Nevin Manimala

J Affect Disord. 2021 Sep 24;296:514-521. doi: 10.1016/j.jad.2021.09.059. Online ahead of print.

ABSTRACT

OBJECTIVE: To compare the mortality risk due to covid-19 with death due to overdose in British Columbia, Canada. The opioid epidemic was declared a public health emergency in 2016.

METHODS: Mortality risk was calculated in micromorts with covid-19 data for January-October 2020, derived from the BC center for Disease Control, and illicit drug toxicity deaths for January 2010-September 2020, derived from the BC Coroners Service. Age-stratified covid-19 incidence and deaths per 100,000 population and age-stratified illicit drug toxicity death rates per 100,000 population were calculated. A micromort is a unit of risk equivalent to a one-in-a-million chance of death.

RESULTS: During the covid-19 pandemic, illicit drug toxicity deaths reached 1.0 micromorts per day, representing an increase of 0.5 micromorts per day relative to 2019 rates. In comparison, covid-19 mortality risk was 0.05 micromorts per day among individuals from the general population living in British Columbia and 21.1 micromorts per day among those infected with covid-19. Covid-related mortality risk was significantly lower among individuals aged <60 years, relative to older adults, whereas drug toxicity-related mortality was highest for individuals aged 30-59 years.

CONCLUSIONS: The mortality associated with covid-19 is apparent and distributed unevenly across subpopulations. The mortality due to overdose has increased during covid-19 and exceeds mortality due to covid-19. Our results instantiate the triple threat caused by covid-19 (i.e., public health crisis, economic crisis and mental health crisis) and quantitatively highlight the externality of increased mortality due to deaths of despair in response to public health efforts to reduce covid-related mortality.

PMID:34656039 | DOI:10.1016/j.jad.2021.09.059

Clin Nutr. 2021 Sep 4;40(11):5494-5499. doi: 10.1016/j.clnu.2021.08.022. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Dietary intake of several specific macronutrients has been linked to risk of coronary heart disease (CHD). However, these associations may depend on overall macronutrient composition rather than effects of one single macronutrient. Therefore, we aimed to investigate the associations of macronutrient intake and CHD and its related risk factors, by taking into account different macronutrient substitutions.

METHODS: This study was performed among 5873 participants from the Rotterdam Study, a population-based cohort study. Macronutrient intake was measured using a semi-quantitative food-frequency questionnaire. Cox proportional hazard regression analyses were used to examine associations between intakes of macronutrients and CHD incidence; and linear regression analyses were used to examine associations with the related risk factors, including triglycerides, total, high-density and low-density cholesterol levels, body mass index (BMI), fat mass index (FMI), and fat-free mass index (FFMI).

RESULTS: We documented 669 CHD cases during 74,776 person-years of follow-up. In multivariable-adjusted models we observed no statistically significant associations between macronutrients and CHD incidence. Although non-significant, a higher plant protein intake tended to be associated with a lower risk of CHD when consumed at the expense of any of the other macronutrients. This association was strongest when 5% of energy (5 E%) of plant protein was consumed at the expense of animal protein (HR = 0.61; 95% CI 0.31, 1,21), mono- and disaccharides (HR = 0.62; 95% CI 0.29, 1.35) or saturated fat (HR = 0.61; 95% CI 0.31, 1.20). No consistent associations were observed for risk factors related to CHD.

CONCLUSIONS: Macronutrient composition was not significantly associated with CHD incidence or cardiometabolic risk factors in an adult population. Future studies should further investigate food sources and quality of macronutrients.

PMID:34656031 | DOI:10.1016/j.clnu.2021.08.022

Clin Nutr. 2021 Oct 1;40(11):5482-5485. doi: 10.1016/j.clnu.2021.09.040. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Immune modulating nutrition (IMN) has been shown to reduce postoperative infectious complications and length of stay in patients with gastrointestinal cancer. Two studies of IMN in patients undergoing surgery for head and neck cancer also suggested that this treatment might improve long-term survival and progression-free survival. In the present study, we analysed follow-up data from our previous randomised controlled trial of IMN, in patients undergoing surgery for oesophagogastric and pancreaticobiliary cancer, in order to evaluate the long-term impact on survival of postoperative IMN versus an isocaloric, isonitrogenous control feed.

METHODS: This study included patients undergoing surgery for cancers of the pancreas, oesophagus and stomach, who had been randomised in a double-blind manner to receive postoperative jejunostomy feeding with IMN (Stresson, Nutricia Ltd.) or an isonitrogenous, isocaloric feed (Nutrison High Protein, Nutricia) for 10-15 days. The primary outcome was long-term overall survival.

RESULTS: There was complete follow-up for all 108 patients, with 54 patients randomised to each group. There were no statistically significant differences between groups by demographics [(age, p = 0.63), sex (p = 0.49) or site of cancer (p = 0.25)]. 30-day mortality was 11.1% in both groups. Mortality in the intervention group was 13%, 31.5%, 70.4%, 85.2%, 88.9%, and 96.3% at 90 days, and 1, 5, 10, 15 and 20 years respectively. Corresponding mortality in the control group was 14.8%, 35.2%, 68.6%, 79.6%, 85.2% and 98.1% (p > 0.05 for all comparisons).

CONCLUSION: Early postoperative feeding with arginine-enriched IMN had no impact on long-term survival in patients undergoing surgery for oesophagogastric and pancreaticobiliary cancer.

PMID:34656029 | DOI:10.1016/j.clnu.2021.09.040

Gait Posture. 2021 Oct 11;91:79-85. doi: 10.1016/j.gaitpost.2021.10.010. Online ahead of print.

ABSTRACT

BACKGROUND: Walking adaptability is an obvious manifestation of Parkinson’s disease (PD). Augmented reality technologies such as interactive walkways may improve walking adaptability in patients with Parkinson’s Disease (PWP).

RESEARCH QUESTION: How effective is C-Mill gait adaptability training in the early and middle stages of PD for improving walking adaptability in motor subtypes of the disease?

METHODS: Fifty-two patients with early- or middle-stage PD were divided into two groups according to motor subtype (postural instability/gait disorder [PIGD] and non-PIGD) and received 7 days of training (0.5 h every day, 2 h after medication) on an augmented reality treadmill with built-in visual targets and obstacles. Functional assessments were performed before and after intervention, including posture control and walking, C-gait assessment, and participant experience. The Parkinson Disease Quality of Life questionnaire was administered at 3-month follow-up.

RESULTS: Both the PIGD (n = 29) and non-PIGD (n = 23) groups showed improved tandem walking, obstacle avoidance, and overall score in C-gait assessment and Timed Up and Go test after C-Mill training. However, there were no differences between the two groups. The PIGD group showed improvement in visually guided stepping and Speed adaptations, whereas the non-PIGD group did not improve. The non-PIGD group reported they could complete the training with less exertion after the intervention and at the 3-month follow-up, these patients reported improvement in quality of life.

SIGNIFICANCE: C-Mill gait adaptation training in the early and middle stages of PD improves walking adaptability in both motor subtypes. Cue strategies are the probable mechanism and may decrease fall risk after training. There was no difference between the groups in the improvements of perceived exertion and quality of life at follow-up. Although PIGD patients showed statistic improvements in visually guided stepping compared with non-PIGD patients, but the difference was not likely to be clinically meaningful. Specific effects of C-mill training for different types of PD were not observed in our study.

PMID:34656008 | DOI:10.1016/j.gaitpost.2021.10.010

J Infect Public Health. 2021 Oct 7;14(11):1701-1707. doi: 10.1016/j.jiph.2021.10.002. Online ahead of print.

ABSTRACT

BACKGROUND: Dengue fever is one of the major viral diseases worldwide transmitted by mosquitoes. Depending on the severity of disease it can range from mild fever to severe fatal cases. Rapid decline of platelet levels is one of indicators of clinical worsening. The role of viral factors in dengue pathogenesis and correlation with clinical and laboratory parameters remain unclear.

METHODS: Between September 2017 to December 2018, 102 dengue confirmed paediatric cases were analysed for various viral and host parameters. Based on symptoms, they were classified into dengue without warning signs (DOS), dengue with warning signs (DWS) and severe dengue (SD) as per 2009 WHO classification. Quantitative analysis of NS1, IgM and IgG in were done by ELISA. IgM/IgG ratio revealed primary or secondary dengue infection. Serotyping of virus in serum was done by nested multiplex RT-PCR. Viral load (VL) was determined by quantitative real time polymerase chain reaction. Association between VL and NS1 in patient sera with clinical and laboratory parameters was statistically analysed.

RESULTS: It was found that disease severity (as per 2009 WHO classification) significantly associated with secondary dengue infection. DENV3 was found to be the only serotype detected. The present study reports neither NS1 nor VL significantly associated with disease severity or type of infection (primary or secondary). However, VL positively correlated with haematocrit (p < 0.05). Viral load above 10⁶ copies/mL was found in 61% of patients. Further, high viral load (>10⁶ copies/mL) negatively correlated with platelet levels (p < 0.05).

CONCLUSION: Thus, viral load could be an important predictive parameter in dengue related severe symptoms like thrombocytopenia and elevated hematocrit when it goes above a certain threshold (>10⁶ copies/ mL).

PMID:34655984 | DOI:10.1016/j.jiph.2021.10.002

Neurobiol Aging. 2021 Sep 17;109:64-77. doi: 10.1016/j.neurobiolaging.2021.09.013. Online ahead of print.

ABSTRACT

In Alzheimer disease, Tau pathology is thought to propagate from cell to cell throughout interconnected brain areas. However, the forms of Tau released into the brain interstitial fluid (ISF) in vivo during the development of Tauopathy and their pathological relevance remain unclear. Combining in vivo microdialysis and biochemical analysis, we find that in Tau transgenic mice, human Tau (hTau) present in brain ISF is truncated and comprises at least 10 distinct fragments spanning the entire Tau protein. The fragmentation pattern is similar across different Tau transgenic models, pathological stages and brain areas. ISF hTau concentration decreases during Tauopathy progression, while its phosphorylation increases. ISF from mice with established Tauopathy induces Tau aggregation in HEK293-Tau biosensor cells. Notably, immunodepletion of ISF phosphorylated Tau, but not Tau fragments, significantly reduces its ability to seed Tau aggregation and only a fraction of Tau, separated by ultracentrifugation, is seeding-competent. These results indicate that ISF seeding competence is driven by a small subset of Tau, which potentially contribute to the propagation of Tau pathology.

PMID:34655982 | DOI:10.1016/j.neurobiolaging.2021.09.013

Spectrochim Acta A Mol Biomol Spectrosc. 2021 Oct 9;267(Pt 2):120471. doi: 10.1016/j.saa.2021.120471. Online ahead of print.

ABSTRACT

The decarboxylation of Δ9-tetrahydrocannabinolic acid (THCA) plays pivotal role in the potency of medical cannabis and its extracts. Our present work aims to draw attention to mid-infrared (MIR) spectroscopy to in-situ monitor and decipher the THCA decarboxylation reaction in the solid state. The initial TG/DTG curves of THCA, for a first time, outlined the solid-solid decarboxylation dynamics, defined the endpoint of the process and the temperature of the maximal conversion rate, which aided in the design of the further IR experiment. Temperature controlled IR spectroscopy experiments were performed on both THCA standard and cannabis flower by providing detailed band assignment and conducting spectra-structure correlations, based on the concept of functional groups vibrations. Moreover, a multivariate statistical analysis was employed to address the spectral regions of utmost importance for the THCA → THC interconversion process. The principal component analysis model was reduced to two PCs, where PC1 explained 94.76% and 98.21% of the total spectral variations in the THCA standard and in the plant sample, respectively. The PC1 plot score of the THCA standard, as a function of the temperature, neatly complemented to the TG/DTG curves and enabled determination of rate constants for the decarboxylation reaction undertaken on several selected temperatures. The predictive capability of MIR was further demonstrated with PLS (R2X = 0.99, R2Y = 0.994 and Q2 = 0.992) using thermally treated flower samples that covered broad range of THCA/THC content. Consequently, a progress in elucidation of kinetic models of THCA decarboxylation in terms of fitting the experimental data for both, solid state standard substance and a plant flower, was achieved. The results open the horizon to promote an appropriate process analytical technology (PAT) in the outgrowing medical cannabis industry.

PMID:34655978 | DOI:10.1016/j.saa.2021.120471

Mult Scler Relat Disord. 2021 Oct 4;56:103311. doi: 10.1016/j.msard.2021.103311. Online ahead of print.

ABSTRACT

BACKGROUND: Obesity is linked to increased risk of multiple sclerosis (MS) and worsening disease severity. Recent experimental and clinical data indicates that adipokines are involved in regulating immune response and serve as cross talk between immune and neural system. Dimethyl fumarate (DMF) is an oral MS medication with unknown mechanism of action. It upregulates the nuclear factor E2-related factor 2 (Nrf2) pathway, a pathway for adipocyte differentiation. To determine a possible relationship between treatment with dimethyl fumarate, serum adipokine profiles and treatment response in patients with MS, we conducted an observational cohort study and measured serum adipokine and Vitamin D levels before and after treatment with DMF and examined their association with treatment response.

METHODS: We identified patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women’s Hospital (CLIMB) study who were treated with dimethyl fumarate and had available serum samples. Longitudinal pre-treatment and on-treatment samples were available in 23 patients. Cross-sectional on-treatment samples were available in 91 patients, who were classified into DMF responders and non-responders based on radiologic and clinical relapse activity or disability progression. We measured serum leptin, adiponectin, resistin, ghrelin, fatty acid binding protein-4 (FABP-4) and-5 (FABP-5), vitamins D2 and D3. Statistical analysis was performed with paired t-tests, Wilcoxon signed-rank and Mann-Whitney U tests.

RESULTS: After treatment with DMF, serum adiponectin levels significantly increased, whereas FABP-4 levels significantly decreased compared to baseline levels, without a statistically significant change in the patients’ BMI. Ghrelin levels were insignificantly lower post-treatment. FABP-4 levels were significantly higher in DMF responders compared to non-responders. This effect was sex-specific, with higher FABP4 levels associated with treatment response in males, but not females.

CONCLUSION: DMF treatment is associated with significant changes in serum adipokine levels, primarily adiponectin and FABP-4. Sex may affect the association between FABP-4 and treatment response.

PMID:34655958 | DOI:10.1016/j.msard.2021.103311

Drug Alcohol Depend. 2021 Sep 28;229(Pt B):109111. doi: 10.1016/j.drugalcdep.2021.109111. Online ahead of print.

ABSTRACT

BACKGROUND: An efficacious pharmacotherapy for cannabis use disorder (CUD) has yet to be established. This study preliminarily evaluated the safety and efficacy of varenicline for CUD in a proof-of-concept clinical trial.

METHODS: Participants in this 6-week randomized, placebo-controlled pilot trial received either varenicline (n = 35) or placebo (n = 37), added to a brief motivational enhancement therapy intervention. Outcomes included cannabis withdrawal, cannabis abstinence, urine cannabinoid levels, percent cannabis use days, and cannabis sessions per day.

RESULTS: Both treatment groups noted significant decreases in self-reported cannabis withdrawal, percentage of days used, and use sessions per day during treatment compared to baseline. While this pilot trial was not powered to detect statistically significant between-group differences, participants randomized to varenicline evidenced numerically greater rates of self-reported abstinence at the final study visit [Week 6 intent-to-treat (ITT): Varenicline: 17.1% vs. Placebo: 5.4%; RR = 3.2 (95% CI: 0.7,14.7)]. End-of-treatment urine creatinine corrected cannabinoid levels were numerically lower in the varenicline group and higher in the placebo group compared to baseline [Change from baseline: Varenicline -1.7 ng/mg (95% CI: -4.1,0.8) vs. Placebo: 1.9 ng/mg (95% CI: -0.4,4.3); Δ = 3.5 (95% CI: 0.1,6.9)]. Adverse events related to study treatment did not reveal new safety signals.

CONCLUSIONS: Findings support the feasibility of conducting clinical trials of varenicline as a candidate pharmacotherapy for CUD, and indicate that a full-scale efficacy trial, powered based on effect sizes and variability yielded in this study, is warranted.

PMID:34655945 | DOI:10.1016/j.drugalcdep.2021.109111

J Mech Behav Biomed Mater. 2021 Sep 30;125:104866. doi: 10.1016/j.jmbbm.2021.104866. Online ahead of print.

ABSTRACT

Accurate biomechanical properties of the human cranial dura mater are paramount for computational head models, artificial graft developments and biomechanical basic research. Yet, it is unclear whether areas of the dura containing meningeal vessels biomechanically differ from avascular areas. Here, 244 dura mater samples with or without vessels from 32 cadavers were tested in a quasi-static uniaxial tensile testing setup. The thicknesses of the meningeal and periosteal dura in vascular and avascular areas were histologically investigated in 36 samples using van Gieson staining. The elastic modulus of 112 MPa from dura samples containing vessels running transversely was significantly lower than samples with vessels running longitudinally (151 MPa; p < 0.001). The ultimate tensile strength of dura samples with transversely running vessels (11.1 MPa) was significantly lower in comparison to both avascular samples (14.9 MPa; p < 0.001) and samples with a longitudinally running vessel (15.0 MPa; p < 0.001). The maximum force of dura samples with longitudinally running vessels was 37 N (p < 0.001), this was significantly higher compared to the other groups which were 23 N (p < 0.001). The meningeal and periosteal dura layer thicknesses were not statistically different in avascular areas (p > 0.222). However, around the vessels, the meningeal dura layer was significantly thicker compared to the periosteal layer (p ≤ 0.019). The sum of the meningeal and periosteal layers was similar between vascular and avascular areas (p ≥ 0.071). Vascular areas of the human cranial dura mater withstand the same forces as avascular areas when being stretched. When stretched along the vessel, the dura-vessel composite can withstand even higher tensile forces compared to avascular areas. Vascular areas of the cranial dura mater seem to be similar when compared to avascular areas making their separate simulation in computational models non-essential.

PMID:34655943 | DOI:10.1016/j.jmbbm.2021.104866