bluuebunny/crossref_metadata_2025 huggingface dataset:
Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking
Authors: Sanderson Leslie E , Lanko Kristina , Alsagob Maysoon , Almass Rawan , Al-Ahmadi Nada , Najafi Maryam , Al-Muhaizea Mohammad A , Alzaidan Hamad , AlDhalaan Hesham , Perenthaler Elena , van der Linde Herma C , Nikoncuk Anita , Kühn Nikolas A , Antony Dinu , Owaidah Tarek Mustafa , Raskin Salmo , Vieira Luana Gabriela Dalla Rosa , Mombach Romulo , Ahangari Najmeh , Silveira Tainá Regina Damaceno , Ameziane Najim , Rolfs Arndt , Alharbi Aljohara , Sabbagh Raghda M , AlAhmadi Khalid , Alawam Bashayer , Ghebeh Hazem , AlHargan Aljouhra , Albader Anoud A , Binhumaid Faisal S , Goljan Ewa , Monies Dorota , Mustafa Osama M , Aldosary Mazhor , AlBakheet Albandary , Alyounes Banan , Almutairi Faten , Al-Odaib Ali , Aksoy Durdane Bekar , Basak A Nazli , Palvadeau Robin , Trabzuni Daniah , Rosenfeld Jill A , Karimiani Ehsan Ghayoor , Meyer Brian F , Karakas Bedri , Al-Mohanna Futwan , Arold Stefan T , Colak Dilek , Maroofian Reza , Houlden Henry , Bertoli-Avella Aida M , Schmidts Miriam , Barakat Tahsin Stefan , van Ham Tjakko J , Kaya Namik
Published: January 2021

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson’s disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.
Discovery or ownership? A new light on an Austrian controversy over entrepreneurship
Authors: Aimar Thierry
Published: January 2021

This article delivers an original analysis of an Austrian controversy between Rothbard and Kirzner about the relationship between entrepreneurship and capital ownership: in real-world markets, must the entrepreneur be a capitalist or not? The two authors were opposed to each other on that issue. Here, we will take a new look at existing literature by proposing a review of the key terms used in the debate. The thesis we defend here is that Rothbard and Kirzner were suffering from a mutual conceptual misunderstanding. Thus, taking an original view aims to steer the debate to a positive outcome and to reconsider the Austrian relationship between entrepreneurship, ownership and exploitation of capital.
Cryoballoon ablation vs. antiarrhythmic drugs: first-line therapy for patients with paroxysmal atrial fibrillation
Authors: Kuniss Malte , Pavlovic Nikola , Velagic Vedran , Hermida Jean Sylvain , Healey Stewart , Arena Giuseppe , Badenco Nicolas , Meyer Christian , Chen Jian , Iacopino Saverio , Anselme Frédéric , Packer Douglas L. , Pitschner Heinz-Friedrich , Asmundis Carlo de , Willems Stephan , Di Piazza Fabio , Becker Daniel , Chierchia Gian-Battista ,   for the Cryo-FIRST Investigators
Published: January 2021

Aims

Treatment guidelines for patients with atrial fibrillation (AF) suggest that patients should be managed with an antiarrhythmic drug (AAD) before undergoing catheter ablation (CA). This study evaluated whether pulmonary vein isolation employing cryoballoon CA is superior to AAD therapy for the prevention of atrial arrhythmia (AA) recurrence in rhythm control naive patients with paroxysmal AF (PAF).

Methods and results

A total of 218 treatment naive patients with symptomatic PAF were randomized (1 : 1) to cryoballoon CA (Arctic Front Advance, Medtronic) or AAD (Class I or III) and followed for 12 months. The primary endpoint was ≥1 episode of recurrent AA (AF, atrial flutter, or atrial tachycardia) >30 s after a prespecified 90-day blanking period. Secondary endpoints included the rate of serious adverse events (SAEs) and recurrence of symptomatic palpitations (evaluated via patient diaries). Freedom from AA was achieved in 82.2% of subjects in the cryoballoon arm and 67.6% of subjects in the AAD arm (HR = 0.48, P = 0.01). There were no group differences in the time-to-first (HR = 0.76, P = 0.28) or overall incidence [incidence rate ratio (IRR)=0.79, P = 0.28] of SAEs. The incidence rate of symptomatic palpitations was lower in the cryoballoon (7.61 days/year) compared with the AAD arm (18.96 days/year; IRR = 0.40, P < 0.001).

Conclusions

Cryoballoon CA was superior to AAD therapy, significantly reducing AA recurrence in treatment naive patients with PAF. Additionally, cryoballoon CA was associated with lower symptom recurrence and a similar rate of SAEs compared with AAD therapy.
Global relationship between Mediterranean diet and the incidence and mortality of ischaemic heart disease
Authors: Sezaki Ayako , Imai Tomoko , Miyamoto Keiko , Kawase Fumiya , Shirai Yoshiro , Abe Chisato , Sanada Masayo , Inden Ayaka , Kato Takumi , Suzuki Norie , Shimokata Hiroshi
Published: January 2021

Background

The purpose of this study was to clarify the global relationship between the Mediterranean diet score (MDS) and country-wise incidence and mortality of ischaemic heart disease (IHD) using an international database.

Methods

We used population data from a global longitudinal database covering 137 countries with a population of over one million. MDS were evaluated based on the total score of the nine foods that comprise the Mediterranean diet. The incidence and mortality of IHD by country was derived from the Global Burden of Disease (GBD) database. Average food (g/day/capita) and energy supply (kcal/day/capita) by country, excluding loss between production and household, were obtained from the Food and Agriculture Organization of the United Nations Statistics Division database. Data from the GBD database were used for body mass index, current smoking rates, physical activity, years of education and percentage of the Muslim population. We identified the percentage of the population over 65 years of age (aging rate) and gross domestic product per capita (US$/capita) using the World Bank database. A linear mixed-effect model was used for evaluating the effects of MDS on incidence and mortality of IHD controlled for socioeconomic and lifestyle variables.

Results

Analysis showed that MDS was significantly associated with IHD incidence after controlling for covariates (–1.01 ± 0.27, P < 0.001). Similarly, there was a significant association between MDS and IHD-related mortality after controlling for covariates (–0.73 ± 0.34, P < 0.05).

Conclusion

Analysis of 27 years of data suggests that a Mediterranean diet might have a preventive effect on IHD.
Judicial self-dealing and unconstitutional constitutional amendments in South Asia
Authors: Yap Po Jen , Abeyratne Rehan
Published: January 2021

Courts around the world today are empowered to strike down unconstitutional constitutional amendments. But can a court strike down amendments that restore parts of the original constitution? The Appellate Division of the Bangladesh Supreme Court did precisely this in Bangladesh v. Asaduzzaman Siddiqui (2017), holding unconstitutional an amendment that restored the judicial removal provision that existed in the original 1972 Constitution. This article analyzes Siddiqui within the comparative constitutional amendment literature and the broader South Asian context. Despite the apparent incongruity of applying the basic structure doctrine to an original constitutional provision, we argue that Siddiqui is defensible on both theoretical and pragmatic grounds. The amendment that was invalidated in this case represented an unconstitutional departure from the judicial removal practice that had existed for several decades and was entrenched by a previous amendment, which “dismembered” the original constitution and safeguarded constitutional democracy in Bangladesh. At a regional level, Siddiqui is similar to recent judgments in India and Pakistan in which apex courts assert their control and limit political influence in judicial appointment and removal proceedings. Such judicial self-dealing, we argue, is more justified in Bangladesh and Pakistan than in India due to their checkered histories with democracy and political interference with judicial functions.
Low-intensity daily smoking and cause-specific mortality in Mexico: prospective study of 150 000 adults
Authors: Thomson Blake , Tapia-Conyer Roberto , Lacey Ben , Lewington Sarah , Ramirez-Reyes Raúl , Aguilar-Ramirez Diego , Gnatiuc Louisa , Herrington William G , Torres Jason , Trichia Eirini , Wade Rachel , Collins Rory , Peto Richard , Kuri-Morales Pablo , Alegre-Díaz Jesus , Emberson Jonathan R
Published: January 2021

Background

Research is needed to determine the relevance of low-intensity daily smoking to mortality in countries such as Mexico, where such smoking habits are common.

Methods

Prospective study of 159 755 Mexican adults recruited from 1998–2004 and followed for cause-specific mortality to 1 January 2018. Participants were categorized according to baseline self-reported smoking status. Confounder-adjusted mortality rate ratios (RRs) at ages 35–89 were estimated using Cox regression, after excluding those with previous chronic disease (to avoid reverse causality).

Results

Among 42 416 men and 86 735 women aged 35–89 and without previous disease, 18 985 men (45%) and 18 072 women (21%) reported current smoking and 8866 men (21%) and 53 912 women (62%) reported never smoking. Smoking less than daily was common: 33% of male current smokers and 39% of female current smokers. During follow-up, the all-cause mortality RRs associated with the baseline smoking categories of <10 cigarettes per day (average during follow-up 4 per day) or ≥10 cigarettes per day (average during follow-up 10 per day), compared with never smoking, were 1.17 (95% confidence interval 1.10–1.25) and 1.54 (1.42–1.67), respectively. RRs were similar irrespective of age or sex. The diseases most strongly associated with daily smoking were respiratory cancers, chronic obstructive pulmonary disease and gastrointestinal and vascular diseases. Ex-daily smokers had substantially lower mortality rates than those who were current daily smokers at recruitment.

Conclusions

In this Mexican population, low-intensity daily smoking was associated with increased mortality. Of those smoking 10 cigarettes per day on average, about one-third were killed by their habit. Quitting substantially reduced these risks.
Myeloid cell dynamics correlating with clinical outcomes of severe COVID-19 in Japan
Authors: Takano Tomohiro , Matsumura Takayuki , Adachi Yu , Terahara Kazutaka , Moriyama Saya , Onodera Taishi , Nishiyama Ayae , Kawana-Tachikawa Ai , Miki Shoji , Hosoya-Nakayama Kaori , Nakamura-Hoshi Midori , Seki Sayuri , Tachikawa Natsuo , Yoshimura Yukihiro , Miyata Nobuyuki , Horiuchi Hiroshi , Sasaki Hiroaki , Miyazaki Kazuhito , Kinoshita Noriko , Sudo Tsutomu , Akiyama Yutaro , Sato Rubuna , Suzuki Tadaki , Matano Tetsuro , Takahashi Yoshimasa
Published: January 2021

Abstract

An expanded myeloid cell compartment is a hallmark of severe coronavirus disease 2019 (COVID-19). However, data regarding myeloid cell expansion have been collected in Europe, where the mortality rate by COVID-19 is greater than those in other regions including Japan. Thus, characteristics of COVID-19-induced myeloid cell subsets remain largely unknown in the regions with low mortality rates. Here, we analyzed cellular dynamics of myeloid-derived suppressor cell (MDSC) subsets and examined whether any of them correlate with disease severity and prognosis, using blood samples from Japanese COVID-19 patients. We observed that polymorphonuclear (PMN)-MDSCs, but not other MDSC subsets, transiently expanded in severe cases but not in mild or moderate cases. Contrary to previous studies in Europe, this subset selectively expanded in survivors of severe cases and subsided before discharge, but such transient expansion was not observed in non-survivors in Japanese cohort. Analysis of plasma cytokine/chemokine levels revealed positive correlation of PMN-MDSC frequencies with IL-8 levels, indicating the involvement of IL-8 on recruitment of PMN-MDSCs to peripheral blood following the onset of severe COVID-19. Our data indicate that transient expansion of the PMN-MDSC subset results in improved clinical outcome. Thus, this myeloid cell subset may be a predictor of prognosis in cases of severe COVID-19 in Japan.
COVID-19 and International Crimes Trials in Germany
Authors: Ritscher Christian
Published: January 2021

With the appearance of the COVID-19 virus, the world faces new challenges in almost every area of social life. Social distancing and protection measures provide new challenges in business relations. This also holds true for criminal trials in general, and for international criminal trials, in particular. In Germany, several trials concerning charges of crimes under international law, established by the German Code of Crimes Against International Law (Völkerstrafgesetzbuch), are currently in progress. In particular, the trial against two former Syrian intelligence officers, which is currently taking place before the Higher Regional Court in Koblenz, has received international attention and will possibly be affected by the restrictions imposed.
US Army Drill Sergeants: Stressors, Behavioral Health, and Mitigating Factors
Authors: Elliman Toby D , Schwalb Molly E , Krauss Stephen , Mikoski Peter , Adler Amy B
Published: January 2021

Introduction

The role of the drill sergeant is one of the most challenging within the US Army, involving unusually long hours and little time off, for a minimum of 2 years. The current study sought to examine the behavioral health of this population and identify risk factors that might be addressed by policy changes.

Materials and Methods

In total, 856 drill sergeants across all Army basic training sites completed surveys from September to November of 2018. Drill sergeants identified factors that had caused stress or worry during their assignment. Rates were measured for behavioral health outcomes including depression, insomnia, anxiety, burnout, functional impairment, alcohol misuse, aggression, and low morale. Potential risk and resilience factors included time as a drill sergeant, sleep, route of assignment, general leadership, health-promoting leadership, and drill sergeant camaraderie. The study was approved by the Walter Reed Army Institute of Research Institutional Review Board.

Results

The most commonly experienced stressors were finding time to exercise, lack of sleep, and long work hours. Percentages of drill sergeants meeting behavioral health screening criteria were 19% for depression, 27% for moderate-to-severe insomnia, 14% for generalized anxiety disorder, 48% for high burnout, 32% for functional impairment, 35% for moderate alcohol misuse, 32% for off-duty aggression, and 25% for low morale. Rates for most outcomes were associated with time spent as a drill sergeant, with behavioral health issues peaking during 13-18 months. Poorer outcomes were also associated with fewer hours of sleep and initial unhappiness regarding involuntary assignment to the role of drill sergeant, while better outcomes were associated with higher ratings of general leadership, health-promoting leadership, and drill sergeant camaraderie.

Conclusions

This study is the first to examine behavioral health and morale of drill sergeants and to identify risk and resilience factors. Suggestions for policy changes include increasing the number of drill sergeants to decrease workload and allow sufficient time for recovery and sleep.
Flares in the Galactic Centre – I. Orbiting flux tubes in magnetically arrested black hole accretion discs
Authors: Porth O , Mizuno Y , Younsi Z , Fromm C M
Published: January 2021

Recent observations of Sgr A* by the GRAVITY instrument have astrometrically tracked infrared (IR) flares at distances of ∼10 gravitational radii (rg). In this paper, we study a model for the flares based on 3D general relativistic magnetohydrodynamic (GRMHD) simulations of magnetically arrested accretion discs (MADs) that exhibit violent episodes of flux escape from the black hole magnetosphere. These events are attractive for flare modelling for several reasons: (i) the magnetically dominant regions can resist being disrupted via magnetorotational turbulence and shear; (ii) the orientation of the magnetic field is predominantly vertical as suggested by the GRAVITY data; and (iii) the magnetic reconnection associated with the flux eruptions could yield a self-consistent means of particle heating/acceleration during the flare events. In this analysis, we track erupted flux bundles and provide distributions of sizes, energies, and plasma parameter. In our simulations, the orbits tend to circularize at a range of radii from ${\sim} 5\hbox{ to }40\, r_{\rm g}$. The magnetic energy contained within the flux bundles ranges up to ${\sim} 10^{40}\,\rm erg$, enough to power IR and X-ray flares. We find that the motion within the magnetically supported flow is substantially sub-Keplerian, in tension with the inferred period–radius relation of the three GRAVITY flares.
The VMC survey – XLI. Stellar proper motions within the Small Magellanic Cloud
Authors: Niederhofer Florian , Cioni Maria-Rosa L , Rubele Stefano , Schmidt Thomas , Diaz Jonathan D , Matijevĭc Gal , Bekki Kenji , Bell Cameron P M , de Grijs Richard , El Youssoufi Dalal , Ivanov Valentin D , Oliveira Joana M , Ripepi Vincenzo , Subramanian Smitha , Sun Ning-Chen , van Loon Jacco Th
Published: January 2021

We used data from the near-infrared Visible and Infrared Telescope for Astronomy (VISTA) survey of the Magellanic Cloud system (VMC) to measure proper motions (PMs) of stars within the Small Magellanic Cloud (SMC). The data analysed in this study comprise 26 VMC tiles, covering a total contiguous area on the sky of ∼40 deg2. Using multi-epoch observations in the Ks band over time baselines between 13 and 38 months, we calculated absolute PMs with respect to ∼130 000 background galaxies. We selected a sample of ∼2160 000 likely SMC member stars to model the centre-of-mass motion of the galaxy. The results found for three different choices of the SMC centre are in good agreement with recent space-based measurements. Using the systemic motion of the SMC, we constructed spatially resolved residual PM maps and analysed for the first time the internal kinematics of the intermediate-age/old and young stellar populations separately. We found outward motions that point either towards a stretching of the galaxy or stripping of its outer regions. Stellar motions towards the North might be related to the ‘Counter Bridge’ behind the SMC. The young populations show larger PMs in the region of the SMC Wing, towards the young Magellanic Bridge. In the older populations, we further detected a coordinated motion of stars away from the SMC in the direction of the Old Bridge as well as a stream towards the SMC.
Postoperative Psychosocial Factors in Health Functioning and Health-Related Quality of Life After Knee Arthroplasty: A 6-Month Follow up Prospective Observational Study
Authors: Terradas-Monllor Marc , Navarro-Fernández Gonzalo , Ruiz Miguel A , Beltran-Alacreu Hector , Fernández-Carnero Josué , Salinas-Chesa Julio , Ochandorena-Acha Mirari
Published: January 2021

Objective

Knee arthroplasty (KA) is an effective and cost-effective treatment for end-stage knee osteoarthritis. Despite high surgical success rates, as many as 25% of patients report compromised postoperative functioning, persistent pain, and reduced quality of life. The purpose of this study was to assess the predictive value of psychological factors in health functioning and quality of life, during a 6-month period after KA.

Design

A prospective observational study.

Setting

Surgery at two hospitals and follow-up was carried out through the domiciliary rehabilitation service.

Subjects

In total, 89 patients (age 70.27 ± 7.99 years) met the inclusion criteria.

Method

A test battery composed of Health functioning associated with osteoarthritis (WOMAC), Health-related quality of life (EQ-5D-5L), Anxiety and Depression (HADS), Pain attitudes (SOPA-B), Pain catastrophizing (PCS), and Fear of Movement (TSK-11) was assessed at 1 week, and 1, 3, and 6 months after surgery. A mixed effects linear model was used to estimate the effect of time and covariates. An exploratory factor analysis was used to identify the number of dimensions underlying the group of psychological measurements.

Results

In WOMAC model, anxiety level (F = 120.8), PCS (F = 103.9), depression level (F = 93.6) and pain score (F = 72.8) were the most influential variables. Regarding EQ-5D-5L model, anxiety level (F = 98.5), PCS (F = 79.8), depression level (F = 78.3) and pain score (F = 45) were the most influential variables. Pain score and the psychosocial variables of PCS, TSK, HADS-A, HADS-D, SOPA-B Emotion, SOPA-B Harm and SOPA-B Disability loaded in one single dimension.

Conclusions

Postoperative acute pain and psychosocial factors of pain catastrophizing, anxiety, depression, and pain attitudes might influence health functioning and quality of life during KA rehabilitation. Such factors could be gathered into one single dimension defined as pain-related psychologic distress.
Chemotype and Aggressiveness Evaluation of Fusarium graminearum and Fusarium culmorum Isolates from Wheat Fields in Wisconsin
Authors: Mueller Brian , Groves Carol L. , Smith Damon L.
Published: January 2021

Fusarium graminearum commonly causes Fusarium head blight on wheat, barley, rice, and oats. F. graminearum produces nivalenol (NIV) and deoxynivalenol (DON) and forms derivatives of DON based on its acetylation sites. The fungus is profiled into chemotypes based on DON derivative chemotypes (3 acetyldeoxynivalenol [3ADON] chemotype; 15 acetyldeoxynivalenol [15ADON] chemotype), and/or the NIV chemotype. This study assessed the Fusarium population found on wheat and the chemotype profile of the isolates collected from 2016 and 2017 in Wisconsin. F. graminearum was isolated from all locations sampled in both 2016 and 2017. Fusarium culmorum was isolated only from Door County in 2016. Over both growing seasons, 91% of isolates were identified as the 15ADON chemotype, while 9% of isolates were identified as the 3ADON chemotype. Aggressiveness was quantified by area under the disease progress curve (AUDPC). The isolates with the highest AUDPC values were from the highest wheat-producing cropping districts in the state. Deoxynivalenol production in grain and sporulation and growth rate in vitro were compared with aggressiveness in the greenhouse. Our results showed that 3ADON isolates in Wisconsin were among the highest in sporulation capacity, growth rate, and DON production in grain. However, there were no significant differences in aggressiveness between the 3ADON and 15ADON isolates. The results of this research detail the baseline frequency and distribution of 3ADON and 15ADON chemotypes observed in Wisconsin. Chemotype distributions within populations of F. graminearum in Wisconsin should continue to be monitored in the future.
Novel Sources of Turnip Yellows Virus Resistance inBrassicaand Impacts of Temperature on Their Durability
Authors: Congdon Benjamin S. , Baulch Jonathan R. , Coutts Brenda A.
Published: January 2021

Turnip yellows virus (TuYV; family Solemoviridae, genus Polerovirus) is the most widespread and economically damaging virus of canola (Brassica napus L.) production in Australia. However, no Australian commercial seed companies market TuYV-resistant canola cultivars, and little information is available on the susceptibility of those available. To identify potential sources of TuYV resistance, 100 B. napus accessions from the ERANET ASSYST diversity set were screened in the field and five of these were selected for further phenotyping via aphid inoculation. Furthermore, 43 Australian canola cultivars, six B. napus genotypes with previously reported resistance, and 33 B. oleracea and B. rapa cultivars were phenotyped. All Australian cultivars were susceptible except for ‘ATR Stingray’. Stronger resistance to systemic TuYV infection (IR) was identified in diversity set accessions ‘Liraspa-A’, ‘SWU Chinese 3’, and ‘SWU Chinese 5’. As indicated by lower relative enzyme-linked immunosorbent assay absorbance values (R-E405) in infected plants, resistance to TuYV accumulation (AR) often accompanied IR. Moderate IR was identified in four B. oleracea cultivars and one B. rapa cultivar. Very strong AR was identified in four B. oleracea cultivars and AR of some degree was common across many cultivars of this species tested. The impact of temperature during the inoculation access period or post-inoculation incubation on the resistance identified was examined. Infection rates were significantly higher in resistant B. napus genotypes when inoculated at 16°C than at 26°C, suggesting an increase in aphid transmission efficiency. IR in B. napus genotypes was strong when incubated at 16°C, but weakened at elevated temperatures with almost total breakdown in most genotypes at 30°C. However, infected plants of B. napus and B. oleracea genotypes with AR maintained lower R-E405values than susceptible controls at all temperatures tested. Novel sources of resistance identified in this study offer potential as breeding material in Australia and abroad.
Bitter Rot of Apple in the Mid-Atlantic United States: Causal Species and Evaluation of the Impacts of Regional Weather Patterns and Cultivar Susceptibility
Authors: Martin Phillip L. , Krawczyk Teresa , Khodadadi Fatemeh , Aćimović Srđan G. , Peter Kari A.
Published: January 2021

Apple growers in the Mid-Atlantic region of the United States have been reporting an increase in losses to bitter rot of apple and are requesting up-to-date management recommendations. Management is complicated by variations in apple cultivar susceptibility, temperature, rainfall, and biology of the Colletotrichum spp. that cause bitter rot. Over 500 apple fruit with bitter rot were obtained from 38 orchards across the Mid-Atlantic and the causal species were identified as Colletotrichum fioriniae and C. nymphaeae of the C. acutatum species complex and C. chrysophilum, C. noveboracense, C. siamense, C. fructicola, C. henanense, and C. gloeosporioides sensu stricto of the C. gloeosporioides species complex, the latter two being first reports. Species with faster in vitro growth rates at higher temperatures were more abundant in warmer regions of the Mid-Atlantic, while those with slower growth rates at higher temperatures were more abundant in cooler regions. Regional bloom dates are earlier and weather data show a gradual warming trend that likely influenced but was not necessarily the main cause of the recent increase in bitter rot in the region. A grower survey of apple cultivar susceptibility showed high variation, with the increase in acres planted to the highly susceptible cultivar Honeycrisp broadly corresponding to the increase in reports of bitter rot. These results form a basis for future studies on the biology and ecology of the Colletotrichum spp. responsible, and suggest that integrated bitter rot management must begin with selection of less-susceptible apple cultivars.
Epidemiology of sepsis and septic shock
Authors: Chiu Catherine , Legrand Matthieu
Published: January 2021

Purpose of review

The epidemiology of sepsis and septic shock has been challenging to study for multiple reasons. These include changing diagnostic definitions, as well a high concentration of sepsis-related studies published from high-income countries (HICs), despite a large global burden. This section attempts to address the incidence of sepsis throughout the years and worldwide.

Recent findings

The incidence of sepsis and septic shock has continued to increase since the first consensus definitions (Sepsis-1) were established in 1991, and the latest definitions (Sepsis-3) provide a better reflection of mortality risk for a diagnosis of sepsis. Several studies argue that the incidence of sepsis is overreported in HICs, based on billing and coding practices, and may lead to overutilization of resources. However, recent estimates of the true global burden of sepsis, including low-income countries, are likely much higher than reported, with calls for better allocation of resources.

The true epidemiology of sepsis worldwide continues to be a highly debated subject, and more research is needed among low-income countries and high-risk subpopulations.
The endocannabinoid system and drug-associated contextual memories
Authors: Asth Laila , Santos Aline C. , Moreira Fabrício A.
Published: January 2021

Drug abuse and addiction can be initiated and reinstated by contextual stimuli previously paired with the drug use. The influence exerted by the context on drug-seeking behaviour can be modelled in experimental animals with place-conditioning protocols. Here, we review the effects of cannabinoids in place conditioning and the therapeutic potential of the endocannabinoid system for interfering with drug-related memories. The phytocannabinoid Δ9-tetrahydrocannabinol (THC) tends to induce conditioned place preference (CPP) at low doses and conditioned place aversion at high doses; cannabidiol is devoid of any effect, yet it inhibits CPP induced by some drugs. Synthetic CB1 receptor agonists tend to recapitulate the biphasic profile observed with THC, whereas selective antagonists/inverse agonists inhibit CPP induced by cocaine, nicotine, alcohol and opioids. However, their therapeutic use is limited by potential psychiatric side effects. The CB2 receptor has also attracted attention, because selective CB2 receptor agonists inhibit cocaine-induced CPP. Inhibitors of endocannabinoid membrane transport and hydrolysis yield mixed results. In targeting the endocannabinoid system for developing new treatments for drug addiction, future research should focus on ‘neutral’ CB1 receptor antagonists and CB2 receptor agonists. Such compounds may offer a well-tolerated pharmacological profile and curb addiction by preventing drug-seeking triggered by conditioned contextual cues.
The Pathology of the Vestibular System in CANVAS
Authors: Ishai Reuven , Seyyedi Mohammad , Chancellor Andrew M. , McLean Catriona A. , Rodriguez Michael L. , Halmagyi Gabor Michael , Nadol Joseph B. , Szmulewicz David J. , Quesnel Alicia M.
Published: January 2021

Objective:

To describe the site of lesion responsible for the severe, bilateral, symmetrical, selective loss of vestibular function in Cerebellar Ataxia with Neuronopathy and Vestibular Areflexia Syndrome (CANVAS), an adult-onset recessively-inherited ataxia, characterized by progressive imbalance due to a combination of cerebellar, somatosensory, and selective vestibular impairment with normal hearing.

Methods:

Histologic examination of five temporal bones and the brainstems from four CANVAS patients and the brainstem only from one more, each diagnosed and followed from diagnosis to death by one of the clinician authors.

Results:

All five temporal bones showed severe loss of vestibular ganglion cells (cell counts 3–16% of normal), and atrophy of the vestibular nerves, whereas vestibular receptor hair cells and the vestibular nuclei were preserved. In contrast, auditory receptor hair cells, the auditory ganglia (cell counts 51–100% of normal), and the auditory nerves were relatively preserved. In addition, the cranial sensory ganglia (geniculate and trigeminal), present in two temporal bones, also showed severe degeneration.

Conclusions:

In CANVAS there is a severe cranial sensory ganglionopathy neuronopathy (ganglionopathy) involving the vestibular, facial, and trigeminal ganglia but sparing the auditory ganglia. These observations, when coupled with the known spinal dorsal root ganglionopathy in CANVAS, indicate a shared pathogenesis of its somatosensory and cranial nerve manifestations. This is the first published account of both the otopathology and neuropathology of CANVAS, a disease that involves the central as well as the peripheral nervous system.
Evaluating the Epley Canalolith Repositioning Procedure With and Without a Visual Assistive Device
Authors: Moroz Matthew , Choy Matthew , Lee Chang Woo , Hadfield Hugo , Lasenby Joan , Stone Thomas , Bance Manohar
Published: January 2021

Hypothesis:

The primary goal of this study was to examine how accuracy is affected when we employ a guidance device to assist with the execution of the Epley canalolith repositioning procedure.

Background:

Benign paroxysmal positional vertigo is a common cause of vestibular vertigo. Treatment is noninvasive and generally effective when performed correctly. Deficiencies in clinical application result in unnecessary failures in response for those affected.

Methods:

Ten participants were each taken through six iterations of the Epley canalolith repositioning procedure. Iterations were divided evenly between those conducted with and without the use of a guidance device. One clinician performed all 60 procedures. Head movements were recorded using motion capture cameras and strategically placed motion tracking markers.

Results:

Results showed that the guidance device significantly improved the latter phase maneuver accuracy. Rotation error was significantly reduced for hold3 with-device (M = 20.23°, SD = 12.08°) versus without-device (M = 40.13°, SD = 14.62°, p 
= 
0.001). Maximal rotation error during rotation4 of the maneuver demonstrated a similar reduction of error with-device (M = 24.44°, SD = 10.43°) versus without-device (M = 41.36°, SD = 12.89°, p 
= 
0.002).

Conclusion:

A simple visual guidance device can increase the execution accuracy of canalith repositioning procedures. Further research is required to show how such improvements influence treatment efficacy.
Predictive Sensitivity and Concordance of Machine-learning Tools for Diagnosing DFNA9 in a Large Series of p.Pro51Ser Variant Carriers in the COCH-gene
Authors: Salah Mahadi , de Varebeke Sebastien Janssens , Fransen Erik , Topsakal Vedat , Van Camp Guy , Van Rompaey Vincent
Published: January 2021

Objective:

In this study we aimed to evaluate the predictive cross-sectional sensitivity and longitudinal concordance of a machine-learning algorithm in a series of genetically confirmed p.(Pro51Ser) variant carriers (DFNA9).

Study Design:

Cross-sectional study.

Setting:

Tertiary and secondary referral center.

Patients:

Audiograms of 111 subjects with the p.(Pro51Ser) mutation in the COCH-gene were analyzed cross-sectionally. A subset of 17 subjects with repeated audiograms were used for longitudinal analysis.

Intervention(s):

All audiological thresholds were run through the web-based AudioGene v4.0 software.

Main Outcome Measure(s):

Sensitivity for accurate prediction of DFNA9 for cross-sectional data and concordance of correct prediction for longitudinal auditory data.

Results:

DFNA9 was predicted with a sensitivity of 93.7% in a series of 222 cross-sectionally collected audiological thresholds (76.1% as first gene locus). When using the hearing thresholds of the best ear, the sensitivity was 94.6%. The sensitivity was significantly higher in DFNA9 patients aged younger than 40 and aged 60 years or older, compared to the age group of 40 to 59 years, with resp. 97.6% (p < 0.0001) and 98.8% (p < 0.0001) accurate predictions. An average concordance of 91.6% was found to show the same response in all successive longitudinal audiometric data per patient.

Conclusions:

Audioprofiling software can accurately predict DFNA9 in an area with a high prevalence of confirmed carriers of the p.(Pro51Ser) variant in the COCH-gene. This algorithm yields high promises for helping clinicians in directing genetic testing in case of a strong family history of progressive hearing loss, especially for very young and old carriers.
Comparative Utilization and Efficacy of Thrombopoietin Receptor Agonists in Relapsed/Refractory Immune Thrombocytopenia
Authors: Arnall Justin R. , DiSogra Kristyn Y. , Downing Lauren , Elmes Joseph B. , Tran Thuy , Moore Donald C.
Published: January 2021

Background:

The thrombopoietin (TPO) agonists, eltrombopag and romiplostim, stimulate the production of platelets and offer an effective treatment option in relapsed/refractory immune thrombocytopenia (ITP). Recently published 2019 ITP guidelines recommend the TPO agonists as second-line therapy following corticosteroids; however, little data offer insights into comparative efficacy and tolerability.

Study Question:

Is there a difference in the efficacy between romiplostim and eltrombopag in relapsed/refractory ITP?

Study Design:

We conducted a single-center, retrospective chart review of patients with ITP treated with romiplostim or eltrombopag.

Measures and Outcomes:

The primary objective was a sustained platelet response, defined as platelets greater than 50,000/μL in more than 66% of clinic visits over a 6-month period. Secondary objectives sought to evaluate response to and tolerability of TPO agonists.

Results:

The study included 107 consecutive patients, 67 (63%) on romiplostim and 40 (37%) on eltrombopag. Previous corticosteroids and rituximab were used in 95% and 50% of patients, respectively. There was no difference identified in platelet responses between the TPO-RAs, 72% romiplostim versus 65% eltrombopag (P = 0.520). In addition, no differences were identified in secondary measures of response.

Conclusions:

In our experience with romiplostim and eltrombopag for ITP, we did not identify a difference in the efficacy of these agents. Further larger and prospective evaluations should be considered.
The Estimated Lifetime Medical Cost of Syphilis in the United States
Authors: Chesson Harrell W. , Peterman Thomas A.
Published: January 2021

Background

The purpose of this study was to estimate the cost of syphilis in the United States, in terms of the average lifetime direct medical cost per infection.

Methods

We used a decision tree model of the natural history of syphilis. The model allowed for numerous possible outcomes of infection, including treatment for syphilis at various stages, inadvertent treatment, and late syphilis outcomes in those who are alive and still infected 30 years after acquisition. Future costs were discounted at 3% annually. Model inputs, such as the cost and probability of each outcome, were based on published sources. The probabilities we applied yielded outcomes consistent with reported cases of syphilis by stage from national surveillance data and number of deaths due to late syphilis from national mortality data.

Results

The estimated, discounted lifetime cost per infection was $1190 under base case assumptions (2019 dollars). Treatment costs associated with late syphilis outcomes, such as cardiovascular syphilis, accounted for only $26 of the average lifetime cost per infection. Results were most sensitive to assumptions regarding the treatment cost per case of unknown duration or late syphilis. In the probabilistic sensitivity analyses, the 2.5th and 97.5th percentiles of the 10,000 simulations of the lifetime cost per infection were $729 and $1884, respectively.

Conclusions

Our estimate of the lifetime cost per infection is about 50% higher than in a previous study, a difference due in large part to our higher cost assumptions for benzathine penicillin G.
The Estimated Number and Lifetime Medical Cost of HIV Infections Attributable to Sexually Transmitted Infections Acquired in the United States in 2018: A Compilation of Published Modeling Results
Authors: Chesson Harrell W. , Song Ruiguang , Bingham Adrienna , Farnham Paul G.
Published: January 2021

Background

The purpose of this study was to estimate the number and lifetime medical cost of HIV infections attributable to incident sexually transmitted infections (STIs) in the United States in 2018.

Methods

We combined data from published models regarding the number or percentage of HIV infections attributable to STIs with updated estimates of the lifetime medical cost per HIV infection. We used 2 distinct calculation methods. Our first calculation used recent estimates of the percentage of HIV infections in men who have sex with men (MSM) attributable to gonorrhea and chlamydia. Our second calculation, based on older studies, used estimates of the expected number of STI-attributable HIV infections per new STI infection, for gonorrhea, chlamydia, syphilis, and trichomoniasis.

Results

Our first calculation method suggested that 2489 (25th–75th percentiles, 1895–3000) HIV infections in 2018 among MSM could be attributed to gonorrhea and chlamydia, at an estimated lifetime medical cost of $1.05 billion (25th–75th percentiles, $0.79–$1.26 billion). Our second calculation method suggested that 2349 (25th–75th percentiles, 1948–2744) HIV infections in the general population (including MSM) could be attributed to chlamydia, gonorrhea, syphilis, and trichomoniasis acquired in 2018, at an estimated lifetime medical cost of $0.99 billion (25th–75th percentiles, $0.80–$1.16 billion).

Conclusions

Despite ambiguity regarding the degree to which STIs affect HIV transmission, our combination of data from published STI/HIV transmission models and an HIV lifetime medical cost model can help to quantify the estimated burden of STI-attributable HIV infections in the United States.
Incidence and Prevalence of Sexually Transmitted Hepatitis B, United States, 2013–2018
Authors: Roberts Henry , Jiles Ruth , Harris Aaron M. , Gupta Neil , Teshale Eyasu
Published: January 2021

Background

Sexual transmission of hepatitis B virus (HBV) is common in the United States. In 2008, an estimated 50% of HBV infections were attributed to sexual transmission. Among 21,600 acute infections that occurred in 2018, the proportion attributable to sexual transmissions is unknown.

Methods

Objectives of this study were to estimate incidence and prevalence of hepatitis B attributable to sexual transmission among the US population 15 years and older for 2013 to 2018. Incidence estimates were calculated for confirmed cases submitted to Centers for Disease Control and Prevention from 14 states. A hierarchical algorithm defining sexually transmitted acute HBV infections as the absence of injection drug use among persons reporting sexual risk factors was applied to determine proportion of hepatitis B infections attributable to sexual transmission nationally. National Health and Nutrition Examination Survey public use data files were analyzed to calculate prevalence estimates of hepatitis B among US households and proportion attributed to sexual transmission was conservatively determined for HBV-infected non–US-born Americans who migrated from HBV endemic countries.

Results

During 2013 to 2018, an estimated 47,000 (95% confidence interval [CI], 27,000–116,000) or 38.2% of acute HBV infections in the United States were attributable to sexual transmission. During 2013 to 2018, among the US noninstitutionalized population, an estimated 817,000 (95% CI, 613,000–1,100,000) persons 15 years and older were living with hepatitis B, with an estimated 103,000 (95% CI, 89,000–118,000) infections or 12.6% attributable to sexual transmission.

Conclusions

These findings provide evidence sexually transmitted HBV infections remain a public health problem and underscore the importance of interventions to improve vaccination among at-risk populations.
Congenital Myenteric Hypoganglionosis
Authors: Kapur Raj P. , Bellizzi Andrew M. , Bond Steffan , Chen Haiying , Han Jeong S. , LeGallo Robin D. , Midgen Craig , Poulin Alysa A. , Uddin Naseem , Warren Mikako , Velázquez Vega José E. , Zuppan Craig W.
Published: January 2021

Congenital myenteric hypoganglionosis is a rare developmental disorder characterized clinically by severe and persistent neonatal intestinal pseudoobstruction. The diagnosis is established by the prevalence of small myenteric ganglia composed of closely spaced ganglion cells with sparse surrounding neuropil. In practice, the diagnosis entails familiarity with the normal appearance of myenteric ganglia in young infants and the ability to confidently recognize significant deviations in ganglion size and morphology. We review clinical, histologic, and immunohistochemical findings from 12 patients with congenital myenteric hypoganglionosis in comparison with similar data from age-matched controls and clearly delineate the diagnostic features of the condition. Practical guidelines are provided to assist surgical pathologists, who are likely to encounter this condition only infrequently. The diagnosis typically requires full-thickness intestinal biopsy as the abnormality is confined to the myenteric plexus in many patients. Immunohistochemistry for Hu C/D may be used to confirm hypoganglionosis. Reduced staining for calretinin and NeuN implicates a selective deficiency of intrinsic primary afferent neurons in this disease.
Distinguishing Features of Patients Evaluated for Multisystem Inflammatory Syndrome in Children
Authors: Kelly Michael S. , Fernandes Neil D. , Carr Audrey V. , Lahoud-Rahme Manuella , Cummings Brian M. , Chiu Joanne S.
Published: January 2021

Objectives

Given the significant overlap of multisystem inflammatory syndrome in children (MIS-C) with other common childhood illnesses presenting to the emergency department, extensive workup of this syndrome has become necessary. Nevertheless, little has been published on the factors differentiating MIS-C from other conditions in the acute care setting. We investigated differences in presentation and laboratory studies between suspected versus confirmed MIS-C patients.

Methods

This was a retrospective cohort study on patients 21 years or younger undergoing investigation for possible MIS-C at a single institution between April 21 and July 1, 2020. The primary outcome was diagnosis of MIS-C or an alternative final diagnosis. Clinical features and laboratory findings from initial presentation were collected and analyzed.

Results

A total of 106 patients (median, 4 years; 55.7% male) were included, of whom 17 (16%) of 106 met the criteria for MIS-C. Multisystem inflammatory syndrome in children patients were significantly more likely to report a coronavirus disease 2019 exposure (odds ratio (OR), 13.17 [3.87–44.9]), have gastrointestinal symptoms (OR, 3.81 [1.02–14.19]), and have a significantly higher odds of having abnormal laboratory values including high-sensitivity troponin T (OR, 13 [4.0–42.2]), N-terminal B-type natriuretic peptide (OR, 8.4 [2.3–30.1]), D-dimer (OR, 13 [1.6–103]), and ferritin (OR, 7.8 [2.2–27.2]). There were also differences between groups in inflammatory markers: C-reactive protein (median, 134.45 mg/L vs 12.6 mg/L; P < 0.05) and procalcitonin (1.71 ng/mL vs 0.14 ng/mL; P < 0.001).

Conclusions

Higher elevations in key laboratory studies may help to distinguish between MIS-C patients and non–MIS-C patients presenting to the emergency department.