bluuebunny/crossref_metadata_2025 huggingface dataset:
Daily nonaccidental mortality associated with short-term PM2.5 exposures in Delhi, India
Authors: Krishna Bhargav , Mandal Siddhartha , Madhipatla Kishore , Reddy K. Srinath , Prabhakaran Dorairaj , Schwartz Joel D.
Published: August 2021

Background:

Ambient particulate matter of aerodynamic diameter less than 2.5 microns PM2.5) levels in Delhi routinely exceed World Health Organization (WHO) guidelines and Indian National Ambient Air Quality Standards (NAAQS) for acceptable levels of daily exposure. Only a handful of studies have examined the short-term mortality effects of PM in India, with none from Delhi examining the contribution of PM2.5.

Objectives:

We aimed to analyze the association between short-term PM2.5 exposures and daily nonaccidental mortality in Delhi, India.

Methods:

Using generalized additive Poisson regression models, we examined the association between daily PM2.5 exposures and nonaccidental mortality between June 2010 and December 2016. Daily exposures to PM2.5 were estimated using an ensemble averaging technique developed by our research group, and mortality data were obtained from the Municipal Corporations of Delhi and the New Delhi Municipal Council.

Results:

Median exposures to PM2.5 were 91.1 µg/m3 (interquartile range = 68.9, 126.2), with minimum and maximum exposures of 21.4 µg/m3 and 276.7 µg/m3, respectively. Total nonaccidental deaths recorded in Delhi during the study period were 700,512. Each 25 µg/m3 increment in exposure was associated with a 0.8% (95% confidence intervals [CI] = 0.3, 1.3%) increase in daily nonaccidental mortality in the study population and a 1.5% (95% CI = 0.8, 2.2%) increase in mortality among those with 60 years of age or over. The exposure-response relationship was nonlinear in nature, with relative risk rising rapidly before tapering off above 125 µg/m3. Meeting WHO guidelines for acceptable levels of exposure over the study period would have likely averted 17,526 (95% CI = 6,837, 25,589) premature deaths, with older and male populations disproportionately affected.

Discussion:

This study provides robust evidence of the impact of short-term exposure to PM2.5 on nonaccidental mortality with important considerations for various stakeholders including policymakers and physicians. Most importantly, we find that reducing exposures significantly below current levels would substantially decrease the mortality burden associated with PM2.5.
Effect of Ginsenoside Rh1 on Proliferation, Apoptosis, and Oxidative Stress in Vascular Endothelial Cells by Regulation of the Nuclear Erythroid 2-related Factor-2/Heme Oxygenase-1 Signaling Pathway
Authors: Xu Hai , Jiang Yicheng , Yu Kun , Zhang Xiwen , Shi Yafei
Published: August 2021

This study aimed to investigate the role of ginsenoside Rh1 in regulating the proliferation, apoptosis, and oxidative stress in oxidized low-density lipoprotein (ox-LDL)-treated human vascular endothelial cells (VECs) and the underlying mechanisms. VECs were treated with ox-LDL to generate an in vitro atherosclerosis model. The effect of ginsenoside Rh1 on cell viability and proliferation was examined by MTT and colony formation assays, respectively, and cell apoptosis was determined by flow cytometry and transferase dUTP nick end-labeling assay. The levels of reactive oxygen species, malondialdehyde, and superoxide dismutase activity were detected using biological assays. Finally, the effect of ginsenoside Rh1 on the levels of BAX and BCL-2 and the nuclear erythroid 2-related factor-2/heme oxygenase (HO)-1 signaling pathway was determined by quantitative real-time polymerase chain reaction and western blot assays. Treatment with ginsenoside Rh1 significantly increased the proliferation and decreased the apoptosis of ox-LDL–treated VECs in a dose-dependent manner. Moreover, ginsenoside Rh1 also relieved oxidative stress in ox-LDL–treated VECs by activating the Nrf2/HO-1 signaling pathway. Thus, ginsenoside Rh1 affects the proliferation, apoptosis, and oxidative stress in ox-LDL–treated VECs by activating the Nrf2/HO-1 signaling pathway.
Healthy Lifestyle and Complementary and Alternative Medicine
Authors: Canales-Ronda Pedro , Küster-Boluda Inés , Vila-López Natalia
Published: August 2021

Having a healthy lifestyle is one of the main personal goals, and multiple behaviors can be used to achieve this goal. However, people do not always develop appropriate health behaviors. One of the consumption alternatives is the use of complementary and alternative medicine (CAM), which has been increasing significantly in recent years, although not always adequately. This study aimed to determine whether CAM use is associated with a healthy lifestyle in Spanish adults. To achieve these objectives, 2486 adults were interviewed as part of the 2018 Barometer of the Centro de Investigaciones Sociológicas about their lifestyle and CAM use. The findings show a relationship between healthy lifestyle and CAM use; our study shows that there are significant differences between people with healthier lifestyles and those with less healthy lifestyles in some of CAM use, such as herbal medicine, meditation, yoga, nutritional therapies, and acupuncture.
OUTCOMES IN PATIENTS RESUMING INTRAVITREAL ANTI–VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY FOLLOWING TREATMENT DELAY DURING THE CORONAVIRUS-19 PANDEMIC
Authors: Rush Ryan B. , Rush Sloan W.
Published: August 2021

Purpose:

To evaluate the outcomes of delay in care secondary to the coronavirus pandemic in patients requiring intravitreal anti–vascular endothelial growth factor therapy.

Methods:

A retrospective review was performed, and subjects were divided into two groups: 1) a study group of patients who experienced a treatment delay of ≥6 weeks from the intended follow-up during the coronavirus pandemic and resumed treatment with ≥2 anti–vascular endothelial growth factor injections over 6 months following treatment delay, and 2) a control group of patients who received regular care throughout the coronavirus pandemic.

Results:

Totally, 234 subjects were analyzed. The mean treatment delay from the intended follow-up in the study group was 11.8 (±4.0) weeks. Visual acuity and central macular thickness worsened from baseline to 6 months after resuming anti–vascular endothelial growth factor therapy in the study group (P < 0.0001 and P = 0.001, respectively). Visual acuity and central macular thickness were better in the control group compared with the study group at the end of the 6-month study period (P < 0.0001 for both).

Conclusion:

Treatment delay in subjects undergoing anti–vascular endothelial growth factor therapy for retina disease during the coronavirus pandemic had worse visual and anatomical outcomes despite reinitiating treatment over 6 months compared with a control group, suggesting irreversibility and permanence of outcomes.
Microscope-Integrated Intraoperative Optical Coherence Tomography–Guided Big-Bubble Deep Anterior Lamellar Keratoplasty
Authors: Santorum Paolo , Yu Angeli Christy , Bertelli Enrico , Busin Massimo
Published: August 2021

Purpose:

The purpose of this study was to evaluate the feasibility of microscope-integrated intraoperative optical coherence tomography (OCT) for real-time quantitative analysis of surgical planes in big-bubble deep anterior lamellar keratoplasty (DALK).

Methods:

In this interventional case series, intraoperative OCT-guided big-bubble DALK was performed in 16 consecutive eyes of 16 patients with keratoconus. Trephination depth was measured using the intraoperative OCT caliper tool. Aiming for a depth within 150 μm from the endothelial surface, the trephination groove was extended to a deeper plane using a 15-degree blade. Repeat OCT scans were taken to measure residual stromal thickness before insertion of the DALK probe from the bottom of the extended trephination. Caliper measurements, success rate of pneumatic dissection, and complications were recorded.

Results:

After trephination, residual stromal thickness exceeded 150 μm in all eyes and averaged 257.1 ± 42.5 μm. In each case, the initial trephination groove was extended to a depth within 150 μm from the endothelial surface (118.9 ± 27.1 μm). Big-bubble formation was achieved in 12 eyes (75%). Type 1 bubble was obtained in 11 eyes. Perforation requiring conversion to penetrating keratoplasty occurred in 4 eyes during insertion of the cannula into a residual stromal bed of <100 μm (n = 2; 63 and 75 μm) or layer-by-layer dissection (n = 2).

Conclusions:

Quantitative analysis of intraoperative OCT scans can be used to assist decision-making on whether to proceed with pneumatic dissection or extend the trephination groove, thereby facilitating insertion of the injection cannula at the desired stromal depth.
Trends in Early Graft Failure Leading to Regrafting After Endothelial Keratoplasty in the United States
Authors: Fliotsos Michael J. , Campbell Jack A. , Li Ximin , Engstrom Marie B. , Stoeger Christopher G. , McClory Cathy , Titus Michael S. , Johnson Patrick , Johnston Kara B. , Fischer Tim , Brooks Lisa K. , Montoya Monty M. , Glasser David B. , Akpek Esen Karamursel , Srikumaran Divya
Published: August 2021

Purpose:

The purpose of this study was to report trends in the prevalence of early graft failure after endothelial keratoplasty in the United States.

Methods:

Descemet membrane endothelial keratoplasty (DMEK) and Descemet stripping automated endothelial keratoplasty (DSAEK) graft volumes were collected from records maintained by 6 major eye banks in the United States from January 1, 2013, to December 31, 2018. The prevalence and presumed cause of early graft failures (defined as a graft with persistent edema or regrafted within 8 weeks after keratoplasty) each year were sourced from surgeon-reported adverse events. Failed graft cases from the 3 eye banks were compared with nonfailures at the donor and recipient levels to perform subset analysis of factors associated with early graft failure.

Results:

A total of 51,887 endothelial keratoplasty tissues were distributed during the study period; 72% were DSAEK grafts. The total number of early graft failures reported was 168 of 14,284 (1.18%) for DMEK and 322 of 37,603 (0.86%) for DSAEK. Early DMEK failures decreased from 2013 (7.69%) to 2018 (0.68%). In generalized linear mixed model analyses adjusting for donor tissue characteristics, recipient age, and diagnosis, an association of borderline significance was found between higher donor age and early failure [odds ratio (95% confidence interval): 1.03 (1.00–1.05); unit change of 1 yr] and DSAEK [odds ratio 1.02 (1.00–1.04); unit of change 1 yr] cases.

Conclusions:

The proportion of early graft failures in DMEK decreased over time and was comparable with failure rates in DSAEK at the end of the study period. The surgical learning curve might have played a role.
Mobile Health Self-management Interventions for Patients With Heart Failure
Authors: Schmaderer Myra S. , Struwe Leeza , Loecker Courtney , Lier Lauren , Lundgren Scott W. , Wichman Chris , Pozehl Bunny , Zimmerman Lani
Published: August 2021

Background

Heart failure (HF) is a multifaceted syndrome that requires self-management for adherence to treatment to control symptoms. Symptoms need to be monitored to prevent impending HF exacerbations. Few HF study authors have assessed efficacy of mobile health (mHealth) interventions particularly with virtual visits to evaluate outcomes such as symptoms and healthcare utilization.

Objective

The aim of this pilot study was to evaluate the potential effect of mHealth self-management interventions on symptom status and health-related quality of life and describe health care utilization in patients with HF.

Methods

This 3-month pilot study included 74 patients with HF and used a randomized 3-group repeated-measures design (enhanced usual care, mHealth, and mHealth plus [+] virtual visits). Surveys included the Heart Failure Symptom Survey, EuroQol, and a specialized phone application for patients to report weights and medications.

Results

The mHealth groups had an overall decrease in most symptom severity and frequency, particularly shortness of breath. Compared to enhanced usual care, both the mHealth+ and mHealth groups showed promise with medium effect sizes (range .55–.60) in relation to shortness of breath and a medium effect (.51) for lower extremity edema for the mHealth+ group. There was a trend toward improvement in health-related quality of life in both intervention groups at month 3. The mHealth+ group had fewer rehospitalizations.

Conclusions

In general, both mHealth groups fared better on symptoms and health care utilization. Small to medium effect sizes on selected symptom outcomes warrant this study to be conducted in a fully powered study. Virtual visits may assist in symptom recognition and self-management.
Stroke Caregiver Depression
Authors: King Rosemarie B. , Raad Jason H. , Flaherty Jennifer , Hartke Robert J.
Published: August 2021

BACKGROUND

Mixed-method studies can shed light on the mechanisms through which interventions effectively reduce caregiver depression.

OBJECTIVE

The objective of this qualitative study was to understand factors contributing to reduced depressive symptoms in stroke caregiver treatment responders compared with nonresponders.

METHODS

A mixed-methods explanatory sequential design was used to assess cognitive behavioral coping use and helpfulness in reducing depression among experimental study treatment responders and nonresponders. Using purposive sampling at 1-year of caregiving, we selected responders who were not depressed or demonstrated reduction to probable depression and nonresponders whose scores indicated worsened or new depression. Participants responded to semistructured interviews on life changes and the use and helpfulness of intervention coping strategies. Thematic analysis identified codes and themes.

RESULTS

Twelve of 25 participants were responders. We identified 2 overarching outcome themes: “It was about me, changing to make life better” (responders) and “Lamenting our changed lives” (nonresponders). Five subthemes related to coping were identified. Whereas responders coped actively and were less dependent on the counseling relationship, nonresponders were passive in coping and more dependent on the initial counseling relationship. Anger or previous psychologic treatment was found in more than a quarter of nonresponders and in no responders. Negative life change was found in 9 of 13 nonresponders compared with 1 responder.

CONCLUSION

Findings support the helpfulness of cognitive behavioral coping. For many caregivers, engagement interviews and a more intense, longer intervention, such as stepped care and anger management, are indicated to mitigate treatment resistance and depressive symptoms, respectively.
An Integrative Review: Early Mobilization of Patients With External Ventriculostomy Drains in the Neurological Intensive Care Unit
Authors: Moyer Megan T. , Hinkle Janice L. , Mendez James D.
Published: August 2021

BACKGROUND: Patients in the intensive care unit (ICU) are at a high risk for immobility due to their high acuity and need for invasive devices including external ventriculostomy drains (EVDs). Prolonged patient immobilization is associated with poor outcomes. METHODS: Whittemore and Knafl's 5-stage framework was used to conduct an integrative review to synthesize findings from quantitative research studies on early patient mobilization for patients with EVDs in the neurological ICU. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist was used as the reporting guideline. RESULTS: In 12 studies, a total of 412 patients with EVDs in neurological ICUs were actively mobilized with a goal of progressing to ambulation. Mobilization out of bed with a ventriculostomy drain was safe and feasible without significant adverse events. CONCLUSION: There is a need to clarify best practices for early mobilization of patients with EVDs in the neurological ICU and to explore the influence of early mobilization on patients' rates of venous thromboembolism, catheter-associated urinary tract infections, catheter line-associated blood stream infections, ventilator-associated pneumonia, and ventriculostomy-related infections. No studies measured the total time the EVD was clamped during the patient mobilization intervention or the total amount of cerebrospinal fluid drainage on the day of mobilization. Early mobilization of patients with EVDs in the neurological ICU who were permitted out of bed was universally safe and feasible, with minimal adverse events when safety checks were integrated into mobilization protocols.
Constipation Management in Parkinson Disease
Authors: Cheesman Molly , Ho Haily , Bishop Krista , Sin Mo-Kyung
Published: August 2021

BACKGROUND: Constipation is the most frequently reported nonmotor gastrointestinal symptom of Parkinson disease and can precede motor symptoms by up to 20 years. The causes of constipation can be multifactorial, but the implications can lead to life-threatening complications. Early recognition of constipation can lead to better health outcomes and quality of life. MANAGEMENT CONSIDERATIONS: The combination of nonpharmacological management through screening tools, nursing assessment, and patient education as well as pharmacological management is considered best practice. IMPLICATIONS FOR PRACTICE: Nurses who are knowledgeable on the current treatment options for constipation in Parkinson disease will be better equipped as active multidisciplinary team players to provide optimal care to their patients and achieve the best health outcomes.
Utilization of High-pressure Suction for EBUS-TBNA Sampling in Suspected Lung Cancer
Authors: Tsaknis George , Naeem Muhammad , Rathinam Sridhar , Caswell Alison , Haycock Jayne , McKenna Jane , Reddy Raja V.
Published: August 2021

Background:

Sample adequacy for immediate molecular testing is paramount in lung cancer. To date, several endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) sampling setups have been evaluated, however, the utilization of high-pressure suction (HPS) has not yet been reported.

The aim of this study was to evaluate the utilization of HPS onto the needle and its effect on sample volume and adequacy for molecular testing in patients with suspected lung cancer.

Methods:

We retrospectively analyzed 128 consecutive EBUS-TBNA performed for suspected lung cancer. This was confirmed in 109 patients. Other diagnoses confirmed in 12, and 7 referred for surgery. Sixty-three patients (89 targets) had HPS (May to September 2020), and compared with 46 (72 targets) who had standard vacuum syringe suction (October 2019 to March 2020). Several parameters and outcomes evaluated, such as number of needle passes, needle strokes, needle size, target size, positron emission tomography avidity, procedure time, blood content score, sample volume, adequacy for molecular testing, as well as baseline patient characteristics and complication rate.

Results:

There was no difference between the 2 groups in all baseline parameters and characteristics. In multivariable analysis, HPS was associated with significantly higher sample volume (11.2 vs. 9.1 mm3, P=0.036) and less additional procedures to achieve full molecular profiling (2/52 vs. 7/40, P=0.042), in necrotic targets of non−small cell lung cancer. Diagnostic yields were comparable.

Conclusion:

HPS appears to be simple, no-cost, and safe, promising higher sample volume compared with vacuum syringe suction, and also appears to be associated with higher success of full molecular testing with less additional procedures, in non−small cell lung cancer necrotic targets.
Efficacy of 68Ga-PSMA PET/CT-derived whole-body volumetric parameters in predicting response to second-generation androgen receptor axis-targeted therapy, and the prognosis in metastatic hormone-refractory prostate cancer patients
Authors: Oruç Zeynep , Güzel Yunus , Ebinç Senar , Kömek Halil , Küçüköner Mehmet , Kaplan Muhammet Ali , Oruç İdris , Urakçi Zuhat , Işikdoğan Abdurrahman
Published: August 2021

Introduction

The present study investigates the role of 68Ga-PSMA PET/CT-derived whole-body metabolic and volumetric parameters in the prediction of treatment response and prognosis among metastatic hormone-refractory prostate cancer patients undergoing second-generation androgen receptor axis-targeted therapy (abiraterone or enzalutamide).

Materials and methods

This retrospective study included 44 metastatic hormone-refractory prostate cancer patients undergoing 68Ga-PSMA PET/CT, including 29 enzalutamide-treated and 15 abiraterone-treated patients.

Results

Of the 44 patients included in the study, 29 received enzalutamide and 15 received abiraterone. During treatment, the changes in PET parameters were correlated with the PSA (biochemical) response. More specifically, a positive correlation was noted between PSA response and percent change in TLP (ΔTLP) response, and there was concordance between the results (r = 0.652, k = 0.42, P < 0.001). Baseline PSA (P =0.05), high MTVw (P = 0.005), the increase in ΔPSA (P = 0.036), ΔTLP (P = 0.039) and percent change in MTV (ΔMTV) (P = 0.049) values were identified as factors associated with mortality risk.Multivariate analysis showed that PSA1 [odds ratio (OR): 1.005, 95% confidence interval (CI) 1.002–1.008, P = 0.004], ΔPSA (OR: 14.7, 95% CI 1.50–143.7, P = 0.02) and MTVw1 (OR: 11.4, 95% CI 1.11–116, 6, P = 0.04) were independent prognostic factors associated with mortality risk.

Conclusion

A statistically significant concordance and correlation was noted between 68Ga-PSMA PET/CT-derived whole-body metabolic parameters (ΔTLP and ΔMTV) and ΔPSA. In addition, the baseline PSA, ΔPSA, ΔTLP, ΔMTV and TMTV were identified as predictive factors for mortality risk.
Development and Results of an Implementation Plan for High-Intensity Gait Training
Authors: Moore Jennifer L. , Bø Elisabeth , Erichsen Anne , Rosseland Ingvild , Halvorsen Joakim , Bratlie Hanne , Hornby T. George , Nordvik Jan Egil
Published: August 2021

Background and Purpose:

High-intensity gait training is recommended in stroke rehabilitation to improve gait speed, walking distance, and balance. However, identifying effective and efficient implementation methods is a challenge for rehabilitation providers. This article describes the development of an implementation plan, presents findings of each implementation phase, and identifies the project's impact on clinicians and the health system.

Methods:

Two inpatient rehabilitation facilities, including 9 physical therapists, collaborated with a knowledge translation center to implement this program. We developed an implementation plan using the Knowledge-to-Action Framework and utilized the Consolidated Framework for Implementation Research to identify barriers and select implementation strategies. Using mix-methods research, including surveys and informal discussions, we evaluated current practice, barriers, outcomes, and the sustainability of high-intensity gait training in practice.

Results:

A multicomponent implementation plan that targeted barriers was developed. Before implementation, clinicians reported providing several balance, strength training, and gait interventions to improve walking. Barriers to using high-intensity gait training included knowledge, beliefs, adaptability of high-intensity gait training, resources, culture, and others. Twenty-six implementation strategies were selected to target the barriers. Surveys and informal discussions identified significant changes in perceived practice, adoption of high-intensity gait training, and positive impacts on the health system. The 2-year follow-up survey indicated that the new practice was sustained.

Discussion and Conclusions:

Using a multicomponent implementation plan that targeted barriers, we successfully implemented high-intensity gait training in clinical practice. Contributors to successful implementation may include the implementation methods, usual care interventions, and clinicians' readiness for this change.

Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A352.)
Temporal But Not Spatial Gait Parameters Associated With Lower Balance Capacity in Moderate-High Functioning Persons With Stroke
Authors: Handelzalts Shirley , Steinberg-Henn Flavia , Farquhar Jenna , Shkedy Rabani Anat , Levy Sigal , Riemer Raziel , Soroker Nachum , Melzer Itshak
Published: August 2021

Background and purpose:

Falls are a major health concern after stroke. Spatial and temporal gait asymmetry and variability can contribute to instability and increased fall risk in persons with stroke (PwS). We aimed to quantify gait spatiotemporal symmetry and variability parameters in PwS undergoing rehabilitation in the subacute stage of the disease, by comparison to healthy participants, and to examine the associations between these parameters and patients' reactive and proactive balance capacity.

Methods:

Twenty-two PwS and 12 healthy adults walked over a computerized treadmill system at their self-selected walking speed. Symmetry and variability of gait parameters (step length, swing time, and stance time) as well as upper extremity and lower extremity angular range of motion in the sagittal plane were extracted. In addition, the Berg Balance Scale (BBS) and the fall threshold in response to sudden surface translations at increasing intensities were assessed.

Results:

PwS demonstrated significantly higher asymmetry in all gait parameters in comparison to controls. Also, PwS demonstrated increased stance time variability in comparison to healthy controls and increased swing time variability in the paretic lower extremity. Significant negative associations were found between fall threshold and stance time asymmetry in PwS (r = −0.48, P = 0.022), between the BBS and swing time asymmetry (r = −0.50, P = 0.018), and between the BBS and stance time variability of the paretic lower extremity (r = −0.56, P = 0.006).

Discussion and Conclusions:

Findings highlight the importance of gait temporal symmetry and variability measures for dynamic balance control after stroke. These parameters should be considered when assessing gait recovery and safety in PwS.

Video Abstract available for more insight from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A355).
Intratumoral Budding and Tumor Microenvironment in Pretreatment Rectal Cancer Biopsies Predict the Response to Neoadjuvant Chemoradiotherapy
Authors: Wen Xiaoyun , Zee Sui Y. , Shroyer Kenneth R. , Bandovic Jela
Published: August 2021

Tumor budding at the invasive tumor front (peritumoral budding) is an established prognostic factor in colorectal cancer. However, the significance of intratumoral budding (ITB) in pretreatment biopsies is still uncertain. Our study aims to investigate the association of ITB and tumor microenvironment in pretreatment rectal cancer biopsies with pathologic response to neoadjuvant chemoradiotherapy. Pretreatment biopsies of low-grade rectal cancer from 37 patients who underwent resection after neoadjuvant chemoradiotherapy were retrospectively reviewed to evaluate ITB, type of tumor stroma, and intraepithelial lymphocytes. ITB was counted on a single hotspot in 1 HPF upon pan-keratin immunohistochemical staining. Intraepithelial lymphocytes was graded semiquantitatively as “absent” (≤2/HPF) or “present” (>2/HPF). The tumor stroma was classified as either immature type or maturing type. In pretreatment biopsies, ITB was observed in 34/37 patients (92%). High-grade ITB was significantly associated with a poor pathologic response to neoadjuvant chemoradiotherapy (tumor regression score 2 to 3, P<0.001; and higher posttreatment T stage, P=0.002). Immature type of stroma was significantly associated with both high-grade ITB in biopsies (P=0.02) and a poor pathologic response to neoadjuvant chemoradiotherapy (tumor regression score 2 to 3, P=0.005). In multivariate analysis, ITB and the type of stroma remained the significant parameters for prediction of response to neoadjuvant treatment. Our study indicates that ITB and tumor microenvironment in pretreatment biopsies are strong predictors of response to neoadjuvant chemoradiotherapy, which may assist risk stratification and clinical management in rectal cancer patients.
Brief Report: Vaginal Viral Shedding With Undetectable Plasma HIV Viral Load in Pregnant Women Receiving 2 Different Antiretroviral Regimens: A Randomized Clinical Trial
Authors: Frenkel Lisa M. , Morrison R. Leavitt , Fuller Trevon L. , Gouvêa Maria Isabel , Benamor Teixeira Maria de Lourdes , Coombs Robert W. , Shapiro David E. , Mirochnick Mark , Hennessey Roslyn , Whitson Kyle , Chakhtoura Nahida , João Esaú C.
Published: August 2021

Background:

Pregnant women using antiretrovirals (ARVs) may have persistent vaginal viral shedding, which could be associated with sexual and perinatal HIV transmission. However, there are scant data on vaginal viral load (VVL) in pregnant women with undetectable plasma viral load (PVL).

Methods:

This study was a post hoc analysis of an open-label randomized trial to evaluate the virologic response of 2 ART regimens. The participants were ART-naive women living with HIV initiating ART regimens between 20 and 36 weeks of pregnancy recruited at 19 clinical sites in 6 countries. Participants were randomized to receive 400 mg of raltegravir 2 times a day or 600 mg of efavirenz 4 times a day in addition to 150 mg of lamivudine and 300 mg of zidovudine 2 times a day. VVL and PVL tests were performed at every study visit. The primary outcome measures were HIV-1 PVL and VVL at maternal study week 4 and rates of perinatal HIV transmission.

Results:

A total of 408 were enrolled, of whom 323 had VVL samples 4 weeks after enrollment and were included in this analysis. Among women with undetectable/nonquantifiable PVL during ART, the overall rate of quantifiable VVL at week 4 was 2.54% (7/275). Of the 275 with nonquantifiable PVL, 99.1% (115/116) and 96.2% (153/159) had nonquantifiable VVL in the efavirenz and raltegravir arms, respectively. None of the 7 women with quantifiable VVL at the week 4 study visit transmitted HIV to their infants.

Conclusions:

Detectable VVL in pregnant women with undetectable/nonquantifiable PVL while receiving ART was rare and not associated with perinatal HIV transmission.
Lumbar Puncture for Diagnosis of Idiopathic Intracranial Hypertension in Typical Patients
Authors: Margolis Mathew S. , DeBusk Adam A. , Moster Mark L. , Falardeau Julie M. , Eggenberger Eric R. , Sergott Robert C. , Van Stavern Gregory P.
Published: August 2021

Background:

Patients with typical features of pseudotumor cerebri syndrome (PTCS) must undergo lumbar puncture (LP) to demonstrate elevated opening pressure and cerebrospinal fluid (CSF) analysis to rule out alternative diagnoses. As LP may be associated with significant morbidity, this study aims to determine its necessity in diagnosing typical PTCS.

Methods:

Retrospective chart review at 3 university-based neuro-ophthalmology practices included women aged 18–45 years with body mass index >25, papilledema, negative neuroimaging, and who met criteria for PTCS or probable PTCS.

Results:

One hundred fifty-six patients were enrolled. Seven (4.5%) had clinically insignificant CSF abnormalities. No diagnoses or management changed based on LP/CSF results.

Conclusion:

LP may not be routinely required in the initial evaluation of typical patients with PTCS evaluated by experienced clinicians We caution, however, that further prospective study is required to determine potential risks and benefits of LP as a tool in the diagnosis of IIH before recommending general practice changes.
Involvement of Ocular Muscles in Patients With Myasthenia Gravis With Nonocular Onset
Authors: Lei Lin , Fan Zhirong , Su Shengyao , Xu Min , Chen Hai , Zhu Wenjia , Luan Qinrong , Da Yuwei
Published: August 2021

Background:

Myasthenia gravis (MG) is an autoimmune disorder involving neuromuscular junctions and more than half of MG patients manifested with extraocular muscle weakness initially. In the remained patients, ocular weakness may occur later in the course of the disease. However, little data are available about ocular involvement in such patients. Therefore, the study aims to investigate ocular weakness in MG patients with nonocular onset and evaluate the associated factors influencing it.

Methods:

In our monocentric retrospective study, 54 adult-onset patients with MG with nonocular onset were included and were followed up for at least 2 years from the onset. The primary outcome was the occurrence of ptosis, diplopia, or both. Kaplan–Meier analysis was performed to estimate the time to the ocular weakness, and log-rank tests were used to analyze the association between clinical characteristics and ocular weakness. Multivariate Cox proportional hazards regression models were used to identify factors associated with ocular involvement.

Results:

A total of 47 (87.0%) patients developed ocular weakness during the study period. The median time to ocular weakness was 6.0 months. Time to the ocular involvement was earlier in patients with bulbar onset (P = 0.007), whereas patients receiving pyridostigmine monotherapy and immunomodulatory therapy had a longer median time of ocular weakness (P < 0.0001). No significant difference was noted between ocular weakness and age of onset, gender, and thymoma. The Cox analysis showed that bulbar onset was a risk factor of ocular weakness (adjusted hazard ratio [HR] 2.65, 95% confidence interval [CI] 1.41–4.99), whereas pyridostigmine monotherapy (adjusted HR 0.28, 95% CI 0.13–0.60) and immunotherapy (adjusted HR 0.09, 95% CI 0.04–0.22) were protective factors.

Conclusions:

Eighty-seven percent of patients with MG with nonocular onset developed ocular weakness. Bulbar onset was an independent risk factor for ocular involvement, whereas pyridostigmine and immunotherapy were protective factors.
Interictal Spikes as an EEG Biomarker of Cognitive Impairment
Authors: Holmes Gregory L.
Published: August 2021

Although interictal spikes (IISs) are a well-established EEG biomarker for epilepsy, whether they are also a biomarker of cognitive deficits is unclear. Interictal spikes are dynamic events consisting of a synchronous discharge of neurons producing high frequency oscillations and a succession of action potentials which disrupt the ongoing neural activity. There are robust data showing that IISs result in transitory cognitive impairment with the type of deficit specific to the cognitive task and anatomic location of the IIS. Interictal spike, particularly if frequent and widespread, can impair cognitive abilities, through interference with waking learning and memory and memory consolidation during sleep. Interictal spikes seem to be particularly concerning in the developing brain where animal data suggest that IISs can lead to adverse cognitive effects even after the disappearance of the spikes. Whether a similar phenomenon occurs in human beings is unclear. Thus, although IISs are a clear biomarker of transitory cognitive impairment, currently, they lack sensitivity and specificity as a biomarker for enduring cognitive impairment.
Neurobehavioral Biomarkers: An EEG Family Reunion
Authors: Ewen Joshua B. , Levin April R.
Published: August 2021

The field of clinical EEG has had an uneasy relationship with the use of this technology for clinical cognitive applications and often for good reason. However, apart from its clinical use, EEG has had a tradition as a major tool in cognitive psychology and cognitive neuroscience dating back at least to the 1960s. Based on accumulated knowledge from its research application, EEG-based biomarkers are beginning to see applications in clinical trials and may eventually enter clinical care. We address concerns surrounding quality control, the treatment of artifact, and normal variants and how developments in engineering, biomarker validation, and implementation science rigorously applied to these tools can lead to well-justified approaches.
Metabolomic and Inflammatory Signatures of Symptom Dimensions in Major Depression
Authors: Brydges Christopher R , Bhattacharyya Sudeepa , Dehkordi Siamak Mahmoudian , Milaneschi Yuri , Penninx Brenda , Jansen Rick , Kristal Bruce S. , Han Xianlin , Arnold Matthias , Kastenmüller Gabi , Bekhbat Mandakh , Mayberg Helen S , Craighead W Edward , Rush A John , Fiehn Oliver , Dunlop Boadie W , Kaddurah-Daouk Rima ,   Mood Disorders Precision Medicine Consortium
Published: August 2021

Background

Major depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Netherlands Study of Depression and Anxiety (NESDA) study. In this study, we aimed to replicate these immunometabolic associations and to characterize the metabolomic correlates of each of the three MDD dimensions.

Methods

Using three clinical rating scales, Melancholic, and Anxious distress, and Immunometabolic (IMD) dimensions were characterized in 158 patients who participated in the Predictors of Remission to Individual and Combined Treatments (PReDICT) study and from whom plasma and serum samples were available. The NESDA-defined inflammatory index, a composite measure of interleukin-6 and C-reactive protein, was measured from pre-treatment plasma samples and a metabolomic profile was defined using serum samples analyzed on three metabolomics platforms targeting fatty acids and complex lipids, amino acids, acylcarnitines, and gut microbiome-derived metabolites among other metabolites of central metabolism.

Results

The IMD clinical dimension and the inflammatory index were positively correlated (r=0.19, p=.019) after controlling for age, sex, and body mass index, whereas the Melancholic and Anxious distress dimensions were not, replicating the previous NESDA findings. The three symptom dimensions had distinct metabolomic signatures using both univariate and set enrichment statistics. IMD severity correlated mainly with gut-derived metabolites and a few acylcarnitines and long chain saturated free fatty acids. Melancholia severity was significantly correlated with several phosphatidylcholines, primarily the ether-linked variety, lysophosphatidylcholines, as well as several amino acids. Anxious distress severity correlated with several medium and long chain free fatty acids, both saturated and polyunsaturated ones, sphingomyelins, as well as several amino acids and bile acids.

Conclusion

The IMD dimension of depression is reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function.
Immune and metabolic beneficial effects of Beta 1,3-1,6 glucans produced by two novel strains of Aureobasidium pullulans in healthy middle-aged Japanese men: An exploratory study
Authors: Ikewaki Nobunao , Sonoda Tohru , Kurosawa Gene , Iwasaki Masaru , Dedeepiya Vidyasagar Devaprasad , Senthilkumar Rajappa , Preethy Senthilkumar , Abraham Samuel JK
Published: August 2021

Background

Imbalances in glucose and lipid metabolism in the background of a declining immune system, along with aging, make one prone to glucolipotoxicity-related diseases such as hepatic steatosis and to high risk of infection-related mortality, as with COVID-19, warranting a safe prophylactic measure to help regulate both metabolism and the immune system. Based on the beneficial effects of the AFO-202 strain of black yeast Aureobasidium pullulans-produced beta 1,3-1,6 glucan in balancing of blood glucose and immune enhancement, and that of the N-163 strain of the same species in lipid metabolism and immune modulation, in this pilot study, we have evaluated their specific benefits in healthy human subjects.

Methods

Sixteen healthy Japanese male volunteers (aged 40 to 60 years) took part in this clinical trial. They were divided into four groups (n = 4 each): Group I consumed AFO-202 beta glucan (2 sachets of 1 g each per day), IA for 35 days and IB for 21 days; Group II consumed a combination of AFO-202 beta glucan (2 sachets of 1 g each) and N-163 beta glucan (1 sachet of 15 g gel each per day), IIA for 35 days and IIB for 21 days. Investigations for immune stimulation, anti-glycaemic, and anti-cholesterolemia biomarkers were undertaken in all four groups.

Results

In terms of metabolic control of glucose, the decrease in HbA1C and glycated albumin (GA) was significantly better in Group I compared with the other groups. Immune enhancement in terms of a significant increase of eosinophils and monocytes and marginal decrease in D-dimer levels, decrease in neutrophil-to-lymphocyte ratio (NLR), with an increase in the lymphocyte-to-CRP ratio (LCR) and leukocyte-to-CRP ratio (LeCR) was observed in Group I. Regulation of lipids by decrease in total and LDL cholesterol was better in Group II, and immunomodulation of coagulation-associated and anti-inflammatory markers by a decrease of CD11b, serum ferritin, galectin-3, fibrinogen was profound in Group II.

Conclusion

A. pullulans, a polythermotolerant black yeast - produced AFO-202 beta glucan has balanced blood glucose with marginal immune enhancement in healthy individuals, which when combined with N-163 beta glucan, balanced the lipid profile and immunomodulation. This outcome warrants larger clinical trials to understand the mechanisms and explore the potentials of these safe food supplements in prevention and prophylaxis of diseases due to dysregulated glucose and lipid metabolism, such as fatty liver disease, and infections such as COVID-19 in which a balanced immune activation and immunomodulation are of utmost importance, besides their administration as an adjunct to existing therapeutic approaches of both communicable and non-communicable diseases.
Differences in the genetic architecture of common and rare variants in childhood, persistent and late-diagnosed attention deficit hyperactivity disorder
Authors: Rajagopal Veera M. , Duan Jinjie , Vilar-Ribó Laura , Grove Jakob , Zayats Tetyana , Ramos-Quiroga J. Antoni , Satterstrom F. Kyle , Soler Artigas María , Bybjerg-Grauholm Jonas , Bækvad-Hansen Marie , Als Thomas D. , Rosengren Anders , Daly Mark J. , Neale Benjamin M. , Nordentoft Merete , Werge Thomas , Mors Ole , Hougaard David M. , Mortensen Preben B. , Ribasés Marta , Børglum Anders D. , Demontis Ditte
Published: August 2021

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder, with onset in childhood (“childhood ADHD”), and around two thirds of affected individuals will continue to have ADHD symptoms in adulthood (“persistent ADHD”). Age at first diagnosis can vary, and sometimes ADHD is first diagnosed in adulthood (“late-diagnosed ADHD”).

In this study, we analyzed a large Danish population-based case-cohort generated by iPSYCH in order to identify common genetic risk loci and perform in-depth characterization of the polygenic architecture of childhood (N=14,878), persistent (N=1,473) and late-diagnosed ADHD (N=6,961) alongside 38,303 controls. Additionally, the burden of rare protein truncating variants in the three groups were evaluated in whole-exome sequencing data from a subset of the individuals (7,650 ADHD cases and 8,649 controls). We identified genome-wide significant loci associated with childhood ADHD (four loci) and late-diagnosed ADHD (one locus). In analyses of the polygenic architecture, we found higher polygenic score (PGS) of ADHD risk variants in persistent ADHD (mean PGS=0.41) compared to childhood (mean PGS=0.26) and late-diagnosed ADHD (mean PGS=0.27), and we found a significant decreased genetic correlation of late-diagnosed ADHD with inattention (rg=0.57) compared to childhood ADHD (rg=0.86). These results suggest that a higher ADHD polygenic risk burden is associated with persistence of symptoms, and that a later diagnosis of ADHD could be due in part to genetic factors. Additionally, childhood ADHD demonstrated both a significantly increased genetic overlap with autism compared to late-diagnosed ADHD as well as the highest burden of rare protein-truncating variants in highly constrained genes among ADHD subgroups (compared to controls: beta=0.13, P=2.41×10−11). Late-diagnosed ADHD demonstrated significantly larger genetic overlap with depression than childhood ADHD and no increased burden in rare protein-truncating variants (compared to controls: beta=0.06). Overall, our study finds genetic heterogeneity among ADHD subgroups and suggests that genetic factors influence time of first ADHD diagnosis, persistence of ADHD and comorbidity patterns in the sub-groups.
Antibody Attributes that Predict the Neutralization and Effector Function of Polyclonal Responses to SARS-CoV-2
Authors: Natarajan Harini , Xu Shiwei , Crowley Andrew R. , Butler Savannah E. , Weiner Joshua A. , Bloch Evan M. , Littlefield Kirsten , Benner Sarah E. , Shrestha Ruchee , Ajayi Olivia , Wieland-Alter Wendy , Sullivan David , Shoham Shmuel , Quinn Thomas C. , Casadevall Arturo , Pekosz Andrew , Redd Andrew D. , Tobian Aaron A.R. , Connor Ruth I. , Wright Peter F. , Ackerman Margaret E.
Published: August 2021

While antibodies provide significant protection from SARS-CoV-2 infection and disease sequelae, the specific attributes of the humoral response that contribute to immunity are incompletely defined. In this study, we employ machine learning to relate characteristics of the polyclonal antibody response raised by natural infection to diverse antibody effector functions and neutralization potency with the goal of generating both accurate predictions of each activity based on antibody response profiles as well as insights into antibody mechanisms of action. To this end, antibody-mediated phagocytosis, cytotoxicity, complement deposition, and neutralization were accurately predicted from biophysical antibody profiles in both discovery and validation cohorts. These predictive models identified SARS-CoV-2-specific IgM as a key predictor of neutralization activity whose mechanistic relevance was supported experimentally by depletion. Validated models of how different aspects of the humoral response relate to antiviral antibody activities suggest desirable attributes to recapitulate by vaccination or other antibody-based interventions.
Viscoelasticity and Noise Properties Reveal the Formation of Biomemory in Cells
Authors: Bakalis Evangelos , Gavriil Vassilios , Cefalas Alkiviadis-Constantinos , Kollia Zoe , Zerbetto Francesco , Sarantopoulou Evangelia
Published: August 2021

Living cells are neither perfectly elastic nor liquid and return a viscoelastic response to external stimuli. Nanoindentation provides force distance curves allowing the investigation of cell mechanical properties, and yet, these curves can differ from point to point on cell surface revealing its inhomogeneous character. In the present work, we propose a mathematical method to estimate both viscoelastic and noise properties of cells, as these are depicted on the values of the scaling exponents of relaxation function and power spectral density respectively. The method uses as input the time derivative of the response force in a nanoindentation experiment. Generalized moments method and/or rescaled range analysis are used to study the resulting time series depending on their non-stationary or stationary nature. We conducted experiments in livingUlocladium Chartarumspores. We found that spores, in the approaching phase present a viscoelastic behavior with the corresponding scaling exponent in the range 0.25-0.52, and in the retracting phase present a liquid-like behavior with exponents in the range 0.67-0.85. This substantial difference of the scaling exponents in the two phases suggests the formation of biomemory as response of the spores to the indenting AFM mechanical stimulus. The retracting phase may be described as a process driven by bluish noises, while the approaching one is driven by persistent noise.