bluuebunny/crossref_metadata_2025 huggingface dataset:
The Preventive Treatment of Migraine with Low-Dose naltrexone and acetaminophen Combination: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial with an Open-Label Extension for None-Responders
Authors: Toledano Annette C.
Published: March 2021

We tested a low-dose naltrexone and acetaminophen combination for episodic migraine prevention. We randomly assigned patients to naltrexone and acetaminophen combination (n=6) or placebo (n=6) for a 12-week double-blind treatment. Non-responders continued into open-label treatment with naltrexone and acetaminophen combination (n=5) for additional 12 weeks. Patients were adults who experienced 5 to 17 (average 9.7) migraine days at baseline. The primary endpoint was the mean change in the monthly migraine days during the last 4 weeks of the double-blind treatment period. The key secondary endpoint was the mean change in the monthly migraine days from the 4-week double-blind follow-up (2nd baseline) to the last 4 weeks of the open-label treatment period.

The magnitude of the treatment effect for the naltrexone and acetaminophen combination observed in the double-blind period was 2.2 fewer monthly migraine days than placebo (p=0.43). Four out of 6 (66.7%) naltrexone and acetaminophen-treated patients experienced 75% reduction in migraine days compared to 1 out of 6 (16.7%) placebo-treated patients (p=0.09).

In the open-label phase, treatment with the naltrexone and acetaminophen combination (n=5) led to 8.2 fewer mean monthly migraine days (from 11.8 to 3.6), representing 69.5% improvement (p=0.03), and 100% of the patients experienced a 50% reduction in monthly migraine days. Adverse events were mild to moderate and transient, included dry mouth, fatigue, sedation, nausea, and feeling jittery.

We postulate that naltrexone’s toll-like receptor (TLR4) antagonism properties prevent pro-inflammatory cytokines’ production in the trigeminal ganglion averting “overactive nerves” (layman’s term) and migraine. Although this trial used low-dose naltrexone (defined as 1 – 5 mg/day), in future phase 3 studies we will test a range of naltrexone and acetaminophen combination doses.
A randomised controlled pilot trial of oral 11β-HSD1 inhibitor AZD4017 for wound healing in adults with type 2 diabetes mellitus
Authors: Ajjan Ramzi , Hensor Elizabeth MA , Shams Kave , Del Galdo Francesco , Abbas Afroze , Woods Janet , Fairclough Rebecca J , Webber Lorraine , Pegg Lindsay , Freeman Adrian , Morgan Ann , Stewart Paul M , Taylor Angela E , Arlt Wiebke , Tahrani Abd , Russell David , Tiganescu Ana
Published: March 2021

Chronic wounds (e.g. diabetic foot ulcers) have a major impact on quality of life, yet treatments remain limited. Glucocorticoids impair wound healing; preclinical research suggests that blocking glucocorticoid activation by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves wound repair. This investigator-initiated double-blind, randomised, placebo-controlled parallel-group phase 2b pilot trial investigated efficacy, safety and feasibility of 11β-HSD1 inhibition for 35 days by oral AZD4017 (AZD) treatment in adults with type 2 diabetes (n=14) compared to placebo (PCB, n=14) in a single-centre secondary care setting. Computer-generated 1:1 randomisation was pharmacy-administered. From 300 screening invitations, 36 attended, 28 were randomised. There was no proof-of-concept that AZD inhibited 24 hour skin 11β-HSD1 activity at day 28 (primary outcome: adjusted difference AZD-PCB 90% CI (diffCI)=-3.4,5.5) but systemic 11β-HSD1 activity (median urinary [THF+alloTHF]/THE ratio) was 87% lower with AZD at day 35 (PCB 1.00, AZD 0.13, diffCI=-1.04,-0.69). Mean wound gap diameter (mm) following baseline 2mm punch biopsy was 34% smaller at day 2 (PCB 1.51, AZD 0.98, diffCI=-0.95,-0.10) and 48% smaller after repeat wounding at day 30 (PCB 1.35, AZD 0.70, diffCI=-1.15,-0.16); results also suggested greater epidermal integrity but modestly impaired barrier function with AZD. AZD was well-tolerated with minimal side effects and comparable adverse events between treatments. Staff availability restricted recruitment (2.9/month); retention (27/28) and data completeness (95.3%) were excellent. These preliminary findings suggest that AZD may improve wound healing in patients with type 2 diabetes and warrant a fully-powered trial in patients with active ulcers. [Trial Registry: www.isrctn.com/ISRCTN74621291.

Funding

MRC Confidence in Concept and NIHR Senior Investigator Award.]

Single Sentence Summary

AZD4017 was safe; data suggested improved skin healing / integrity, and modestly reduced epidermal barrier function in patients with type 2 diabetes.

Disclosure Summary

I certify that neither I nor my co-authors have a conflict of interest as described above that is relevant to the subject matter or materials included in this Work.
Toward Community Surveillance: Detecting Intact SARS-CoV-2 Using Exogeneous Oligonucleotide Labels
Authors: Carey Thomas R. , Kozminsky Molly , Hall Jennifer , Vargas-Zapata Valerie , Geiger Kristina , Coscoy Laurent , Sohn Lydia L.
Published: March 2021

The persistence of the COVID-19 pandemic demands a dramatic increase in testing efficiency. Testing pooled samples for SARS-CoV-2 could meet this need; however, the sensitivity of RT-qPCR, the gold standard, significantly decreases with an increasing number of samples pooled. Here, we introduce DIVER, a method that quantifies intact virus and is robust to sample dilution. DIVER first tags viral particles with exogeneous oligonucleotides, then captures the tagged particles on ACE2-functionalized beads, and finally quantifies the oligonucleotide tags using qPCR. Using spike-presenting liposomes and Spike-pseudotyped lentivirus as SARS-CoV-2 models, we show that DIVER can detect 1×105 liposomes and 100 pfu lentivirus and can successfully identify positive samples in pooling experiments. Overall, DIVER is well-positioned for efficient sample pooling and expanded community surveillance.
Association between the physical work environment and work functioning impairment while working from home under the COVID-19 pandemic in Japanese workers
Authors: Okawara Makoto , Ishimaru Tomohiro , Tateishi Seiichiro , Hino Ayako , Tsuji Mayumi , Ikegami Kazunori , Nagata Masako , Matsuda Shinya , Fujino Yoshihisa ,   for the CORoNaWork project
Published: March 2021

Objective

This study examined the relationship between the physical work environment and work functioning impairment while working from home in the context of rapid changes associated with the COVID-19 pandemic.

Methods

This cross-sectional study of internet monitors was conducted between December 22 and 26, 2020. Of a total of 33,302 participants, 5,760 who worked from home at least 1 day a month, excluding those who met the exclusion criteria, were included in the analysis. A binary subjective assessment of the physical work environment while working from home was used as an exposure factor. We examined 9 items related to the physical work environment, including level of illuminance and use of suitable desks and chairs, traditionally recommended for health and safety management when working at a desk. The number of non-conformities to 7 items was also used as an exposure factor. The presence of severe work functioning impairment was measured using the Work Functioning impairment Scale (WFun), a self-reported outcome measure of the degree of work functioning impairment. Odds ratios of severe work functioning impairment were estimated using mixed-effects logistic regression analysis with the prefecture of residence as a random effect.

Results

Multivariate analysis showed that the odds ratio of severe work functioning impairment was significantly higher among those who indicated “No” to all recommended items except for “I work at a desk/chair for office use.” The highest odds ratio of work functioning impairment was associated with a “No” response to “There is enough light to do my work” (aOR: 2.02, 95%CI: 1.73–2.35, p<0.01). Our results also suggest the presence of a dose-response relationship between the number of non-conformities to recommendations for work environments while working from home and work functioning impairment.

Conclusions

Our findings suggest that it is important for both companies and individual workers to create a work environment that prevents negative health outcomes and improves productivity while working from home.
Trends in clinical characteristics and associations of severe non-respiratory events related to SARS-CoV-2
Authors: El-Hay Tal , Karavani Ehud , Peretz Asaf , Ninio Matan , Ravid Sivan , Chorev Michal , Rosen-Zvi Michal , Patalon Tal , Shimoni Yishai , Jain Anil
Published: March 2021

Background

The 2019 novel coronavirus (SARS-CoV-2) is reported to result in both respiratory and non-respiratory severe health outcomes, but quantitative assessment of the risk – while adjusting for underlying risk driven by comorbidities – is not yet established.

Methods

A retrospective observational study using electronic health records of 9,344,021 individuals across the U.S. with at-least 1 year of clinical history and followed up throughout 2020.

Results

131,329 individuals were associated with SARS-CoV-2 infection by January 6, 2021 in three distinct surges. While the age and number of preexisting conditions had decreased throughout the pandemic, the characteristics of those who experienced severe health events did not.

During the second surge, between June 7 and November 18, 2020, 425,988 individuals in the base cohort were admitted to emergency rooms or hospitals. Among them, 15,486 were detected with SAR-CoV-2 within few days of admission. Significant adjusted odds ratios were observed between SARS-CoV-2 infection and the following severe health events: respiratory (4.38, 95% confidence interval 4.16– 4.62), bacterial pneumonia (3.25, 2.76–3.83), sepsis (1.71, 1.53–1.91), renal (1.69, 1.57–1.83), hematologic/immune (1.32, 1.20–1.45), neurological (1.23, 1.09–1.38).

Conclusions

SARS-CoV-2 infection among hospitalized patients is associated with non-negligible increased risk of severe events including multiple non-respiratory ones. These associations, which complement recent studies, are persistent even after accounting for sources of selection and confounding bias, increasing the confidence they are not spurious.
Tenofovir-DF versus Hydroxychloroquine in the Treatment of Hospitalized Patients with COVID-19: An Observational Study (TEDHICOV)
Authors: Cornejo-Giraldo Mario , Rosado Nelson , Salinas Jesús , Aspilcueta Nelson , Bernales Eduardo , Lipa Jimmy , Coacalla Johanna , Flores Yoisi , Leon Pamela , Chamby Claudia
Published: March 2021

Background

Although several therapeutic agents have been suggested for the treatment of the disease caused by the Coronavirus of the year 2019 (COVID-19), no antiviral has yet demonstrated consistent efficacy.

Methods

The results of an observational study comparing Tenofovir-DF (TDF) with Hydroxychloroquine (HCQ) in the treatment of hospitalized patients with COVID-19 with evidence of pulmonary compromise and the vast majority with supplemental oxygen requirement are presented. Patients received HCQ consecutively at the dose of 400 mg. 12 hourly for 01 day and then 200 mg. every 8 to 12 hours PO for 5 to10 days; or TDF 300 mg. per day PO for 7 to 10 days. The primary outcomes of the study were the differences between the two groups regarding: hospital stay, the need for intensive care or mechanical ventilation (ICU / MV) and mortality.

Results

104 patients were included: 36 in the HCQ group and 68 in the TDF group. The unadjusted primary outcomes were: LOS (length of stay) 16.6 ± 12.1 for HCQ versus 12.2 ± 7.0 days for TDF (p = o.o102); need for admission to ICU / mechanical ventilation (MV): 61.1% for HCQ versus 11.8% for TDF (p = o.ooo); and mortality: 50.0% for HCQ and 8.8% for TDF (p = o.ooo). The patients in the HCQ group had significant differences at admission compared to those in the TDF group regarding: male sex, cardiovascular risk factor, greater respiratory involvement and higher glucose and creatinine levels, lower albumin levels and higher. Inflammatory markers. When the outcomes were adjusted for these baseline differences, in the multiple regression model for LOS, it was found that TDF decreased the hospital stay by 6.10 days (C.I.: −11.97 to −2.40, p = o.o42); In the logistic regression model for the need for ICU / MV, it was found that the use of TDF had an O.R. of 0.15 (C.I.: 0.03-0.76, p = o.o22); and for the Cox proportional hazards model for mortality, the H.R. was 0.16 for TDF (C.I.: 0.03-0.96, p = o.o41). In the estimation model of the treatment effects by regression adjustment, it was found that TDF decreased the stay by −6.38 days (C.I.: −12.34 to −0.42, p = o.o36); the need for ICU / MV at −41.74% (C.I.: −63.72 to −19.7, p = o.ooo); and mortality by −35.22% (C.I.: −56.47 to −13.96, p = o.oo1).

Conclusion

TDF may be an effective antiviral in the treatment of COVID-19. Some of its advantages include: its wide availability, cost and oral presentation. Randomized clinical trials are imperatively required to confirm this possibility.
Hospital mortality in COVID-19 patients in Belgium treated with statins, ACE inhibitors and/or ARBs
Authors: Byttebier Geert , Belmans Luc , Alexander Myriam , Saxberg Bo E.H. , De Spiegeleer Bart , De Spiegeleer Anton , Devrecker Nick , Van Praet Jens T. , Vanhove Karolien , Reybrouck Reinhilde , Wynendaele Evelien , Fedson David S.
Published: March 2021

The COVID-19 pandemic has disrupted life throughout the world. Newly developed vaccines promise relief to people who live in high-income countries, although vaccines and expensive new treatments are unlikely to arrive in time to help people who live in low-and middle-income countries. The pathogenesis of COVID-19 is characterized by endothelial dysfunction. Several widely available drugs like statins, ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have immunometabolic activities that (among other things) maintain or restore endothelial cell function. For this reason, we undertook an observational study in four Belgian hospitals to determine whether in-hospital treatment with these drugs could improve survival in 959 COVID-19 patients. We found that treatment with statins and ACEIs/ARBs reduced 28-day mortality in hospitalized COVID-19 patients. Moreover, combination treatment with these drugs resulted in a 3-fold reduction in the odds of hospital mortality (OR=0.33; 95% CI 0.17-0.69). These findings were in general agreement with other published studies. Additional observational studies and clinical trials are needed to convincingly show that in-hospital treatment with statins, ACEIs/ARBs, and especially their combination saves lives.
Effect of control measures on the pattern of COVID-19 Epidemics in Japan
Authors: Konishi Tomokazu
Published: March 2021

Background

COVID-19 has spread worldwide since its emergence in 2019. In contrast to many other countries with epidemics, Japan differed in that it avoided lockdowns and instead asked people for self-control. A travel campaign was conducted with a sizable budget, but the number of PCR tests was severely limited. These choices may have influenced the course of the epidemic.

Methods

The increase or decrease in the classes of SARS-CoV-2 variants was estimated by analyzing the published sequences with an objective multivariate analysis. This approach observes the samples in multiple directions, digesting complex differences into simpler forms. The results were compared over time with the number of confirmed cases, PCR tests, and overseas visitors. The kinetics of infection were analyzed using the logarithmic growth rate.

Results

The declared states of emergency failed to alter the movement of the growth rate. Three epidemic peaks were caused by domestically mutated variants. In other countries, there are few cases in which multiple variants have peaked. However, due to the relaxation of immigration restrictions, several infective variants have been imported from abroad and are currently competing for expansion, creating the fourth peak. By April 2021, these foreign variants exceeded 80%. The chaotic situation in Japan will continue for some time, in part because no effort has been made to identify asymptomatic carriers, and details of the vaccination program are undecided.
Dysregulated anterior insula reactivity as robust functional biomarker for chronic pain – convergent evidence from neuroimaging meta-analysis
Authors: Ferraro Stefania , Klugah-Brown Benjamin , Tench Christopher R , Yao Shuxia , Nigri Anna , Demichelis Greta , Bruzzone Maria Grazia , Becker Benjamin
Published: March 2021

Neurobiological pain models propose that the transition from acute to chronic pain is accompanied by neuropathological adaptations that mediate progressive pain processing dysfunctions. In contrast, meta-analytic studies on neurofunctional dysregulations in chronic pain have not revealed convergent evidence for robust alterations during experimental pain induction. Against this background, the present neuroimaging meta-analysis combined three different meta-analytic approaches with stringent study selection criteria for case-control functional magnetic resonance imaging experiments during acute pain processing with a focus on chronic pain disorders (i.e., fibromyalgia, irritable bowel syndrome, chronic low back pain, neuropathic pain; n = 295 patients, n = 211 controls; 86 foci). Across the meta-analytic approaches, convergent neurofunctional dysregulations in chronic pain patients were observed in the left anterior insula cortex, with study characteristics indicating generalized pain processing abnormalities. Seed-based resting-state functional connectivity based on a large publicly available dataset combined with a meta-analytic task-based approach identified the anterior insular region as a key node of an extended bilateral insula-fronto-cingular network, resembling the salience network. Moreover, the meta-analytic decoding showed that this region presents a high probability to be specifically activated during pain-related processes. Together, the present findings indicate that dysregulated left anterior insular activity represents a robust neurofunctional maladaptation and potential treatment target in chronic pain disorders.
Mapping dopaminergic projections in the human brain with resting-state fMRI
Authors: Oldehinkel Marianne , Llera Alberto , Faber Myrthe , Huertas Ismael , Buitelaar Jan K. , Bloem Bastiaan R. , Marquand Andre F. , Helmich Rick C. , Haak Koen V. , Beckmann Christian F.
Published: March 2021

The striatum receives dense dopaminergic projections making it a key region of the dopaminergic system. Its dysfunction has been implicated in various conditions including Parkinson’s disease and substance use disorder. However, the investigation of dopamine-specific functioning in humans is problematic as the striatum is highly interconnected and current MRI approaches are unable to differentiate between dopaminergic and other projections. Here, we demonstrate that “connectopic mapping” –a novel approach for characterizing fine-grained and overlapping modes of functional connectivity– can be used to map dopaminergic projections and as such, enables the investigation of dopamine-related functioning both in health and disease.

We applied connectopic mapping to resting-state functional MRI data of the Human Connectome Project (population cohort; N=839) and selected the second-order striatal connectivity mode for further analyses. We first validated its specificity to dopaminergic projections by demonstrating a very high spatial correlation (r=0.884) with dopamine transporter availability –a marker of dopaminergic projections– derived from DaT-SPECT scans of 209 healthy control subjects of the Parkinson’s Progression Markers Initiative. Next, we obtained the subject-specific second-order modes from 20 controls, and 39 Parkinson’s disease patients scanned under placebo and under dopamine replacement therapy (L-DOPA), and show that our proposed marker of dopamine function indeed tracks Parkinson’s disease diagnosis, symptom severity and sensitivity to L-DOPA. Finally, across 30 daily alcohol users and 38 daily smokers of the Human Connectome Project, we establish strong associations between the second-order striatal connectivity mode and self-reported weekly use of alcohol and nicotine.

Our findings provide compelling evidence that the second-order mode of functional connectivity in striatum maps onto dopaminergic projections, tracks inter-individual differences in symptom severity and L-DOPA sensitivity in Parkinson’s disease patients, and exhibits strong associations with levels of nicotine and alcohol use in a population-based cohort. We hereby provide a new biomarker for dopamine-related dysfunction in the human brain with potential clinical utility that could foster insights into the neurobiological underpinnings of various dopamine-associated conditions.
A comparative analysis of the health, financial, equity, and cost-effectiveness impacts of maxillofacial surgery in Guinea
Authors: Hamer Mirjam , Alcorn Dennis , Diallo Ibrahima , Bah Fatoumata B.Y , Conde Alhassane , Traoré Lancinè , Millimounou Etienne , Peacock Chelsea , Glasgo Chris , Linz Peter E. , Shrime Mark , Diallo Oumar Raphiou
Published: March 2021

Background

Non-governmental organizations (NGOs) play a substantive role in the delivery of surgical services in in low- and middle-income countries (LMICs).

Assessment of their outcomes, especially as they relate to outcomes of surgery done in country, remains limited.

Methods

A prospective analysis of maxillofacial surgery in Guinea. Outcomes of interest were changes in patient health, subjective well-being, and financial status; hardship financing and catastrophic expenditure; equitable distribution of surgical access; and cost-effectiveness.

Results

We followed 569 patients requiring maxillofacial surgery in Conakry, Guinea, 114 of whom got care at local university hospitals, and 455 of whom got their care with Mercy Ships, a surgical NGO. Patients were followed for between three months (local) and one year (NGO). All patients reported significant improvement in objective and subjective measures of health and in financial status. Approximately half had to borrow and sell to get care, with NGO patients borrowing less, on average. However, NGO patients faced more risk of catastrophic expenditure (41.2% vs. 28.1%, p < 0.001). NGO patients were significantly poorer, whether financial status was measured by asset wealth or monthly income (p < 0.001). Finally, surgical care by the NGO was cost effective.

Conclusions

In a prospective analysis of surgical patients in an LMIC, we find that surgery improves health and financial well-being. NGOs may be able to reach patients who would not be able to get care through their local system; however, this comes at a cost of increased initial financial risk. Finally, NGO-based surgical care is cost-effective.
Remote Assessment of Cognition in Kids and Adolescents with Daytime Sleepiness: A pilot study of feasibility and reliability
Authors: Worhach Jennifer , Boduch Madeline , Zhang Bo , Maski Kiran
Published: March 2021

In this pilot study, we assessed the reliability of cognitive testing for kids and adolescents ages 8-19 years of age with narcolepsy or subjective daytime sleepiness compared to healthy controls. Forty-six participants took part in the study (n=18 with narcolepsy type 1, n=6 with subjective daytime sleepiness, and n= 22 healthy controls recruited from the community). Participants completed verbal (vocabulary testing) and non-verbal intelligence quotient (IQ) tasks (block design, matrix reasoning) from the Weschler Abbreviated Scale of Intelligence-Second Edition (WASI-II) in-person or remotely in their home through a HIPAA compliant telehealth web platform with conditions counterbalanced. We found that vocabulary T-scores showed good reliability with intraclass correlation coefficient (ICC) of 0.76 (95% CI: 0.64, 0.85) between remote and in-person testing conditions. Matrix Reasoning T-scores showed moderate reliability (ICC 0.69, 95% CI: 0.68, 0.90) and Block Design T-scores was poor between testing conditions. Bland-Altman plots showed outliers on vocabulary and matrix reasoning tasks performed better on remote assessments. Overall, the results of this pilot study support the feasibility and reliability of verbal and non-verbal IQ scores collected by telehealth. Use of telehealth to collect verbal and non-verbal IQ scores may offer a means to acquire cognitive data for pediatric sleep research through the COVID-19 pandemic and beyond.
Individual social contact data reflected SARS-CoV-2 transmission dynamics during the first wave in Germany better than population mobility data – an analysis based on the COVIMOD study
Authors: Tomori Damilola Victoria , Rübsamen Nicole , Berger Tom , Scholz Stefan , Walde Jasmin , Wittenberg Ian , Lange Berit , Mikolajczyk Rafael , Jaeger Veronika K , Karch André
Published: March 2021

Background

The effect of contact reduction measures on infectious disease transmission can only be assessed indirectly and with considerable delay. However, individual social contact data and population mobility data can offer near real-time proxy information.

Aim

To compare social contact data and population mobility data with respect to their ability to predict transmission dynamics during the first wave of the SARS-CoV-2 pandemic in Germany.

Methods

We quantified the change in social contact patterns derived from self-reported contact survey data collected by the German COVIMOD study from 04/2020-06/2020 (compared to the pre-pandemic period), and estimated the percentage mean reduction in the effective reproduction number R(t) over time. We compared these results to the ones based on R(t) estimates from open-source mobility data and to R(t) values provided by the German Public Health Institute.

Results

We observed the largest reduction in social contacts (90%, compared to pre-pandemic data) in late April corresponding to the strictest contacts reduction measures. Thereafter, the reduction in contacts dropped continuously to a minimum of 73% in late June. R(t) estimates based on social contacts underestimated measured R(t) values slightly in the time of strictest contact reduction measures but predicted R(t) well thereafter. R(t) estimates based on mobility data overestimated R(t) considerably throughout the study.

Conclusions

R(t) prediction accuracy based on contact survey data was superior to the one based on population mobility data, indicating that measuring changes in mobility alone is not sufficient for understanding changes in transmission dynamics triggered by public health measures.
A cost-effectiveness analysis of front-line treatment strategies in early stage follicular lymphoma
Authors: Tobin Joshua W.D. , Crothers Anna , Ma Ti Eric , Mollee Peter , Gandhi Maher K. , Scuffham Paul , Hapgood Greg
Published: March 2021

Recent data suggests the use of radiotherapy alone (RT) in Early-Stage Follicular Lymphoma is declining. Cost-effectiveness analysis of treatments has not been performed. We constructed a partitioning model (15-year horizon) to compare RT, combined-modality therapy (CMT) and immunochemotherapy with rituximab maintenance (ICT+RM) from a PET-staged cohort from the Australian Lymphoma Alliance. Lifetime direct health care costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. AUD $75,000 was defined as the willingness-to-pay threshold (WTP). The direct healthcare costs were: RT $12,791, CMT $29,391 and ICT+RM $42,644. Compared with RT, CMT demonstrated minimal improvement in QALYs (+0.01) and an ICER well above the WTP threshold ($1,535,488). Compared with RT, ICT+RM demonstrated an improvement in QALYs (+0.41) with an ICER of $73,319. Modelling a 25% cost reduction with a rituximab biosimilar led to further ICER reductions with ICT+RM ($52,476). ICT+RM is cost-effective in early stage FL from the Australian taxpayer perspective.
Investigating the evolution of undergraduate medical students’ perception and performance in relation to an innovative curriculum-based research module: a convergent mixed methods study launching the 8A-Model
Authors: Otaki Farah , AlHashmi Deena , Khamis Amar Hassan , Azar Aida Joseph
Published: March 2021

Embedding an experiential research curriculum into medical programs is still not widely adopted. This study investigated, using convergent mixed methods design, the journey of medical students in relation to a research module. The students’ perception of the experience was qualitatively explored using thematic analysis. The students’ performance data were quantitatively analyzed using multi-repeated ANOVA.

The exploration generated four themes: 1-Attend-Acquire, 2-Accumulate-Assimilate, 3-Apply-Appreciate, and 4-Articulate-Affect. Quantitatively, two distinct clusters of mean Grade Point Average were revealed (p<0.01). Joint display analysis enabled integrating the qualitative and quantitative findings, generating the 8A-Model. The students start appreciating the experience upon conducting their research.
Pooling-in-a-pod: A Strategy for COVID-19 Testing to Facilitate Safe Return to School
Authors: Berke Ethan M. , Newman Lori M. , Jemsby Suzanna , Hyde Bethany , Bhalla Natasha , Sheils Natalie E. , Oomman Nandini , Reppas John , Verma Prateek , Cangelosi Gerard A.
Published: March 2021

The COVID-19 pandemic prompted widespread primary and secondary school closures. Routine testing of asymptomatic students and staff, as part of a comprehensive program, can help schools open safely. “Pooling-in-a-pod” is a public health surveillance strategy whereby testing cohorts (pods) are based on social relationships and physical proximity. Pooled testing provides one laboratory result for the entire pod, rather than separate results for each individual. Pooling-in-a-pod allowed for weekly on-site point-of-care testing of all staff and students at an independent preschool to grade 12 school in Washington, D.C. Staff and older students self-collected anterior nares samples, and trained staff collected samples from younger students. Overall, 12,885 samples were tested in 1,737 pools for 863 students and 264 staff between November 30, 2020, and April 30, 2021. The average pool size was 7.4 people. Sample collection to pool result time averaged 40 minutes. Direct testing cost per person per week was $$24.24, including swabs. Four surveillance test pools were positive. During the study period, daily new cases in Washington, D.C., ranged from 10 to 46 per 100,000 population. A post-launch survey found most parents (90.3%), students (93.4%), and staff (98.8%) were willing to participate in pooled testing with confirmatory tests for positive pool members. The school reported a 73.4% decrease in virtual learning after program initiation. Pooling-in-a-pod is a feasible and cost-effective surveillance strategy that was acceptable to staff and families and may be appropriate for some schools. School officials and policymakers can leverage this strategy to facilitate safe, sustainable, in-person schooling.
Slow Motion Analysis of Repetitive Tapping (SMART) test: measuring bradykinesia in recently diagnosed Parkinson’s disease and idiopathic anosmia
Authors: Simonet C. , Galmes MA. , Lambert C. , Rees RN. , Haque T. , Bestwick JP. , Lees AJ. , Schrag A. , Noyce AJ.
Published: March 2021

Background

Bradykinesia is the defining motor feature of Parkinson’s disease (PD). There are limitations to its assessment using standard clinical rating scales, especially in the early stages of PD when a floor effect may be observed.

Objectives

To develop a quantitative method to track repetitive finger tapping movements and to compare people in the early stages of PD, healthy controls, and individuals with idiopathic anosmia.

Methods

This was a cross-sectional study of 99 participants (early-stage PD=26, controls=64, idiopathic anosmia=9). For each participant, repetitive finger tapping was recorded over 20 seconds using a smartphone at 240 frames per second. Three parameters were extracted from videos: amplitude between fingers, frequency (number of taps per second), and velocity (distance travelled per second). Clinical assessment was based on the motor section of MDS-UPDRS.

Results

People in the early stage of PD performed the task with slower velocity (p<0.001) and with greater decrement in frequency than controls (p=0.003). The combination of slower velocity and greater decrement in frequency obtained the best accuracy to separate early-stage PD from controls based on metric thresholds alone (AUC = 0.88). Individuals with anosmia exhibited slower velocity (p=0.001) and smaller amplitude (p<0.001) compared with controls.

Conclusions

We present a new simple method to detect early motor dysfunction in PD. Mean tap velocity appeared to be the best parameter to differentiate patients with PD from controls. Patients with anosmia also showed detectable differences in motor performance compared with controls which may be important indication of the prodromal phase of PD.
SARS-CoV-2 new infections among health care workers after the first dose of the BNT162b2 mRNA Covid-19 Vaccine
Authors: Guijarro Carlos , Galán Isabel , MartÍnez-Ponce Diana , Pérez-Fernández Elia , Goyanes Maria José , Castilla Virgilio , Velasco MarÍa
Published: March 2021

Objectives

To evaluate the effect of mRNA SARS-Cov-2 vaccination on the incidence of new SARS-CoV-2 infections in health care workers (HCW).

Methods

The evolution of the incident rate of microbiologically confirmed SARS-CoV-2 infection in a cohort of 2590 HCW after BNT162b2 mRNA SARS-CoV-2 vaccination, as compared to the rate in the community (n=170513) was evaluated by mixed Poisson regression models

Results

A total of 1820 HCW (70,3% of total) received the first dose of the BNT162b2 mRNA vaccine between January 10-16, 2021), and 296 (11,4%) the following week. All of them completed vaccination 3 weeks later. Incidence rates of SARS-CoV-2 infection after the first dose of mRNA SARS-CoV-2 vaccine declined by 71% (Incidence Rate Ratio (IRR) 0.286, 95% confidence interval (CI) 0.174-0.468, p< 0.001) and by 97% (IRR 0.03 95% CI 0.013-0.068, p<0.001) after the second dose as compared to the perivaccine time. SARS-CoV-2 incidence rates in the community (with a negligible vaccination rate) had a much lower decline: 2% (IRR 0.984; 95% CI 0.943-1.028; p = 0.47) and 61% (IRR 0.390, 95% CI 0.375-0.406; p<.001) for equivalent periods. Adjusting for the decline in the community, the reduction in the incident rates among HCW were 73% (IRR 0.272; 95% CI 0.164-0.451 p<0.001) after the first dose of the vaccine and 92 % (IRR 0.176, 95% CI 0.033-0.174; p<0.001) after the second dose.

Conclusions

mRNA SARS-CoV-2 vaccination is associated with a dramatic decline in new SARS-CoV-2 infection among HCW, even before the administration of the second dose of the vaccine.
Antibody response to first and second dose of BNT162b2 in a cohort of characterized healthcare workers
Authors: Padoan Andrea , Dall’Olmo Luigi , Rocca Foscarina della , Barbaro Francesco , Cosma Chiara , Basso Daniela , Cattelan Annamaria , Cianci Vito , Plebani Mario
Published: March 2021

Background

Vaccine-induced population immunity is a key global strategy to control coronavirus disease 2019 (COVID-19). The rapid implementation and availability of several COVID-19 vaccines is now a global health-care priority but more information about humoral responses to single- and double-dose vaccine is needed

Methods

163 health care workers (HCW) of the Padua University Hospitals, who underwent a complete vaccination campaign with BNT162b2 vaccine were asked to collect serum samples at 12 (t12) and 28 (t28) days after the first inoculum to allow the measurement of SARS-CoV-2 Antibodies (Ab) using chemiluminescent assays against the spike (S) protein and the Receptor Binding Domain (RBD) of the virus, respectively.

Results

Significant differences were found at t12 for infection-naïve and subjects with previous-natural infection who present higher values of specific antibodies, while no significant differences have been found between t12 and t28. No statistically significant difference was found between male and female, while lower Ab levels have been observed in subjects older than 60 years at t12 but not at t28.

Conclusions

Our study confirms observed differences in vaccine responses between infection-naïve and subjects with previous natural infection at t12 but not for a longer time. The influence of sex and age deserves further studies, even if the relationship with age seems particularly significant.
The interplay of policy, behavior, and socioeconomic conditions in early COVID-19 epidemiology in Georgia
Authors: Harris Mallory J. , Tessier-Lavigne Ella , Mordecai Erin A.
Published: March 2021

To investigate the impact of local public health orders, behavior, and population factors on early epidemic dynamics, we investigated variation among counties in the U.S. state of Georgia. We conducted regressions to identify predictors of (1) local public health orders, (2) mobility as a proxy for behavior, and (3) epidemiological outcomes (i.e., cases and deaths). We used an event study to determine whether social distancing and shelter-in-place orders caused a change in mobility.

Counties at greater risk for large early outbreaks (i.e., larger populations and earlier first cases) were more likely to introduce local public health orders. Social distancing orders gradually reduced mobility by 19% ten days after their introduction, and lower mobility was associated with fewer cases and deaths. Air pollution and population size were predictors of cases and deaths, while larger elderly or Black population were predictors of lower mobility and greater cases, suggesting self-protective behavior in vulnerable populations. Early epidemiological outcomes reflected responses to policy orders and existing health and socioeconomic disparities related to disease vulnerability and ability to socially distance. Teasing apart the impact of behavior changes and population factors is difficult because the epidemic is embedded in a complex social system with multiple potential feedbacks.
Trajectories of imitation skills in preschoolers with Autism Spectrum Disorders
Authors: Pittet Irène , Kojovic Nada , Franchini Martina , Schaer Marie
Published: March 2021

Imitation skills play a crucial role in social cognitive development from early childhood. Many studies have shown a deficit in imitation skills in children with Autism Spectrum Disorders (ASD). Little is known about the development of imitation behaviors in children with ASD. This study aims to measure the trajectories of early imitation skills in preschoolers with ASD and how these skills impact other areas of early development. For this purpose, we assessed imitation, language and cognition skills in 177 children with ASD and 43 typically developing children (TD) aged 2 to 5 years old, 126 of which were followed longitudinally, yielding a total of 396 time-points. Our results confirmed the presence of an early imitation deficit in toddlers with ASD compared to TD children. The study of the trajectories showed that these difficulties were marked at the age of two years, and gradually decreased until the age of 5 years old. Imitation skills were strongly linked with cognitive, language skills and level of symptoms in our ASD group at baseline. Moreover, the imitation skills at baseline were predictive of the language gains a year later in our ASD group. Using a data-driven clustering method, we delineated different developmental trajectories of imitation skills within the ASD group. The clinical implications of the findings are discussed, particularly the impact of an early imitation deficit on other areas of competence of the young child.
SARS-CoV-2 Antibody persistence in COVID-19 convalescent plasma donors
Authors: Di Germanio Clara , Simmons Graham , Kelly Kathleen , Martinelli Rachel , Darst Orsolya , Azimpouran Mahzad , Stone Mars , Hazegh Kelsey , Grebe Eduard , Zhang Shuting , Ma Peijun , Orzechowski Marek , Gomez James E , Livny Jonathan , Hung Deborah T. , Vassallo Ralph , Busch Michael P. , Dumont Larry J.
Published: March 2021

Background

Antibody response duration following SARS-CoV-2 infection tends to be variable and depends on severity of disease and method of detection.

Study design and methods

COVID-19 convalescent plasma (CCP) from 18 donors was collected longitudinally for a maximum of 63 - 129 days following resolution of symptoms. All the samples were initially screened by the Ortho Total Ig test to confirm positivity and subsequently tested with 7 additional direct sandwich or indirect binding assays (Ortho, Roche, Abbott, Broad Institute) directed against a variety of antigen targets (S1, RBD, and NC), along with 2 neutralization assays (Broad Institute live virus PRNT and Vitalant Research Institute Pseudovirus RVPN).

Results

The direct detection assays (Ortho Total Ig total and Roche Total Ig) showed increasing levels of antibodies over the time period, in contrast to the indirect IgG assays that showed a decline.

Neutralization assays also demonstrated declining responses; the VRI RVPN pseudovirus had a greater rate of decline than the Broad PRNT live virus assay.

Discussion

These data show that in addition to variable individual responses and associations with disease severity, the detection assay chosen contributes to the heterogeneous results in antibody stability over time. Depending on the scope of the research, one assay may be preferable over another. For serosurveillance studies, direct, double Ag-sandwich assays appear to be the best choice due to their stability; in particular, algorithms that include both S1 and NC based assays can help reduce the rate of false-positivity and discriminate between natural infection and vaccine-derived seroreactivity.
Evaluation of Clinical Threshold Policies for Cataract Surgery and the Regional Variation in Rates of Surgery
Authors: Lisle J. , Ansari N. , Jabir M.
Published: March 2021

Background/Aims

To characterise the national patterns in rates of cataract surgery across England, review clinical thresholds against NICE guidance, and determine how far variable access to cataract surgery is attributable to regional variation in policy stringency and social deprivation.

Methods

127 Clinical Commissioning Groups (“CCGs”) provided cataract surgery data and threshold policies in response to a Freedom of Information request. Local cataract surgery rates were grouped by threshold stringency and analysed on an age group-corrected basis. ANOVA testing was used to assess effect of policy stringency on regional rates of cataract surgery.

Results

In England, rates of cataract surgery vary threefold across CCGs, from 1,980 to 6,427 per 100,000 population over 60, with a standard deviation (784.76) of 22% of the mean value, 3,598. Threshold policies vary across CCGs: 33 had no policy, 45 utilised policies accessible on the basis of Quality of Life (“QoL”) impact, and 39, against NICE guidance, required a Visual Acuity (“VA”) threshold be exceeded. Rates of surgery by CCG were negatively correlated with restrictiveness of policy (η2=0.18, p<0.01), and positively correlated with the Index of Multiple Deprivation (IMD), (r2□=□0.11, p<0.01). Prior approval processes are not significantly associated with reduced rates of surgery.

Conclusion

Over two-thirds of CCGs continue to use threshold-based policies for access to cataract surgery, with one-third doing so solely on the basis of VA requirements, despite NICE guidance to the contrary. For NHS operations, variation in policy restrictiveness accounts for more of the variation in surgery rates than socioeconomic deprivation.
Comparison of cough particle exposure for indoor commercial and aircraft cabin spaces
Authors: Davis Angela C. , Menard Danny J. , Clark Andrew D. , Cummins Joshua J. , Olson Nels A.
Published: March 2021

To compare the transport of respiratory pathogens, computational fluid dynamics (CFD) simulations were performed to track particles released by coughing from a passenger on a Boeing 737 aircraft, and by a person in a comparable indoor commercial space. Simulation data were post-processed to calculate the amounts of particles inhaled by nearby persons in both environments. The effects of different airflow rates, placement of air inlets, positioning and distances between index (coughing) and susceptible (inhaling) persons were also analyzed. The removal of airborne particles from the indoor environment, due ventilation and deposition onto surfaces, was compared to that of an aircraft cabin. In an aircraft cabin 80% of the particles were removed 5 to 12 times faster than in the indoor commercial space; ultimately resulting in 7 times less particulate mass inhaled in the aircraft cabin.
Development and Evaluation of a new Swiss Made SARS-CoV-2 antigen-detecting rapid test
Authors: P.J. Ducrest
Published: March 2021

There is an urgent need in rapid diagnostic test (RDT) to detect antigen of SARS-CoV-2 to reduce the spread of COVID-19 outbreak. We have developed a rapid and simple point-of-care lateral flow immunoassay (LFIA) detecting nucleocapsid antigen of SARS-CoV-2 in 10 minutes. The aim of this study is to evaluate the diagnostic performance and analytical sensitivity of this RDT. RT-PCR positive nasopharyngeal swab samples (n=20) for SARS-CoV-2 and 40 negative control samples were studied. Analytical sensitivity was assessed using Gamma-irradiated SARS-CoV-2 and the limit of detection (LOD) was determined at 1.4 × 102 TCID50/ml. Overall, RDT diagnostic sensitivity was 90% (95% confidence interval [95%CI]: 67-98%) and specificity 98% (95% CI: 85-100%). The sensitivity was 100% (95% CI: 75-100%) when using only samples with a RT-PCR Cycle threshold lower than 30. This antigen RDT displays a high diagnostic accuracy for SARS-CoV-2 antigen detection in high COVID-19 prevalence settings. Its use could be considered in the absence of routine RT-PCR facilities such in low-income countries.
Early onset leprosy reveals a joint effect of LRRK2 and NOD2 variants
Authors: Dallmann-Sauer Monica , Xu Yong Zhong , da Costa Ana Lúcia França , Tao Shao , Correa-Macedo Wilian , Manry Jérémy , Abel Laurent , Alcaïs Alexandre , Cobat Aurélie , Fava Vinicius M. , Probst Christian M. , Mira Marcelo T. , Schurr Erwin
Published: March 2021

Leprosy, caused by Mycobacterium leprae, has a long incubation period and cases with age-of-onset <5 years are rare. Here, we studied a three-generational multiplex leprosy family which included monozygotic twins age <24 months suffering from paucibacillary leprosy. Whole genome sequencing identified a homozygous double mutation in the LRRK2 gene (N551K, R1398H) and a heterozygous mutation in NOD2 (R702W) as candidate variants underlying the early onset phenotype in the twins. The same amino acid substitutions had previously been identified as shared risk-modulating factors for Crohn’s disease and Parkinson’s disease. To evaluate the functional impact of the LRRK2 mutations, we employed genome editing in RAW264.7 cells. Cells expressing the LRRK2 variants displayed reduced respiratory burst and apoptosis following mycobacterial challenge. Moreover, the BCG-induced respiratory burst was significantly lower in LRRK2 wild-type-expressing cells transfected with NOD2 R702W compared with NOD2 wild-type constructs. Employing co-immunoprecipitation, we showed that LRRK2 and NOD2 wild-type proteins interact in RAW cells. This interaction was independent of the LRRK2 variants but strongly reduced for NOD2 R702W. However, N-glycolyl MDP-triggered RIP2 phosphorylation and NF-kB activation were additively reduced by both LRRK2 and NOD2 mutations. Finally, we observed a joint effect of LRRK2 and NOD2 variants on cytokine/chemokine secretion with the most significant reduction of secretion observed for the mutant genotypes carried by the twins. These data demonstrated the pleiotropic effects of LRRK2 and NOD2 in response to mycobacterial infection consistent with a role of the identified mutations in the development of early onset leprosy.

One Sentence Summary

Variants of NOD2 and LRRK2 shared between early onset leprosy, Parkinson’s and Crohn’s disease jointly impact the anti-mycobacterial host response.