bluuebunny/crossref_metadata_2025 huggingface dataset:
High prevalence of hepatitis C virus infection and low level of awareness among people who recently started injecting drugs in a cross-sectional study in Germany, 2011–2014: missed opportunities for hepatitis C testing
Authors:   DRUCK Study group, Enkelmann Julia , Gassowski Martyna , Nielsen Stine , Wenz Benjamin , Roß Stefan , Marcus Ulrich , Bremer Viviane , Zimmermann Ruth
Published: January 2020

Background

In Germany, risk of hepatitis C virus (HCV) infection is highest among people who inject drugs (PWID). New injectors (NI) are particularly vulnerable for HCV-acquisition, but little is known about health seeking behaviour and opportunities for intervention in this group. We describe characteristics, HCV prevalence, estimated HCV incidence and awareness of HCV-status among NIs and missed opportunities for hepatitis C testing.

Methods

People who had injected drugs in the last 12 months were recruited into a cross-sectional serobehavioural study using respondent-driven sampling in 8 German cities, 2011–2014. Data on sociodemographic characteristics, previous HCV testing and access to care were collected through questionnaire-based interviews. Capillary blood was tested for HCV. People injecting drugs < 5 years were considered NI.

Results

Of 2059 participants with available information on duration of injection drug use, 232 (11% were NI. Estimated HCV incidence among NI was 19.6 infections/100 person years at risk (95% CI 16–24). Thirty-six percent of NI were HCV-positive (thereof 76% with detectable RNA) and 41% of those HCV-positive were unaware of their HCV-status. Overall, 27% of NI reported never having been HCV-tested. Of NI with available information, more than 80% had attended low-threshold drug services in the last 30 days, 24% were released from prison in the last 12 months and medical care was most commonly accessed in hospitals, opioid substitution therapy (OST)-practices, practices without OST and prison hospitals.

Conclusion

We found high HCV-positivity and low HCV-status awareness among NI, often with missed opportunities for HCV-testing. To increase early diagnosis and facilitate treatment, HCV-testing should be offered in all facilities, where NI can be reached, especially low-threshold drug services and addiction therapy, but also prisons, hospitals and practices without OST.
Stimulant safe supply: a potential opportunity to respond to the overdose epidemic
Authors: Fleming Taylor , Barker Allison , Ivsins Andrew , Vakharia Sheila , McNeil Ryan
Published: January 2020

Background

Occurring against the backdrop of an overdose crisis, stimulant use and stimulant-involved deaths in North America are increasing at an alarming rate. Many of these deaths are being attributed to fentanyl and related analogs, which have been increasingly found within street-level stimulant supplies. Within this, people experiencing socio-economic marginalization are at the greatest risk of overdose and other harms from adulterated stimulants. Current treatments for stimulant use disorder have limited effectiveness, and even less applicability to the lived realities of marginalized stimulant users. Emerging technologies, such as drug checking, are being implemented to support safer stimulant use, but the accessibility and utility of these technologies to stimulant users are framed by experiences of vulnerability that render them largely ineffective.

Stimulant safe supply

Solutions that provide a legal and safe supply of non-adulterated stimulants of known quality, and within a health care framework, are needed to directly address the risk of an increasingly adulterated stimulant supply. Similar innovative opioid-focused interventions are being piloted with medications that have a similar pharmacological effect as their illicit counterparts. While there are currently no approved pharmacotherapies for stimulant use, research has demonstrated a number of stimulant medications that are promising substitutes for cocaine and methamphetamine use. Much like with opioid-focused pharmacotherapies, having a consistent and safe supply of stimulants can lead to improved health outcomes and will drastically reduce overdose risk. However, for a stimulant safe supply intervention to be a success, it must provide the high and performance-enhancing effects that people seek from the illicit market, which requires doses and user agency that trials to date have not provided.

Conclusion

Efforts are needed to investigate the feasibility of pharmacological stimulant-based interventions that address safe supply needs. The promise of similar opioid-focused approaches in addressing both overdose-related risks and experiences related to vulnerability underscores the need to advance safe supply approaches targeted towards people who use stimulants. Given the current overdose crisis and rising stimulant use across North America, the implementation and evaluation of such novel stimulant-focused interventions should be a public health priority.
Health economic evaluation of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma: a systematic review
Authors: Wang Haiyin , Jin Chunlin , Fang Liang , Sun Hui , Cheng Wendi , HU Shanlian
Published: January 2020

Stereotactic body radiotherapy (SBRT) is a novel noninvasive treatment for hepatocellular carcinoma. SBRT can achieve effective local control, but it requires a relatively high input of resources; this systematic review was performed to assess the cost effectiveness of SBRT in the treatment of hepatocellular carcinoma to provide a basis for government pricing and medical insurance decision-making. The PubMed, EMBASE, Cochrane Library, CNKI, Wanfang and SinoMed databases were searched to collect economic evaluations of SBRT for the treatment of hepatocellular carcinoma from the date of database inception through December 31, 2018. Two reviewers independently screened the studies, extracted the data and performed a descriptive analysis of the basic characteristics, methods of economic evaluation and main results, as well as the quality and heterogeneity of the reports. A total of 5 studies were included. Among them, the level of heterogeneity was relatively acceptable, with a median score of 90%. Four studies were cost-utility analyses (CUAs), and 1 was a cost-effectiveness analysis (CEA). The incremental cost effectiveness ratio (ICER) for sorafenib compared to SBRT was US $114,795 per quality-adjusted life year gained (cost/QALY) in patients with advanced hepatocellular carcinoma. The ICER for proton beam therapy compared to SBRT was US $6465 in patients with inoperable advanced hepatocellular carcinoma. The ICER for SBRT compared to RFA was US $164,660 for patients with unresectable colorectal cancer (CRC) with liver metastases and US $56,301 for patients with early-stage hepatocellular carcinoma. For patients with inoperable localized hepatocellular carcinoma, compared with RFA–SBRT therapy, the ICERs for SBRT–SBRT and SBRT–RFA were US $558,679 and US $2197,000, respectively; RFA–RFA was dominated. In conclusion, there is limited evidence suggesting that SBRT could be cost-effective for highly specific subpopulations of HCC patients, and further economic evaluations based on randomized controlled trials (RCTs) or cohort studies are needed.
Sepsis-associated encephalopathy: a vicious cycle of immunosuppression
Authors: Ren Chao , Yao Ren-qi , Zhang Hui , Feng Yong-wen , Yao Yong-ming
Published: January 2020

Sepsis-associated encephalopathy (SAE) is commonly complicated by septic conditions, and is responsible for increased mortality and poor outcomes in septic patients. Uncontrolled neuroinflammation and ischemic injury are major contributors to brain dysfunction, which arises from intractable immune malfunction and the collapse of neuroendocrine immune networks, such as the cholinergic anti-inflammatory pathway, hypothalamic-pituitary-adrenal axis, and sympathetic nervous system. Dysfunction in these neuromodulatory mechanisms compromised by SAE jeopardizes systemic immune responses, including those of neutrophils, macrophages/monocytes, dendritic cells, and T lymphocytes, which ultimately results in a vicious cycle between brain injury and a progressively aberrant immune response. Deep insight into the crosstalk between SAE and peripheral immunity is of great importance in extending the knowledge of the pathogenesis and development of sepsis-induced immunosuppression, as well as in exploring its effective remedies.
Comparison of concomitant injuries and patient-reported outcome in patients that have undergone both primary and revision ACL reconstruction—a national registry study
Authors: Svantesson Eleonor , Hamrin Senorski Eric , Kristiansson Frida , Alentorn-Geli Eduard , Westin Olof , Samuelsson Kristian
Published: January 2020

Background

Anterior cruciate ligament (ACL) revision surgery has been associated with inferior outcome compared with primary ACL reconstruction. However, this has rarely been investigated in a consecutive cohort limited to patients that have undergone both primary and revision ACL reconstruction. This study aimed to assess differences in outcome and concomitant injuries between primary and revision ACL reconstruction in such a cohort, and to identify predictors of the patient-reported outcome after ACL revision.

Methods

Patients who had undergone both primary and revision ACL reconstruction were identified in the Swedish National Knee Ligament Registry. Patients aged 13–49 years with hamstring tendon primary ACL reconstruction and data on the Knee Injury and Osteoarthritis Outcome Score (KOOS) on at least one occasion (preoperative or one year postoperatively) at both surgeries were eligible. Concomitant injuries and the KOOS were compared between each patient’s primary and revision ACL reconstruction. Linear regression analyses were performed to determine predictors of the one-year KOOS after ACL revision.

Results

A total of 1014 patients were included. Cartilage injuries increased at ACL revision (p < 0.001), as 23.0% had a cartilage injury at ACL revision that was not present at primary ACL reconstruction. The 1-year KOOS was lower after ACL revision compared with primary ACL reconstruction, with the largest difference in the KOOS sports and recreation (5.2 points, SD 32.2, p = 0.002). A posterolateral corner (PLC) injury at ACL revision was a negative predictor of KOOS, with the largest effect on the sports and recreation subscale (β = − 29.20 [95% CI − 50.71; − 6.69], p = 0.011). The use of allograft for ACL revision was an independent predictor of a poorer KOOS QoL (β = − 12.69 [95% CI − 21.84; − 3.55], p = 0.0066) and KOOS4 (β = − 11.40 [95% CI − 19.24; − 3.57], p = 0.0044).

Conclusion

Patients undergoing ACL revision reported a 1-year outcome that was slightly inferior to the 1-year outcome after their primary ACL reconstruction. An ACL revision was associated with an increase in cartilage injuries. A PLC injury at ACL revision and the use of allograft for ACL revision predicted a clinically relevant poorer KOOS one year after ACL revision.
Huoxue Wentong Formula ameliorates myocardial infarction in rats through inhibiting CaMKII oxidation and phosphorylation
Authors: Liu Tiantian , Wang Qingqing , Yao Kuiwu
Published: January 2020

Background

The Chinese medicine Huoxue Wentong Formula (HXWTF) was used to treat thoracic obstruction and angina pectoris in clinic, which has not been investigated in myocardial ischemia-induced apoptosis and angiogenic function. Here we aimed to investigate the roles of HXWTF in rats with myocardial ischemia-induced apoptosis and angiogenesis disorders, as well as to reveal the potential mechanisms.

Methods

Male SD rats were subjected to coronary artery ligation followed by HXWTF (420, 840 and 1680 mg/kg/day, p.o.) or isosorbide mononitrate (6.3 mg/kg/day, p.o.) treatment for 4 weeks. Electrocardiogram (ECG) and Echocardiography (ECHO) were used to measure cardiac function. Hematoxylin and eosin (H&E) staining and CD34/α-SMA immunohistochemical staining were performed to observe the ischemic heart sections pathological changes and angiogenesis. Then, the effects on cardiomyocyte apoptosis of H9c2 and tube formation of HCMECs were observed, as well as the changes in the levels of total calmodulin dependent protein kinase II (t-CaMKII), phosphorylated CaMKII (p-CaMKII), oxidized CaMKII (ox-CaMKII), CD34, and Bcl-2/Bax ratio were detected.

Results

Rats with coronary artery ligation exhibited abnormal cardiac function, enlarged myocardial space, disorderly arranged myocardial fibers, inflammatory cells infiltrated, and aggravated myocardial cell apoptosis, along with angiogenesis dysfunction. The expressions of CD34, p-CaMKII, and ox-CaMKII were elevated and Bcl-2/Bax ratio was diminished in ischemic hearts and H/SD-treated H9c2 or HCMECs, while HXWTF treatment completely rescued angiogenic dysfunction, inhibited cardiomyocyte apoptosis, and down-regulated cardiac CaMKII oxidation and phosphorylation activities.

Conclusion

Our study demonstrates that HXWTF improves myocardial infarction possibly through inhibiting CaMKII oxidation and phosphorylation levels, facilitating angiogenic function and alleviating cardiomyocyte apoptosis. Thus, therapeutics targeting CaMKII activities may be a promising strategy for rescuing ischemic cardiomyopathy.
VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice
Authors: El Gaamouch Farida , Audrain Mickael , Lin Wei-Jye , Beckmann Noam , Jiang Cheng , Hariharan Siddharth , Heeger Peter S. , Schadt Eric E. , Gandy Sam , Ehrlich Michelle E. , Salton Stephen R.
Published: January 2020

Background

Multiomic studies by several groups in the NIH Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD) identified VGF as a major driver of Alzheimer’s disease (AD), also finding that reduced VGF levels correlate with mean amyloid plaque density, Clinical Dementia Rating (CDR) and Braak scores. VGF-derived peptide TLQP-21 activates the complement C3a receptor-1 (C3aR1), predominantly expressed in the brain on microglia. However, it is unclear how mouse or human TLQP-21, which are not identical, modulate microglial function and/or AD progression.

Methods

We performed phagocytic/migration assays and RNA sequencing on BV2 microglial cells and primary microglia isolated from wild-type or C3aR1-null mice following treatment with TLQP-21 or C3a super agonist (C3aSA). Effects of intracerebroventricular TLQP-21 delivery were evaluated in 5xFAD mice, a mouse amyloidosis model of AD. Finally, the human HMC3 microglial cell line was treated with human TLQP-21 to determine whether specific peptide functions are conserved from mouse to human.

Results

We demonstrate that TLQP-21 increases motility and phagocytic capacity in murine BV2 microglial cells, and in primary wild-type but not in C3aR1-null murine microglia, which under basal conditions have impaired phagocytic function compared to wild-type. RNA sequencing of primary microglia revealed overlapping transcriptomic changes induced by treatment with TLQP-21 or C3a super agonist (C3aSA). There were no transcriptomic changes in C3aR1-null or wild-type microglia exposed to the mutant peptide TLQP-R21A, which does not activate C3aR1. Most of the C3aSA- and TLQP-21-induced differentially expressed genes were linked to cell migration and proliferation. Intracerebroventricular TLQP-21 administration for 28 days via implanted osmotic pump resulted in a reduction of amyloid plaques and associated dystrophic neurites and restored expression of subsets of Alzheimer-associated microglial genes. Finally, we found that human TLQP-21 activates human microglia in a fashion similar to activation of murine microglia by mouse TLQP-21.

Conclusions

These data provide molecular and functional evidence suggesting that mouse and human TLQP-21 modulate microglial function, with potential implications for the progression of AD-related neuropathology.
A window-of-opportunity trial of the CXCR1/2 inhibitor reparixin in operable HER-2-negative breast cancer
Authors: Goldstein Lori J. , Perez Raymond P. , Yardley Denise , Han Linda K. , Reuben James M. , Gao Hui , McCanna Susan , Butler Beth , Ruffini Pier Adelchi , Liu Yi , Rosato Roberto R. , Chang Jenny C.
Published: January 2020

Background

Cancer stem cells (CSCs) are purported to be responsible for tumor initiation, treatment resistance, disease recurrence, and metastasis. CXCR1, one of the receptors for CXCL8, was identified on breast cancer (BC) CSCs. Reparixin, an investigational allosteric inhibitor of CXCR1, reduced the CSC content of human BC xenograft in mice.

Methods

In this multicenter, single-arm trial, women with HER-2-negative operable BC received reparixin oral tablets 1000 mg three times daily for 21 days before surgery. Primary objectives evaluated the safety of reparixin and the effects of reparixin on CSC and tumor microenvironment in core biopsies taken at baseline and at treatment completion. Signal of activity was defined as a reduction of ≥ 20% in ALDH+ or CD24−/CD44+ CSC by flow cytometry, with consistent reduction by immunohistochemistry.

Results

Twenty patients were enrolled and completed the study. There were no serious adverse reactions. CSC markers ALDH+ and CD24−/CD44+ measured by flow cytometry decreased by ≥ 20% in 4/17 and 9/17 evaluable patients, respectively. However, these results could not be confirmed by immunofluorescence due to the very low number of CSC.

Conclusions

Reparixin appeared safe and well-tolerated. CSCs were reduced in several patients as measured by flow cytometry, suggesting targeting of CXCR1 on CSC.

Clinical trial registration

Clinicaltrials.gov, NCT01861054. Registered on April 18, 2013.
Evaluation of the Teaching Recovery Techniques community-based intervention for unaccompanied refugee youth experiencing post-traumatic stress symptoms (Swedish UnaccomPanied yOuth Refugee Trial; SUPpORT): study protocol for a randomised controlled trial
Authors: Sarkadi Anna , Warner Georgina , Salari Raziye , Fängström Karin , Durbeej Natalie , Lampa Elin , Baghdasaryan Zaruhi , Osman Fatumo , Gupta Löfving Sandra , Perez Aronsson Anna , Feldman Inna , Sampaio Filipa , Ssegonja Richard , Calam Rachel , Bjärtå Anna , Leiler Anna , Rondung Elisabet , Wasteson Elisabet , Oppedal Brit , Keeshin Brooks
Published: January 2020

Background

In 2015, 162,877 persons sought asylum in Sweden, 35,369 of whom were unaccompanied refugee minors (URMs). Refugee children, especially URMs, have often experienced traumas and are at significant risk of developing mental health problems, such as symptoms of post-traumatic stress disorder (PTSD), depression and anxiety, which can continue years after resettlement. The Swedish UnaccomPanied yOuth Refugee Trial (SUPpORT) aims to evaluate a community-based intervention, called Teaching Recovery Techniques (TRT), for refugee youth experiencing PTSD symptoms.

Methods/design

A randomised controlled trial will be conducted in which participants will be randomly allocated to one of two possible arms: the intervention arm (n = 109) will be offered the TRT programme, and the waitlist-control arm (n = 109) will receive services as usual, followed by the TRT programme around 20 weeks later. Outcome data will be collected at three points: pre-intervention (T1), post-intervention (T2; about 8 weeks after randomisation) and follow-up (T3; about 20 weeks after randomisation).

Discussion

This study will provide knowledge about the effect and efficiency of a group intervention for URMs reporting symptoms of PTSD in Sweden.

Trial registration

ISRCTN, ISRCTN47820795. Prospectively registered on 20 December 2018.
Effect of temperature-control liner materials on long-term outcomes of lower limb prosthesis use: a randomized controlled trial protocol
Authors: Fiedler Goeran , Singh Anita , Zhang Xueyi
Published: January 2020

Background

In people living with limb loss, addressing the resulting functional deficit with prostheses increases the risk for secondary conditions such as pressure sores, impaired blood perfusion, and injuries from accidental falls. Any of those occurrences can render the prosthesis temporarily useless, making it challenging for users to engage in many activities of daily life, including work, exercise, and social participation. Many of the described issues originate at the interface between residual limb and prosthetic socket, where the objectives of sufficient weight distribution and suspension are conflicting with the necessity to facilitate heat exchange and limit contact pressure and friction.

Recently, prosthesis liners that contain phase-change material have become commercially available, holding the promise that the micro climate at the interface between the residual limb skin and the prosthetic socket can be regulated to reduce the users’ tendency to sweat. Preliminary studies on these liners indicate that the socket temperatures inside the socket stayed lower and rose slower than in conventional liners. However, the clinical relevance of those findings remains unclear.

The purpose of this study is to investigate whether longer (6+ months) periods of use of phase-change material based temperature-control liners have clinically meaningful effects.

Methods

The protocol is a double-blind longitudinal cross-over research design. A sample of trans-tibial prosthesis users are wearing their regular gel or silicone liners for six months and phase-change material liners for another six months in a randomized sequence. Their prostheses is equipped with activity monitors to detect days when they could not wear their prosthesis. In six-week intervals, individuals’ activity, physical performance, and overall prosthesis assessment is recorded using standardized methods.

Discussion

Expected results will inform prescription and reimbursement practice of phase-change material-based prosthesis liners and will help improve and economize prosthetic fitting for people with limb loss. The design and duration of the protocol, including randomization, blinding, and within-subject comparison, will generate scientific evidence of a comparably high level. Inclusion of a comparably large sample and different climates, e.g. across all four seasons, will make findings applicable to a large number of prosthesis users.

Trial registration

Clinicaltrials.gov,NCT03428815. Registered on 12 February 2018.
Clinician–researchers and custodians of scarce resources: a qualitative study of health professionals’ views on barriers to the involvement of teenagers and young adults in cancer trials
Authors: Hart Ruth I. , Hallowell Nina , Harden Jeni , Jesudason Angela B. , Lawton Julia
Published: January 2020

Background

Equipoise and role conflict have been previously identified as important factors in professionals’ engagement with trials, inducing behaviours which can impact on recruitment. We explored these phenomena as potential explanations for the low levels of involvement of teenagers and young adults (TYA) with cancer in clinical trials in oncology.

Methods

We report findings from interviews with 30 purposively sampled direct-care professionals involved in delivering cancer care and/or facilitating clinical trials in Scotland. We undertook qualitative descriptive analysis, focussed on identifying key issues and themes.

Results

Interviewees largely identified as clinician–researchers and portrayed oncology as a specialty in which research was integral to care. They saw their primary responsibility as ensuring patients received the best treatment, but asserted that, in general, trials provided a vehicle for optimal care. Role conflict in its traditional form was rarely evident; however, other tensions were manifest. Professionals found the significant time costs of delivering trials difficult to reconcile with the increasing pressures on clinical services. They felt a responsibility to make prudent choices about the trials with which to engage. Guided by utilitarian principles, these choices were oriented towards benefiting the largest number of patients. This favoured trials in high volume diseases; as TYA tend to have rarer forms of cancer, professionals’ support for—and TYA’s access to—relevant trials was, by default, more limited.

Conclusions

Neither lack of individual equipoise nor experiences of traditional forms of role conflict accounted for the low levels of involvement of TYA with cancer in clinical trials. However, prominent tensions around the management of scarce resources provided an alternative explanation for TYA’s limited access to cancer trials. The prevailing approach to decision-making about whether and which trials to support was recognised as contributing to inequalities in access and care. Professionals’ choices, however, were made in the context of scarcity, and structured by incentives and sanctions understood by them as signalling governmental priorities. A franker discussion of the extent and distribution of the costs and benefits of trials work is needed, for change to be achieved.
A DIVA vaccine strain lacking RpoS and the secondary messenger c-di-GMP for protection against salmonellosis in pigs
Authors: Gil Carmen , Latasa Cristina , García-Ona Enrique , Lázaro Isidro , Labairu Javier , Echeverz Maite , Burgui Saioa , García Begoña , Lasa Iñigo , Solano Cristina
Published: January 2020

Salmonellosis is the second most common food-borne zoonosis in the European Union, with pigs being a major reservoir of this pathogen. Salmonella control in pig production requires multiple measures amongst which vaccination may be used to reduce subclinical carriage and shedding of prevalent serovars, such as Salmonella enterica serovar Typhimurium. Live attenuated vaccine strains offer advantages in terms of enhancing cell mediated immunity and allowing inoculation by the oral route. However, main failures of these vaccines are the limited cross-protection achieved against heterologous serovars and interference with serological monitoring for infection. We have recently shown that an attenuated S. Enteritidis strain (ΔXIII) is protective against S. Typhimurium in a murine infection model. ΔXIII strain harbours 13 chromosomal deletions that make it unable to produce the sigma factor RpoS and synthesize cyclic-di-GMP (c-di-GMP). In this study, our objectives were to test the protective effects of ΔXIII strain in swine and to investigate if the use of ΔXIII permits the discrimination of vaccinated from infected pigs. Results show that oral vaccination of pre-weaned piglets with ΔXIII cross-protected against a challenge with S. Typhimurium by reducing faecal shedding and ileocaecal lymph nodes colonization, both at the time of weaning and slaughter. Vaccinated pigs showed neither faecal shedding nor tissue persistence of the vaccine strain at weaning, ensuring the absence of ΔXIII strain by the time of slaughter. Moreover, lack of the SEN4316 protein in ΔXIII strain allowed the development of a serological test that enabled the differentiation of infected from vaccinated animals (DIVA).
Goats naturally devoid of PrPC are resistant to scrapie
Authors: Salvesen Øyvind , Espenes Arild , Reiten Malin R. , Vuong Tram T. , Malachin Giulia , Tran Linh , Andréoletti Olivier , Olsaker Ingrid , Benestad Sylvie L. , Tranulis Michael A. , Ersdal Cecilie
Published: January 2020

Prion diseases are progressive and fatal, neurodegenerative disorders described in humans and animals. According to the “protein-only” hypothesis, the normal host-encoded prion protein (PrPC) is converted into a pathological and infectious form (PrPSc) in these diseases. Transgenic knockout models have shown that PrPC is a prerequisite for the development of prion disease. In Norwegian dairy goats, a mutation (Ter) in the prion protein gene (PRNP) effectively blocks PrPC synthesis. We inoculated 12 goats (4 PRNP+/+, 4 PRNP+/Ter, and 4 PRNPTer/Ter) intracerebrally with goat scrapie prions. The mean incubation time until clinical signs of prion disease was 601 days post-inoculation (dpi) in PRNP+/+ goats and 773 dpi in PRNP+/Ter goats. PrPSc and vacuolation were similarly distributed in the central nervous system (CNS) of both groups and observed in all brain regions and segments of the spinal cord. Generally, accumulation of PrPSc was limited in peripheral organs, but all PRNP+/+ goats and 1 of 4 PRNP+/Ter goats were positive in head lymph nodes. The four PRNPTer/Ter goats remained healthy, without clinical signs of prion disease, and were euthanized 1260 dpi. As expected, no accumulation of PrPSc was observed in the CNS or peripheral tissues of this group, as assessed by immunohistochemistry, enzyme immunoassay, and real-time quaking-induced conversion. Our study shows for the first time that animals devoid of PrPC due to a natural mutation do not propagate prions and are resistant to scrapie. Clinical onset of disease is delayed in heterozygous goats expressing about 50% of PrPC levels.
Clinical pharmacokinetics of 3-h extended infusion of meropenem in adult patients with severe sepsis and septic shock: implications for empirical therapy against Gram-negative bacteria
Authors: Kothekar Amol T. , Divatia Jigeeshu Vasishtha , Myatra Sheila Nainan , Patil Anand , Nookala Krishnamurthy Manjunath , Maheshwarappa Harish Mallapura , Siddiqui Suhail Sarwar , Gurjar Murari , Biswas Sanjay , Gota Vikram
Published: January 2020

Background

Optimal anti-bacterial activity of meropenem requires maintenance of its plasma concentration (Cp) above the minimum inhibitory concentration (MIC) of the pathogen for at least 40% of the dosing interval (fT > MIC > 40). We aimed to determine whether a 3-h extended infusion (EI) of meropenem achieves fT > MIC > 40 on the first and third days of therapy in patients with severe sepsis or septic shock. We also simulated the performance of the EI with respect to other pharmacokinetic (PK) targets such as fT > 4 × MIC > 40, fT > MIC = 100, and fT > 4 × MIC = 100.

Methods

Arterial blood samples of 25 adults with severe sepsis or septic shock receiving meropenem 1000 mg as a 3-h EI eight hourly (Q8H) were obtained at various intervals during and after the first and seventh doses. Plasma meropenem concentrations were determined using a reverse-phase high-performance liquid chromatography assay, followed by modeling and simulation of PK data. European Committee on Antimicrobial Susceptibility Testing (EUCAST) definitions of MIC breakpoints for sensitive and resistant Gram-negative bacteria were used.

Results

A 3-h EI of meropenem 1000 mg Q8H achieved fT > 2 µg/mL > 40 on the first and third days, providing activity against sensitive strains of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. However, it failed to achieve fT > 4 µg/mL > 40 to provide activity against strains susceptible to increased exposure in 33.3 and 39.1% patients on the first and the third days, respectively. Modeling and simulation showed that a bolus dose of 500 mg followed by 3-h EI of meropenem 1500 mg Q8H will achieve this target. A bolus of 500 mg followed by an infusion of 2000 mg would be required to achieve fT > 8 µg > 40. Targets of fT > 4 µg/mL = 100 and fT > 8 µg/mL = 100 may be achievable in two-thirds of patients by increasing the frequency of dosing to six hourly (Q6H).

Conclusions

In patients with severe sepsis or septic shock, EI of 1000 mg of meropenem over 3 h administered Q8H is inadequate to provide activity (fT > 4 µg/mL > 40) against strains susceptible to increased exposure, which requires a bolus of 500 mg followed by EI of 1500 mg Q8H. While fT > 8 µg/mL > 40 require escalation of EI dose, fT > 4 µg/mL = 100 and fT > 8 µg/mL = 100 require escalation of both EI dose and frequency.
Two multi-cubic functional equations and some results on the stability in modular spaces
Authors: Park Choonkil , Bodaghi Abasalt
Published: January 2020

In this article, we study n-variable mappings which are cubic in each variable. We also show that such mappings can be described by an equation, say, multi-cubic functional equation. Furthermore, we study the stability of such functional equations in the modular space $X_{\rho }$Xρ by applying $\Delta _{2}$Δ2-condition and the Fatou property (in some cases) on the modular function ρ. Finally, we show that, under some mild conditions, one of these new multi-cubic functional equations can be hyperstable.
New results on global asymptotic stability for a nonlinear density-dependent mortality Nicholson’s blowflies model with multiple pairs of time-varying delays
Authors: Cao Qian , Wang Guoqiu , Zhang Hong , Gong Shuhua
Published: January 2020

This paper is concerned with a class of Nicholson’s blowflies model involving nonlinear density-dependent mortality terms and multiple pairs of time-varying delays. By using differential inequality techniques and the fluctuation lemma, we establish a delay-independent criterion on the global asymptotic stability of the addressed model, which improves and complements some existing ones. The effectiveness of the obtained result is illustrated by some numerical simulations.
Linear difference operator with multiple variable parameters and applications to second-order differential equations
Authors: Li Feifan , Bi Zhonghua , Yao Shaowen , Xin Yun
Published: January 2020

In this article, we first investigate the linear difference operator $(Ax)(t):=x(t)-\sum_{i=1}^{n}c_{i}(t)x(t- \delta _{i}(t))$(Ax)(t):=x(t)−∑i=1nci(t)x(t−δi(t)) in a continuous periodic function space. The existence condition and some properties of the inverse of the operator A are explicitly pointed out. Afterwards, as applications of properties of the operator A, we study the existence of periodic solutions for two kinds of second-order functional differential equations with this operator. One is a kind of second-order functional differential equation, by applications of Krasnoselskii’s fixed point theorem, some sufficient conditions for the existence of positive periodic solutions are established. Another one is a kind of second-order quasi-linear differential equation, we establish the existence of periodic solutions of this equation by an extension of Mawhin’s continuous theorem.
Local existence and uniqueness of increasing positive solutions for non-singular and singular beam equation with a parameter
Authors: Wang Hui , Zhang Lingling
Published: January 2020

This paper is concerned with a class of beam equations with a parameter. By using the fixed point theorems of mixed monotone operator and the properties of cone, we study the non-singular and singular case, respectively, and obtain the sufficient conditions which guarantee the local existence and uniqueness of increasing positive solutions. Also, we present an iterative algorithm that converges to the solution. Moreover, we get some pleasant properties of the solutions for the boundary value problem dependent parameter. At last, two examples are given to illustrate the main results.
Head-on collision between capillary–gravity solitary waves
Authors: Marin Marin , Bhatti M. M.
Published: January 2020

The present study deals with the head-on collision process between capillary–gravity solitary waves in a finite channel. The present mathematical modeling is based on Nwogu’s Boussinesq model. This model is suitable for both shallow and deep water waves. We have considered the surface tension effects. To examine the asymptotic behavior, we employed the Poincaré–Lighthill–Kuo method. The resulting series solutions are given up to third-order approximation. The physical features are discussed for wave speed, head-on collision profile, maximum run-up, distortion profile, the velocity at the bottom, and phase shift profile, etc. A comparison is also given as a particular case in our study. According to the results, it is noticed that the free parameter and the surface tension tend to decline the solitary-wave profile significantly. However, the maximum run-up amplitude was affected in great measure due to the surface tension and the free parameter.
Stress state along the western Nankai Trough subduction zone inferred from b-values, long-term slow-slip events, and low-frequency earthquakes
Authors: Chiba Keita
Published: January 2020

Theb-value of the Gutenberg–Richter law represents the ratio of earthquake magnitude to frequency of occurrence and is inversely proportional to differential stress. Repeating long-term slow-slip events (SSEs) and low-frequency earthquakes (LFEs) occur at subducting plate interfaces and have stress-dependent characteristics near the interface. In this study, a comprehensive regionalb-value distribution is produced for the western Nankai Trough region, which highlights the relationship betweenb-values, SSEs, and LFEs.b-values vary along the strike direction of the subducting plate and are significantly lower$$ \left( {b \sim 0.6} \right) $$b∼0.6in central Shikoku district than elsewhere, where LFEs frequently occur. However,b-values in the source regions of other LFEs are moderate to high. These findings imply thatb-values in the focal region are controlled by more than the LFE source process; indeed, if this source process were solely responsible, then highb-values would be expected. Meanwhile, the$$ V_{P} /V_{S} $$VP/VSand QParound the plate interface in central Shikoku estimated from seismic velocity and attenuation structure are smaller and larger than those in other regions with LFEs, respectively. SSEs with the migration toward central Shikoku also occurred during the analysis period, suggesting significant accumulation of shear stresses in the focal region, which reduced theb-values. These findings suggest that the spatial distributions ofb-values are influenced by complicated stress and shear strength perturbations caused by SSEs and LFEs. On the other hand, theb-values in the region that underwent the greatest slip during the 1946 Nankai earthquake are not necessarily low, although the area covered by theb-value distribution is small owing to the lack of events on the updip side. Whereas the asperity areas of huge earthquakes are characterized by lowb-values, theb-value distribution in the Nankai megathrust area is more complicated. It is considered that slow earthquakes, including SSEs and LFEs, are related to megathrust earthquakes via stress transfer from slow earthquakes to adjacent megathrust source regions. A unified analysis ofb-values in the source regions of slow and megathrust earthquakes may be required to make precise estimates of the seismic hazard produced by a megathrust event.
Cloth simulation-based construction of pit-free canopy height models from airborne LiDAR data
Authors: Zhang Wuming , Cai Shangshu , Liang Xinlian , Shao Jie , Hu Ronghai , Yu Sisi , Yan Guangjian
Published: January 2020

Background

The universal occurrence of randomly distributed dark holes (i.e., data pits appearing within the tree crown) in LiDAR-derived canopy height models (CHMs) negatively affects the accuracy of extracted forest inventory parameters.

Methods

We develop an algorithm based on cloth simulation for constructing a pit-free CHM.

Results

The proposed algorithm effectively fills data pits of various sizes whilst preserving canopy details. Our pit-free CHMs derived from point clouds at different proportions of data pits are remarkably better than those constructed using other algorithms, as evidenced by the lowest average root mean square error (0.4981 m) between the reference CHMs and the constructed pit-free CHMs. Moreover, our pit-free CHMs show the best performance overall in terms of maximum tree height estimation (average bias = 0.9674 m).

Conclusion

The proposed algorithm can be adopted when working with different quality LiDAR data and shows high potential in forestry applications.
Evaluation of the association between KIR polymorphisms and systemic sclerosis: a meta-analysis
Authors: Karimizadeh Elham , Mostafaei Shayan , Aslani Saeed , Gharibdoost Farhad , Xavier Ricardo Machado , Salim Patricia Hartstein , Kavosi Hoda , Farhadi Elham , Mahmoudi Mahdi
Published: January 2020

Background

The results of investigations on the association between killer cell immunoglobulin-like receptor (KIR) gene polymorphisms and the risk of systemic sclerosis (SSc) are inconsistent. To comprehensively evaluate the influence of KIR polymorphisms on the risk of SSc, this meta-analysis was performed.

Methods

A systematic literature search was performed in electronic databases including Scopus and PubMed/MEDLINE to find all available studies involving KIR gene family polymorphisms and SSc risk prior to July 2019. Pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were measured to detect associations between KIR gene family polymorphisms and SSc risk.

Results

Five articles, comprising 571 patients and 796 healthy participants, evaluating the KIR gene family polymorphisms were included in the final meta-analysis according to the inclusion and exclusion criteria, and 16 KIR genes were assessed. None of the KIR genes were significantly associated with the risk of SSc.

Conclusions

The current meta-analysis provides evidence that KIR genes might not be potential risk factors for SSc risk.
Discrete unified gas kinetic scheme for multiscale anisotropic radiative heat transfer
Authors: Song Xinliang , Zhang Chuang , Zhou Xiafeng , Guo Zhaoli
Published: January 2020

In this work, a discrete unified gas kinetic scheme (DUGKS) is developed for radiative transfer in anisotropic scattering media. The method is an extension of a previous one for isotropic radiation problems [1]. The present scheme is a finite-volume discretization of the anisotropic gray radiation equation, where the anisotropic scattering phase function is approximated by the Legendre polynomial expansion. With the coupling of free transport and scattering processes in the reconstruction of the flux at cell interfaces, the present DUGKS has the nice unified preserving properties such that the cell size is not limited by the photon mean free path even in the optical thick regime. Several one- and two-dimensional numerical tests are conducted to validate the performance of the present DUGKS, and the numerical results demonstrate that the scheme is a reliable method for anisotropic radiative heat transfer problems.
Grounding urban resilience through transdisciplinary risk mapping
Authors: Bendito América
Published: January 2020

During 2015, three key global agreements were established which converged on enhancing resilience as an overall strategy towards sustainable development. This paper builds an argument and a structured process for future research and practice that succinctly links urban resilience enhancement with the transdisciplinary development of risk maps. Risk maps are highlighted as useful tools improving a shared understanding of risk, raising awareness, and effectively guiding land use planning and zoning towards enhanced urban resilience. Building codes incorporating past and recent disaster experiences, and multi-hazard maps with high quality data for different performance levels, should be the foundation of transdisciplinary risk mapping.
TNF-α -308 G>A and IL10 -1082A>G polymorphisms as potential risk factors for lymphoproliferative disorders in autoimmune rheumatic diseases
Authors: Tayel Manal Y. , Nazir Aida , Abdelhamid Ibtessam M. , Helmy Myriam A. S. , Zaki Nadia E. , Elsharkawy Nehad S. , Fayad Amira I.
Published: January 2020

Background

Chronic inflammation with sustained unregulated immune stimulation in autoimmune rheumatic diseases (ARD) may be a risk factor for developing lymphoproliferative disorders (LPD). Markers of ARD activity as high erythrocyte sedimentation rate or erosive joint diseases and the development of B-symptoms were accounted as risk factors for LPD development. We investigated the association of five inflammatory cytokine genes single nucleotide polymorphisms (SNPs): TNF-α -308G>A; TGF-β1 gene codon 10 T>C and 25 G>C; IL-10 promoter SNPs -1082 A>G, -819T>C, and -592A>C; IL-6 -174G>C; and IFN-γ 874 T>A with the risk of LPD development in ARD patients. The study was conducted on 70 patients divided into group I, 25 ARD patients diagnosed as RA (n = 15) and SLE (n = 10) and with no history of malignancy; group II, 25 patients diagnosed with LPD and had no ARD; and group III, 20 patients diagnosed with both diseases: ARD and LPD. Cytokine genotyping was analyzed by PCR-sequence-specific primer (PCR-SSP).

Results

ARD+LPD patients had significantly higher frequency of TNF-α -308A allele and AA+AG genotype (high TNF-α producers) and IL-10 -1082A allele and AA genotype (low IL-10 producers) than ARD patients (p = 0.003, p = 0.024, p = 0.003, p = 0.03, respectively) with a significantly increased risk of LPD development in ARD patients expressing the corresponding alleles and genotypes. No significant differences were detected in the distribution frequency of either TGF-β1, IL-6, or IFN-γ SNPs between groups I and III or any of the studied SNPs between groups II and III. The distribution frequency of IL-10 ATA haplotype was significantly increased in group III as compared to group I (p = 0.037).

Conclusion

The significantly increased frequency of the high-TNF-α- and low-IL-10-producing alleles and genotypes in ARD patients may participate in the provision of a proinflammatory milieu that eventually increases the risk of LPD development.
Prospective Feasibility Trial of a Novel Strategy of Facilitated Cascade Genetic Testing Using Telephone Counseling
Authors: Frey Melissa K. , Kahn Ryan M. , Chapman-Davis Eloise , Tubito Francesca , Pires Maira , Christos Paul , Anderson Samantha , Mukherjee Semanti , Jordan Bailey , Blank Stephanie V. , Caputo Thomas A. , Sharaf Ravi N. , Offit Kenneth , Holcomb Kevin , Lipkin Steven
Published: January 2020

PURPOSE

A powerful consequence of detecting cancer-associated pathogenic variants is the ability to test at-risk relatives (ARRs), termed cascade testing. However, historical studies suggest cascade testing uptake of 30% or less. Here, we tested the feasibility of a novel, streamlined method of cascade testing using telephone genetic counseling and mailed saliva-based genetic testing.

PATIENTS AND METHODS

Probands with newly diagnosed cancer-associated pathogenic variants were offered facilitated cascade testing whereby the genetics team identified and contacted ARRs by telephone to disclose the familial pathogenic variant and offer telephone counseling and mailed saliva testing. Results and guideline-based recommendations were reviewed by telephone and shared with the primary care physician.

RESULTS

Thirty probands were enrolled, and 114 ARRs were identified. Twelve ARRs were excluded (lived outside of the United States, n = 5; proband did not approve of contact, n = 7). Among 102 ARRs telephoned, contact was established with 95 (93%). Among 114 identified ARRs, 66 (58%) completed genetic testing. Among those completing testing, 27 (41%) carried the familial pathogenic variant. Surveys of ARRs at the time of genetic testing and 6 months later demonstrated low levels of anxiety, depression, distress, and uncertainty and high levels of satisfaction with testing. At 6 months, 7 ARRs with pathogenic variants had undergone cancer surveillance interventions and 4 had undergone cancer risk-reducing surgery.

CONCLUSION

Facilitated cascade testing with telephone genetic counseling and mailed saliva kits resulted in high testing uptake among ARRs. Positive genetic testing resulted in utilization of genetically targeted primary disease prevention at short-term follow-up. Facilitated cascade testing is a straightforward, low-cost, easily implemented strategy with significant potential to promote early detection for affected ARRs and reduce cancer mortality and should be evaluated in larger scale clinical trials.