Investigation of the Effect of Peptide p5 Targeting CDK5-p25 Hyperactivity on Munc18-1 (P67) Regulating Neuronal Exocytosis Using Molecular Simulations.

Munc18-1 is an SM (sec1/munc-like) family protein involved in vesicle fusion and neuronal exocytosis. Munc18-1 is known to regulate the exocytosis process by binding with closed- and open-state conformations of Syntaxin1, a protein belonging to the SNARE family established to be central to the exocytosis process. Our previous work studied peptide p5 as a promising drug candidate for CDK5-p25 complex, an Alzheimer's disease (AD) pathological target. Experimental in vivo and in vitro studies suggest that Munc18-1 promotes p5 to selectively inhibit the CDK5-p25 complex without affecting the endogenous CDK5 activity, a characteristic of remarkable therapeutic implications. In this paper, we identify several binding modes of p5 with Munc18-1 that could potentially affect the Munc18-1 binding with SNARE proteins and lead to off-target effects on neuronal communication using molecular dynamics simulations. Recent studies indicate that disruption of Munc18-1 function not only disrupts neurotransmitter release but also results in neurodegeneration, exhibiting clinical resemblance to other neurodegenerative conditions such as AD, causing diagnostic and treatment challenges. We characterize such interactions between p5 and Munc18-1, define the corresponding pharmacophores, and provide guidance for the in vitro validation of our findings to improve therapeutic efficacy and safety of p5.

Weight change and mental health status in a behavioral weight loss trial.

BACKGROUND: Obesity, depression, and anxiety often co-occur, but research on weight change and mental health status is limited. This analysis examined how the mental component score (MCS-12) from the Short Form health survey changed over 24 months in weight loss trial participants with vs. without treatment seeking for affective symptoms (TxASx) and by weight change quintiles. METHODS: Participants with complete data (n = 1163) were analyzed from enrollees in a cluster-randomized, behavioral weight loss trial in rural U.S. Midwestern primary care practices. Participants received a lifestyle intervention with different delivery models, including in-clinic individual, in-clinic group, or telephone group counseling visits. Participants were stratified by baseline TxASx status and 24-month weight change quintiles. Mixed models were used to estimate MCS-12 scores. RESULTS: There was a significant group-by-time interaction at the 24-month follow-up. The largest 0-24 month increase in MCS-12 scores (+5.3 points [12 %]) was observed in participants with TxASx who lost the most weight during the trial, while the largest decrease in MCS-12 scores (-1.8 points [-3 %]) was observed in participants without TxASx who gained the most weight (p < 0.001). LIMITATIONS: Notable limitations included self-reported mental health, the observational analytical design, and a largely homogenous source population, as well as the possibility of reverse causation biasing some findings. CONCLUSIONS: Mental health status generally improved, particularly among participants with TxASx who experienced significant weight loss. Those without TxASx who gained weight, however, had a decline in mental health status over 24 months. Replication of these findings is warranted.

Above and below-ground growth, accumulated dry matter and nitrogen remobilization of wheat (Triticum aestivum) genotypes grown in PVC tubes under well- and deficit-watered conditions.

The continuing decline in water resources under the ever-changing climate compels us to re-orient our focus to a more sustainable practice. This study investigates the performance of Triticum aestivum wheat genotypes viz. HD-2967, HD-3086, HD-3249, DBW-187, and HD-3226 under well- and deficit-watered conditions for their root-traits, biomass and nitrogen accumulation and remobilization, and water use efficiencies, grown in PVC-tubes. The genotypes HD-2967, HD-3086, HD-3249, DBW-187, and HD-3226 under well-watered (WW) resulted in 36, 35, 38, 33, and 42% more grain yield compared to deficit-watered (DW). Among the genotypes, HD-3249 had the highest grain yield under both well- and deficit-watered conditions. Compared to DW, the WW had 28%, 30%, and 28% greater root length, biomass, and root length density at flowering {102 days (d), Z61}, while among the genotypes, HD-3249 had relatively greater root-traits. At flowering (Z61) and maturity (132 d, Z89), genotypes under WW accumulated 30-46% and 30-53%, respectively greater shoot biomass over the DW. Furthermore, the shoot biomass remobilised for HD-2967, HD-3086, HD-3249, DBW-187, and HD-3226 under the WW was 32, 37, 39, 35, and 35% greater than the DW. The nitrogen partitioning to different plant parts at flowering (Z61) and maturity (Z89) was significantly greater with the WW than with DW. The total nitrogen- remobilized and contribution to grain-N under the WW was 55, 58, 52, 53, 58% and 9, 19, 15, 17, 17% greater than the DW for the genotypes HD-2967, HD-3086, HD-3249, DBW-187, and HD-3226. The irrigation water use efficiency (WUE) at flowering (Z61) was more under the deficit-watered, but the biomass and grain total WUE was improved with the well-watered condition. Hence, it is apparent that proper scheduling of irrigation and N applications, along with the adoption of a genotype suited to a particular environment, will result in better WUE and grain yields, along with better utilization of scarce resources.

Computational Study of the Allosteric Effects of p5 on CDK5-p25 Hyperactivity as Alternative Inhibitory Mechanisms in Neurodegeneration.

The cyclin-dependent kinase (CDK5) forms a stable complex with its activator p25, leading to the hyperphosphorylation of tau proteins and to the formation of plaques and tangles that are considered to be one of the typical causes of Alzheimer's disease (AD). Hence, the pathological CDK5-p25 complex is a promising therapeutic target for AD. Small peptides, obtained from the truncation of CDK5 physiological activator p35, have shown promise in inhibiting the pathological complex effectively while also crossing the blood-brain barrier. One such small 24-residue peptide, p5, has shown selective inhibition toward the pathological complex in vivo. Our previous research focused on the characterization of a computationally predicted CDK5-p5 binding mode and of its pharmacophore, which was consistent with competitive inhibition. In continuation of our previous work, herein, we investigate four additional binding modes to explore other possible mechanisms of interaction between CDK5 and p5. The quantitative description of the pharmacophore is consistent with both competitive and allosteric p5-induced inhibition mechanisms of CDK5-p25 pathology. The gained insights can direct further in vivo/in vitro tests and help design small peptides, linear or cyclic, or peptidomimetic compounds as adjuvants of orthosteric inhibitors or as part of a cocktail of drugs with enhanced effectiveness and lower side effects.

Dark clouds and silver linings: impact of COVID-19 on internet users' privacy.

OBJECTIVES: To examine the impact of coronavirus disease 2019 (COVID-19) pandemic on the extent of potential violations of Internet users' privacy. MATERIALS AND METHODS: We conducted a longitudinal study of the data sharing practices of the top 1000 websites in the United States between April 9 and August 27, 2020. We fitted a conditional latent growth curve model on the data to examine the longitudinal trajectory of the third-party data sharing over the 21 weeks period of the study and examine how website characteristics affect this trajectory. We denote websites that asked for permission before placing cookies on users' browsers as "privacy-respecting." RESULTS: As the weekly number of COVID-19 deaths increased by 1000, the average number of third parties increased by 0.26 (95% confidence interval [CI] 0.15-0.37) P < 0.001 units in the next week. This effect was more pronounced for websites with higher traffic as they increased their third parties by an additional 0.41 (95% CI 0.18-0.64); P < 0.001 units per week. However, privacy respecting websites that experienced a surge in traffic reduced their third parties by 1.01 (95% CI -2.01 to 0); P = 0.05 units per week in response to every 1000 COVID-19 deaths in the preceding week. DISCUSSION: While in general websites shared their users' data with more third parties as COVID-19 progressed in the United States, websites' expected traffic and respect for users' privacy significantly affect such trajectory. CONCLUSIONS: Attention should also be paid to the impact of the pandemic on elevating online privacy threats, and the variation in third-party tracking among different types of websites.

The role of eicosapentaenoic acid in reducing important cardiovascular events, including coronary revascularization.

The omega-3 fatty acid eicosapentaenoic acid has an important role in human health. The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) examined the prescription omega-3 fatty acid icosapent ethyl (IPE) in patients with established cardiovascular disease (CVD) or with diabetes plus additional CVD risk factors. The trial found a large reduction in CVD events, including significant reductions in CVD death, myocardial infarction, stroke, coronary revascularization, and hospitalization for unstable angina. These results led to the regulatory approval of IPE in a population similar to REDUCE-IT participants in the United States, Canada, United Kingdom, and the European Union. Moreover, multiple international guidelines have endorsed the use of IPE in such individuals. A secondary analysis of REDUCE-IT examined the endpoint of coronary artery revascularization. This analysis showed a significant reduction not only in coronary revascularization overall but also in elective, urgent, and emergent coronary revascularization. Additionally, IPE significantly reduced the need for both percutaneous coronary intervention and for coronary artery bypass graft surgery. Coronary imaging studies have demonstrated significant decreases in rates of plaque progression with IPE, with significant effects within 6-9 months. In parallel, experimental findings corroborate several effects of IPE that provide mechanisms that could contribute to the profound reductions in multiple types of ischemic events, including percutaneous and surgical coronary revascularization. Future trials should explore potential benefits of initiation of IPE at the time of revascularization in broader populations, potentially in conjunction with loading doses.

Predicting Type 2 Diabetes Using Logistic Regression and Machine Learning Approaches.

Diabetes mellitus is one of the most common human diseases worldwide and may cause several health-related complications. It is responsible for considerable morbidity, mortality, and economic loss. A timely diagnosis and prediction of this disease could provide patients with an opportunity to take the appropriate preventive and treatment strategies. To improve the understanding of risk factors, we predict type 2 diabetes for Pima Indian women utilizing a logistic regression model and decision tree-a machine learning algorithm. Our analysis finds five main predictors of type 2 diabetes: glucose, pregnancy, body mass index (BMI), diabetes pedigree function, and age. We further explore a classification tree to complement and validate our analysis. The six-fold classification tree indicates glucose, BMI, and age are important factors, while the ten-node tree implies glucose, BMI, pregnancy, diabetes pedigree function, and age as the significant predictors. Our preferred specification yields a prediction accuracy of 78.26% and a cross-validation error rate of 21.74%. We argue that our model can be applied to make a reasonable prediction of type 2 diabetes, and could potentially be used to complement existing preventive measures to curb the incidence of diabetes and reduce associated costs.

Affective disorders, weight change, and patient engagement in a rural behavioral weight loss trial.

BACKGROUND: Adults in rural areas have a higher prevalence of obesity and some mental health conditions. The degree to which mental health influences weight loss among rural residents remains unclear. This study evaluated changes in body weight, physical activity, diet, and program engagement outcomes in a cohort of participants with vs. without an affective disorder in a behavioral weight loss trial. METHODS: A sample of 1407 adults with obesity were recruited from rural U.S. primary care practices to participate in a weight loss trial. In this secondary analysis, participants were stratified by those with vs. without an affective disorder at baseline. Mixed models were used to estimate changes in outcomes over 24 months. RESULTS: One-third of participants (n = 468) had an affective disorder. After covariate adjustment, both groups experienced significant weight loss over 24 months, but weight loss was significantly less among those with an affective disorder at all follow-up times (all p's < 0.001; 24-month weight loss -2.7 ±â€¯0.4 vs. -4.8 ±â€¯0.3 kg). Compared to those without an affective disorder, participants with an affective disorder also had significantly less improvement in physical activity and fruit/vegetable consumption, lower attendance at weight loss sessions, and less engagement in setting weight loss goals and strategies. CONCLUSION: Participants with an affective disorder lost less body weight and less improvement in lifestyle measures over 24 months. These trends paralleled reduced engagement in critical intervention activities such as weight loss session attendance. Future interventions should consider additional methods to minimize disengagement in adults with underlying affective disorders.

Chronic pain and weight regain in a lifestyle modification trial.

OBJECTIVE: Obesity and chronic pain often co-occur and exert bidirectional influences on one another. How patients with obesity and chronic pain respond to weight loss treatments, however, remains unclear. This study evaluated body weight, physical activity, and diet outcomes in participants with and without chronic pain in a 2-year behavioral weight loss trial. METHODS: An analytical cohort of 397 adults was assembled from a Midwestern healthcare system that participated in the larger trial. Participants with chronic pain 1 year prior to, or during, the trial were identified using a validated medical records algorithm. Mixed models were used to estimate changes in outcomes over 24 months. RESULTS: One-third of participants (n = 130) had chronic pain. After adjustment for age, sex, body mass index, and trial arm, weight loss was similar in both groups at 6-months (-7.0 ± 0.8 kg with chronic pain vs. -7.7 ± 0.6 kg without). Participants with chronic pain had significantly less weight loss at 24-months relative to those without (-3.6 ± 0.5 vs. -5.2 ± 0.4 kg; p = 0.007). Physical activity, screen time, dietary fat, fruit/vegetable consumption, and sugar-sweetened beverage intake improved similarly in both groups over time. CONCLUSIONS: Participants with chronic pain lost ∼33% less weight over 2 years, which was driven by greater weight regain after the first 6 months. Future research should test tailored weight loss maintenance strategies for individuals with chronic pain.

Effect of Behavioral Therapy With In-Clinic or Telephone Group Visits vs In-Clinic Individual Visits on Weight Loss Among Patients With Obesity in Rural Clinical Practice: A Randomized Clinical Trial.

Importance: Rural populations have a higher prevalence of obesity and poor access to weight loss programs. Effective models for treating obesity in rural clinical practice are needed. Objective: To compare the Medicare Intensive Behavioral Therapy for Obesity fee-for-service model with 2 alternatives: in-clinic group visits based on a patient-centered medical home model and telephone-based group visits based on a disease management model. Design, Setting, and Participants: Cluster randomized trial conducted in 36 primary care practices in the rural Midwestern US. Inclusion criteria included age 20 to 75 years and body mass index of 30 to 45. Participants were enrolled from February 2016 to October 2017. Final follow-up occurred in December 2019. Interventions: All participants received a lifestyle intervention focused on diet, physical activity, and behavior change strategies. In the fee-for-service intervention (n = 473), practice-employed clinicians provided 15-minute in-clinic individual visits at a frequency similar to that reimbursed by Medicare (weekly for 1 month, biweekly for 5 months, and monthly thereafter). In the in-clinic group intervention (n = 468), practice-employed clinicians delivered group visits that were weekly for 3 months, biweekly for 3 months, and monthly thereafter. In the telephone group intervention (n = 466), patients received the same intervention as the in-clinic group intervention, but sessions were delivered remotely via conference calls by centralized staff. Main Outcomes and Measures: The primary outcome was weight change at 24 months. A minimum clinically important difference was defined as 2.75 kg. Results: Among 1407 participants (mean age, 54.7 [SD, 11.8] years; baseline body mass index, 36.7 [SD, 4.0]; 1081 [77%] women), 1220 (87%) completed the trial. Mean weight loss at 24 months was -4.4 kg (95% CI, -5.5 to -3.4 kg) in the in-clinic group intervention, -3.9 kg (95% CI, -5.0 to -2.9 kg) in the telephone group intervention, and -2.6 kg (95% CI, -3.6 to -1.5 kg) in the in-clinic individual intervention. Compared with the in-clinic individual intervention, the mean difference in weight change was -1.9 kg (97.5% CI, -3.5 to -0.2 kg; P = .01) for the in-clinic group intervention and -1.4 kg (97.5% CI, -3.0 to 0.3 kg; P = .06) for the telephone group intervention. Conclusions and Relevance: Among patients with obesity in rural primary care clinics, in-clinic group visits but not telephone-based group visits, compared with in-clinic individual visits, resulted in statistically significantly greater weight loss at 24 months. However, the differences were small in magnitude and of uncertain clinical importance. Trial Registration: ClinicalTrials.gov Identifier: NCT02456636.

Quantitative Electroencephalography in Patients With Depression and Epilepsy Spectrum Disorder and Its Correlation With Clinical Features of Depression.

OBJECTIVES: To determine the associations of epilepsy spectrum disorder (ESD) with brain insult and certain quantitative electroencephalographic (QEEG) and clinico-demographic parameters in patients with depression. METHODS: 21 right-handed patients aged 18 to 50 years with the diagnosis of depression and ESD (scored ≥70 in Iowa Interview for Partial seizure-like symptoms) were compared with 21 patients with depression but without ESD (scored <70) and 21 normal subjects with <3 positive scores on the 12-Item General Health Questionnaire. Their QEEG parameters such as power spectrum and coherence of five frequency bands in 11 regions were compared. RESULTS: Patients with ESD had more minor traumatic brain injury along with more severe and multiple depressive episodes. Patients with ESD had significantly higher beta1 power over all regions on the left scalp than did normal subjects. Patients with ESD had significantly higher beta2 power over the left central region than did patients with no ESD and normal subjects. CONCLUSIONS: For patients with severe recurrent depression, clinicians should systematically check for episodic partial seizure-like phenomena, especially when QEEG shows electrical disorganisation in the left side in those with mild traumatic brain injury.

Transforming Health Care through Digital Revolutions.

The Internet, which has spanned several networks in a broad range of domains, is having a significant impact on every aspect of our lives. The next generation of networks will utilize a wide variety of resources with significant sensing capabilities. Such networks will extend beyond physically linked computers to include multimodal-information from biological, cognitive, semantic, and social networks. This paradigm shift will involve symbiotic networks of smart medical devices, and smart phones or mobile personal computing and communication devices. These devices-and the network-will be constantly sensing, monitoring, and interpreting the environment; this is sometimes referred to as the Internet of Things (IoT). We are also witnessing considerable interest in the "Omics" paradigm, which can be viewed as the study of a domain in a massive scale, at different levels of abstraction, in an integrative manner. The IoT revolution, combined with the Omics revolution (genomics and socio-omics or social networks) and artificial intelligence resurgence, will have significant implications for the way health care is delivered in the United States. After discussing a vision for health care in the future, we introduce the P9 health care concept, followed by a discussion of a framework for smart health care. Then, we present a case study and research directions, followed by examples of ongoing work at the National Institute of Standards and Technology (NIST).

Artificial Intelligence and Digital Tools: Future of Diabetes Care.

Diabetes mellitus has become a global threat, especially in the emerging economies. In the United States, there are about 24 million people with diabetes mellitus. Diabetes represents a trove of physiologic and sociologic data that are only superficially understood by the health care system. Artificial intelligence can address many problems posed by the prevalence of diabetes mellitus and the impact of diabetes on individual and societal health. We provide a brief overview of artificial intelligence and discuss case studies that illustrate how artificial intelligence can enhance diabetes care.

(How) did attack advertisements increase Affordable Care Act enrollments?

We examine the effects of exposure to negative information in attack advertisements in the context of Affordable Care Act (ACA) and Common Core (CC) education standards and show that they lead to an increase in the ACA enrollments and support of the CC standards. To explain this effect, we rely on the knowledge-gap theory and show that individuals who were exposed to more attack advertisements were also more likely to independently seek information, become more knowledgeable, and consequently support these subjects. In addition to an observational study, to test our hypotheses on the link between exposure to negative information, curiosity, and shifts in knowledge and support levels, we design and conduct a randomized experiment using a sample of 300 unique individuals. Our multi-methods research contributes to marketing literature by documenting a rare occasion in which exposure to attack advertisements leads to increased demand and unveiling the mechanisms through which this effect takes place.

Attitudes of EAPD members toward using the "knee-to-knee" position.

AIM: This survey assessed the attitude of paediatric dental EAPD members toward using "knee-to-knee" positioning for dental examinations and minor procedures in infants and toddlers. METHODS: An anonymous electronic online questionnaire was distributed among EAPD members. The survey consisted of 12 questions and assessed demographic characteristics, professional experience and attitudes toward the use of the "knee-to-knee" position. RESULTS: Of the 162 respondents, 148 (91%) reported using "knee-to-knee" positioning for dental examination. In addition, 97 (63%) reported performing other procedures in the "knee-to-knee" position. Fluoride application and oral hygiene instructions were the most common procedures performed in the "knee-to-knee" position. CONCLUSIONS: Most of the paediatric dentists who responded to this survey reported performing dental examinations in toddlers up to 2 years old using the "knee-to-knee" position. Majority of respondents also used this position to instruct parents regarding oral hygiene and to apply fluoride varnish.

Dentists, dental hygienists and dental students' knowledge regarding recommended fluoride concentration in toothpaste for children.

PURPOSE: The objective of this study was to assess the knowledge of dentists, dental hygienists and dental students regarding the Israeli Ministry of Health guidelines for using fluoridated toothpaste. MATERIALS AND METHODS: An anonymous questionnaire was distributed to dentists, dental hygienists, and dental students in their final years at the Hebrew University-Hadassah School of Dental Medicine. Participants were queried regarding their knowledge of Ministry of Health fluoride concentration guidelines in toothpaste by the following age categories: under 2 years, 2-6 years, and above 6 years. RESULTS: Thirty-two paediatric dentists (specialists and residents), 63 general dentists, 68 dental hygienists, and 69 students responded to the survey. Analysis of survey respondent's knowledge of Ministry of Health fluoride toothpaste guidelines by age group found that 81%, 75% and 88% of participants selected a fluoride concentration within the recommended range for those under 2 years, 2-6 years and greater than 6 years, respectively. Only 58% of respondents were aware of the recommended fluoride concentration for all three age groups. Among respondents who answered all three questions, there was a significant association between correctly answering the fluoride questions and respondent's profession (P = 0.026), with a larger percentage of paediatric dentist (76%) and dental students (66%) correctly answering all three questions. CONCLUSIONS: Israeli dental practitioners should be educated about the Israeli Ministry of Health fluoride concentrations in toothpaste guidelines. The guidelines should be emphasised at annual meetings and in continuing education courses.

Severity of domestic abuse and its relationship with distress tolerance and medication adherence in women with mental illness in South India.

Domestic abuse is prevalent in all strata of society and has been associated with various mental health problems. However, the severity of abuse in women with mental illness has not been studied much. The amount of distress experienced often depends on the severity of domestic abuse. Ability to tolerate distress may buffer the effect of abuse-this determines the perceived level of abuse. Both the severity of abuse and distress tolerance may in turn determine adherence behaviour towards treatment in mentally ill women. There is a paucity of research examining these variables. Hence this study was undertaken to examine the severity of abuse and distress tolerance and their relationship with medication adherence in women with mental illness. This study took place on an outpatient basis in the department of psychiatry at a tertiary care centre in South India. One hundred women with a mental illness currently in remission for at least two months -living in the community with family members after an episode of mental illness- were consecutively recruited by purposive sampling method after obtaining an informed consent. Due to issues related to reliability, patients with a diagnosis of mental retardation or dementia or psychotic symptoms were not included. All participants were initially assessed using socio-demographic and clinical forms. The severity of abuse was assessed with Composite Abuse Scale (CAS) and the level of distress tolerance was evaluated with Distress Tolerance Scale (DTS). Medication adherence status was assessed with the commonly used Morisky Medication Adherence Scale (MMAS). There was a high level of abuse (mean 20.33, SD=20.55) and distress tolerance (mean 26.80, SD=12.07) in this sample as compared to those in general population. Scores in domestic abuse had a significant positive association with Tolerance (p=0.001) and Absorption (p=0.014) subscales of distress tolerance. Scores in domestic abuse had no statistically significant association with level of medication adherence. With the findings of this study, it can be concluded that women with mental illness face considerable level of domestic abuse and they have a higher capacity to tolerate distress. Severity of domestic abuse is inversely associated with their perceived ability to tolerate emotional distress; and positively associated with the level of attention being absorbed by negative emotions. The study was constrained by its cross-sectional design and small sample size, and further replication of data is needed with bigger sample size and control group.

Oncological benefits of postoperative radiotherapy in node-negative early stage cancer of the oral cavity with isolated perineural invasion.

Perineural invasion has been widely regarded as a poor prognostic factor in cancer of the oral cavity, but adjuvant treatment based only on this is still debatable. We have made an effort to address the question in a retrospective analysis of data from 2009-15 of patients with early node-negative cancers of the oral cavity. Patients with perineural invasion were divided into those who were treated with radiotherapy and those who were not. The records of a total of 169 patients were analysed, and 118 were given adjuvant radiotherapy and 51 were not. The median (range) duration of follow up was 45 (26-86) months. Of 169 patients, 47 (28%) developed recurrence, 28 in the treated, and 19 in the untreated, group. There was a significant disease-free survival benefit for adjuvant treatment (p = 0.047) but no overall survival benefit (p = 0.54). We conclude that adjuvant radiotherapy should be considered for patients with perineural invasion, even in early cancers of the oral cavity.