bluuebunny/crossref_metadata_2025 huggingface dataset:
Fertility preservation in children and young adults with cancer
Authors: Brungardt Joseph G. , Burns Karen C. , Dasgupta Roshni
Published: December 2021

Purpose of review

The issue of fertility preservation has become increasingly relevant as survival rates of children with cancer exceeds 80% at 5 years. Fertility preservation options are being utilized alongside less gonadotoxic therapeutic regimens in the treatment of these patients. The purpose of this review is to summarize the recent advances in fertility preservation in the pediatric, adolescent, and young adult population.

Recent findings

Education research involves both patient and provider; to increase understanding on both sides for improved adoption of techniques and higher rates of posttreatment fertility. Basic science research, specific to the pediatric population, has worked to further understanding of protective techniques and cryopreserved tissue transfer. Research on the techniques of preservation confirms the safety of surgical gonadal (ovarian and testicular) tissue retrieval for cryopreservation but a viable pathway for testicular tissue utilization, as it has for ovarian, has yet to be realized. Outcomes may be improving but it is apparent that robust registries are necessary to track patients long-term. Possibly the largest advancement in the recent past are group efforts, such as by PanCareLIFE, to create guidelines for these issues using larger cohorts and registries than were available.

Current research implies the need for the development of a national strategy to ensure that pediatric patients undergoing gonadotoxic regimens are educated, alongside their family, about fertility options and outcomes thereafter.
The use of marginal kidneys in dual kidney transplantation to expand kidney graft utilization
Authors: Stratta Robert J. , Harriman David , Gurram Venkat , Gurung Komal , Sharda Berjesh
Published: December 2021

Purpose of review

The purpose of this review is to chronicle the history of dual kidney transplantation (DKT) and identify opportunities to improve utilization of marginal deceased donor (MDD) kidneys through DKT.

Recent findings

The practice of DKT from adult MDDs dates back to the mid-1990s, at which time the primary indication was projected insufficient nephron mass from older donors. Multiple subsequent studies of short- and long-term success have been reported focusing on three major aspects: Identifying appropriate selection criteria/scoring systems based on pre- and postdonation factors; refining technical aspects; and analyzing longer-term outcomes. The number of adult DKTs performed in the United States has declined in the past decade and only about 60 are performed annually. For adult deceased donor kidneys meeting double allocation criteria, >60% are ultimately not transplanted. MDDs with limited renal functional capacity represent a large proportion of potential kidneys doomed to either discard or nonrecovery.

DKT may reduce organ discard and optimize the use of kidneys from MDDs. New and innovative technologies targeting ex vivo organ assessment, repair, and regeneration may have a major impact on the decision whether or not to use recovered kidneys for single or DKT.
Excellent Tolerability of Ifosfamide and Mesna Via Continuous Infusion in a Pediatric Patient Population
Authors: Plutt Alexa A. , Stanton Michael P. , Zembillas Anthony S. , Pierson Catherine E. , Zahler Stacy , Anderson Peter M.
Published: December 2021

Ifosfamide is an antitumor agent with activity against various malignancies in pediatric patients. As a prodrug, ifosfamide requires metabolic activation, which occurs via a saturable, multistep equilibrium-based process. Due to these metabolic characteristics, the method of administration can affect its therapeutic and toxic effects. This single-center, retrospective review describes the tolerability of continuous infusion and bolus administration of ifosfamide in 10 pediatric patients with Ewing sarcoma. The primary objective was to report the hematologic toxicities of patients with differing administration methods. Secondary objectives included collecting information on nonhematologic toxicities and incidence of treatment delays and dose reductions. Ultimately, 48 cycles of ifosfamide were administered as bolus administration and 24 as continuous infusion. Patients receiving bolus administration had lower hemoglobin and platelet nadirs resulting in more transfusions and treatment delays when compared proportionally to continuous infusion. With the results of this case series, continuous infusion ifosfamide appears to be safe and feasible for outpatient administration and may offer an advantage from a hematologic adverse event profile but would need to be confirmed in a larger cohort.
Management of Peripheral T-Cell Lymphoma in Children and Adolescents Including STAT 3 Mutation Hyper-IgE Syndrome: One Size Does Not Fit All
Authors: Ravichandran Nikila , Uppuluri Ramya , Vellaichamy Swaminathan Venkateswaran , Melarcode Ramanan Kesavan , Meena Satishkumar , Varla Harika , Chandar Rumesh , Jayakumar Indira , Raj Revathi
Published: December 2021

Peripheral T-cell lymphoma (PTCL) is a rare form of lymphoma in children with limited published data on treatment and lack of a uniformly accepted treatment algorithm. We retrospectively analyzed the data in children up to 18 years of age diagnosed to have PTCL from January 2016 to June 2020. The study included six children with a median age of 10 years, the youngest being a 7-month-old girl. According to the WHO-PTCL classification, three had PTCL-not otherwise specified (NOS), 2 had hepatosplenic TCL, and 1 had subcutaneous panniculitis-like TCL. All children had presented with advanced disease, 4 in St. Jude stage IV, 2 in St. Jude stage III. Three children received CHOEP chemotherapy including cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide, while 1 child received CHOP. Two children received induction as per acute lymphoblastic leukemia followed by Bendamustine. Two patients succumbed to progressive disease, the infant with PTCL-NOS and 1 child with hepatosplenic TCL. Three children were in remission (median follow up of 44 mo). One child with PTCL-NOS Stage IV had an underlying STAT3 mutated hyperimmunoglobulin E syndrome and was in remission 12 months post a matched unrelated donor hematopoietic stem cell transplantation. He had grade 4 skin graft versus host disease and required extracorporeal photopheresis and ibrutinib, to which he had responded. CHOEP chemotherapy is well-tolerated and subcutaneous panniculitis-like TCL has the best prognosis thus far.
Claudin-18 as a Promising Surrogate Marker for Endocervical Gastric-type Carcinoma
Authors: Kiyokawa Takako , Hoang Lien , Pesci Anna , Alvarado-Cabrero Isabel , Oliva Esther , Park Kay J. , Soslow Robert A. , Stolnicu Simona
Published: December 2021

HIK1083 and trefoil factor 2 (TFF2) are known to be expressed in gastric-type carcinoma (GAS), but they do not reliably mark all GASs, and focal expression can be missed in biopsy specimens. We aimed to investigate whether claudin-18 and alpha-methylacyl-CoA racemase (AMACR) could be surrogate markers to separate GAS from other types of endocervical adenocarcinoma (ECA) and to compare their usefulness with that of HIK1083 and TFF2. Claudin-18 and AMACR immunohistochemistry was performed, and the results were compared with that of TFF2 and HIK1083, using whole sections of 75 ECAs (22 GASs and 53 non-GASs) and 179 ECAs with tissue microarrays (TMAs). TMAs were built to simulate the assessment of immunohistochemical stains in small biopsies. Any membranous (claudin-18) or cytoplasmic/membranous (AMACR, TFF2, HIK1083) staining of >5% of tumor cells was considered positive. Of 75 ECAs with whole sections, claudin-18 was significantly more frequently expressed in GASs (21/22) compared with non-GASs (8/53) (P<0.01). In ECAs with TMAs, claudin-18 expression was significantly frequent in GASs (15/23, 65.2%) than in non-GASs (3/152, 2.0%; all usual-type) (P<0.01). All claudin-18-positive GASs showed intense staining except 1 case. Claudin-18 shared the same degree of sensitivity and specificity with HIK1083 and TFF2. Three clear cell carcinomas were positive for claudin-18, but none showed intense staining. AMACR was expressed in a subset of ECAs and showed no impact in distinguishing between GAS and other ECAs. Our results suggest that claudin-18 is a promising surrogate marker to separate GAS from other types of ECA, including clear cell carcinoma.
Conducting a Systematic Review and Meta-analysis in Rehabilitation
Authors: Furlan Andrea D. , Irvin Emma
Published: December 2021

Systematic reviews are reviews of the literature using a step-by-step approach in a systematic way. Meta-analyses are systematic reviews that use statistical methods to combine the included studies to generate an effect estimate. In this article, we summarize 10 steps for conducting systematic reviews and meta-analyses in the field of rehabilitation medicine: protocol, review team and funding, objectives and research question, literature search, study selection, risk of bias, data extraction, data analysis, reporting of results and conclusions, and publication and dissemination. There are currently 64,958 trials that contain the word “rehabilitation” in CENTRAL (the database of clinical trials in the Cochrane Library), only 1246 reviews, and 237 protocols. There is an urgent need for rehabilitation physicians to engage and conduct systematic reviews and meta-analysis of a variety of rehabilitation interventions. Systematic reviews have become the foundation of clinical practice guidelines, health technology assessments, formulary inclusion decisions and to guide funding additional research in that area.
Is There an Optimal Interval for Medal Winning Performance in World Para Powerlifting Competition?
Authors: Lopes-Silva João Paulo , Richardson Dillon , Fukuda David H. , Franchini Emerson
Published: December 2021

The aim of the study was to determine the optimal interval between competitions for success in World Para Powerlifting events. A total of 1034 female (age = 34.4 ± 9.1 yrs) and 1,697 male (age = 33.7 ± 8.3 yrs) competition results from international Paralympic powerlifting events conducted between 2014 and 2020 were analyzed. Odds ratios for preparations intervals between competitive events were evaluated considering the dependent variable, earning a medal, and the independent variable, level of competition. There was an increased probability of winning a medal when the preparation interval was in the range of 22–30 wks (P = 0.004), as compared with less than 11 wks, while competing at World Cup events, whereas for World Championships and Paralympic Games, there was an increased probability of winning a medal when the interval range was 23–31 wks (P = 0.002) and 40 wks or more (P = 0.011) compared with less than 23 wks. However, there were no significant differences between preparation intervals for Regional Games/Championships. The Para Powerlifting athletes participating in the World Cup events, World Championships, and Paralympic Games share an optimal interval for success of approximately 21–31 wks and results from the World Championships and Paralympic Games, which can also be optimized with an interval of 40 wks or more.
Complete Foot Drop With Normal Electrodiagnostic Studies
Authors: Peters Blair R. , Pripotnev Stahs , Chi David , Mackinnon Susan E.
Published: December 2021

Common peroneal neuropathy is a peripheral neuropathy of multifactorial etiology often left undiagnosed until foot drop manifests and electrodiagnostic abnormalities are detected. However, reliance on such striking symptoms and electrodiagnostic findings for diagnosis stands in contrast to other commonly treated neuropathies, such as carpal tunnel and cubital tunnel syndrome. Poor recognition of common peroneal neuropathy without foot drop or the presence of foot drop with normal electrodiagnostic studies thus often results in delayed or no surgical treatment. Our cases document 2 patients presenting with complete foot drop who had immediate resolution after decompression. The first patient presented with normal electrodiagnostic studies representing an isolated Sunderland Zero nerve ischemia. The second patient presented with severe electrodiagnostic studies but also had an immediate improvement in their foot drop representing a Sunderland VI mixed nerve injury with a significant contribution from an ongoing Sunderland Zero ischemic conduction block. In support of recent case series, these patients demonstrate that common peroneal neuropathy can present across a broad diagnostic spectrum of sensory and motor symptoms, including with normal electrodiagnostic studies. Four clinical subtypes of common peroneal neuropathy are presented, and surgical decompression may thus be indicated for these patients that lack the more conventional symptoms of common peroneal neuropathy.
Renal Resistive Index on Intensive Care Unit Admission Correlates With Tissue Hypoperfusion Indices and Predicts Clinical Outcome
Authors: Fotopoulou Georgia , Poularas Ioannis , Kokkoris Stelios , Charitidou Efstratia , Boletis Ioannis , Brountzos Elias , Benetos Athanasios , Zakynthinos Spyros , Routsi Christina
Published: December 2021

Background:

Renal resistive index (RRI) has been used to evaluate renal blood flow. Our aim was to investigate the relation between RRI and global tissue hypoperfusion indices and their association with clinical outcome, in intensive care unit (ICU) patients.

Methods:

RRI was measured within 24 h of ICU admission. Gas exchange and routine hemodynamic variables at the time of RRI assessment were recorded. An elevated RRI was defined as >0.7. The ratio of central venous-to-arterial carbon dioxide partial pressure difference by arterial-to-central venous oxygen content difference (P(cv-a)CO2/C(a-cv)O2) and lactate were used as global tissue hypoperfusion indices.

Results:

A total of 126 patients were included [median age 61 (IQR 28) years, 74% males]. P(cv-a)CO2/C(a-cv)O2 ratio and arterial lactate were significantly higher in patients with RRI >0.7 compared with those with RRI ≤0.7 [2.88 (3.39) vs. 0.62 (0.57) mmol/L and 2.4 (2.2) vs. 1.2 (0.6)] respectively, both P < 0.001)]. RRI was significantly correlated with P(cv-a)CO2/C(a-cv)O2 ratio and arterial lactate for the whole patient population (rho = 0.64, both P < 0.0001) and for the subset of patients with shock (rho = 0.47, P = 0.001; and r = 0.64, P < 0.0001 respectively). Logistic regression models showed a significant association between RRI and P(cv-a)CO2/C(a-cv)O2 ratio with clinical outcome. The combination of RRI with P(cv-a)CO2)/(C(a-cv)O2 ratio and lactate better predicted mortality than RRI alone [AUC 84.8% (95% CI 5.1% –94.4%)] vs. [AUC 74.9% (95% CI 61%–88.8%)] respectively, P < 0.001.

Conclusions:

Renal blood flow assessed by RRI, on ICU admission, correlates with global tissue hypoperfusion indices. In addition, RRI in combination with tissue perfusion estimation better predicts clinical outcome than RRI alone.
Vestibular and auditory manifestations of migraine
Authors: Benjamin Tania , Gillard Danielle , Abouzari Mehdi , Djalilian Hamid R. , Sharon Jeffrey D.
Published: December 2021

Purpose of review

The purpose of this narrative review is to discuss current literature about vestibular migraine and other cochleovestibular symptoms related to migraine.

Recent findings

Vestibular migraine affects 2.7% of the US population. Misdiagnosis is common. The pathophysiology is currently unknown but new research shows that calcitonin gene-related peptide, which is implicated in migraine headaches, is expressed in the audiovestibular periphery. A recent large-scale placebo-controlled trial looking at metoprolol for vestibular migraine was terminated early due to poor recruitment; however, at study completion, no differences were seen between treatment arms. Many other audiovestibular symptoms have been shown to be associated with migraine, including tinnitus, hearing loss, aural fullness, otalgia, and sinus symptoms. Migraine is also associated with risk for developing numerous otologic conditions, including Meniere's disease, vestibular loss, Benign Paroxysmal Positional Vertigo, and sudden sensorineural hearing loss. There is now some evidence that patients may experience fluctuating hearing loss and aural fullness without vertigo in association with migraine, which is called cochlear migraine.

Migraine can cause a variety of audiologic and vestibular symptoms, and further research is required to understand how migraine affects the inner ear.
A six-month periodic fasting reduces microalbuminuria and improves metabolic control in patients with type 2 diabetes and diabetic nephropathy: a randomized controlled study
Authors: Sulaj Alba , Kopf Stefan , von Rauchhaupt Ekaterina , Kliemank Elisabeth , Brune Maik , Kender Zoltan , Bartl Hannelore , Cortizo Fabiola Garcia , Klepac Katarina , Han Zhe , Kumar Varun , Longo Valter , Teleman Aurelio , Okun Jürgen G. , Morgenstern Jakob , Fleming Thomas , Szendroedi Julia , Herzig Stephan , Nawroth Peter P.
Published: December 2021

Aim

Novel dietary interventions focused on fasting, have gained scientific and public attention. Periodic fasting has emerged as a dietary modification promoting beneficial effects on metabolic syndrome. This study aimed to assess whether periodic fasting reduces albuminuria in patients with type 2 diabetes and diabetic nephropathy and determine whether a reduction in albuminuria relates to activation of nephropathy-driven pathways.

Methods

Forty patients with type 2 diabetes (HbA1c 7.8±0.2% [62.1±2.3 mmol/mol]) and increased albumin-to-creatinine ratio (ACR) were randomized to fasting-mimicking diet (FMD) (n=21) or Mediterranean diet (n=19) for six months with three-month follow-up. Primary endpoint was the difference of the change in ACR from baseline to after six months between study groups. Subgroup analysis for patients with micro-versus macroalbuminuria at baseline was performed. Secondary endpoints comprised HOMA-IR, circulating markers of dicarbonyl detoxification (MG-H1, glyoxalase-1 and hydroxyacetone), lipid oxidation (acylcarnitines), DNA-damage/repair, (yH2Ax) and senescence (suPAR). Comparison was done by ANCOVA adjusted for age, sex, weight loss and baseline values of the respective outcome.

Results

Difference of change in ACR between FMD and control group after six months was 110.3mg/g (95% CI 99.2, 121.5mg/g; P=0.45) in all patients, -30.3mg/g (95% CI -35.7, -24.9mg/g; P≤0.05] in patients with microalbuminuria, and 434.0mg/g (95% CI 404.7, 463.4mg/g; P=0.23) in those with macroalbuminuria at baseline. FMD led to change in HOMA-IR of -3,8 (95% CI -5,6, -2.0; P≤0.05) and in suPAR of - 156.6pg/ml (95% CI -172.9, -140.4pg/ml; P≤0.05) after six months, while no change was observed in markers of dicarbonyl detoxification or DNA-damage/repair. Change in AC profile was related to patient responsiveness to ACR improvement. At follow-up only HOMA-IR reduction (−1.9 [95% CI -3.7, -0.1], P≤0.05) was sustained.

Conclusions

When accompanied by intensive diabetes care, FMD improves microalbuminuria, HOMA-IR and suPAR levels. Lack of changes in markers of dicarbonyl detoxification and DNA-damage/repair might explain the relapse of albuminuria at follow-up.

Trial registration

German Clinical Trials Register(Deutsches Register Klinischer Studien DRKS), DRKS-ID: DRKS00014287
Treatment-seeking for children with suspected severe malaria attending community health workers and primary health centres in Adamawa State, Nigeria
Authors: Lee Tristan T. , Omoluabi Elizabeth , Ayodeji Kazeem , Yusuf Ocheche , Okon Charles , Brunner Nina C. , Delvento Giulia , Signorell Aita , Lambiris Mark , Kwiatkowski Marek , Burri Christian , Lengeler Christian , Emedo Emmanuel , Cheshi Fatima , Hetzel Manuel W.
Published: December 2021

Background

The Community Access to Rectal Artesunate for Malaria project investigated the feasibility of introducing pre-referral rectal artesunate into existing community-based health services. In that study, the case fatality rate of children visiting primary health centres (PHCs) was 19% compared to 6% in children first visiting community health workers, locally called Community Oriented Resource Persons (CORPs). As case management practices did not fully explain this finding, this publication investigates other reasons underlying the observed difference in case fatality.

Methods

The observational study enrolled 589 children under the age of five years with fever and danger signs indicative of severe malaria attending CORPs and PHCs in Adamawa State, Nigeria, between June 2018 and July 2020. After 28 days, follow-up visits were conducted with caregivers to understand background characteristics, severity of symptoms, home treatment administration, and treatment seeking practices during the child’s illness. These factors were compared between children visiting CORPs versus those visiting PHCs as their first health provider.

Results

Children visiting PHCs were more likely to display danger signs indicative of central nervous system involvement (90% vs. 74%, p < 0.01) and have four or more danger signs (50% vs. 39%, p = 0.02). The delay between illness onset and visiting the community-based provider did not differ between children attending a CORP and children attending a PHC. PHC attendances more often lived in urban areas (16% vs 4%, p=0.01) and travelled farther to their first health provider, which was usually a community-based provider. Although practicing home treatment was common, especially among children attending PHCs (42% vs 33%, p=0.04), almost none of the children were given an antimalarial. PHCs were visited for their professionalism and experience while CORPs were visited for their low cost and because caregivers personally knew and trusted the provider.

Conclusions

Our comparison of children with suspected severe malaria seeking care from two kinds of community-based health care providers in Nigeria suggest that illness severity may be the primary driver behind the observed difference in case fatality rate.
Trans-ancestry genome-wide association study identifies novel genetic mechanisms in rheumatoid arthritis
Authors: Ishigaki Kazuyoshi , Sakaue Saori , Terao Chikashi , Luo Yang , Sonehara Kyuto , Yamaguchi Kensuke , Amariuta Tiffany , Too Chun Lai , Laufer Vincent A , Scott Ian C , Viatte Sebastien , Takahashi Meiko , Ohmura Koichiro , Murasawa Akira , Hashimoto Motomu , Ito Hiromu , Hammoudeh Mohammed , Al Emadi Samar , Masri Basel K , Halabi Hussien , Badsha Humeria , Uthman Imad W , Wu Xin , Lin Li , Lin Ting , Plant Darren , Barton Anne , Orozco Gisela , Verstappen Suzanne MM , Bowes John , MacGregor Alexander J , Honda Suguru , Koido Masaru , Tomizuka Kohei , Kamatani Yoichiro , Tanaka Hiroaki , Tanaka Eiichi , Suzuki Akari , Maeda Yuichi , Yamamoto Kenichi , Miyawaki Satoru , Xie Gang , Zhang Jinyi , Amos Chris , Keystone Ed , Wolbink Gertjan , van der Horst-Bruinsma Irene , Cui Jing , Liao Katherine P , Carroll Robert J , Lee Hye-Soon , Bang So-Young , Siminovitch Katherine A , de Vries Niek , Alfredsson Lars , Rantapää-Dahlqvist Solbritt , Karlson Elizabeth W , Bae Sang-Cheol , Kimberly Robert P , Edberg Jeffrey C , Mariette Xavier , Huizinga Tom , Dieudé Philippe , Schneider Matthias , Kerick Martin , Denny Joshua C ,   The Biobank Japan Project, Matsuda Koichi , Matsuo Keitaro , Mimori Tsuneyo , Matsuda Fumihiko , Fujio Keishi , Tanaka Yoshiya , Kumanogoh Atsushi , Traylor Matthew , Lewis Cathryn M , Eyre Stephen , Xu Huji , Saxena Richa , Arayssi Thurayya , Kochi Yuta , Ikari Katsunori , Harigai Masayoshi , Gregersen Peter K , Yamamoto Kazuhiko , Bridges S. Louis , Padyukov Leonid , Martin Javier , Klareskog Lars , Okada Yukinori , Raychaudhuri Soumya
Published: December 2021

Trans-ancestry genetic research promises to improve power to detect genetic signals, fine-mapping resolution, and performances of polygenic risk score (PRS). We here present a large-scale genome-wide association study (GWAS) of rheumatoid arthritis (RA) which includes 276,020 samples of five ancestral groups. We conducted a trans-ancestry meta-analysis and identified 124 loci (P< 5 × 10-8), of which 34 were novel. Candidate genes at the novel loci suggested essential roles of the immune system (e.g.,TNIP2andTNFRSF11A) and joint tissues (e.g.,WISP1) in RA etiology. Trans-ancestry fine mapping identified putatively causal variants with biological insights (e.g.,LEF1). Moreover, PRS based on trans-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between European and East Asian populations. Our study provides multiple insights into the etiology of RA and improves genetic predictability of RA.
Factors associated with fatal stroke in glioma patients: a population analysis
Authors: Jin Kai , Brennan Paul M , Poon Michael TC , Sudlow Cathie LM , Figueroa Jonine D
Published: December 2021

Importance

Brain tumour patients have the highest stroke mortality rates among all cancer types, but the factors associated with fatal stroke in brain tumour remain unknown.

Objective

We aimed to examine to what extent brain tumour grade, a marker of biological aggressiveness, tumour size and cancer treatment each associated with stroke mortality in glioma. Gliomas include the most common malignant types of brain cancer.

Design, setting, participants

A retrospective, observational cohort study using the US National Cancer Institute’s Surveillance Epidemiology and End Results program. We identified adult patients with a primary diagnosis of malignant gliomas in 2000 to 2018 (N=72,252). The primary outcome of interest was death from cerebrovascular disease. Adjusted hazard ratio (aHR) and 95% confidence interval (CI) were calculated using cause-specific Cox regression model to determine associations with tumour characteristics: grades II-IV, tumour size and cancer treatment (surgery, radiotherapy, chemotherapy) associated with stroke mortality after adjustment for age, sex, race, marital status and calendar years.

Results

In patients with glioma, increased risk for stroke mortality was observed in patients with higher grade (Grade III: aHR=1.19, 95% CI=0.88-1.61, p>0.05; Grade IV: aHR=1.94, 95% CI=1.39-2.71 compared to Grade II, p<0.001), and those with larger brain tumours (size=3-6 cm: aHR=1.93, 95%CI 1.31 -2.85, p<0.001, size>9cm: aHR=2.07, 95% CI=1.40-3.06, p<0.001 compared to size < 3cm). Having treatment was associated with decreased risk: surgery (yes VS no: aHR= 0.65; p<0.01), radiation (yes VS no: aHR= 0.66, p<0.01), chemotherapy (yes VS no: aHR=0.49, p<0.001).

Conclusions

Higher grade and tumour size are strongly associated with increased stroke mortality. This implicates tumour biology and/or the systemic tumour response which require further investigation in prospective studies to determine strategies to mitigate this risk.
Epidemiology of myocarditis and pericarditis following mRNA vaccines in Ontario, Canada: by vaccine product, schedule and interval
Authors: Buchan Sarah A. , Seo Chi Yon , Johnson Caitlin , Alley Sarah , Kwong Jeffrey C. , Nasreen Sharifa , Calzavara Andrew , Lu Diane , Harris Tara M. , Yu Kelly , Wilson Sarah E.
Published: December 2021

Importance

Increased rates of myocarditis/pericarditis following COVID-19 mRNA vaccines have been observed. However, little data are available related to product-specific differences, which have important programmatic impacts.

Objective

The objective of this study was to estimate reporting rates of myocarditis/pericarditis following COVID-19 mRNA vaccine by product, age, sex, and dose number, as well inter-dose interval.

Design

We conducted a population-based cohort study using passive vaccine safety surveillance data. All individuals in Ontario, Canada who received at least one dose of COVID-19 mRNA vaccine between December 14, 2020 and September 4, 2021 were included.

Setting

This study was conducted in Ontario, Canada (population: 14.7 million) using the provincial COVID-19 vaccine registry and provincial adverse events following immunization database.

Participants

We included all individuals with a reported episode of myocarditis/pericarditis following COVID-19 vaccine in the study period. We obtained information on all doses administered in the province to calculate reporting rates.

Exposure

Receipt of COVID-19 mRNA vaccine (mRNA-1273 [Moderna Spikevax] or BNT162b2 [Pfizer-BioNTech Comirnaty]).

Main Outcome(s) and Measure(s)

Reported rate of myocarditis/pericarditis meeting level 1-3 of the Brighton Collaboration case definitions.

Results

There were 19,740,741 doses of mRNA vaccines administered and 297 reports of myocarditis/pericarditis meeting our inclusion criteria. Among these, 69.7% occurred following the second dose of COVID-19 mRNA vaccine and 76.8% occurred in males. The median age of individuals with a reported event was 24 years. The highest reporting rate of myocarditis/pericarditis was observed in males aged 18-24 years following mRNA-1273 as the second dose; the rate in this age group was 5.1 (95% CI 1.9-15.5) times higher than the rate following BNT162b2 as the second dose. Overall reporting rates were higher when the inter-dose interval was shorter (i.e., ≤30 days) for both vaccine products. Among individuals who received mRNA-1273 for the second dose, rates were higher for those who had a heterologous as opposed to homologous vaccine schedule.

Conclusions and Relevance

Our results suggest that vaccine product, inter-dose interval and vaccine schedule combinations may play a role in the risk of myocarditis/pericarditis, in addition to age and sex. Certain programmatic strategies could reduce the risk of myocarditis/pericarditis following mRNA vaccines.
Seroprevalence of Brucella antibodies among vaccine manufacturing workers in contact with the Brucella melitensis Rev.1 vaccine strain
Authors: Vives-Soto Manuel , Puerta-García Amparo , Pereira José-Luis , Rodríguez-Sánchez Esteban , Solera Javier
Published: December 2021

Background

Cattle vaccination remains an essential measure for the control of brucellosis. Strict preventive measures are applied to protect vaccine manufacturing workers (VMW) employed in processing these live attenuated vaccines. We analyzed the serological responses of VMW in contact with the Brucella melitensis Rev.1 strain.

Methods

We conducted an observational study of a cohort of VMW in a Spanish biopharmaceutical company, a leader in manufacturing veterinary products. The results of the Brucella serological tests carried out on these workers between 2012 and 2019 were reviewed, as well as demographic data, length of time in the company (seniority), and level of exposure. Multivariate analysis was performed with the logistic regression test.

Results

Of the 115 VMW studied, 47 (41%) showed positive Rose Bengal tests during company check-ups. Exposure levels were correlated with seropositivity, with an adjusted OR of 6.6 (95% CI: 2.1-20.3) for the high exposure and 2.0 (95% CI: 0.6-6.7) for the medium exposure groups. Sixteen (34%) seropositive VMW demonstrated an acute serologic pattern of IgG and IgM antibodies seropositivization, while 31 (66%) manifested a chronic serologic pattern of constant or intermittent positive IgG antibodies with persistently negative IgM antibodies. Seniority was inversely associated with the acute pattern: adjusted OR of 0.88 (95% CI: 0.79-0.97) for each year added. No seropositive VMW showed evidence of active brucellosis during follow up.

Conclusion

Despite strict safety measures, a percentage of VMW were exposed to the Rev.1 strain. Exposure levels were correlated with seropositivity. None of them developed symptomatic infection during follow-up. Two different serological patterns were observed: an acute IgM-positive pattern or a chronic IgM-negative pattern. Seniority was associated with the chronic pattern.
Cohort Identification Using Semantic Web Technologies: Triplestores as Engines for Complex Computable Phenotyping
Authors: Pfaff Emily R. , Bradford Robert , Clark Marshall , Balhoff James P. , Wang Rujin , Preisser John S. , Walters Kellie , Nielsen Matthew E.
Published: December 2021

Background

Computable phenotypes are increasingly important tools for patient cohort identification. As part of a study of risk of chronic opioid use after surgery, we used a Resource Description Framework (RDF) triplestore as our computable phenotyping platform, hypothesizing that the unique affordances of triplestores may aid in making complex computable phenotypes more interoperable and reproducible than traditional relational database queries.

To identify and model risk for new chronic opioid users post-surgery, we loaded several heterogeneous data sources into a Blazegraph triplestore: (1) electronic health record data; (2) claims data; (3) American Community Survey data; and (4) Centers for Disease Control Social Vulnerability Index, opioid prescription rate, and drug poisoning rate data. We then ran a series of queries to execute each of the rules in our “new chronic opioid user” phenotype definition to ultimately arrive at our qualifying cohort.

Results

Of the 4,163 patients in the denominator, our computable phenotype identified 248 patients as new chronic opioid users after their index surgical procedure. After validation against charts, 228 of the 248 were revealed to be true positive cases, giving our phenotype a PPV of 0.92.

Conclusion

We successfully used the triplestore to execute the new chronic opioid user phenotype logic, and in doing so noted some advantages of the triplestore in terms of schemalessness, interoperability, and reproducibility. Future work will use the triplestore to create the planned risk model and leverage the additional links with ontologies, and ontological reasoning.
Post-Translational Modifications Optimize the Ability of SARS-CoV-2 Spike for Effective Interaction with Host Cell Receptors
Authors: Kapoor Karan , Chen Tianle , Tajkhorshid Emad
Published: December 2021

SARS-CoV2 spike glycoprotein is prime target for vaccines and for diagnostics and therapeutic antibodies against the virus. While anchored in the viral envelope, for effective virulance, the spike needs to maintain structural flexibility to recognize the host cell surface receptors and bind to them, a property that can heavily hinge upon the dynamics of the unresolved domains, most prominently the stalk. Construction of the complete, membrane-bound spike model and the description of its dynamics remain critical steps in understanding the inner working of this key element in viral infection. Using a hybrid approach, combining homology modeling, protein-protein docking and MD simulations, guided by biochemical and glycomics data, we have developed a full-length, membrane-bound, palmitoylated and fully-glycosylated spike structure in a native membrane. Multi-microsecond MD simulations of this model, the longest known trajectory of the full-spike, reveals conformational dynamics employed by the protein to explore the crowded surface of the host cell. In agreement with cryoEM, three flexiblele hinges in stalk allow for global conformational heterogeneity of spike in the fully-glycosyslated system mediated by glycan-glycan and glycan-lipid interactions. Dynamical range of spike is considerably reduced in its non-glycosylated form, confining the area explored by the spike on the host cell surface. Furthermore, palmitoylation of the membrane domain amplify the local curvature that may prime the fusion. We show that the identified hinge regions are highly conserved in SARS coronaviruses, highlighting their functional importance in enhancing viral infection, and thereby provide novel points for discovery of alternative therapeutics against the virus.

Significance

SARS-CoV2 Spike protein, which forms the basis for high pathogenicity and transmissibility of the virus, is also prime target for the development of both diagnostics and vaccines for the debilitating disease caused by the virus. We present a full model of spike methodically crafted and used to study its atomic-level dynamics by multiple-µs simulations. The results shed new light on the impact of posttranslational modifications in the pathogenicity of the virus. We show how glycan-glycan and glycan-lipid interactions broaden the protein’s dynamical range, and thereby, its effective interaction with the surface receptors on the host cell. Palmitoylation of spike membrane domain, on the other hand, results in a unique deformation pattern that might prime the membrane for fusion.
Steroid hormone signaling activates thermal nociception during Drosophila peripheral nervous system development
Authors: Jaszczak Jacob S. , DeVault Laura , Jan Lily Yeh , Jan Yuh Nung
Published: December 2021

Sensory neurons enable animals to detect environmental changes and avoid harm. An intriguing open question concerns how the various attributes of sensory neurons arise in development. Drosophila melanogaster larvae undergo a behavioral transition by robustly activating a thermal nociceptive escape behavior during the second half of larval development (3rd instar). The Class 4 dendritic arborization (C4da) neurons are multimodal sensors which tile the body wall of Drosophila larvae and detect nociceptive temperature, light, and mechanical force. In contrast to the increase in nociceptive behavior in the 3rd instar, we find that ultraviolet light-induced Ca2+ activity in C4da neurons decreases during same period of larval development. Loss of ecdysone receptor has previously been shown to reduce nociception in 3rd instar larvae. We find that ligand dependent activation of ecdysone signaling is sufficient to promote nociceptive responses in 2nd instar larvae and suppress expression of subdued (encoding a TMEM16 channel). Reduction of subdued expression in 2nd instar C4da neurons not only increases thermal nociception but also decreases the response to ultraviolet light. Thus, steroid hormone signaling suppresses subdued expression to facilitate the sensory switch of C4da neurons. This regulation of a developmental sensory switch through steroid hormone regulation of channel expression raises the possibility that ion channel homeostasis is a key target for tuning the development of sensory modalities.
Single immunization with recombinant ACAM2000 vaccinia viruses expressing the spike and the nucleocapsid proteins protect hamsters against SARS-CoV-2 caused clinical disease
Authors: Deschambault Yvon , Lynch Jessie , Warner Bryce , Tierney Kevin , Huynh Denise , Vendramelli Robert , Tailor Nikesh , Frost Kathy , Booth Stephanie , Sajesh Babu , LeBlanc Kyle , Layne Christine , Lin Lisa , Beniac Daniel , Carpenter Michael , Safronetz David , Li Xuguang , Kobasa Darwyn , Cao Jingxin
Published: December 2021

Increasing cases of SARS-CoV-2 breakthrough infections from immunization with predominantly spike protein based COVID-19 vaccines highlight the need for alternative vaccines using different platforms and/or antigens. In this study, we expressed SARS-CoV-2 spike and nucleocapsid proteins in a novel vaccinia virus ACAM2000 platform (rACAM2000). Following a single intramuscular immunization, the rACAM2000 co-expressing the spike and nucleocapsid proteins induced significantly improved protection against SARS-CoV-2 challenge in comparison to rACAM2000 expressing the individual proteins in a hamster model, as shown by reduced weight loss and quicker recovery time. The protection was associated with reduced viral loads, increased neutralizing antibody titre and reduced neutrophil-to-lymphocyte ratio. Thus, our study demonstrates that the rACAM2000 expressing a combination of the spike and nucleocapsid antigens is a promising COVID-19 vaccine candidate and further studies will investigate if the rACAM2000 vaccine candidate can induce a long lasting immunity against infection of SARS-CoV-2 variants of concern.
Systems immune profiling of variant-specific vaccination against SARS-CoV-2
Authors: Peng Lei , Park Jonathan J. , Fang Zhenhao , Zhou Xiaoyu , Dong Matthew B. , Xiong Qiancheng , Lin Chenxiang , Chen Sidi
Published: December 2021

Lipid-nanoparticle(LNP)-mRNA vaccines offer protection against COVID-19. However, multiple variant lineages caused widespread breakthrough infections. There is no report on variant-specific vaccines to date. Here, we generated LNP-mRNAs specifically encoding wildtype, B.1.351 and B.1.617 SARS-CoV-2 spikes, and systematically studied their immune responses in animal models. All three LNP-mRNAs induced potent antibody responses in mice. However, WT-LNP-mRNA vaccination showed reduced neutralization against B.1.351 and B.1.617; and B.1.617-specific vaccination showed differential neutralization. All three vaccine candidates elicited antigen-specific CD8 and CD4 T cell responses. Single cell transcriptomics of B.1.351-LNP-mRNA and B.1.617-LNP-mRNA vaccinated animals revealed a systematic landscape of immune cell populations and global gene expression. Variant-specific vaccination induced a systemic increase in reactive CD8 T cell population, with a strong signature of transcriptional and translational machineries in lymphocytes. BCR-seq and TCR-seq unveiled repertoire diversity and clonal expansions in vaccinated animals. These data provide direct systems immune profiling of variant-specific LNP-mRNA vaccinationin vivo.
Urinary cell-free DNA as a noninvasive liquid biopsy for hepatocellular carcinoma: a novel tool for diagnostics and monitoring
Authors: Kim Amy K. , Lin Selena Y. , Liu Hsin-Ni , Jain Surbhi , Gade Terence P. , Shieh Fwu-Shan , Chao Max , Hamilton James , Hann Hie-Won , Chang Ting-Tsung , Goryunov Dmitry , Wang Zhili , Su Ying-Hsiu
Published: December 2021

Background & Aims

Cell-free DNA (cfDNA) has advanced cancer genetic profiling through liquid biopsy. While plasma is traditionally the primary source, emerging evidence highlights urinary cfDNA as a novel and noninvasive alternative. This study aimed to comprehensively assess transrenal DNA (trDNA) as a novel noninvasive biomarker source in HCC patients, compared to blood-based liquid biopsy.

Approach & Results

HBV DNA was used as a biomarker for trDNA. HBV-targeted and HCC-focused next generation sequencing (NGS) and whole genome sequencing (WGS) were used to compare fragment insert-sizes, the genome coverage, and germline genotyping accuracy. Urinary cfDNA overall exhibited a predominantly mononucelosomal pattern similar to plasma cfDNA, but with shorter fragments, broader size distribution and a more pronounced 10-bp periodicity. In contrast, trDNA were shorter and more variable among all patients. In HCC patients, trDNA was even shorter, with distinct 4-mer end motifs, compared to non-HCC trDNA. Higher concentrations of HCC-distinctive 4-mer end motif and TP53 mutations were found in urine compared to plasma. The overall genome coverage breadth by WGS was similar between urine and plasma cfDNA, with a higher fraction of covered cancer-associated mutation hotspots in urine cfDNA. In 101 HCC patients, there was a 78% overall concordance of HCC-associated mutations (TP53, CTNNB1,andhTERT) and in select 15 patients, 97% overall position-level concordance by targeted NGS between plasma and urine cfDNA.

Conclusion

Urine cfDNA has comparable features with distinct characteristics to plasma cfDNA and is a promising tool for liver cancer studies.
ROR1 is a novel putative druggable target for diffuse glioma
Authors: John Miya , Rao Padmashree , Noor Humaira , Ford Caroline
Published: December 2021

The cell surface receptor ROR1 is a therapeutic target of growing interest in oncology; however, its role in glioma has not been established thus far. This study analyzed associations between ROR1 mRNA expression and clinical outcomes, and histological and molecular subtypes in four independent glioma (grades II-IV) transcriptomic datasets (The Cancer Genome Atlas-GBMLGG, Chinese Glioma Genome Atlas, Repository for Molecular Brain Neoplasia, and GSE16011), encompassing a total of 2,388 cases. The data strongly suggests that ROR1 may be associated with poorer outcomes and more aggressive disease. Taken together, ROR1 should be further examined as a novel putative druggable target for glioma, a cancer that currently has very limited therapeutic options.
Persistent Symptoms Among Frontline Health Workers Post-acute COVID-19 Infection
Authors: Wose Kinge CN , Hanekom S , Smith A-L , Akpan F , Mothibi E , Maotoe T , Lebatie F , Majuba P , Sanne I , Chasela C
Published: December 2021

Background

Growing evidence shows that a significant number of patients with COVID-19 experience prolonged/persistent symptoms, also known as Long COVID. Reports of Long COVID are rising but little is known about prevalence in non-hospitalized patients.

Objective

We sought to identify the persistent symptoms of COVID-19 in frontline workers at Right to Care (RTC) South Africa who have past the acute phase of illness with a view to establishing rehabilitation programs for its employees and the community at large.

Methods

This was a cross-sectional survey. We analysed data from 207 eligible COVID-19 positive RTC frontline workers who participated in a post-COVID online self-administered survey. The survey was active for two months. Frequencies and median were calculated for categorical and continuous variables, respectively.

Results

The survey response rate was 30% (62 out of 207); of the 62 respondents with a median age of 33.5 years (IQR= 30–44 years), 47 (76%) were females. The majority (n=55; 88.7%) self-isolated and 7 (11.3%) were admitted to hospital at time of diagnosis. The most common comorbid condition reported was hypertension particularly among workers aged 45–55 years. Headache, body ache, fatigue, loss of smell, dry cough, fever, and loss of appetite were the most common reported symptoms at time of diagnosis. Persistent symptoms were characterized by fatigue, anxiety, difficulty sleeping, chest pain, muscle pain and brain fog, being the six most reported.

Conclusion

The impact of persistent/Long COVID-19 on the health of frontline workers could have direct impact in health service delivery. Given the rise in cases of COVID-19 in South Africa and the world at large, the prevalence of Long COVID is likely to be substantial and therefore need for rehabilitation programs targeted at each of the persistent (Long) COVID symptoms is critical.
Smartphone Movement Sensors for Remote Monitoring of Respiratory Rate: Observational Study
Authors: Valentine Sophie , Klasmer Benjamin , Dabbah Mohammad , Balabanovic Marko , Plans David
Published: December 2021

Background

Mobile health offers potential benefits to patients and healthcare systems alike. Existing remote technologies to measure respiratory rate (RR) have limitations, such as cost, accessibility and reliability. Using smartphone sensors to measure RR may offer a potential solution.

Objective

The aim of this study was to conduct a comprehensive assessment of a novel mHealth smartphone application designed to measure RR using movement sensors.

Methods

In Study 1, 15 participants simultaneously measured their RR with the app, and an FDA cleared reference device. A novel reference method to allow the app to be evaluated ‘in the wild’ was also developed. In Study 2, 165 participants measured their RR using the app, and these measures were compared to the novel reference. Usability of the app was also assessed in both studies.

Results

The app, when compared to the FDA-cleared and novel references, respectively, showed a mean absolute error (MAE) of 1.65 (SD=1.49) and 1.14 (1.44), relative MAE of 12.2 (9.23) and 9.5 (18.70) and bias of 0.81 (limits of agreement (LoA) =-3.27-4.89) and 0.08 (−3.68-3.51). Pearson correlation coefficients were 0.700 and 0.885. 93% of participants successfully operated the app on their first use.

Conclusions

The accuracy and usability of the app demonstrated here show promise for the use of mHealth solutions employing smartphone sensors to remotely monitor RR. Further research should validate the benefits that this technology may offer patients and healthcare systems.