bluuebunny/crossref_metadata_2025 huggingface dataset:
In search of the Aplysia immunome: an in silico study
Authors: Kron Nicholas S.
Published: July 2022

The immune repertoires of mollusks beyond commercially important organisms such as the pacific oysterCrassostrea gigasor vectors for human pathogens like the bloodfluke planorbBiomphalaria glabrataare understudied. Despite being an important model for neural aging and the role of inflammation in neuropathic pain, the immune repertoire ofAplysia californicais poorly understood. Recent discovery of a neurotropic nidovirus inAplysiahas highlighted the need for a better understanding of theAplysiaimmunome. To address this gap in the literature, theAplysiareference genome was mined using InterProScan and OrthoFinder for putative immune genes. TheAplysiagenome encodes orthologs of all critical components of the classical Toll-like receptor (TLR) signaling pathway. The presence of many more TLRs and TLR associated adapters than known from vertebrates suggest yet uncharacterized, novel TLR associated signaling pathways.Aplysiaalso retains many nucleotide receptors and antiviral effectors known to play a key role in viral defense in vertebrates. However, the absence of key antiviral signaling adapters MAVS and STING in theAplysiagenome suggests divergence from vertebrates and bivalves in these pathways. The resulting immune gene set of this in silico study provides a basis for interpretation of future immune studies in this important model organism.
Interaction of silicon and manganese in nutritional and physiological aspects of energy cane with high fiber content
Authors: Oliveira Kamilla Silva , de Mello Prado Renato , Checchio Mirela Vantini , Gratão Priscila Lupino
Published: July 2022

Background

Silicon (Si) is a multiple stress attenuator element in plants, however more research is needed to elucidate the actions in the plants defense system with low nutrition of manganese (Mn) for a prolonged period, and the attenuation mechanisms involved in the effects of Mn deficiency on energy cane with high fiber content. Thus, the objective of this study was to evaluate whether Si reduces the oxidative stress of the energy cane grown in low Mn in nutrient solution, to mitigate the effects of Mn deficiency, improving enzymatic and non-enzymatic defense, uptake of Mn the plant growth.

Methods

An experiment was carried out with pre-sprouted seedlingsof Saccharum spontaneumL. in a 2 × 2 factorial scheme in five replications in which the plants were grown under sufficiency (20.5 μmol L−1) and deficiency (0.1 μmol L−1) of Mn combined with the absence and presence of Si (2.0 mmol L−1) for 160 days from the application of the treatments. The following parameters were evaluated: accumulation of Mn and Si, H2O2,MDA, activity of SOD and GPOX, total phenol content, pigments, and quantum efficiency of PSII.

Results

Mn deficiency induced the oxidative stress for increase the H2O2and MDA content in leaves of plants and reduce the activity of antioxidant enzymes and total phenols causing damage to quantum efficiency of photosystem II and pigment content. Si attenuated the effects of Mn deficiency even for a longer period of stress by reducing H2O2(18%) and MDA (32%) content, and increased the Mn uptake efficiency (53%), SOD activity (23%), GPOX (76%), phenol contents, thus improving growth.

Conclusions

The supply of Si promoted great nutritional and physiological improvements in energy cane with high fiber content in Mn deficiency. The results of this study propose the supply of Si via fertirrigation as a new sustainable strategy for energy cane cultivation in low Mn environments.
Multimodal opioid-sparing pain management for emergent cesarean delivery under general anesthesia: a quality improvement project
Authors: Anyaehie Kelechi B. , Duryea Elaine , Wang Jenny , Echebelem Chinedu , Macias Devin , Sunna Mary , Ogunkua Olutoyosi , Joshi Girish P. , Gasanova Irina
Published: July 2022

Background

Opioid-sparing multimodal analgesic approach has been shown to provide effective postoperative pain relief and reduce postoperative opioid consumption and opioid-associated adverse effects. While many studies have evaluated analgesic strategies for elective cesarean delivery, few studies have investigated analgesic approaches in emergent cesarean deliveries under general anesthesia. The primary aim of this quality improvement project is to evaluate opioid consumption with the use of a multimodal opioid-sparing pain management pathway in patients undergoing emergent cesarean delivery under general anesthesia.

Methods

Seventy-two women (age > 16 years) undergoing emergent cesarean delivery under general anesthesia before (n = 36) and after (n = 36) implementation of a multimodal opioid-sparing pain management pathway were included. All patients received a standardized general anesthetic. Prior to implementation of the pathway, postoperative pain management was primarily limited to intravenous patient-controlled opioid administration. The new multimodal pathway included scheduled acetaminophen and non-steroidal anti-inflammatory medications and ultrasound-guided classic lateral transversus abdominis plane blocks with postoperative opioids reserved only for rescue analgesia. Data obtained from electronic records included demographics, intraoperative opioid use, and pain scores and opioid consumption upon arrival to the recovery room, at 2, 6, 12, 24, 48, and 72 h postoperatively.

Results

Patients receiving multimodal opioid sparing analgesia (AFTER group) had lower opioid use for 72 h, postoperatively. Only 2 of the 36 patients (5.6%) in the AFTER group required intravenous opioids through patient-controlled analgesia while 30 out of 36 patients (83.3%) in the BEFORE group required intravenous opioids.

Conclusions

Multimodal opioid-sparing analgesia is associated with reduced postoperative opioid consumption after emergent cesarean delivery.
Persistent hiccup as one of the initial symptoms of leucine-rich glioma-inactivated-1 encephalitis: a case report
Authors: Hou Lan , Wan Li , Li Hongshan , Wang Zhehui , Guan Hongzhi , Ren Haitao , Wang Pei
Published: July 2022

Background

Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis, an autoimmune disorder, is characterized by faciobrachial dystonic seizures, epilepsy, memory deficits and altered mental status while hiccup is not commonly found in patients.

Case presentation

A 62-year-old male was presented with slurred speech, abnormal gait, faciobrachial dystonic seizures and impaired cognition. Besides, the hiccup was one of the initial symptoms. His brain magnetic resonance images (MRI) revealed multiple lesions with left caudate nucleus, putamen, insula and left hippocampus involvement. Because a diagnosis of antibody-related limbic encephalitis was suspected, studies including an autoimmune profile were done by cell-based assays. After anti-LGI1 antibodies were detected in both cerebrospinal fluid and serology, pulse methylprednisolone and intravenous immunoglobulin were started and hence hiccups disappeared along with other symptoms.

Conclusions

Clinicians should be aware that persistent hiccups might be one of the initial manifestations of LGI1 subtype of voltage-gated potassium channel complex antibody associated autoimmune encephalitis.
Behavioral activation / inhibition systems and lifestyle as predictors of mental disorders in adolescent athletes during Covid19 pandemic
Authors: Firoozjah Morteza Homayounnia , Homayouni Alireza , Shahrbanian Shahnaz , Shahriari Shaghayegh , Janinejad Diana
Published: July 2022

Background

The following study investigates the correlational relationship between behavioral activation/inhibition systems, lifestyle and mental disorders in Adolescent Athletes during the Covid-19 pandemic. Methods: Research methods are descriptive and correlational; “Of the eligible participants who were available during a COVID-19 quarantine period from June through August 2020 (N = 180), the Krejcie and Morgan Sampling Method was used to simplify the process of determining the sample size for a finite population [46], resulting in a calculation of N = 130 sample participants. to respond to Carver & White’s Behavioral activation/inhibition systems Scale (BIS/BAS), Mille’s Lifestyle Questionnaire and Goldberg & Williams’s General Health Questionnaire (GHQ-12). Data was analyzed using linear regression analysis and Pearson’s correlation coefficient. Results: Findings showed a positive correlation of statistical significance between behavioral inhibition systems (BIS) and mental disorders in Adolescent Athletes at the 0.01 level and a negative correlation of statistical significance between scaling components of the behavioral activation systems (BAS), lifestyle and mental disorders in Adolescent Athletes at the 0.05 level. Conclusions: Analyzing the data, it can thus be concluded that whilst behavioral inhibition and activation systems seem to work together to significantly predict mental disorders, lifestyle cannot.
Preference and usage pattern of mobile medical apps for drug information purposes among hospital pharmacists in Sarawak, Malaysia
Authors: Kho Boon Phiaw , Wong Sheng Ming Andy , Chiu Jin Wei Timothy , Liew Eon
Published: July 2022

Introduction

Pharmacists are frequent users of mobile medical apps (MMA) for drug information (DI) and clinical decision-making purposes. However, the wide range of available MMA may be of variable credibility and results in heterogeneous recommendations. The need for subscription may also influence choice of apps.

Objective

The objective of this study was to determine the usage pattern of MMA among hospital pharmacists, including their perceptions and factors affecting their choice of apps.

Methods

This cross-sectional study required respondents to fill in an online questionnaire. The questionnaire included sections on respondents' demographic data, MMA usage pattern, perceived usefulness and opinion on subscription fees. Items were adapted from available literature and validated locally. It was made accessible for 6 weeks starting November 2019 for all pharmacists working in the 23 public hospitals in Sarawak to response (universal sampling). Collected data were analysed using descriptive and inferential statistics.

Results

A response rate of 37.2% was achieved (n = 162). Respondents were heavily reliant on MMA, with 78.4% accessing them multiple times daily. The majority also agreed that MMA contain correct and up-to-date information. A median of 5 apps were downloaded, suggesting an ultimate app catering for all DI needs was lacking. The Malaysian Drug Formulary was the most downloaded app (88.3%), whereas Lexicomp® was the most “well-rounded” in terms of functionality. Clinical pharmacists were significantly more likely to purchase MMA, in particular UpToDate® (p < 0.01) due to their need to access clinical updates. Respondents highly recommended institutional access for either UpToDate® or Lexicomp® be made available. Pre-registration pharmacists should be guided on judicious MMA usage, as they downloaded significantly more apps and were more likely to indicate not knowing which DI recommendation to follow (both p < 0.01).

Conclusion

MMA has become an indispensable tool for hospital pharmacists, however there was a tendency to download multiple apps for DI needs. Institutional access can be considered for credible apps identified to ensure accuracy and uniformity of DI recommendations, with purchase decision made after surveying the needs and preferences of end users.
Drivers of irrational use of antibiotics among children: a mixed-method study among prescribers and dispensers in Tanzania
Authors: Nkinda Lilian , Kilonzi Manase , Felix Fatuma F. , Mutagonda Ritah , Myemba David T. , Mwakawanga Dorkasi L. , Kibwana Upendo , Njiro Belinda J. , Ndumwa Harrieth P. , Mwakalukwa Rogers , Makuka Gerald , Kubigwa Samson W. , Marealle Alphonce I. , Mikomangwa Wigilya P. , Sambayi Godfrey , Kunambi Peter P. , Maganda Betty A. , Sirili Nathanael , Mfaume Rashid , Nshau Arapha Bashir , Bwire George M. , Scherpbier Robert , Nyankesha Elevanie , Ndayishimiye Pacifique
Published: July 2022

Background

Misuse of antibiotics has been associated with poor knowledge, attitude and practice (KAP). Therefore, this study aimed to assess if KAP of prescribers and dispensers could drive irrational use of antibiotics among children in Tanzania.

Methods

A convergent parallel mixed-methods study design that employed quantitative and qualitative approaches was conducted in 14 regional referral hospitals (RRHs). A total of 108 participants, prescribers [54] and dispensers [54] working with the pediatric population in the respective regions participated in a quantitative survey, by filling the standard questionnaire while 28 key informant interviews were conducted with in-charges of units from the pharmacy and pediatric departments. Two key informants (prescriber and dispenser) were selected from each RRH.

Results

Overall, among prescribers and dispensers, there was adequate knowledge; 81.5% and 79.6%, p = 0.53, those with positive attitudes were 31.5% and 81.5%, p < 0.001 and poor practices were among 70.4% and 48% p = 0.0312 respectively. Among prescribers, 14.8% agreed and strongly agreed that prescribing antibiotics that a patient did not need does not contribute to resistance. Moreover 19% disagreed to prescribe antibiotics according to local guidelines. Among dispensers, a-quarter of the dispensers thought individual efforts to implement antibiotic stewardship would not make a difference, 17% agreed and strongly agreed that antibiotics can treat viral infection and 7% agreed and strongly agreed antibiotics can be stopped upon resolution of symptoms. From qualitative interviews, both participants displayed an adequate understanding of multi-contributors of antibiotic resistance (AR) including polypharmacy, community self-medication, among others. Regardless, both professions declared to prescribed and dispensed antibiotics according to the antibiotics available in stock at the facility. Furthermore, prescribers perceived laboratory investigation took a long time, hence wasting their time. On the other hand, Dispensers reported not to provide adequate instruction to the patients, after dispensing antibiotics.

Conclusions

Both prescribers and dispensers had adequate knowledge, few prescribers had positive attitudes and the majority had poor practices. Few dispensers had poor attitude and practice. These findings highlight the need to provide adequate training on antimicrobial stewardship and enforce regulation that foster appropriate medical practice.
Effect of a GLP-1 mimetic on the insulin response to oral sugar testing in horses
Authors: Stefanovski Darko , Robinson Mary A. , Van Eps Andrew
Published: July 2022

Background

Insulin dysregulation (ID) is the most important risk factor for the development of laminitis in horses and therapies to control it are needed.

Hypothesis/objectives

To assess the effects of a single dose of the synthetic GLP-1 analog exenatide on postprandial insulin dynamics. We hypothesized that exenatide would improve insulin sensitivity and lower postprandial blood insulin concentrations.

Study design

Randomized, crossover, experimental study.

Animals

Six horses (3 mares, 3 geldings; 2 with normal insulin regulation [NIR] and 4 with mild ID).

Methods

Horses completed both study arms: subcutaneous administration of exenatide (or no treatment) 30 min before an oral sugar test (0.15 ml/kg of Karo Syrup). Blood samples obtained over 240 min were assayed for glucose, insulin, lactate, c-peptide and total GLP-1. The area under the curve (AUC) was calculated using the trapezoidal rule. Insulin sensitivity (SI) was estimated using a mathematical model.

Results

Exenatide resulted in a postprandial decrease of 20% (effect size: 2673 µU·min/ml; 95% CI: 900 – 4446 µU·min/ml; P = 0.003) in AUC of plasma insulin (control; mean AUC insulin: 11,989 µU·min/ml; 95% CI: 9673 – 14,305 µU·min/ml, exenatide; mean AUC insulin: 9316 µU·min/ml; 95% CI: 7430 – 11,202 µU·min/ml). Exenatide resulted in an approximately threefold increase (effect size: 5.56 10–4· µU/ml−1·min−1; 95% CI: 0.95 – 10.1 10–4· µU/ml−1·min−1; P = 0.02) in estimated insulin sensitivity (control mean SI: 1.93 10–4· µU/ml−1·min−1; 95% CI: 0.005 – 3.86 10–4·µU/ml−1·min−1 vs. exenatide mean SI: 7.49 10–4· µU/ml−1·min−1; 95% CI: 3.46 – 11.52 10–4· µU/ml−1·min−1).

Conclusions

The decrease in insulin response to carbohydrates was due to an increase in whole-body insulin sensitivity. GLP-1 agonists may have therapeutic potential for ID in horses.
Association of childhood BMI trajectory with post-adolescent and adult lung function is mediated by pre-adolescent DNA methylation
Authors: Rathod Rutu , Zhang Hongmei , Karmaus Wilfried , Ewart Susan , Mzayek Fawaz , Arshad S. Hasan , Holloway John W.
Published: July 2022

Background

Body mass index (BMI) has been shown to be associated with lung function. Recent findings showed that DNA methylation (DNAm) variation is likely to be a consequence of changes in BMI. However, whether DNAm mediates the association of BMI with lung function is unknown. We examined the mediating role of DNAm on the association of pre-adolescent BMI trajectories with post-adolescent and adulthood lung function (forced expiratory volume (FEV1), forced vital capacity (FVC), and FEV1/FVC).

Methods

Analyses were undertaken in the Isle of Wight birth cohort (IOWBC). Group-based trajectory modelling was applied to infer latent BMI trajectories from age 1 to 10 years. An R package, ttscreening, was applied to identify CpGs at 10 years potentially associated with BMI trajectories for each sex. Linear regressions were implemented to further screen CpGs for their association with lung function at 18 years. Path analysis, stratified by sex, was applied to each screened CpG to assess its role of mediation. Internal validation was applied to further examine the mediation consistency of the detected CpGs based on lung function at 26 years. Mendelian randomization (MR-base) was used to test possible causal effects of the identified CpGs.

Results

Two BMI trajectories (high vs. low) were identified. Of the 442,475 CpG sites, 18 CpGs in males and 33 in females passed screening. Eight CpGs in males and 16 CpGs in females (none overlapping) were identified as mediators. For subjects with high BMI trajectory, high DNAm at all CpGs in males were associated with decreased lung function, while 8 CpGs in females were associated with increased lung function at 18 years. At 26 years, 6 CpGs in males and 14 CpGs in females showed the same direction of indirect effects as those at 18 years. DNAm at CpGs cg19088553 (GRIK2) and cg00612625 (HPSE2) showed a potential causal effect on FEV1.

Conclusions

The effects of BMI trajectory in early childhood on post-adolescence lung function were likely to be mediated by pre-adolescence DNAm in both males and females, but such mediation effects were likely to diminish over time.
Triglyceride-glucose index in the prediction of adverse cardiovascular events in patients with premature coronary artery disease: a retrospective cohort study
Authors: Wu Zhenguo , Liu Li , Wang Weiwei , Cui Huiliang , Zhang Yerui , Xu Jiechang , Zhang Wencheng , Zheng Tengfei , Yang Jianmin
Published: July 2022

Background

Premature coronary artery disease (PCAD) has become more common in recent years and is often associated with poor outcomes. Triglyceride-glucose (TyG) index is a simple and reliable surrogate for insulin resistance (IR) and is an independent predictor of cardiovascular prognosis. However, the prognostic value of the TyG index in patients with PCAD remains uncertain. Thus, this study aimed to investigate the prognostic value and predictive performance of the TyG index in patients with PCAD.

Methods

A total of 526 young subjects (male < 45 years, female < 55 years) with angiographically proven CAD from January 2013 to December 2018 were included consecutively in this study. Their clinical and laboratory parameters were collected, and the TyG index was calculated as $$\mathrm{Ln}[\mathrm{fasting triglyceride }(\mathrm{TG}) (\mathrm{mg}/\mathrm{dL})\times \mathrm{fasting plasma glucose }(\mathrm{FPG}) (\mathrm{mg}/\mathrm{dL})/2]$$

Ln
[

fasting
triglyceride

(
TG
)
(
mg
/
dL
)
×

fasting
plasma
glucose

(
FPG
)
(
mg
/
dL
)
/
2
]

. The follow-up time after discharge was 40–112 months (median, 68 months; interquartile range, 49‒83 months). The primary endpoint was the occurrence of the major adverse cardiovascular events (MACE), defined as the composite of all-cause death, non-fatal myocardial infarction (MI), coronary artery revascularization, and non-fatal stroke.

Results

The TyG index was significantly associated with traditional cardiovascular risk factors and the Gensini score (GS). Kaplan–Meier survival (MACE-free) curves by tertiles of the TyG index showed statistically significant differences (log-rank test, p = 0.001). In the fully adjusted Cox regression model, the Hazard ratio (95% CI) of MACE was 2.17 (1.15–4.06) in tertile 3 and 1.45 (1.11–1.91) for per SD increase in the TyG index. Time-dependent ROC analyses of the TyG for prediction of MACE showed the area under the curves (AUC) reached 0.631 at 3 years, 0.643 at 6 years, and 0.710 at 9 years. Furthermore, adding TyG index to existing risk prediction model could improve outcome prediction [C-statistic increased from 0.715 to 0.719, p = 0.007; continuous net reclassification improvement (NRI) = 0.101, p = 0.362; integrated discrimination improvement (IDI) = 0.011, p = 0.017].

Conclusion

The TyG index is an independent predictor of MACE in patients with PCAD, suggesting that the TyG index has important clinical implications for risk stratification and early intervention of PCAD.
The development of task sharing policy and guidelines in Kenya
Authors: Kinuthia Rosemary , Verani Andre , Gross Jessica , Kiriinya Rose , Hepburn Kenneth , Kioko Jackson , Langat Agnes , Katana Abraham , Waudo Agnes , Rogers Martha
Published: July 2022

Background

The global critical shortage of health workers prevents expansion of healthcare services and universal health coverage. Like most countries in sub-Saharan Africa, Kenya’s healthcare workforce density of 13.8 health workers per 10,000 population falls below the World Health Organization (WHO) recommendation of at least 44.5 doctors, nurses, and midwives per 10,000 population. In response to the health worker shortage, the WHO recommends task sharing, a strategy that can increase access to quality health services. To improve the utilization of human and financial health resources in Kenya for HIV and other essential health services, the Kenya Ministry of Health (MOH) in collaboration with various institutions developed national task sharing policy and guidelines (TSP). To advance task sharing, this article describes the process of developing, adopting, and implementing the Kenya TSP.

Case presentation

The development and approval of Kenya’s TSP occurred from February 2015 to May 2017. The U.S. Centers for Disease Control and Prevention (CDC) allocated funding to Emory University through the United States President’s Emergency Plan for AIDS Relief (PEPFAR) Advancing Children’s Treatment initiative. After obtaining support from leadership in Kenya’s MOH and health professional institutions, the TSP team conducted a desk review of policies, guidelines, scopes of practice, task analyses, grey literature, and peer-reviewed research. Subsequently, a Policy Advisory Committee was established to guide the process and worked collaboratively to form technical working groups that arrived at consensus and drafted the policy. The collaborative, multidisciplinary process led to the identification of gaps in service delivery resulting from health workforce shortages. This facilitated the development of the Kenya TSP, which provides a general orientation of task sharing in Kenya. The guidelines list priority tasks for sharing by various cadres as informed by evidence, such as HIV testing and counseling tasks. The TSP documents were disseminated to all county healthcare facilities in Kenya, yet implementation was stopped by order of the judiciary in 2019 after a legal challenge from an association of medical laboratorians.

Conclusions

Task sharing may increase access to healthcare services in resource-limited settings. To advance task sharing, TSP and clinical practice could be harmonized, and necessary adjustments made to other policies that regulate practice (e.g., scopes of practice). Revisions to pre-service training curricula could be conducted to ensure health professionals have the requisite competencies to perform shared tasks. Monitoring and evaluation can help ensure that task sharing is implemented appropriately to ensure quality outcomes.
Cost–benefit analysis of kidney transplant in patients with chronic kidney disease: a case study in Iran
Authors: Abdi Farzaneh , Alinia Cyrus , Taghizadeh Afshari Ali , Yusefzadeh Hasan
Published: July 2022

Background

Chronic kidney disease (CKD) is a health problem due to its increasing prevalence and imposes a significant economic burden on the health system. This study aimed to analyze the cost–benefit of kidney transplantation through the valuation of patients with ESRD for a kidney transplant and its costs to help decide this regard.

Material and methods

This study was a descriptive-analytical and cross-sectional economic evaluation study of health interventions performed in Imam Khomeini Hospital in Urmia from the patient’s perspective. The records of kidney recipients were used to calculate the direct costs of kidney transplantation based on the government tariff rate in 2021. The willingness to pay for kidney transplantation (benefit) was measured through a questionnaire and with a contingent valuation method from 266 samples of patients with ESRD. The questionnaire designed by the researchers had four scenarios with different chances for kidney transplant success. Validation and test–retest methods were used to check the validity and reliability of the questionnaire. Stata software was used to estimate the regression of the factors affecting the willingness to pay and the kidney transplant demand function.

Results

The average cost of a kidney transplant was $877.4. The average willingness to pay for a kidney transplant for four scenarios was estimated at $4733. The mean cost–benefit ratio (BCR) and net present value (NPV) for the four kidney transplant scenarios were 5.39 and $3855. The variables of employment status, awareness of kidney function, number of years with ESRD, insurance coverage, and patients’ income significantly affected their willingness to pay. However, the effect of other variables was not significant. The absolute value of price elasticity of kidney transplant demand was also equal to 2.13.

Conclusion

According to the cost–benefit analysis indexes, the study results showed that a kidney transplant has a net positive benefit for all levels of its probability of success, so the willingness to pay or valuation of patients is about five times the cost of a kidney transplant. Also, the demand for kidney transplantation shows the high sensitivity of the demand for this service to the price. Therefore, preparations for kidney transplantation in patients with ESRD should be considered in situations where the price and cost of transplantation change. The results can help health policy-makers decide to allocate financial resources more efficiently.
Dose escalation based on 18F-FDG PET/CT response in definitive chemoradiotherapy of locally advanced esophageal squamous cell carcinoma: a phase III, open-label, randomized, controlled trial (ESO-Shanghai 12)
Authors: Zhu Hongcheng , Liu Qiufang , Xu Hao , Mo Miao , Wang Zezhou , Lu Kui , Zhou Jialiang , Chen Junqiang , Zheng Xiangpeng , Ye Jinjun , Ge Xiaolin , Luo Honglei , Liu Qi , Deng Jiaying , Ai Dashan , Hao Shengnan , Zhang Junhua , Tseng I Hsuan , Song Shaoli , Chen Yun , Zhao Kuaile
Published: July 2022

Introduction

Definitive chemoradiotherapy has established the standard non-surgical treatment for locally advanced esophageal cancer. The standard dose of 50–50.4 Gy has been established decades ago and been confirmed in modern trials. The theorical advantage of better local control and technical advances for less toxicity have encouraged clinicians for dose escalation investigation. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) have the potential to tailor therapy for esophageal patients not showing response to CRT and pioneers the PET-based dose escalation.

Methods and analysis

The ESO-Shanghai 12 trial is a prospective multicenter randomized phase 3 study in which patients are randomized to either 61.2 Gy or 50.4 Gy of radiation dose by PET response. Both groups undergo concurrent chemoradiotherapy with paclitaxel/cisplatin regimen for 2 cycles followed by consolidation chemotherapy for 2 cycles. Patients with histologically confirmed ESCC [T1N1-3M0, T2-4NxM0, TxNxM1 (Supraclavicular lymph node metastasis only), (AJCC Cancer Staging Manual, 8th Edition)] and without any prior treatment of chemotherapy, radiotherapy or surgery against esophageal cancer will be eligible. The primary endpoints included overall survival in PET/CT non-responders (SUVmax > 4.0) and overall survival in total population. Patients will be stratified by standardized uptake volume, gross tumor volume and tumor location. The enrollment could be ended, when the number of PET/CT non-responder reached 132 and the total population reached 646 for randomization.

Ethics and dissemination

This trial has been approved by the Fudan University Shanghai Cancer Center Institutional Review Board. Trial results will be disseminated via peer reviewed scientific journals and conference presentations.

Trial registration The trial was initiated in 2018 and is currently recruiting patients. Trial registration number NCT03790553.
Lifecycle management of orphan drugs approved in Japan
Authors: Seki Kiyoshi , Suzuki Hiroshi , Abe Seiji , Saotome Chikako
Published: July 2022

Background

The development of orphan drugs (ODs) is challenging from both development and business perspectives because of their small patient populations. To overcome such business challenges, lifecycle management (LCM), which maximizes profits by increasing sales and extending product lifetimes, is important to overcome the business challenges arising from their small patient populations. To clarify the activities of the LCM of ODs, we investigated additional indications that contribute to market expansion and marketing exclusivity using the patent extension and re-examination system of ODs approved in Japan between 2004 and 2019.

Results

The 203 ODs consisting of 173 active ingredients were approved in Japan between 2004 and 2019. Sixty-eight (39%) of the 173 active ingredients have additional indications, of which 57 have at least one non-OD indication. Three-fourths of the 203 ODs had patent rights, and most of them included substance or use claims. Although the re-examination period for most ODs was 10 years after the approval, most patents had a longer duration than the re-examination period.

Conclusions

Pharmaceutical companies were actively adding non-OD indications and were emphasizing the use of patent rights by registering extensions of substance or use patents for exclusive marketing periods. These results indicate that LCM through the addition of indications and registration of patent extensions is carried out as a strategy for many ODs in Japan, similar to the LCM of general non-ODs.
Use of the bibliometric in rare diseases: taking Wilson disease personally
Authors: Chen Lin , Lou Zhuoqi , Fang Yangxin , Pan Liya , Zhao Jianhua , Zeng Yifan , Wang Ying , Wang Nan , Ruan Bing
Published: July 2022

Background

Bibliometric have been widely applied to the evaluation of academic productivity. However, those of individuals or institutions on a specific disease have not been explored. The aim of the present study is to conduct a bibliometric analysis of particular rare disease and investigate whether those doctors and hospitals with higher index screened by this method specialize in this disease.

Methods

A representative rare disease, Wilson disease (WD), was searched on Clarivate Analytics’ Web of Science and Elsevier’s Scopus, which was published in English between 1 January 2001 and 31 December 2020. Clinical authors and medical institutions with the most papers were screened, and their total number of publications and citations, h-index and g-index were computed and then ranked by h-index.

Results

A total of 6856 and 6193 papers and 200 and 160 authors were got from WoS and Scopus, respectively. Scopus provided 160 institutions. The above bibliometric indices were calculated in 100 researchers and 80 institutions, and top 30 authors (Top-30a) and top 20 institutions (Top-20i) of them based on the h-index were listed in the tables. Top-30a came from seven specialties and 13 countries whose median (interquartile range) h-index was 14 (12–19.5) (range 10–28) which was located between associate and full professors in some other disciplines. Top-20i was distributed in 13 countries whose mean ± standard deviation of the h-index was 15 ± 4.9 (range 10–27).

Conclusions

The related specialists and medical institutions of WD screened by specific disease bibliometric analysis are eminent and credible and benefit WD patients to obtain reliable medical treatment. This model may be suitable for other rare diseases.
Estimating the risk of environmental contamination by forest users in African Swine Fever endemic areas
Authors: Gervasi Vincenzo , Marcon Andrea , Guberti Vittorio
Published: July 2022

Background

African Swine Fever (ASF) is a highly lethal viral disease caused by the African Swine Fever Virus (ASFV), the only virus of the Asfaviridae family, which affects different species of wild and domestic suids, and for which no vaccination or effective medical treatment is currently available. The virus can survive for long periods in the environment, and humans can unintentionally act as vectors through infected fomites, a risk that is linked to the ASF introduction into pig farms. We ran a simulation study, in which we reconstructed the probability process leading to the different forms of human-mediated ASF contamination in ASF endemic areas. We compared the infection risks related to different types of human forest activities and produced estimates of the minimum expected number of human-induced contamination events occurring annually at the scale of some European countries.

Results

When analysed on a short temporal scale and in a relatively small spatial context, ASF environmental contamination appeared as a rather unlikely event for most of the simulated forest uses, with contamination probabilities often lower than 0.1%. When scaling up the contamination process to a whole year and to large geographic areas, though, the accumulation of the same forest activities, repeated several times per month within the same patch of forest, produced the expectation that thousands of contamination events would occur each year, with potentially relevant epidemiological consequences. Wild boar supplemental feeding and forest logging emerged as the riskiest activities in terms of contamination probabilities, but risk was highly influenced by the frequency and intensity of the different types of forest use.

Conclusions

The risk of human-mediated ASF environmental contamination should not be disregarded when planning management actions to reduce ASF circulation and prevent its breach into the pig farming system. Supplemental feeding should be strongly reduced or avoided in ASF affected areas. Wild boar hunting, which is often employed as an active management tool in ASF affected areas, should be seen as both a tool for controlling wild boar density and as a potential risk for further contamination. It is essential to implement and enforce strict biosecurity measures for all forest-based human activities in ASF endemic areas.
Neurological vertigo in the emergency room in pediatric and adult age: systematic literature review and proposal for a diagnostic algorithm
Authors: Pellegrino Noemi , Di Stefano Vincenzo , Rotondo Eleonora , Graziosi Alessandro , Rispoli Marianna Gabriella , Torrente Angelo , Lupica Antonino , Brighina Filippo , Raucci Umberto , Parisi Pasquale
Published: July 2022

Neurological vertigo is a common symptom in children and adults presenting to the emergency department (ED) and its evaluation may be challenging, requiring often the intervention of different medical specialties. When vertigo is associated with other specific symptoms or signs, a differential diagnosis may be easier. Conversely, if the patient exhibits isolated vertigo, the diagnostic approach becomes complex and only through a detailed history, a complete physical examination and specific tests the clinician can reach the correct diagnosis. Approach to vertigo in ED is considerably different in children and adults due to the differences in incidence and prevalence of the various causes. The aim of this systematic review is to describe the etiopathologies of neurological vertigo in childhood and adulthood, highlighting the characteristics and the investigations that may lead clinicians to a proper diagnosis. Finally, this review aims to develop an algorithm that could represent a valid diagnostic support for emergency physicians in approaching patients with isolated vertigo, both in pediatric and adult age.
Chromatin accessibility landscape and active transcription factors in primary human invasive lobular and ductal breast carcinomas
Authors: Lee Sanghoon , Osmanbeyoglu Hatice Ulku
Published: July 2022

Background

Invasive lobular breast carcinoma (ILC), the second most prevalent histological subtype of breast cancer, exhibits unique molecular features compared with the more common invasive ductal carcinoma (IDC). While genomic and transcriptomic features of ILC and IDC have been characterized, genome-wide chromatin accessibility pattern differences between ILC and IDC remain largely unexplored.

Methods

Here, we characterized tumor-intrinsic chromatin accessibility differences between ILC and IDC using primary tumors from The Cancer Genome Atlas (TCGA) breast cancer assay for transposase-accessible chromatin with sequencing (ATAC-seq) dataset.

Results

We identified distinct patterns of genome-wide chromatin accessibility in ILC and IDC. Inferred patient-specific transcription factor (TF) motif activities revealed regulatory differences between and within ILC and IDC tumors. EGR1, RUNX3, TP63, STAT6, SOX family, and TEAD family TFs were higher in ILC, while ATF4, PBX3, SPDEF, PITX family, and FOX family TFs were higher in IDC.

Conclusions

This study reveals the distinct epigenomic features of ILC and IDC and the active TFs driving cancer progression that may provide valuable information on patient prognosis.
Interdisciplinary intervention (GAIN) for adults with post-concussion symptoms: a study protocol for a stepped-wedge cluster randomised trial
Authors: Næss-Schmidt Erhard Trillingsgaard , Thastum Mille Møller , Stabel Henriette Holm , Odgaard Lene , Pedersen Asger Roer , Rask Charlotte Ulrikka , Silverberg Noah D. , Schröder Andreas , Nielsen Jørgen Feldbæk
Published: July 2022

Background

Persistent post-concussion symptoms (PCS) are associated with prolonged disability, reduced health-related quality of life and reduced workability. At present, no strong evidence for treatments for people with persistent PCS exists. Our research group developed a novel intervention, “Get going After concussIoN (GAIN)”, that incorporates multiple evidence-based strategies including prescribed exercise, cognitive behavioural therapy, and gradual return to activity advice. In a previous randomised trial, GAIN provided in a hospital setting was effective in reducing symptoms in 15–30-year-olds with PCS 2–6 months post-injury. In the current study, we describe the protocol for a trial designed to test the effectiveness of GAIN in a larger municipality setting. Additionally, we test the intervention within a broader age group and evaluate a broader range of outcomes. The primary hypothesis is that participants allocated to enhanced usual care plus GAIN report a higher reduction in PCS 3 months post-intervention compared to participants allocated to enhanced usual care only.

Methods

The study is a stepped-wedge cluster-randomised trial with five clusters. The 8-week interdisciplinary GAIN program will be rolled out to clusters in 3-month intervals. Power calculation yield at least 180 participants to be enrolled. Primary outcome is mean change in PCS measured by the Rivermead Post-Concussion Symptoms Questionnaire from enrolment to 3 months after end of treatment. Secondary outcomes include participation in and satisfaction with everyday activities, labour market attachment and other behavioural measures. Self-reported outcomes are measured at baseline, by end of treatment and at 3, 6, and 18 months after end of treatment. Registry-based outcomes are measured up to 36 months after concussion.

Discussion

The trial will provide important information concerning the effectiveness of the GAIN intervention in a municipality setting. Furthermore, it will provide knowledge of possible barriers and facilitators that may be relevant for future implementation of GAIN in different settings.

Trial registration

The current GAIN trial is registered in ClinicalTrials.gov (study identifier:NCT04798885) on 20 October 2020.
Simultaneous spectrophotometric determination of finasteride and tadalafil in recently FDA approved Entadfi™ capsules
Authors: Abdelazim Ahmed H. , Ramzy Sherif
Published: July 2022

Entadfi™ is a recently FDA approved pharmaceutical combination capsule of finasteride and tadalafil. It was prescribed for the treatment of urinary tract disorders caused by benign prostatic hyperplasia in men. This paper introduced the first spectrophotometric methods for simultaneous determination of finasteride and tadalafil in the pure form and in the pharmaceutical capsules. UV absorption spectra of finasteride and tadalafil exhibited overlap hindered the direct simultaneous determination of the cited drugs. The UV absorption spectra of finasteride and tadalafil were transformed to the second order derivative. Finasteride could be determined selectively at 230.80 nm without interference from tadalafil. Moreover, tadalafil could be determined selectively at 292 nm without interference from finasteride. The ratio spectra of the studied drugs were derived and the derived ratio spectra of each drug were transformed to the first order derivative. Finasteride could be determined selectively at 218.80 nm without interference from tadalafil. Moreover, tadalafil could be determined selectively at 289.60 nm without interference from finasteride. The methods showed linearity with an excellent correlation coefficient in the concentration range of 10–140 µg/mL for finasteride and 3–40 µg/mL for tadalafil. The methods were validated following ICH guidelines for accuracy, precision, robustness, limit of detection, limit of quantification, and selectivity. The methods were found to be sensitive with LOD values for finasteride and tadalafil of 2.406 µg/mL and 0.876 µg/mL using the second derivative with zero crossing method and 2.229 µg/mL and 0.815 µg/mL using the first derivative of ratio spectra method. The methods were successfully applied for the determination of the studied drugs in their laboratory prepared mixtures, with mean percent recovery for finasteride and tadalafil of 99.37% and 99.17% using the second derivative with zero crossing method and 99.74% and 99.56% using the first derivative of ratio spectra method. Furthermore, the described methods were successfully applied for determination of the studied drugs in Entadfi™ capsules without interference from excipients. Based on the proposed results, the described methods could be utilized as simple method for the quality control of the studied drugs.
Signature pattern of gene expression and signaling pathway in premature diabetic patients uncover their correlation to early age coronary heart disease
Authors: Ahmadloo Salma , Ling King-Hwa , Fazli Ahmad , Larijani Ghazaleh , Ghodsian Nooshin , Mohammadi Sanaz , Amini Naser , Hosseinpour Sarmadi Vahid , Ismail Patimah
Published: July 2022

Background

Coronary Heart Disease (CHD) is the leading cause of death in industrialized countries. There is currently no direct relation between CHD and type 2 diabetes mellitus (T2D), one of the major modifiable risk factors for CHD. This study was carried out for genes expression profiling of T2D associated genes to identify related biological processes/es and modulated signaling pathway/s of male subjects with CHD.

Method

the subjects were divided into four groups based on their disease, including control, type 2 diabetes mellitus (T2D), CHD, and CHD + T2D groups. The RNA was extracted from their blood, and RT2 Profiler™ PCR Array was utilized to determine gene profiling between groups. Finally, the PCR Array results were validated by using Q-RT-PCR in a more extensive and independent population.

Result

PCR Array results revealed that the T2D and T2D + CHD groups shared 11 genes significantly up-regulated in both groups. Further analysis showed that the mRNA levels of AKT2, IL12B, IL6, IRS1, IRS2, MAPK14, and NFKB1 increased. Consequently, the mRNA levels of AQP2, FOXP3, G6PD, and PIK3R1 declined in the T2D + CHD group compared to the T2D group. Furthermore, in silico analysis indicated 36 Gene Ontology terms and 59 signaling pathways were significantly enriched in both groups, which may be a culprit in susceptibility of diabetic patients to CHD development.

Conclusion

Finally, the results revealed six genes as a hub gene in altering various biological processes and signaling pathways. The expression trend of these identified genes might be used as potential markers and diagnostic tools for the early identification of the vulnerability of T2D patients to develop premature CHD.

Graphical Abstract
Confirmed diagnosis of classic Wiskott–Aldrich syndrome in East Africa: a case report
Authors: Kiputa Mpokigwa , Urio Obrey , Maghembe Anna , Kombo David , Dhalla Sajda , Ndembo Victoria , Muze Kandi , Kahwa Mariam , Fakih Zameer , Kija Edward
Published: July 2022

Introduction

Wiskott–Aldrich syndrome is a rare X-linked primary immunodeficiency that mostly presents with a classic triad of eczema, microthrombocytopenia, recurrent infections, and increased risk of autoimmunity/malignancies.

Case presentation

We present an 8-month-old African male, born from nonconsanguineous parents and who presented with a history of eczematous skin rash since day 9 of life, with recurrent sinus infections, otitis media, and skin abscesses. An elder male sibling who had similar symptoms passed away during infancy. Investigations were consistent with microthrombocytopenia and significantly raised immunoglobulin E, while immunoglobulin A and immunoglobulin G were moderately elevated with normal immunoglobulin M. Genetic testing revealed the patient to be hemizygous for a pathogenic Wiskott–Aldrich syndrome gene variant (NM_000377.2:c.403C>T). He was managed conservatively with supportive treatment until he died a year later.

Conclusion

Despite Wiskott–Aldrich syndrome being a rare disease, it should be considered as a differential in any male child who presents with microthrombocytopenia and recurrent infections, especially in low-resource settings where genetic testing is not routinely available.