bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors Associated With Physical Therapy Engagement During the Period of Posttraumatic Amnesia
Authors: Spiteri Courtney , Williams Gavin , Kahn Michelle , Ponsford Jennie , McKay Adam
Published: October 2021

Background and Purpose:

Physical therapy is important in the management of traumatic brain injury (TBI) and associated multitrauma. Providing therapy during the posttraumatic amnesia (PTA) phase is challenging, given that hallmark features including confusion, amnesia, agitation, and fatigue may impede the person's ability to engage in and benefit from rehabilitation. To date, there is little empirical evidence to guide the provision of therapy during PTA. This observational study aimed to explore the frequency, duration, location, and engagement of physical therapy provision during PTA and the impact of cognition, agitation, and fatigue.

Summary of Key Points:

The majority of patients were found to meaningfully engage and participate in physical therapy for the majority of sessions. Only a small proportion were unable to participate in physical therapy. Patient refusal and fatigue were identified as the most prominent barriers to rehabilitation. Despite fatigue and agitation reaching clinical levels, therapy could still successfully proceed on most occasions.

Recommendations for Clinical Practice:

Physical therapy is feasible during the acute recovery stages after TBI. Current results support the notion that therapy should commence early to minimize secondary complications and promote the recovery of mobility. A patient-centered therapeutic model that tailors the therapeutic approach to meet the individual's current physical and fluctuating cognitive capabilities may be most suited for this population. Clinicians working with people after TBI need experience in understanding and managing the cognitive limitations and associated symptoms of PTA to optimize the provision of therapy. These findings could inform guidelines for the management of patients in PTA.

Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A368).
Association Between Posttraumatic Stress Disorder and Epigenetic Age Acceleration in a Sample of Twins
Authors: Wang Zeyuan , Hui Qin , Goldberg Jack , Smith Nicholas , Kaseer Belal , Murrah Nancy , Levantsevych Oleksiy M. , Shallenberger Lucy , Diggers Emily , Bremner J. Douglas , Vaccarino Viola , Sun Yan V.
Published: October 2021

Objective

Posttraumatic stress disorder (PTSD) has been related to accelerated biological aging processes, but objective evidence for this association is limited. DNA methylation (DNAm) age acceleration is a novel measure of biological aging that may help clarify if PTSD is related to biological aging processes. We aim to examine whether PTSD is associated with biological aging using a comprehensive set of DNAm age acceleration markers and to what extent the unshared environment contributes to the association.

Methods

Using a cross-sectional co-twin control study design, we investigated the association of the clinical diagnosis and symptom severity of PTSD with six measurements of DNAm age acceleration based on epigenome-wide data derived from peripheral blood lymphocytes of 296 male twins from the Vietnam Era Twin Registry.

Results

Twins with current PTSD had significantly advanced DNAm age acceleration compared with twins without PTSD for five of six measures of DNAm age acceleration. Across almost all measures of DNAm age acceleration, twins with current PTSD were “epigenetically older” than their twin brothers without PTSD: estimated differences ranged between 1.6 (95% confidence interval = 0.0–3.1) and 2.7 (95% confidence interval = 0.5–4.8) biological age year-equivalents. A higher Clinician-Administered PTSD Scale score was also associated with a higher within-pair DNAm age acceleration. Results remained consistent after adjustment for behavioral and cardiovascular risk factors.

Conclusions

PTSD is associated with epigenetic age acceleration, primarily through unshared environmental mechanisms as opposed to genetic or familial factors. These results suggest that PTSD is related to systemic processes relevant to biological aging.
A Comparison of Oral Health Outcomes of Self-Reported and Agency-Notified Child Maltreatment in a Population-Based Birth Cohort at 30-Year-Old Follow-Up
Authors: Kisely Steve , Strathearn Lane , Najman Jake Moses
Published: October 2021

Objective

Information on the oral health outcomes of childhood maltreatment in adulthood is limited and reliant on retrospective questionnaires that are subject to recall bias. There are no data from prospective studies using maltreatment reports to statutory agencies. We therefore assessed the effect on dental outcomes and oral health care at 30-year follow-up using both prospective agency notifications and retrospective self-reports of child maltreatment in the same birth cohort.

Methods

There were 2456 adults with data on dental outcomes and oral health care at follow-up. Information on self-reported abuse was collected using the Child Trauma Questionnaire and linked to child maltreatment notifications to statutory agencies.

Results

The prevalence of self- and agency-reported maltreatment was 599 (24.4%) and 142 (5.8%), respectively. At follow-up, 850 participants (34.6%) had undergone a dental extraction for infection or decay, and 810 had experienced significant dental pain over their lifetime. One-third had not visited a dental clinic in the previous 2 years, and 40% failed to brush their teeth at least twice daily. On adjusted analyses, both self- and agency-reported maltreatment showed significant associations with dental extraction (odds ratio = 1.47 [95% confidence interval = 1.21–1.80] and odds ratio = 1.44 [95% confidence interval = 1.01–2.06], respectively). There were similar results for brushing frequency, whereas self-reported maltreatment was associated with dental pain. However, associations were weaker for dental clinic visits and some child maltreatment subtypes.

Conclusions

Child maltreatment is associated with adverse oral health consequences in adulthood and is thus a dental and wider public health issue.
Interferon Gamma Release Assay and Tuberculin Skin Test Performance in Pregnant Women Living With and Without HIV
Authors: Kaplan Samantha R. , Escudero Jaclyn N. , Mecha Jerphason , Richardson Barbra A. , Maleche-Obimbo Elizabeth , Matemo Daniel , Kinuthia John , John-Stewart Grace C. , LaCourse Sylvia M.
Published: October 2021

Background:

HIV and pregnancy may affect latent TB infection (LTBI) diagnostics. Tuberculin skin test (TST) and newer generation QuantiFERON-TB Gold Plus (QFT-Plus) evaluations in pregnant women living with HIV (WLHIV) and without HIV are lacking.

Methods:

In this cross-sectional study, pregnant women underwent TST and QFT-Plus testing during antenatal care in Kenya. We estimated LTBI prevalence and TST and QFT-Plus performances. Diagnostic agreement was assessed with kappa statistic, participant characteristics associated with LTBI and HIV were assessed with generalized linear models, and QFT-Plus quantitative responses were assessed with Mann–Whitney U test.

Results:

We enrolled 400 pregnant women (200 WLHIV/200 HIV-negative women) at median 28 weeks gestation (interquartile range 24–30). Among WLHIV (all on antiretroviral therapy), the median CD4 count was 464 cells/mm3 (interquartile range 325–654); 62.5% (125) had received isoniazid preventive therapy. LTBI prevalence was 35.8% and similar among WLHIV and HIV-negative women. QFT-Plus testing identified 3-fold more women with LTBI when compared with TST (32% vs. 12%, P < 0.0001). QFT-Plus positivity prevalence was similar regardless of HIV status, although TB-specific antigen responses were lower in WLHIV than in HIV-negative women with LTBI (median QFT-TB1 1.05 vs. 2.65 IU/mL, P = 0.035; QFT-TB2 1.26 vs. 2.56 IU/mL, P = 0.027). TST positivity was more frequent among WLHIV than among HIV-negative women (18.5% vs 4.6%; P < 0.0001).

Conclusions:

QFT-Plus assay had higher diagnostic yield than TST for LTBI in WLHIV and HIV-negative women despite lower TB-specific antigen responses in WLHIV. Higher TST positivity was observed in WLHIV. LTBI diagnostic performance in the context of pregnancy and HIV has implications for clinical use and prevention studies, which rely on these diagnostics for TB infection entry criteria or outcomes.
Applications of Mechanical Arm in the Virtual Touch Tissue Imaging Quantification and the Differential Diagnosis of Breast Tumors
Authors: Li Ling , Lv Guorong , Shen Haolin , Liao Liping , Zhong Rong , Zheng Chunnuan , Yang Shuping
Published: October 2021

To assess the diagnostic performance of quantitative parameters for virtual touch tissue imaging quantification by the mechanical arm probe, 128 women with 152 breast lesions (90 benign and 62 malignant) were included and maximum elasticity (V
max), median elasticity (V
mean), maximum elasticity minus minimum (V
max-min), and minimum elasticity (V
min) were measured. Intercorrelation coefficients and Bland-Altman plots were used to compare the repeatability and consistency of handheld probe and mechanical arm measurements. Receiver operating characteristic curve was used to evaluate the diagnostic efficiency. The results showed that intercorrelation coefficients were 0.694 to 0.951 by the mechanical arm and 95% limits of agreement were wider than handheld probe. Using 4.36 m/s as cutoff value for V
max by the mechanical arm, we achieved sensitivity (88.7%) and specificity (90.0%). We concluded that the mechanical arm can reduce the influence of different scanning pressures on the elastic modulus of breast tissue.
Low Titer Group O Whole Blood In Injured Children Requiring Massive Transfusion
Authors: Gaines Barbara A. , Yazer Mark H. , Triulzi Darrell J. , Sperry Jason L. , Neal Matthew D. , Billiar Timothy R. , Leeper Christine M.
Published: October 2021

Objective:

The aim of this study was to assess the survival impact of low-titer group O whole blood (LTOWB) in injured pediatric patients who require massive transfusion.

Summary Background Data:

Limited data are available regarding the effectiveness of LTOWB in pediatric trauma.

Methods:

A prospective observational study of children requiring massive transfusion after injury at UPMC Children’s Hospital of Pittsburgh, an urban academic pediatric Level 1 trauma center. Injured children ages 1 to 17 years who received a total of >40 mL/kg of LTOWB and/or conventional components over the 24 hours after admission were included. Patient characteristics, blood product utilization and clinical outcomes were analyzed using Kaplan-Meier survival curves, log rank tests and Cox proportional hazards regression analyses. The primary outcome was 28-day survival.

Results:

Of patients analyzed, 27 of 80 (33%) received LTOWB as part of their hemostatic resuscitation. The LTOWB group was comparable to the component therapy group on baseline demographic and physiologic parameters except older age, higher body weight, and lower red blood cell and plasma transfusion volumes. After adjusting for age, total blood product volume transfused in 24 hours, admission base deficit, international normalized ratio (INR), and injury severity score (ISS), children who received LTOWB as part of their resuscitation had significantly improved survival at both 72 hours and 28 days post-trauma [adjusted odds ratio (AOR) 0.23, P = 0.009 and AOR 0.41, P = 0.02, respectively]; 6-hour survival was not statistically significant (AOR = 0.51, P = 0.30). Survivors at 28 days in the LTOWB group had reduced hospital LOS, ICU LOS, and ventilator days compared to the CT group.

Conclusion:

Administration of LTOWB during the hemostatic resuscitation of injured children requiring massive transfusion was independently associated with improved 72-hour and 28-day survival.
Surgical stabilization of severe chest wall injury following cardiopulmonary resuscitation
Authors: DeVoe William B. , Abourezk Matthew , Goslin Brent J. , Saraswat Nirvana , Kiel Brandon , Bach John A. , Suh Kwang I. , Eriksson Evert A.
Published: October 2021

BACKGROUND

Cardiopulmonary resuscitation (CPR) contributes to significant chest wall injury similar to blunt trauma. With benefits realized for surgical stabilization of rib fractures (SSRFs) for flail injuries and severely displaced fractures following trauma, SSRF for chest wall injury following CPR could be advantageous, provided good functional and neurologic outlook. Experience is limited. We present a review of patients treated with SSRF at our institution following CPR.

METHODS

A retrospective analysis of patients undergoing SSRF following CPR was performed between 2019 and 2020. Perioperative inpatient data were collected with outpatient follow-up as able.

RESULTS

Five patients underwent SSRF over the course of the 2-year interval. All patients required invasive ventilation preoperatively or had impending respiratory. Mean age was 59 ± 12 years, with all patients being male. Inciting events for cardiac arrest included respiratory, ventricular tachycardia, ventricular fibrillation, pulseless electrical activity, and anaphylaxis. Time to operation was 6.6 ± 3 days. Four patients demonstrated anterior flail injury pattern with or without sternal fracture, with one patient having multiple severely displaced fractures. Surgical stabilization of rib fracture was performed appropriately to restore chest wall stability. Mean intensive care unit length of stay was 9.8 ± 6.4 days and overall hospital length of stay 24.6 ± 13.2 days. Median postoperative ventilation was 2 days (range, 1–15 days) with two patients developing pneumonia and one requiring tracheostomy. There were no mortalities at 30 days. One patient expired in hospice after a prolonged hospitalization. Disposition destination was variable. No hardware complications were noted on outpatient follow-up, and all surviving patients were home.

CONCLUSION

Chest wall injuries are incurred frequently following CPR. Surgical stabilization of these injuries can be considered to promote ventilator liberation and rehabilitation. Careful patient selection is paramount, with surgery offered to those with reversible causes of arrest and good functional and neurologic outcome. Experience is early, with further investigation needed.

LEVEL OF EVIDENCE

Therapeutic, Level V.
Rapid detection of platelet inhibition and dysfunction in traumatic brain injury: A prospective observational study
Authors: Alvikas Jurgis , Zenati Mazen , Campwala Insiyah , Jansen Jan O. , Hassoune Adnan , Phelos Heather , Okonkwo David O. , Neal Matthew D.
Published: October 2021

BACKGROUND

Rapid platelet function testing is frequently used to determine platelet function in patients with traumatic intracranial hemorrhage (tICH). Accuracy and clinical significance of decreased platelet response detected by these tests is not well understood. We sought to determine whether VerifyNow and whole blood aggregometry (WBA) can detect poor platelet response and to elucidate its clinical significance for tICH patients.

METHODS

We prospectively enrolled patients with isolated tICH between 2018 and 2020. Demographics, medical history, injury characteristics, and patient outcomes were recorded. Platelet function was determined by VerifyNow and WBA testing at the time of arrival to the trauma bay and 6 hours later.

RESULTS

A total of 221 patients were enrolled, including 111 patients on no antiplatelet medication, 78 on aspirin, 6 on clopidogrel, and 26 on aspirin and clopidogrel. In the trauma bay, 29.7% and 67.7% of patients on no antiplatelet medication had poor platelet response on VerifyNow and WBA, respectively. Among patients on aspirin, 72.2% and 82.2% had platelet dysfunction on VerifyNow and WBA. Among patients on clopidogrel, 67.9% and 88.9% had platelet dysfunction on VerifyNow and WBA. Patients with nonresponsive platelets had similar in-hospital mortality (3 [3.0%] vs. 6 [6.3%], p = 0.324), tICH progression (26 [27.1%] vs. 24 [26.1%], p = 0.877), intensive care unit admission rates (34 [34.3%] vs. 38 [40.0%), p = 0.415), and length of stay (3 [interquartile range, 2–8] vs. 3.2 [interquartile range, 2–7], p = 0.818) to those with responsive platelets. Platelet transfusion did not improve platelet response or patient outcomes.

CONCLUSION

Rapid platelet function testing detects a highly prevalent poor platelet response among patients with tICH, irrespective of antiplatelet medication use. VerifyNow correlated fairly with whole blood aggregometry among patients with tICH and platelet responsiveness detectable by these tests did not correlate with clinical outcomes. In addition, our results suggest that platelet transfusion may not improve clinical outcomes in patients with tICH.

LEVEL OF EVIDENCE

Diagnostic tests, level II.
Leukemic and Lymphomatous Optic Neuropathy: A Case Series
Authors: Lee Victoria , Farooq Asim V. , Shah Hassan A.
Published: October 2021

Background:

Optic neuropathy in the context of leukemia and lymphoma raises concern for central nervous system involvement or relapse and warrants prompt evaluation and treatment. To date, a gold standard for the diagnosis and management of leukemic optic neuropathy has yet to be established.

Methods:

Case series and review of the literature. Two illustrative cases were selected to discuss their treatment course and outcome.

Results:

We report 7 cases of patients with leukemia or lymphoma presenting with optic nerve infiltration. All patients received steroid therapy for presumed infiltrative optic neuropathy, and 4 patients underwent radiation therapy. Along with systemic chemotherapy, all patients received intrathecal chemotherapy except one. Three patients received chimeric antigen receptor T-cell therapy.

Conclusions:

Leukemic and lymphomatous optic neuropathy is difficult to diagnose and treat, and there is no gold standard for diagnosis or treatment in the current literature. We help clarify how this disease should be approached in a multidisciplinary fashion and on an individual basis to correctly diagnose and treat the vision loss, while considering the patient's long-term prognosis based on their systemic disease.
Personal observations on COVID-19 and the conduct and application of biomedical science
Authors: Smith J. C. , Goodhew David W.
Published: October 2021

We begin by describing our observations of the ways in which the conduct of research has changed during the COVID-19 pandemic and go on to comment on the quality of the scientific advice that is provided to UK citizens, and especially to schools. Researchers, like many, have suffered from the effects of the pandemic. Those hardships notwithstanding, we suggest that research into COVID-19 has benefitted from a ‘seed corn’ of discovery science that has provided the basis for routine diagnostic PCR and antibody tests; for structural analyses of the way in which the SARS-CoV-2 virus interacts with cells; for the development of new treatments (and the debunking of ineffective ones); for studies of the genetics of susceptibility to SARS-CoV-2; and for the development of vaccines. The speed of dissemination of research has benefitted from the widespread use of pre-prints, and researchers and funders have become more nimble in their approaches to research and more willing to change their priorities in the face of the pandemic. In our experience, the advice provided to schools on the basis of this research was, however, often published at the last minute and was frequently flawed or inconsistent. This has led to a widening of the attainment gap between children from disadvantaged backgrounds and their peers and it has exacerbated the digital divide and holiday hunger. The consequences will be felt for many years to come and will jeopardize diversity in research and other careers.
Formal and informal science advice in emergencies: COVID-19 in the UK
Authors: Whitty Christopher J. M. , Collet-Fenson Luke B.
Published: October 2021

The importance of scientific advice to government gains greater recognition in emergencies but inevitably has to be done in an environment of uncertainty, with limited data and at high speed. Adapting existing structures is more effective than creating new ones in an emergency. Between emergencies, the UK has a structured scientific advice system, including Chief Scientific Advisers, scientists in government, regulatory bodies and independent expert committees, which were adapted to COVID-19 under the umbrella of the Scientific Advisory Group for Emergencies. These worked alongside networks of informal scientific advice, including internationally. Multiple sciences were needed, including from the social sciences and engineering in addition to clinical science and epidemiology, and these had to be integrated. A centrally directed clinical research programme helped provide practitioners robust evidence, with observational and interventional trials providing data for policy and testing treatments and vaccines. The scale of the emergency meant unavoidable tension between detailed work and speed, and between an integrated scientific view usable in decision-making and constructive challenge. While a final judgement of the UK scientific response will take time, everyone should be grateful to the thousands of scientists involved for the research, synthesis and advice, which improved outcomes for the public.
Pectobacterium quasiaquaticum sp. nov., isolated from waterways
Authors: Ben Moussa Hajar , Pédron Jacques , Bertrand Claire , Hecquet Amandine , Barny Marie-Anne
Published: October 2021

Through this study, we established the taxonomic status of seven strains belonging to the genus

Pectobacterium

(A477-S1-J17T, A398-S21-F17, A535-S3-A17, A411-S4-F17, A113-S21-F16, FL63-S17 and FL60-S17) collected from four different river streams and an artificial lake in south-east France between 2016 and 2017. Ecological surveys in rivers and lakes pointed out different repartition of strains belonging to this clade compared to the closest species,

Pectobacterium aquaticum

. The main phenotypic difference observed between these strains and the

P. aquaticum

type strain was strongly impaired growth with rhamnose as the sole carbon source. This correlates with three different forms of pseudogenization of the l-rhamnose/proton symporter gene rhaT in the genomes of strains belonging to this clade. Phylogenetic analysis using gapA gene sequences and multi locus sequence analysis of the core genome showed that these strains formed a distinct clade within the genus

Pectobacterium

closely related to P. aquaticum. Digital DNA–DNA hybridization (dDDH) and average nucleotide identity (ANI) values showed a clear discontinuity between the new clade and

P. aquaticum

. However, the calculated values are potentially consistent with either splitting or merging of this new clade with

P. aquaticum

. In support of the split, ANI coverages were higher within this new clade than between this new clade and

P. aquaticum

. The split is also consistent with the range of observed ANI or dDDH values that currently separate several accepted species within the genus

Pectobacterium

. On the basis of these data,strains A477-S1-J17T, A398-S21-F17, A535-S3-A17, A411-S4-F17, A113-S21-F16, FL63-S17 and FL60-S17 represent a novel species of the genus

Pectobacterium

, for which the name Pectobacterium quasiaquaticum sp. nov. is proposed. The type strain is A477-S1-J17T (=CFBP 8805T=LMG 32181T).
Factors Associated with the Risk of HIV Infection among HIV-exposed Infants in Malawi: 2013-2020
Authors: Ng’ambi Wingston , Estill Janne , Merzouki Fatma Aziza , Orel Erol , Chimpandule Tiwonge , Nyirenda Rose , Keiser Olivia
Published: October 2021

Background

Despite the high availability of individual-level data of infants accessing HIV DNA polymerase chain reaction (DNA-PCR) testing service, there has been little in-depth analysis of such data. Therefore, we describe spatial and temporal trends in risk of HIV infection among Malawi’s HIV-exposed infants (HEI) with DNA-PCR HIV test result from 2013 to 2020.

Methods

This is an implementation study using routinely collected patient-level HIV DNA-PCR test result data extracted from the national Laboratory Management Information System database managed by the Department of HIV/AIDS between 1 January 2013 and 30 June 2020. We calculated frequencies, proportions and odds ratios (OR) with their associated 95% confidence intervals (95%CI). We performed a random-effects logistic regression to determine the risk factors associated with HIV infection in infants, controlling for the spatial autocorrelation between districts and adjusting for other variables.

Results

We evaluated 255,229 HEI across 750 facilities in 28 districts. The overall risk of HIV infection among all tested HEI between 2013 and 2020 was 7.2% (95%CI: 7.1-7.3). We observed a decreasing trend in the proportion of HEI that tested HIV positive from 7.0% (95%CI: 6.6-7.4) in 2013 to 5.7% (95%CI: 5.4-5.9) in 2015 followed by an increase to 9.9% (95%CI: 9.6-10.2) in 2017 and then a decreasing trend to 4.2% (95%CI: 3.7-4.6) in 2020. The risk of HIV infection increased by age of the HEI. There was spatial heterogeneity of HIV prevalence between districts of Malawi.

Conclusion

We summarised spatial and temporal trends of risk of HIV infection amongst HEI in Malawi between 2013 and 2020. There is need for further strengthening of EID program to ensure that all the HEI are enrolled in care by eight weeks of age in order to further reduce mother-to-child transmission of HIV.

Key message

There is need for further strengthening of the Malawi early infant diagnosis program to ensure that all the HIV-exposed infants are enrolled in care by eight weeks of age in order to eliminate mother-to-child transmission of HIV by 2030.

What is known about the study?

Malawi has implemented the Early Infant Diagnosis (EID) since 2009. Most of the studies on EID in Malawi have focused on just one or two health facilities.

What the study adds?

This is to our knowledge the first in-depth analysis of national routine data on HIV DNA-PCR tests among HIV-exposed infants with in Malawi. Our study has shown that there is spatial and temporal heterogeneity in risk of HIV infection amongst the HEI in Malawi between 2013 and 2020.
DIETARY MANIPULATION OF THE GUT MICROBIOME IN INFLAMMATORY BOWEL DISEASE PATIENTS: PROOF OF CONCEPT
Authors: Olendzki Barbara , Bucci Vanni , Cawley Caitlin , Maserati Rene , McManus Margaret , Olendzki Effie , Madziar Camilla , Chiang David , Ward Doyle V. , Pellish Randall , Foley Christine , Bhattarai Shakti , McCormick Beth A. , Maldonado-Contreras Ana
Published: October 2021

Diet is a modifiable, non-invasive, inexpensive behavior that is crucial in shaping the intestinal microbiome. A microbiome “imbalance” or dysbiosis in inflammatory bowel disease (IBD) is linked to inflammation. Here, we aim to define the impact of specific foods on bacterial species commonly depleted in patients with IBD to better inform dietary treatment. We performed a single-arm, pre-post intervention trial. After a baseline period, a dietary intervention with the IBD-Anti-Inflammatory Diet (IBD-AID) was initiated. We collected stool and blood samples and assessed dietary intake throughout the study. We applied advanced computational approaches to define and model complex interactions between the foods reported and the microbiome. A dense dataset comprising 553 dietary records and 340 stool samples was obtained from 22 participants. Consumption of prebiotics, probiotics, and beneficial foods correlated with increased abundance of Clostridia and Bacteroides, commonly depleted in IBD cohorts. We further show that the IBD-AID intervention affects the immune tone by lowering IL-8 and increasing GM-CSF with certain foods correlating with levels of those cytokines. By using robust predictive analytics, this study represents the first steps to detangle diet-microbiome interactions to inform personalized nutrition for patients suffering from dysbiosis-related IBD.
Improved morpho-syntax in discourse following intensive voice treatment in Parkinson’s disease: Secondary outcome variables from a Randomized Controlled Trial (RCT)
Authors: Ramage Amy E. , Greenslade Kathryn J. , Cote Kaila , Lee Jessica N. , Fox Cynthia M. , Halpern Angela , Ramig Lorraine O.
Published: October 2021

It is well established that voice is disordered in nearly 90% of individuals with Parkinson’s disease (PD). Given the role of voice in language expression, we pose that optimizing vocal function may lead to improved language production. Verb production is an area of language deficit in PD, particularly for verbs associated with an individual’s location of impairment (upper vs. lower limbs). It is thought that damage to the motor system, given its connection to action verbs, underlies this lexical effect. If this is the case, then treatment improving vocal motor function may also improve access to verbs. Nineteen participants with PD underwent Lee Silverman Voice Treatment (LSVT LOUD®), a 4-week intensive voice treatment (TXPD), in an IRB-approved randomized controlled voice treatment trial. Language production was contrasted with 20 untreated PD (UNTXPD) and 20 age-matched neurotypical control participants. Each provided 1-minute picture description narratives at baseline and after 4-weeks. Pre-post treatment within- and between-group comparisons identified effects of assessment time point and isolated treatment effects in the TXPD relative to UNTXPD and Controls. Given the intervention, the TXPD group demonstrated a significant increase in loudness during the picture description, as well as increased utterance length, diversity of word types used, verbs per utterance, and lexical density.
Evaluation of determinants of the serological response to the split-inactivated influenza vaccine
Authors: Wu Shaohuan , Ross Ted M. , Carlock Michael A. , Ghedin Elodie , Choi Hyungwon , Vogel Christine
Published: October 2021

The seasonal influenza vaccine is only effective in half of the vaccinated population. To identify determinants of vaccine efficacy, we used data from >1,300 vaccination events to predict the response to vaccination measured as seroconversion as well as hemagglutination inhibition (HAI) levels one year after. We evaluated the predictive capabilities of age, body mass index (BMI), sex, race, comorbidities, prevaccination history, and baseline HAI titers, as well as vaccination month and vaccine dose in multiple linear regression models. The models predicted the categorical response for >75% of the cases in all subsets with one exception. Prior vaccination, baseline titer level, and age were the strongest determinants on seroconversion, all of which had negative effects. Further, we identified a gender effect in older participants, and an effect of vaccination month. BMI played a surprisingly small role, likely due to its correlation with age. Comorbidities, vaccine dose, and race had negligible effects. Our models can generate a new seroconversion score that is corrected for the impact of these factors which can facilitate future biomarker identification.
Leveraging large multi-center cohorts of Alzheimer Disease endophenotypes to understand the role of Klotho heterozygosity on disease risk
Authors: Ali Muhammad , Sung Yun Ju , Wang Fengxian , Fernández Maria V. , Morris John C. , Fagan Anne M. , Blennow Kaj , Zetterberg Henrik , Heslegrave Amanda , Johansson Per M , Svensson Johan , Nellgård Bengt , Lleo Alberto , Alcolea Daniel , Clarimon Jordi , Rami Lorena , Molinuevo José Luis , Suárez-Calvet Marc , Morenas-Rodríguez Estrella , Kleinberger Gernot , Haass Christian , Ewers Michael ,   the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Cruchaga Carlos
Published: October 2021

Two genetic variants (rs9536314 and rs9527025) in the Klotho gene, encoding a transmembrane protein, implicated on longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively healthy individuals that are APOE4 carriers. Specifically, the individuals heterozygous for this variant (KL-SVHET+), showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+has been suggested against amyloid burden for cognitively normal individuals. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we have performed a well-powered association analysis between KL-VSHET+and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+status with biomarkers for brain amyloidosis (e.g. CSF Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55-0.78], β = 0.72,P= 0.007) and tau pathology (e.g. biomarker negative for CSF Tau; OR = 0.39 [95% CI, 0.19-0.77], β = -0.94,P= 0.007, and pTau; OR = 0.50 [95% CI, 0.27-0.96], β = -0.68,P= 0.04) in elderly (60-80 years old) individuals that are cognitively normal and APOE4 carriers. Our work supports previous findings and suggests that the KL-VSHET+on a APOE4 genotype background may exert a protective effect by modulating the Aβ, Tau, and pTau burden and resulting cognitive decline in older controls susceptible to AD. The biological mechanism underlying APOE4 and KL-VSHET+interaction and the neuroprotective effect of KL-related pathways against amyloid accumulation may warrant future investigation as a target for preclinical pharmacological studies to explore novel AD drug targets.
DIRC3-IGFBP5 is a shared genetic risk locus and therapeutic target for carpal tunnel syndrome and trigger finger
Authors: Patel Benjamin , Kleeman Sam O. , Neavin Drew , Powell Joseph , Baskozos Georgios , Ng Michael , Ahmed Waheed-Ul-Rahman , Bennett David L. , Schmid Annina , Furniss Dominic , Wiberg Akira
Published: October 2021

Trigger finger (TF) and carpal tunnel syndrome (CTS) are two common non-traumatic hand disorders that frequently co-occur. By identifying TF and CTS cases in UK Biobank (UKB), we confirmed a highly significant phenotypic association between the diseases. To investigate the genetic basis for this association we performed a genome-wide association study (GWAS) including 2,908 TF cases and 436,579 European controls in UKB, identifying five independent loci. Colocalization with CTS summary statistics identified a co-localized locus at DIRC3 (lncRNA), which was replicated in FinnGen and fine-mapped to rs62175241. Single-cell and bulk eQTL analysis in fibroblasts from healthy donors (n=79) and tenosynovium samples from CTS patients (n=77) showed that the disease-protective rs62175241 allele was associated with increased DIRC3 and IGFBP5 expression. IGFBP5 is a secreted antagonist of IGF-1 signaling, and elevated IGF-1 levels were associated with CTS and TF in UKB, thereby implicating IGF-1 as a driver of both diseases.
ATP-citrate lyase as a therapeutic target in chronic kidney disease: a Mendelian Randomization analysis
Authors: Mohammadi-Shemirani Pedrum , Chong Michael , Perrot Nicolas , Pigeyre Marie , Steinberg Gregory R. , Paré Guillaume , Krepinsky Joan C. , Lanktree Matthew B.
Published: October 2021

Background

ATP-citrate lyase (ACLY) inhibition is a promising therapeutic target for dyslipidemia, atherosclerotic cardiovascular disease, non-alcoholic steatohepatitis, and metabolic syndrome. Genetic analysis of its role in chronic kidney disease (CKD) has not been performed.

Methods

We constructed a genetic instrument by selecting variants associated with ACLY expression level in the expression quantitative trait loci genetics consortium (eQTLGen) that includes blood samples from 31,684 participants. In a two-sample Mendelian randomization analysis, we then evaluated the effect of genetically predicted ACLY expression on risk of CKD, estimated glomerular filtration rate (eGFR), and microalbuminuria using the CKD Genetics consortium (CKDGen), United Kingdom biobank, and the Finnish Genetics consortium (FinnGen) totaling 66,396 CKD cases and 958,517 controls.

Results

ACLY is constitutively expressed in all cell types including in whole blood. The genetic instrument included 13 variants and explained 1.5% of variation in whole blood ACLY gene expression. A 34% reduction in genetically predicted ACLY expression was associated with a 0.04 mmol/L reduced low-density lipoprotein cholesterol (P = 3.4 × 10−4) and a 9% reduced risk of CKD (stage 3,4,5, dialysis or eGFR below 60 ml/min/1.73m2) (OR = 0.91, 95% C.I. 0.85-0.98, P = 0.008), but no association was observed with eGFR nor microalbuminuria.

Conclusion

Mendelian Randomization analysis provides cautious optimism regarding the possibility of ACLY as a therapeutic target for CKD.
Monitoring and forecasting the COVID-19 epidemic in Moscow: model selection by balanced identification technology - version: September 2021
Authors: Sokolov Alexander , Sokolova Lyubov
Published: October 2021

A mathematical model is a reflection of knowledge on the real object studied. The paper shows how the accumulation of data (statistical data and knowledge) about the COVID-19 pandemic lead to gradual refinement of mathematical models, to the expansion of the scope of their use. The resulting model satisfactorily describes the dynamics of COVID-19 in Moscow from 19.03.2020 to 01.09.2021 and can be used for forecasting with a horizon of several months. The dynamics of the model is mainly determined by herd immunity. Monitoring the situation in Moscow has not yet (as of 01.09.2021) revealed noticeable seasonality of the disease nor an increase in infectivity (due to the Delta strain). The results of using balanced identification technology to monitor the COVID-19 pandemic are:

models corresponding to the data available at different points in time (from March 2020 to August 2021);

new knowledge (dependencies) acquired;

forecasts for the third and fourth waves in Moscow.

Discrepancies that manifested after 01.09.2021 and possible further modifications of the model are discussed
TNFα SIGNALLING IN THE CUTANEOUS IMMUNE NETWORK INSTRUCTS LOCAL Th17 ALLERGEN-SPECIFIC INFLAMMATORY RESPONSES IN ATOPIC DERMATITIS
Authors: Sirvent Sofia , Vallejo Andres , Corden Emma , Teo Ying , Davies James , Clayton Kalum , Seaby Eleanor , Lai Chester , Ennis Sarah , Alyami Rfeef , Dean Lareb , Loxham Matthew , Horswill Sarah , Healy Eugene , Roberts Graham , Hall Nigel J. , Bennett Clare L. , Friedmann Peter , Singh Harinder , Ardern-Jones Michael , Polak Marta E
Published: October 2021

Accurate regulation of cutaneous immunity is fundamental for human health and quality of life but is severely compromised in inflammatory skin disease. To investigate the molecular crosstalk underpinning tolerance vs inflammation in human skin, we set up a human in vivo allergen challenge study, exposing patients with atopic dermatitis (AD) to house dust mite (HDM). Analyses of transcriptional programmes at the population and single cell levels in parallel with immunophenotyping of resident and infiltrating immune cells indicated that inflammatory responses to HDM were associated with immune activation in Langerhans cells (LCs) and cutaneous T cells. High basal level of TNFα production by cutaneous Th17 T cells predisposed to an inflammatory reaction and resulted in formation of hub structures where LCs and T cells interacted, leading to loss of functional programming in LCs. Additionally, single nucleotide polymorphisms in MT1X gene associated with enhanced expression of metallothioneins and transcriptional programmes encoding antioxidant defences across skin cell types in non-reactive patients, were protective against T cell mediated inflammation. Our results provide a unique insight into the dynamics of immune regulation in the human skin and define regulatory circuits that can be harnessed to improve skin health and treat disease.
Linking Profiles of Pathway Activation with Clinical Motor Improvements – a Retrospective Computational Study
Authors: Butenko Konstantin , Li Ningfei , Neudorfer Clemens , Roediger Jan , Horn Andreas , Wenzel Gregor R. , Eldebakey Hazem , Kühn Andrea A. , Reich Martin , Volkmann Jens , van Rienen Ursula
Published: October 2021

Deep brain stimulation (DBS) is an established therapy for patients with Parkinson’s disease.In silicocomputer models for DBS allow to pre-select a set of potentially optimal stimulation parameters. If efficacious, they could further carry insight into the mechanism of action of DBS and foster the development of more efficient stimulation approaches. In recent years, the focus has shifted towards DBS-induced firing in myelinated axons, deemed particularly relevant for the external modulation of neural activity. We use the concept of pathway activation modeling, which incorporates advanced volume conductor models and anatomically authentic fiber trajectories to estimate DBS-induced action potential initiation in anatomically plausible pathways that traverse in close proximity to targeted nuclei. We apply the method on a retrospective dataset with the aim of providing a model-based prediction of clinical improvement following DBS (as measured by the motor part of the Unified Parkinson’s Disease Rating Scale). Based on differences in outcome and activation rates for two DBS protocols in a training cohort, we compute a theoretical 100% improvement profile and enhance it by analyzing the importance of profile matching for individual pathways. Finally, we validate the performance of our profile-based predictive model in a test cohort. As a result, we demonstrate the clinical utility of pathway activation modeling in the context of motor symptom alleviation in Parkinson’s patients treated with DBS.
Diagnostic accuracy of point-of-care lung ultrasound for COVID-19: A systematic review and meta-analysis
Authors: Matthies Ashley K. , Trauer Michael M. , Chopra Karl , Jarman Robert
Published: October 2021

Background

Point-of-care (POC) lung ultrasound (LUS) is widely used in the emergency setting and there is an established evidence base across a range of respiratory diseases, including previous viral epidemics. The necessity for rapid testing combined with the limitations of other diagnostic tests has led to the proposal of various potential roles for LUS during the COVID-19 pandemic. This systematic review and meta-analysis focused specifically on the diagnostic accuracy of LUS in adult patients presenting with suspected COVID-19.

Methods

Traditional and grey-literature searches were performed on June 1st2021. Two authors independently carried out the searches, selected studies and completed the Quality Assessment Tool for Diagnostic Test Accuracy Studies (QUADAS-2). Meta-analysis was carried out using established open-source packages inR. We report overall sensitivity, specificity, positive and negative predictive values and the hierarchical summary receiver operating characteristic curve for LUS. Heterogeneity was determined using the I2statistic.

Results

Twenty studies were included, providing data from a total of 4,314 patients. The prevalence and admission rates were generally high across all studies. Overall LUS was found to be 87.2% sensitive (95% CI 83.6-90.2) and 69.5% specific (95% CI 62.2-72.5) and demonstrated overall positive and negative predictive values of 3.0 (95% 2.3-4.1) and 0.16 (95% 0.12-0.22) respectively. Separate analyses for each reference standard revealed similar sensitivities and specificities for LUS. Heterogeneity between studies was found to be high, and QUADAS-2 assessment identified risks of bias in many studies.

Conclusion

During a period of high prevalence, LUS is a highly sensitive diagnostic test for COVID-19. However, more research is required to confirm these results in more generalisable populations, including those less likely to be admitted to hospital.
Meeting Measurement Precision Requirements for Effective Engineering of Genetic Regulatory Networks
Authors: Beal Jacob , Teague Brian , Sexton John T. , Castillo-Hair Sebastian , DeLateur Nicholas A. , Samineni Meher , Tabor Jeffery J. , Weiss Ron
Published: October 2021

Reliable, predictable engineering of cellular behavior is one of the key goals of synthetic biology. As the field matures, biological engineers will become increasingly reliant on computer models that allow for the rapid exploration of design space prior to the more costly construction and characterization of candidate designs. The efficacy of such models, however, depends on the accuracy of their predictions, the precision of the measurements used to parameterize the models, and the tolerance of biological devices for imperfections in modeling and measurement. To better understand this relationship, we have derived an Engineering Error Inequality that provides a quantitative mathematical bound on the relationship between predictability of results, model accuracy, measurement precision, and device characteristics. We apply this relation to estimate measurement precision requirements for engineering genetic regulatory networks given current model and device characteristics, recommending a target standard deviation of 1.5-fold. We then compare these requirements with the results of an interlaboratory study to validate that these requirements can be met via flow cytometry with matched instrument channels and an independent calibrant. Based on these results, we recommend a set of best practices for quality control of flow cytometry data and discuss how these might be extended to other measurement modalities and applied to support further development of genetic regulatory network engineering.
Extremely thermophilic endospores germinate and metabolise organic carbon in sediments heated to above 80°C
Authors: Bell Emma , Rattray Jayne E. , Sloan Kathryn , Sherry Angela , Pilloni Giovanni , Hubert Casey R. J.
Published: October 2021

Endospores of thermophilic bacteria are widespread in cold seabed environments where they remain dormant during initial burial in accumulating sediments. The temperature increase during sedimentation can be simulated in experimental heating of sediments, resulting in the temperature-dependent activation of different endospore populations from the microbial seed bank. Here we investigated the response of endospore populations to heating at extreme high temperature (80– 99°C). Metabolites for germination and organic matter degradation (dipicolinic acid and organic acids) revealed both endospore germination and subsequent metabolism at ≥80°C. Endospore-forming Firmicutes with the genomic potential for organic carbon and nitrogen transformation were recovered by genome-resolved metagenomics. Genomes from Symbiobacteriales, Thermosediminibacteriales, Moorellales and Calditerricolales encode multiple mechanisms for high temperature degradation of sedimentary organic carbon and features of necromass that accumulate during sediment burial including saccharides, amino and nucleic acids. The results provide insight into the metabolism of novel carbon cycling microorganisms activated at high temperature, and suggest that extremely thermophilic Firmicutes dispersed in the ocean are poised to germinate in response to sediment heating during burial and transform a wide range of organic substrates.