, 95% CI 0.16 to 0.26), language (β=0.08, 95% CI 0.004 to 0.15), executive function (β=0.13, 95% CI 0.05 to 0.20), episodic verbal memory (β=0.68, 95% CI 0.59 to 0.77) and attention (β=0.20, 95% CI 0.11 to 0.28) but not in episodic visual memory (β=0.006, 95% CI -0.07 to 0.09) adjusting for age and education independent of diabetes status. We did not find an interaction between sex and diabetes status for any of the cognitive outcomes.ConclusionsWomen in late mid-life have better cognitive performance than men in many cognitive domains independent of the presence of T1D or T2D. Further work is required to understand whether these differences change over time or in older cohorts and to understand their relationship to subsequent dementia.

IntroductionDiabetic ketoacidosis (DKA) is a serious complication of diabetes. DKA is associated with poorer cognition in children with type 1 diabetes (T1D), but whether this is the case in older adults with T1D is unknown. Given the increasing life expectancy in T1D, understanding the role of DKA on brain health in older adults is crucial.Research design and methodsWe examined the association of DKA with cognitive function in 714 older adults with T1D from the Study of Longevity in Diabetes. Participants self-reported lifetime exposure to DKA resulting in hospitalization; DKA was categorized into 0 hospitalization, 1 hospitalization or ≥2 hospitalizations (recurrent DKA). Global and domain-specific cognition (language, executive function/psychomotor speed, episodic memory and simple attention) were assessed. The association of DKA with cognitive function was evaluated via linear and logistic regression models.ResultsTwenty-eight percent of participants (mean age=67 years; mean age at diagnosis=28 years; average duration of diabetes=39 years) reported a lifetime history of DKA resulting in hospitalization (18.5% single DKA; 9.7% recurrent DKA). In fully adjusted models, those with recurrent DKA had lower global cognitive function (β=-0.13; 95% CI -0.22 to 0.02) and lower scores on the executive function/psychomotor speed domain (β=-0.34; 95% CI -0.51 to 0.17). Individuals with recurrent DKA were also more likely to have the lowest level of cognitive function on the executive function/psychomotor speed domain (defined as 1.5 SD below the population mean; OR=3.26, 95% CI 1.43 to 7.42).ConclusionsAmong 714 older adults with T1D, recurrent DKA was associated with lower global cognitive function, lower scores on the executive function/psychomotor speed domain and 3.3 times greater risk of having the lowest level of cognitive function in our sample on the executive function/psychomotor speed domain. These findings suggest that recurrent DKA may negatively impact the brain health of older patients with T1D and highlight the importance of DKA prevention.

ObjectiveIn children with type 1 diabetes (T1D), severe hypoglycemia (SH) is associated with poorer cognition, but the association of SH with cognitive function in late life is unknown. Given the increasing life expectancy in people with T1D, understanding the role of SH in brain health is crucial.Research design and methodsWe examined the association between SH and cognitive function in 718 older adults with T1D from the Study of Longevity in Diabetes (SOLID). Subjects self-reported recent SH (previous 12 months) and lifetime history of SH resulting in inpatient/emergency department utilization. Global and domain-specific cognition (language, executive function, episodic memory, and simple attention) were assessed. The associations of SH with cognitive function and impaired cognition were evaluated via linear and logistic regression models, respectively.ResultsThirty-two percent of participants (mean age 67.2 years) reported recent SH and 50% reported lifetime SH. Compared with those with no SH, subjects with a recent SH history had significantly lower global cognition scores. Domain-specific analyses revealed significantly lower scores on language, executive function, and episodic memory with recent SH exposure and significantly lower executive function with lifetime SH exposure. Recent SH was associated with impaired global cognition (odds ratio [OR] 3.22, 95% CI 1.30, 7.94) and cognitive impairment on the language domain (OR 3.15, 95% CI 1.19, 8.29).ConclusionsAmong older adults with T1D, recent SH and lifetime SH were associated with worse cognition. Recent SH was associated with impaired global cognition. These findings suggest a deleterious role of SH on the brain health of older patients with T1D and highlight the importance of SH prevention.

Study objectiveThe objective was to examine the association between sleep quality and global and domain-specific cognitive function among older individuals with type 1 diabetes (T1D).MethodsWe evaluated 695 individuals with T1D aged 60 years or above who participated in the baseline assessment of the Study of Longevity in Diabetes (SOLID), which captured subjective sleep quality (Pittsburgh Sleep Quality Index) and global and domain-specific (language, executive function, episodic memory, and simple attention) cognitive function. Multivariable linear regressions estimated the associations between sleep quality quartiles and overall and domain-specific cognitive function adjusting for age, sex, race/ethnicity, education, depressive symptoms, and severe hypoglycemic episodes. Sensitivity analyses examined the associations between aspects of sleep quality and global cognitive function.ResultsThe worst sleep quality quartile was associated with lower global cognition (β=-0.08; 95% confidence interval: -0.17, -0.01) and lower executive function (β=-0.17, 95% confidence interval: -0.30, -0.03) compared with the best quartile of sleep quality adjusting for demographics and comorbidities. Sleep quality was not associated with language, episodic memory, or simple attention. Sleep medications and daytime dysfunction were most strongly associated with global cognition.ConclusionOur results suggest that sleep quality may be a modifiable risk factor for global cognitive function and executive function among elderly individuals with T1D.

ObjectiveLife expectancy for individuals with type 1 diabetes mellitus (T1DM) has increased recently; however, it is unknown how diabetes care attitudes affect late-life brain health.Research design and methodsThe Study of Longevity in Diabetes (SOLID) consists of 734 older adults with T1DM, reporting diabetes locus of control (dLOC), age of diabetes diagnosis and other demographics, history of hypoglycemic episodes, and depressive symptoms. Global and domain-specific (language, executive function, episodic memory, simple attention) cognitive functioning was assessed at in-person interviews. Cross-sectional associations between dLOC and cognition were estimated using covariate-adjusted linear regression models in pooled and sex-stratified models.ResultsIn pooled analyses, a 1-point increase in dLOC (more internal) was positively associated with global cognition [β=0.05, 95% confidence interval (CI): 0.02, 0.07], language (β=0.04, 95% CI: 0.01, 0.07), and executive function (β=0.04, 95% CI: 0.01, 0.07), but not episodic memory or simple attention. However, in sex-stratified analyses, this effect was seen only in males and not females.ConclusionsIn elderly individuals with T1DM, we found associations between dLOC and cognition overall and in men but not women. Underlying sex differences should be considered in future research or interventions on psychosocial characteristics for cognition.

Objectives The aim of this study is to look at spatial and temporal trends in undernutrition in children under 5 years age in Burkina Faso.Setting We used data from annual National Nutrition Surveys using Standardised Monitoring and Assessment of Relief and Transitions methodology (anthropometry, morbidity) over 7 years (2012–2018) in Burkina Faso.Participants Children of under 5 years from households selected through systemic sampling at countrywide level.Main outcome measures Prevalence of stunting (height-for-age z-score,

Background Little is known about the impact of transcatheter mitral valve edge‐to‐edge repair on changes in left ventricular ejection fraction (LVEF) and the effect of an acute reduction in LVEF on prognosis. We aimed to assess changes in LVEF after transcatheter mitral valve edge‐to‐edge repair for both primary and secondary mitral regurgitation (PMR and SMR, respectively), identify rates and predictors of LVEF reduction, and estimate its impact on prognosis. Methods and Results In this international multicenter registry, patients with both PMR and SMR undergoing transcatheter mitral valve edge‐to‐edge repair were included. We assessed rates of acute LVEF reduction (LVEFR), defined as an acute relative decrease of >15% in LVEF, its impact on all‐cause mortality, major adverse cardiac event (composite end point of all‐cause death, mitral valve surgery, and residual mitral regurgitation grade ≥2), and LVEF at 12 months, as well as predictors for LVEFR. Of 2534 patients included (727 with PMR, and 1807 with SMR), 469 (18.5%) developed LVEFR. Patients with PMR were older (79.0±9.2 versus 71.8±8.9 years; P

We explore two complementary mechanisms that are designed to work together to reduce spatial inequality—redrawing municipal borders and the redistribution of tax resources. This study’s methodology is based on the empirical analysis of 376 decisions of boundary commissions and permanent geographic commissions that resulted in land transfers and redistributed tax resources in Israel. Our findings indicate that the impact on spatial inequality is mixed. Over time, the amount of land transferred to low socio-economic municipalities has increased, provided that these municipalities are located in the center of the country, or have a Jewish ethnic majority, are politically affiliated with the Minister of the Interior and the ultra-Orthodox right, are financially sound, and have a large population and a large area. In contrast, the redistribution of tax resources provides revenue increases for low socio-economic municipalities that are in the periphery, largely populated by Arabs, are unaffiliated with powerful politicians, are financially weak and small in size and population.

ObjectiveDepression afflicts 14% of individuals with type 1 diabetes (T1D). Depression is a robust risk factor for dementia but it is unknown if this holds true for individuals with T1D, who recently started living to an age conferring dementia risk. We examined if depression is a dementia risk factor among elderly individuals with T1D.Methods3,742 individuals with T1D age ≥50 were followed for dementia from 1/1/96-9/30/2015. Depression, dementia, and comorbidities were abstracted from electronic medical records. Cox proportional hazard models estimated the association between depression and dementia adjusting for demographics, glycosylated hemoglobin, severe dysglycemic epidsodes, stroke, heart disease, nephropathy, and end stage renal disease. The cumulative incidence of dementia by depression was estimated conditional on survival dementia-free to age 55.ResultsFive percent (N = 182) were diagnosed with dementia and 20% had baseline depression. Depression was associated with a 72% increase in dementia (fully adjusted HR = 1.72; 95% CI:1.12-2.65). The 25-year cumulative incidence of dementia was more than double for those with versus without depression (27% vs. 12%).ConclusionsFor people with T1D, depression significantly increases dementia risk. Given the pervasiveness of depression in T1D, this has major implications for successful aging in this population recently living to old age.

ObjectiveTo determine whether classes of diabetes medications are associated with cognitive health and dementia risk, above and beyond their glycemic control properties.Research design and methodsFindings were pooled from 5 population-based cohorts: the Framingham Heart Study, the Rotterdam Study, the Atherosclerosis Risk in Communities (ARIC) Study, the Aging Gene-Environment Susceptibility-Reykjavik Study (AGES) and the Sacramento Area Latino Study on Aging (SALSA). Differences between users and non-users of insulin, metformin and sulfonylurea were assessed in each cohort for cognitive and brain MRI measures using linear regression models, and cognitive decline and dementia/AD risk using mixed effect models and Cox regression analyses, respectively. Findings were then pooled using meta-analytic techniques, including 3,590 individuals with diabetes for the prospective analysis.ResultsAfter adjusting for potential confounders including indices of glycemic control, insulin use was associated with increased risk of new-onset dementia (pooled HR (95% CI) = 1.58 (1.18, 2.12);p = 0.002) and with a greater decline in global cognitive function (β = -0.014±0.007;p = 0.045). The associations with incident dementia remained similar after further adjustment for renal function and excluding persons with diabetes whose treatment was life-style change only. Insulin use was not related to cognitive function nor to brain MRI measures. No significant associations were found between metformin or sulfonylurea use and outcomes of brain function and structure. There was no evidence of significant between-study heterogeneity.ConclusionsDespite its advantages in controlling glycemic dysregulation and preventing complications, insulin treatment may be associated with increased adverse cognitive outcomes possibly due to a greater risk of hypoglycemia.

Background The coronavirus outbreak has demonstrated the crucial effect of the public’s compliance with the government’s health instructions on the population’s health. However, evidence shows that some communities are less likely to comply with such instructions than others. This study highlights the factors related to intentions to comply with newly issued health directives during an ongoing extreme crisis, such as the current pandemic. In addition, it compares the impact of these factors on different minority groups and the general population in Israel. Methods Using an online survey (N = 1005), we examined the impact of compliance-related factors on compliance intentions with newly issued health directives in two minority groups in Israel: the ultra-Orthodox Jewish community (N = 323) and the Arab community (N = 361), as well as in the general population (N = 321), during the first outbreak of coronavirus disease 2019 (COVID-19). Participants were presented with a new made-up COVID-19-related instruction simulated to be issued by the Israeli Ministry of Health. Compliance intentions and compliance-related factors were measured. Results The Arab minority expressed greater intentions of complying with the instructions than the other groups. Perceptions on risk and the effectiveness of the instruction were the only two significantly associated factors with compliance intentions in all of the social groups. Additional factors affected different groups to different extents. Trust in government was related to compliance intentions only in the Arab minority. Conclusion Intentions to comply with health instructions during a crisis differ in various minority groups and in comparison to the general population, both in their levels and in the factors related to them. Policy-makers and health authorities should consider providing information about the risks and negative outcomes of the crisis as well as the expected effectiveness of the recommended behaviors. Future research should examine other minority groups and other types of instructions in different stages of a crisis.

Abstract Background Evidence suggests a gradual decrease in the effectiveness of the anti-COVID-19 vaccines, stressing the potential need for periodical booster shots. However, it is hard to tell whether previously applied policies for enhancing vaccine acceptance will be as effective for repeated periodical booster shots during a pandemic. Hence, this study aims to explore the effectiveness of different health policies on periodical vaccination acceptance amidst an ongoing pandemic. Methods A cross sectional online experiment was performed in a representative sample of 929 Israeli citizens. Participants were randomly allocated to 4 groups simulating different hypothetical periodical-vaccination-promoting policy scenarios: (1) Mandate (N = 229); (2) a negative monetary incentive (N = 244); (3) a positive monetary incentive (N = 228) and (4) information provision (N = 228). Compliance intentions and vaccine-acceptance-related variables were measured. Analysis included multivariate hierarchic logistic and linear regressions. Results Compliance intentions levels were medium (M = 3.13 on a 1–5 scale). Only 20.2% of the sample demonstrated strong acceptance of periodical vaccination, which is lower than the acceptance rate of the seasonal flu shot in the country in the year preceding the pandemic. Type of policy was related to the extent to which a respondent strongly agreed to be periodically vaccinated or not. Specifically, strong acceptance was more likely when positive or negative incentives were presented in comparison to the mandate or information provision conditions. However, when examining the extent of compliance among respondents who were less decisive, the type of policy did not predict the extent to which these respondents intended to comply. In addition, compliance intentions were related with the perceived benefits and barriers of the vaccine, the perceived efficacy of getting vaccinated and social norms. Hesitator’s intentions were additionally associated with anti-COVID-19 vaccination history, perceived severity of the disease and trust in government. Conclusions Pandemic-containing vaccines may be perceived as less effective and beneficial than pandemic-preventing vaccines. Individuals with different levels of motivation for periodical vaccination during a pandemic may be affected by different factors. While strongly opinionated individuals are affected by the type of vaccination-promoting policy, hesitators are affected by a larger number of factors, which provide policy makers with greater opportunities to enhance their vaccination intentions.

BackgroundAdiposity has been previously associated with cognitive impairment and Alzheimer’s disease and related disorders (ADRD). Body mass index (BMI) is the most common measure of global adiposity, but inconsistent results were found since it is a global measurement. BMI does not represent regional fat distribution which differs between sexes, race, and age. Regional fat distribution may contribute differently to cognitive decline and Alzheimer’s disease (AD)-related brain changes. Fat-specific targeted therapies could lead to personalized improvement of cognition. The goal of this systematic review is to explore whether regional fat depots, rather than central obesity, should be used to understand the mechanism underlying the association between adiposity and brain.MethodsThis systematic review included 33 studies in the English language, conducted in humans aged 18 years and over with assessment of regional adiposity, cognitive function, dementia, and brain measures. We included only studies that have assessed regional adiposity using imaging technics and excluded studies that were review articles, abstract only or letters to editor. Studies on children and adolescents, animal studies, and studies of patients with gastrointestinal diseases were excluded. PubMed, PsychInfo and web of science were used as electronic databases for literature search until November 2022.ResultsBased on the currently available literature, the findings suggest that different regional fat depots are likely associated with increased risk of cognitive impairment, brain changes and dementia, especially AD. However, different regional fat depots can have different cognitive outcomes and affect the brain differently. Visceral adipose tissue (VAT) was the most studied regional fat, along with liver fat through non-alcoholic fatty liver disease (NAFLD). Pancreatic fat was the least studied regional fat.ConclusionRegional adiposity, which is modifiable, may explain discrepancies in associations of global adiposity, brain, and cognition. Specific regional fat depots lead to abnormal secretion of adipose factors which in turn may penetrate the blood brain barrier leading to brain damage and to cognitive decline.

Abstract Currently there are no reliable biomarkers for early detection of Alzheimer's disease (AD) at the preclinical stage. This study assessed the pupil light reflex (PLR) for focal red and blue light stimuli in central and peripheral retina in 125 cognitively normal middle age subjects (45–71 years old) at high risk for AD due to a family history of the disease (FH+), and 61 age-similar subjects with no family history of AD (FH−) using Chromatic Pupilloperimetry coupled with Machine Learning (ML). All subjects had normal ophthalmic assessment, and normal retinal and optic nerve thickness by optical coherence tomography. No significant differences were observed between groups in cognitive function and volumetric brain MRI. Chromatic pupilloperimetry-based ML models were highly discriminative in differentiating subjects with and without AD family history, using transient PLR for focal red (primarily cone-mediated), and dim blue (primarily rod-mediated) light stimuli. Features associated with transient pupil response latency (PRL) achieved Area Under the Curve Receiver Operating Characteristic (AUC-ROC) of 0.90 ± 0.051 (left-eye) and 0.87 ± 0.048 (right-eye). Parameters associated with the contraction arm of the rod and cone-mediated PLR were more discriminative compared to parameters associated with the relaxation arm and melanopsin-mediated PLR. Significantly shorter PRL for dim blue light was measured in the FH+ group in two test targets in the temporal visual field in right eye that had highest relative weight in the ML algorithm (mean ± standard error, SE 0.449 s ± 0.007 s vs. 0.478 s ± 0.010 s, p = 0.038). Taken together our study suggests that subtle focal changes in pupil contraction latency may be detected in subjects at high risk to develop AD, decades before the onset of AD clinical symptoms. The dendrites of melanopsin containing retinal ganglion cells may be affected very early at the preclinical stages of AD.

Daboia (Vipera) palaestinae (Dp), accounts for most envenomations in humans and dogs in Israel. In humans envenomed by Dp, serum cholesterol concentration (sChol) is inversely correlated with envenomation severity. This study examined the utility of sChol upon admission in dogs envenomed by Dp as an envenomation severity and outcome marker. Data upon admission, including sChol, were retrospectively collected from the medical records of dogs with proven Dp envenomation. The study included 415 dogs. The mortality rate was 11%. The heart rate upon admission was higher in non-survivors than in survivors. Signs of bleeding or hematoma and circulatory shock signs were more frequent among non-survivors compared to survivors. sChol, the platelet count, and serum albumin concentration (sAlb) were lower, while serum creatinine concentration was higher among non-survivors. sChol and sAlb were moderately, positively, and significantly correlated. sChol was significantly, negatively, albeit weakly, correlated with the length of hospitalization and the heart rate. sChol was lower in dogs admitted >12 h post-envenomation than in those admitted later. In dogs, sChol upon admission is a potential marker of severity and outcome of Dp envenomation. The platelet count, sAlb, and sCreat might also be potential markers.

Advances in information technology and communication through new social media platforms have enormous benefits in many contexts, including education. At the same time, self-distractive use of technology -- or 'absent presenteeism' -- can have negative effects in the classroom. The main research question of this study is the relationship between organisational leadership, enforcement of discipline and self-distractive use of technology in the secondary school setting. The finding indicated that the permissive style of discipline appeared to be the most effective at reducing self-distractive mobile phone use. However, a more authoritative style of discipline, short teacher tenure and the principal's transformational leadership style contributed to high self-distractive mobile phone use. The authors rely on empirical data collected in Israeli public high schools from two independent sources: 144 teachers and 591 students, which yielded 4440 teacher-student events. Implications of the findings are discussed in the context of the school setting characterised by rapid changes in technology.

Abstract Metallography is crucial for a proper assessment of material properties. It mainly involves investigating the spatial distribution of grains and the occurrence and characteristics of inclusions or precipitates. This work presents a holistic few-shot artificial intelligence model for Quantitative Metallography, including Anomaly Detection, that automatically quantifies the degree of the anomaly of impurities in alloys. We suggest the following examination process: (1) deep semantic segmentation is performed on the inclusions (based on a suitable metallographic dataset of alloys and corresponding tags of inclusions), producing inclusions masks that are saved into a separated dataset. (2) Deep image inpainting is performed to fill the removed inclusions parts, resulting in ‘clean’ metallographic images, which contain the background of grains. (3) Grains’ boundaries are marked using deep semantic segmentation (based on another metallographic dataset of alloys), producing boundaries that are ready for further inspection on the distribution of grains’ size. (4) Deep anomaly detection and pattern recognition is performed on the inclusions masks to determine spatial, shape, and area anomaly detection of the inclusions. Finally, the end-to-end model recommends an expert on areas of interest for further examination. The physical result can re-tune the model according to the specific material at hand. Although the techniques presented here were developed for metallography analysis, most of them can be generalized to a broader set of microscopy problems that require automation. All source-codes as well as the datasets that were created for this work, are publicly available at https://github.com/Scientific-Computing-Lab-NRCN/MLography .

IntroductionRecently, interest has emerged in subjective cognitive decline (SCD) as a potential precursor to Alzheimer’s disease (AD) dementia. Whether individuals with SCD harbor brain alterations in midlife, when AD-related pathology begins, is yet to be elucidated. Furthermore, the role of apolipoprotein ε4 (APOE ε4) allele, a robust AD risk factor, in the relationship between SCD and brain alterations is unknown. We examined whether APOE genotype modulates the association of SCD with brain measures in individuals at high AD risk.MethodsMiddle-aged adults with parental history of AD dementia underwent magnetic resonance imaging (MRI) and the Memory Functioning Questionnaire. Regression analysis tested the extent to which SCD was associated with activation during an functional MRI (fMRI) working-memory task, and white-matter microstructure. APOE ε4 genotype was tested as a moderator.ResultsAmong APOE ε4 carriers, but not among non-carriers, SCD was associated with higher activation in the anterior cingulate (p = 0.003), inferior, middle, and superior frontal cortices (p = 0.041, p = 0.048, p = 0.037, respectively); and with lower fractional anisotropy in the uncinate fasciculus (p = 0.002), adjusting for age, sex, and education.ConclusionIn middle aged, cognitively normal individuals at high AD risk, higher SCD was associated with greater brain alterations possibly reflecting incipient AD pathology. When accompanied by a family history of AD and an APOE ε4 allele, SCD may have important clinical value, allowing a window for early intervention and for participants’ stratification in AD prevention clinical trials.

Evidence that nutrition-specific and nutrition-sensitive interventions can improve maternal and child nutrition status in sub-Saharan Africa is inconclusive. Using behaviour change theory and techniques in intervention design may increase effectiveness and make outcomes more predictable. This systematic review aimed to determine whether interventions that included behaviour change functions were effective. Six databases were searched systematically, using MeSH and free-text terms, for articles describing nutrition-specific and nutrition-sensitive behaviour change interventions published in English until January 2022. Titles, abstracts and full-text papers were double-screened. Data extraction and quality assessments followed Centre for Reviews and Dissemination guidelines. Behaviour change functions of interventions were mapped onto the COM-B model and Behaviour Change Wheel. PROSPERO registered (135054). The search yielded 1193 articles: 79 articles met inclusion criteria, ranging from low (n = 30) to high (n = 11) risk of bias. Many that applied behaviour change theory, communication or counselling resulted in significant improvements in infant stunting and wasting, household dietary intake and maternal psychosocial measures. Interventions with >2 behaviour change functions (including persuasion, incentivisation, environmental restructuring) were the most effective. We recommend incorporating behaviour change functions in nutrition interventions to improve maternal and child outcomes, specifically drawing on the Behaviour Change Wheel, COM-B model (SORT B recommendation). To enhance the designs of these interventions, and ultimately improve the nutritional and psychosocial outcomes for mothers and infants in sub-Saharan Africa, collaborations are recommended between behaviour change and nutrition experts, intervention designers, policy makers and commissioners to fund and roll-out multicomponent behaviour change interventions.

ObjectiveTo examine the association between traumatic brain injury (TBI) and dementia risk among a cohort of middle-aged and elderly individuals with type 1 diabetes (T1D).MethodsWe evaluated 4,049 members of an integrated health care system with T1D ≥50 years old between January 1, 1996, and September 30, 2015. Dementia and TBI diagnoses throughout the study period were abstracted from medical records. Cox proportional hazards models estimated associations between time-dependent TBI and dementia adjusting for demographics, HbA1c, nephropathy, neuropathy, stroke, peripheral artery disease, depression, and dysglycemic events. Fine and Gray regression models evaluated the association between baseline TBI and dementia risk accounting for competing risk of death.ResultsA total of 178 individuals (4.4%) experienced a TBI and 212 (5.2%) developed dementia. In fully adjusted models, TBI was associated with 3.6 times the dementia risk (hazard ratio [HR] 3.64; 95% confidence interval [CI] 2.34, 5.68). When accounting for the competing risk of death, TBI was associated with almost 3 times the risk of dementia (HR 2.91; 95% CI 1.29, 5.68).ConclusionThis study demonstrates a marked increase in risk of dementia associated with TBI among middle-aged and elderly people with T1D. Given the complexity of self-care for individuals with T1D, and the comorbidities that predispose them to trauma and falls, future work is needed on interventions protecting brain health in this vulnerable population, which is now living to old age.

ObjectiveSevere hyperglycemia and hypoglycemia ("severe dysglycemia") are serious complications of type 1 diabetes (T1D). Depression has been associated with severe dysglycemia in type 2 diabetes but has not been thoroughly examined specifically in T1D. We evaluated bidirectional associations between depression and severe dysglycemia among older people with T1D.Research design and methodsWe abstracted depression and severe dysglycemia requiring emergency room visit or hospitalization from medical health records in 3,742 patients with T1D during the study period (1996-2015). Cox proportional hazards models estimated the associations between depression and severe dysglycemia in both directions, adjusting for demographics, micro- and macrovascular complications, and HbA1c.ResultsDuring the study period, 41% had depression and 376 (11%) and 641 (20%) had hyperglycemia and hypoglycemia, respectively. Depression was strongly associated with a 2.5-fold increased risk of severe hyperglycemic events (hazard ratio [HR] 2.47 [95% CI 2.00, 3.05]) and 89% increased risk of severe hypoglycemic events (HR 1.89 [95% CI 1.61, 2.22]). The association was strongest within the first 6 months (HRhyperglycemia 7.14 [95% CI 5.29, 9.63]; HRhypoglycemia 5.58 [95% CI 4.46, 6.99]) to 1 year (HRhyperglycemia 5.16 [95% CI 3.88, 6.88]; HRhypoglycemia 4.05 [95% CI 3.26, 5.04]) after depression diagnosis. In models specifying severe dysglycemia as the exposure, hyperglycemic and hypoglycemic events were associated with 143% (HR 2.43 [95% CI 2.03, 2.91]) and 74% (HR 1.75 [95% CI 1.49, 2.05]) increased risk of depression, respectively.ConclusionsDepression and severe dysglycemia are associated bidirectionally among patients with T1D. Depression greatly increases the risk of severe hypoglycemic and hyperglycemic events, particularly in the first 6 months to 1 year after diagnosis, and depression risk increases after severe dysglycemia episodes.

m6A and m6Am are two prevalent mRNA modifications which are target for removal by the fat mass and obesity gene FTO. Here the authors capture the differential profile of these two modifications in the liver of obese mice and identify dynamic translation regulation by the m6Am modification.

Summary: Background: As control efforts progress towards elimination, malaria is likely to become more spatially concentrated in few local areas. The purpose of this study was to quantify and characterise spatial heterogeneity in malaria transmission-intensity across highly endemic Indonesian Papua. Methods: We analysed individual-level malaria surveillance data for nearly half a million cases (2019–2020) reported in the Papua and West Papua provinces and adapted the Gini index approach to quantify spatial heterogeneity at the district and health-unit levels. In this context, high Gini index implies disproportionately distributed malaria cases across the region. We showed malaria incidence trends and the spatial and temporal distribution of sociodemographic characteristics and aetiological parasites among cases. Findings: While Papua province accounted for the majority of malaria cases reported in the region and had seen a rise in transmission since 2015, West Papua province had maintained a comparatively low incidence. We observed that Gini index estimates were high, particularly when the lower spatial scale of health units was evaluated. The Gini index appears to be inversely associated to annual parasite-incidence, as well as the proportions of vivax malaria, male sex, and adults. Interpretation: This study suggests that areas with varying levels of transmission-intensities exhibited distinct characteristics. Malaria was distributed in a markedly disproportionate manner throughout the region, emphasising the need for spatially targeted interventions. Periodic quantification and characterisation of risk heterogeneity at various spatial levels using routine malaria surveillance data may aid in tracking progress towards elimination and guiding evidence-informed prioritisation of resource allocation. Funding: The study was funded by the Australian Government Department of Foreign Affairs and Trade Indo-Pacific Centre for Health Security through the Strengthening Preparedness in the Asia-Pacific Region through Knowledge (SPARK) project.