bluuebunny/crossref_metadata_2025 huggingface dataset:
What passive euthanasia is
Authors: Brassington Iain
Published: May 2020

Background

Euthanasia can be thought of as being either active or passive; but the precise definition of “passive euthanasia” is not always clear. Though all passive euthanasia involves the withholding of life-sustaining treatment, there would appear to be some disagreement about whether all such withholding should be seen as passive euthanasia.

Main text

At the core of the disagreement is the question of the importance of an intention to bring about death: must one intend to bring about the death of the patient in order for withholding treatment to count as passive euthanasia, as some sources would indicate, or does withholding in which death is merely foreseen belong to that category? We may expect that this unclarity would be important in medical practice, in law, and in policy. The idea that withholding life-sustaining treatment is passive euthanasia is traced to James Rachels’s arguments, which lend themselves to the claim that passive euthanasia does not require intention to end life. Yet the argument here is that Rachels’s arguments are flawed, and we have good reasons to think that intention is important in understanding the moral nature of actions. As such, we should reject any understanding of passive euthanasia that does not pay attention to intent.

Short conclusion

James Rachels’s work on active and passive euthanasia has been immensely influential; but this is an influence that we ought to resist.
Measuring lung mechanics of expiratory tidal breathing with non-invasive breath occlusion
Authors: Howe Sarah L. , März Melanie , Krüger-Ziolek Sabine , Laufer Bernhard , Pretty Chris , Shaw Geoffery M. , Desaive Thomas , Möller Knut , Chase J. Geoffrey
Published: May 2020

Background and objective

Lung mechanics measurements provide clinically useful information about disease progression and lung health. Currently, there are no commonly practiced methods to non-invasively measure both resistive and elastic lung mechanics during tidal breathing, preventing the important information provided by lung mechanics from being utilised. This study presents a novel method to easily assess lung mechanics of spontaneously breathing subjects using a dynamic elastance, single-compartment lung model.

Methods

A spirometer with a built-in shutter was used to occlude expiration during tidal breathing, creating exponentially decaying flow when the shutter re-opened. The lung mechanics measured were respiratory system elastance and resistance, separated from the exponentially decaying flow, and interrupter resistance calculated at shutter closure. Progressively increasing resistance was added to the spirometer mouthpiece to simulate upper airway obstruction. The lung mechanics of 17 healthy subjects were successfully measured through spirometry.

Results

N = 17 (8 female, 9 male) healthy subjects were recruited. Measured decay rates ranged from 5 to 42/s, subjects with large variation of decay rates showed higher muscular breathing effort. Lung elastance measurements ranged from 3.9 to 21.2 cmH$$_2$$2O/L, with no clear trend between change in elastance and added resistance. Resistance calculated from decay rate and elastance ranged from 0.15 to 1.95 cmH$$_2$$2Os/L. These very small resistance values are due to the airflow measured originating from low-resistance areas in the centre of airways. Occlusion resistance measurements were as expected for healthy subjects, and increased as expected as resistance was added.

Conclusions

This test was able to identify reasonable dynamic lung elastance and occlusion resistance values, providing new insight into expiratory breathing effort. Clinically, this lung function test could impact current practice. It does not require high levels of cooperation from the subject, allowing a wider cohort of patients to be assessed more easily. Additionally, this test can be simply implemented in a small standalone device, or with standard lung function testing equipment.
Motor improvement estimation and task adaptation for personalized robot-aided therapy: a feasibility study
Authors: Giang Christian , Pirondini Elvira , Kinany Nawal , Pierella Camilla , Panarese Alessandro , Coscia Martina , Miehlbradt Jenifer , Magnin Cécile , Nicolo Pierre , Guggisberg Adrian , Micera Silvestro
Published: May 2020

Background

In the past years, robotic systems have become increasingly popular in upper limb rehabilitation. Nevertheless, clinical studies have so far not been able to confirm superior efficacy of robotic therapy over conventional methods. The personalization of robot-aided therapy according to the patients’ individual motor deficits has been suggested as a pivotal step to improve the clinical outcome of such approaches.

Methods

Here, we present a model-based approach to personalize robot-aided rehabilitation therapy within training sessions. The proposed method combines the information from different motor performance measures recorded from the robot to continuously estimate patients’ motor improvement for a series of point-to-point reaching movements in different directions. Additionally, it comprises a personalization routine to automatically adapt the rehabilitation training. We engineered our approach using an upper-limb exoskeleton. The implementation was tested with 17 healthy subjects, who underwent a motor-adaptation paradigm, and two subacute stroke patients, exhibiting different degrees of motor impairment, who participated in a pilot test undergoing rehabilitative motor training.

Results

The results of the exploratory study with healthy subjects showed that the participants divided into fast and slow adapters. The model was able to correctly estimate distinct motor improvement progressions between the two groups of participants while proposing individual training protocols. For the two pilot patients, an analysis of the selected motor performance measures showed that both patients were able to retain the improvements gained during training when reaching movements were reintroduced at a later stage. These results suggest that the automated training adaptation was appropriately timed and specifically tailored to the abilities of each individual.

Conclusions

The results of our exploratory study demonstrated the feasibility of the proposed model-based approach for the personalization of robot-aided rehabilitation therapy. The pilot test with two subacute stroke patients further supported our approach, while providing encouraging results for the applicability in clinical settings.

Trial registrationThis study is registered in ClinicalTrials.gov (NCT02770300, registered 30 March 2016,https://clinicaltrials.gov/ct2/show/NCT02770300)
Associations between maternal serum HDL-c concentrations during pregnancy and neonatal birth weight: a population-based cohort study
Authors: Wang Hongliang , Dang Qinyu , Zhu Haiyan , Liang Ning , Le Zhiyin , Huang Dongxu , Xiao Rong , Yu Huanling
Published: May 2020

Background

To evaluate the associations between maternal serum concentrations of high-density lipoprotein cholesterol (HDL-c) throughout pregnancy and neonatal birth weight (BW) and small for gestational age (SGA) births.

Methods

A prospective cohort of 2241 pregnant women was followed from recruitment to delivery in three hospitals in Beijing, China between January 2014 and December 2017. Maternal fasting serum lipids concentrations were measured at gestational week 6–12, 16, 24 and 36. Major outcome was neonatal BW. The associations between maternal HDL-c and BW were estimated by linear regression and linear mixed-effects models. Odds ratios (ORs) and 95% confidence intervals of SGA births in relation to HDL-c were evaluated via logistic regression analysis.

Results

There was a tendency that mothers with higher HDL-c concentrations throughout gestation gave birth to infants with lower BW. A negative association was found between maternal HDL-c concentrations and BW at 24th and 36th gestational weeks (B = − 34.044, P = 0.034; B = − 53.528, P = 0.000). The HDL-c trend of change was inversely associated with BW (B = − 442.736, P = 0.000). Mothers with SGA neonates had higher serum HDL-c concentration at the 36th gestational week (P < 0.01). The incidences of SGA in the three groups (HDL-c: 1.84–2.23 mmol/L, 2.24–2.59 mmol/L and ≥ 2.60 mmol/L) were higher than the group with the lowest concentration of HDL-c (< 1.83 mmol/L) (P < 0.01, P < 0.01, P < 0.001) at 36th week. Higher maternal HDL-c concentrations at 36th week (HDL-c: 1.84–2.23 mmol/L, 2.24–2.59 mmol/L and ≥ 2.60 mmol/L) were positively associated with the incidence of SGA (OR = 1.900, P = 0.008; OR = 1.893, P = 0.008; OR = 1.975, P = 0.004). The HDL-c trend of change was positively associated with SGA births (OR = 9.772, P = 0.000).

Conclusions

Maternal serum HDL-c concentrations were inversely associated with BW at 24th and 36th gestational weeks. The high concentrations of HDL-c at the 36th gestational week increased the risk of SGA. The maternal HDL-c trend of change across pregnancy was associated with smaller neonatal size.
Facile synthesis and nanoscale features of a nanostructured nordihydroguaiaretic acid analog for therapeutic applications
Authors: John Geraldine Sandana Mala , Vuttaradhi Veena Kumari , Takeuchi Satoru , Pitani Ravi Shankar , Venkatraman Ganesh , Rayala Suresh Kumar
Published: May 2020

Background

Nordihydroguaiaretic acid (NDGA) is a plant lignan obtained from creosote bush, known to possess anti-oxidant, anti-cancer and anti-viral activities and is being used in traditional medicine. However, toxicity studies indicated liver and kidney damage despite its immense medicinal properties. There has been a recent increase of curiosity in the chemical synthesis of NDGA derivatives for therapeutic applications. NDGA derivatives have been developed as better alternatives to NDGA and for targeted delivery to the site of tissue by chemical derivatives. In this regard, an analog of NDGA, Acetyl NDGA (Ac-NDGA), has been synthesized based on a previous procedure and formulated as a nanostructured complex with Polycaprolactone/Polyethylene glycol polymer matrices, by o/w solvent evaporation method.

Results

The drug-incorporated polymeric nanospheres exhibited a drug load of 10.0 ± 0.5 µg drug per mg of nanospheres in acetonitrile solvent with 49.95 ± 10% encapsulation efficiency and 33–41% drug loading capacity with different batches of nanospheres preparation. The in vitro drug release characteristics indicated 82 ± 0.25% drug release at 6 h in methanol. Further, the nanospheres have been characterized extensively to evaluate their suitability for therapeutic delivery.

Conclusions

The present studies indicate a new and efficient formulation of the nanostructured AcNDGA with good therapeutic potential.
Health-related qualify of life, angina type and coronary artery disease in patients with stable chest pain
Authors: Rieckmann Nina , Neumann Konrad , Feger Sarah , Ibes Paolo , Napp Adriane , Preuß Daniel , Dreger Henryk , Feuchtner Gudrun , Plank Fabian , Suchánek Vojtěch , Veselka Josef , Engstrøm Thomas , Kofoed Klaus F. , Schröder Stephen , Zelesny Thomas , Gutberlet Matthias , Woinke Michael , Maurovich-Horvat Pál , Merkely Béla , Donnelly Patrick , Ball Peter , Dodd Jonathan D. , Hensey Mark , Loi Bruno , Saba Luca , Francone Marco , Mancone Massimo , Berzina Marina , Erglis Andrejs , Vaitiekiene Audrone , Zajanckauskiene Laura , Harań Tomasz , Suckiel Malgorzata Ilnicka , Faria Rita , Gama-Ribeiro Vasco , Benedek Imre , Rodean Ioana , Adjić Filip , Čemerlić Adjić Nada , Rodriguez-Palomares José , Garcia del Blanco Bruno , Brooksbank Katriona , Collison Damien , Davis Gershan , Thwaite Erica , Knuuti Juhani , Saraste Antti , Kępka Cezary , Kruk Mariusz , Benedek Theodora , Ratiu Mihaela , Neskovic Aleksandar N. , Vidakovic Radosav , Diez Ignacio , Lecumberri Iñigo , Fisher Michael , Ruzsics Balasz , Hollingworth William , Gutiérrez-Ibarluzea Iñaki , Dewey Marc , Müller-Nordhorn Jacqueline
Published: May 2020

Background

Health-related quality of life (HRQoL) is impaired in patients with stable angina but patients often present with other forms of chest pain. The aim of this study was to compare the pre-diagnostic HRQoL in patients with suspected coronary artery disease (CAD) according to angina type, gender, and presence of obstructive CAD.

Methods

From the pilot study for the European DISCHARGE trial, we analysed data from 24 sites including 1263 patients (45.9% women, 61.1 ± 11.3 years) who were clinically referred for invasive coronary angiography (ICA; 617 patients) or coronary computed tomography angiography (CTA; 646 patients). Prior to the procedures, patients completed HRQoL questionnaires: the Short Form (SF)-12v2, the EuroQoL (EQ-5D-3 L) and the Hospital Anxiety and Depression Scale.

Results

Fifty-five percent of ICA and 35% of CTA patients had typical angina, 23 and 33% had atypical angina, 18 and 28% had non-anginal chest discomfort and 5 and 5% had other chest discomfort, respectively. Patients with typical angina had the poorest physical functioning compared to the other angina groups (SF-12 physical component score; 41.2 ± 8.8, 43.3 ± 9.1, 46.2 ± 9.0, 46.4 ± 11.4, respectively, all age and gender-adjusted p < 0.01), and highest anxiety levels (8.3 ± 4.1, 7.5 ± 4.1, 6.5 ± 4.0, 4.7 ± 4.5, respectively, all adjusted p < 0.01). On all other measures, patients with typical or atypical angina had lower HRQoL compared to the two other groups (all adjusted p < 0.05). HRQoL did not differ between patients with and without obstructive CAD while women had worse HRQoL compared with men, irrespective of age and angina type.

Conclusions

Prior to a diagnostic procedure for stable chest pain, HRQoL is associated with chest pain characteristics, but not with obstructive CAD, and is significantly lower in women.

Trial registration

Clinicaltrials.gov, NCT02400229.
Association between endometrial thickness and neonatal outcomes in intrauterine insemination cycles: a retrospective analysis of 1,016 live-born singletons
Authors: Huang Jialyu , Lin Jiaying , Lu Xuefeng , Gao Hongyuan , Song Ning , Cai Renfei , Kuang Yanping
Published: May 2020

Background

Decreased endometrial thickness (EMT) has been suggested to be associated with reduced birthweight of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) newborns. Considering the differences in ovarian stimulation degree and laboratory procedures between IVF/ICSI and IUI treatment, we aim to investigate whether EMT has any influence on IUI infant outcomes as well.

Methods

This was a retrospective cohort study of 1016 patients who had singleton livebirths after IUI treatment cycles from January 2008 to December 2018 at a tertiary-care academic medical center in China. Patients were categorized into three groups by the 10th and 90th percentile of peak EMT: ≤7.6, 7.7–13.0 and ≥ 13.1 mm. The primary outcomes of the study were preterm birth (PTB), low birthweight (LBW) and small-for-gestational age (SGA). Multiple regression analyses were performed after controlling for a variety of potential confounders.

Results

No significant differences were found among the three groups in gestational age, birthweight and birthweight Z-score. Compared with the EMT 7.7–13.0 mm group, the incidences of PTB, LBW and SGA were 5.5% (adjusted odds ratio [aOR] 0.81, 95% confidence interval [CI] 0.33–2.01), 6.4% (aOR 1.44, 95% CI 0.58–3.58) and 7.3% (aOR 1.21, 95% CI 0.53–2.76) in the EMT ≤7.6 mm group, respectively. Similarly, EMT ≥13.1 mm was not significantly associated with risks of PTB (aOR 0.63, 95% CI 0.24–1.65), LBW (aOR 0.57, 95% CI 0.17–1.95) and SGA (aOR 0.73, 95% CI 0.28–1.92). The odds of other adverse neonatal outcomes, including macrosomia, large-for-gestational age and major congenital malformations, did not show significant differences before and after adjustment in both EMT ≤7.6 and ≥ 13.1 mm groups.

Conclusions

EMT is not independently associated with adverse perinatal outcomes in IUI cycles. This novel finding would provide reassuring information for IUI patients with thin endometrial linings regarding their neonatal health. However, further prospective cohort studies with larger datasets are needed to confirm the conclusion.
Two forms of CX3CL1 display differential activity and rescue cognitive deficits in CX3CL1 knockout mice
Authors: Winter Aimee N. , Subbarayan Meena S. , Grimmig Bethany , Weesner Jason A. , Moss Lauren , Peters Melinda , Weeber Edwin , Nash Kevin , Bickford Paula C.
Published: May 2020

Background

Fractalkine (CX3CL1; FKN) is a chemokine expressed by neurons that mediates communication between neurons and microglia. By regulating microglial activity, CX3CL1 can mitigate the damaging effects of chronic microglial inflammation within the brain, a state that plays a major role in aging and neurodegeneration. CX3CL1 is present in two forms, a full-length membrane-bound form and a soluble cleaved form (sFKN), generated by a disintegrin and metalloproteinase (ADAM) 10 or 17. Levels of sFKN decrease with aging, which could lead to enhanced inflammation, deficits in synaptic remodeling, and subsequent declines in cognition. Recently, the idea that these two forms of CX3CL1 may display differential activities within the CNS has garnered increased attention, but remains unresolved.

Methods

Here, we assessed the consequences of CX3CL1 knockout (CX3CL1-/-) on cognitive behavior as well as the functional rescue with the two different forms of CX3CL1 in mice. CX3CL1-/- mice were treated with adeno-associated virus (AAV) expressing either green fluorescent protein (GFP), sFKN, or an obligate membrane-bound form of CX3CL1 (mFKN) and then subjected to behavioral testing to assess cognition and motor function. Following behavioral analysis, brains were collected and analyzed for markers of neurogenesis, or prepared for electrophysiology to measure long-term potentiation (LTP) in hippocampal slices.

Results

CX3CL1−/− mice showed significant deficits in cognitive tasks for long-term memory and spatial learning and memory in addition to demonstrating enhanced basal motor performance. These alterations correlated with deficits in both hippocampal neurogenesis and LTP. Treatment of CX3CL1−/− mice with AAV-sFKN partially corrected changes in both cognitive and motor function and restored neurogenesis and LTP to levels similar to wild-type animals. Treatment with AAV-mFKN partially restored spatial learning and memory in CX3CL1−/− mice, but did not rescue long-term memory, or neurogenesis.

Conclusions

These results are the first to demonstrate that CX3CL1 knockout causes significant cognitive deficits that can be rescued by treatment with sFKN and only partially rescued with mFKN. This suggests that treatments that restore signaling of soluble forms of CX3CL1 may be a viable therapeutic option for aging and disease.
Psychosocial interventions targeting mental health in pregnant adolescents and adolescent parents: a systematic review
Authors: Laurenzi Christina A. , Gordon Sarah , Abrahams Nina , du Toit Stefani , Bradshaw Melissa , Brand Amanda , Melendez-Torres G. J. , Tomlinson Mark , Ross David A. , Servili Chiara , Carvajal-Aguirre Liliana , Lai Joanna , Dua Tarun , Fleischmann Alexandra , Skeen Sarah
Published: May 2020

Background

Pregnancy and parenthood are known to be high-risk times for mental health. However, less is known about the mental health of pregnant adolescents or adolescent parents. Despite the substantial literature on the risks associated with adolescent pregnancy, there is limited evidence on best practices for preventing poor mental health in this vulnerable group. This systematic review therefore aimed to identify whether psychosocial interventions can effectively promote positive mental health and prevent mental health conditions in pregnant and parenting adolescents.

Methods

We used the standardized systematic review methodology based on the process outlined in the World Health Organization’s Handbook for Guidelines Development. This review focused on randomized controlled trials of preventive psychosocial interventions to promote the mental health of pregnant and parenting adolescents, as compared to treatment as usual. We searched PubMed/Medline, PsycINFO, ERIC, EMBASE and ASSIA databases, as well as reference lists of relevant articles, grey literature, and consultation with experts in the field. GRADE was used to assess the quality of evidence.

Results

We included 17 eligible studies (n = 3245 participants). Interventions had small to moderate, beneficial effects on positive mental health (SMD = 0.35, very low quality evidence), and moderate beneficial effects on school attendance (SMD = 0.64, high quality evidence). There was limited evidence for the effectiveness of psychosocial interventions on mental health disorders including depression and anxiety, substance use, risky sexual and reproductive health behaviors, adherence to antenatal and postnatal care, and parenting skills. There were no available data for outcomes on self-harm and suicide; aggressive, disruptive, and oppositional behaviors; or exposure to intimate partner violence. Only two studies included adolescent fathers. No studies were based in low- or middle-income countries.

Conclusion

Despite the encouraging findings in terms of effects on positive mental health and school attendance outcomes, there is a critical evidence gap related to the effectiveness of psychosocial interventions for improving mental health, preventing disorders, self-harm, and other risk behaviors among pregnant and parenting adolescents. There is an urgent need to adapt and design new psychosocial interventions that can be pilot-tested and scaled with pregnant adolescents and adolescent parents and their extended networks, particularly in low-income settings.
Survival of people aged 50 years and older by HIV and HIV treatment status: findings from three waves of the SAGE-Wellbeing of Older People Study (SAGE-WOPS) in Uganda
Authors: Mugisha Okello Joseph , Nash Stephen , Kowal Paul , Naidoo Nirmala , Chatterji Somnath , Boerma Ties , Seeley Janet
Published: May 2020

Background

Data on the survival status of older adults on antiretroviral treatment (ART) are scarce in sub-Saharan Africa. The objective of this study was to determine the survival status of people aged 50 years and older who were HIV-negative, HIV-positive not on ART, and HIV-positive on ART.

Methods

We used three waves of data from the World Health Organisation Study on Global Ageing and adult health- Well Being of Older People Study cohort in Uganda, conducted in 2009, 2012–2013 and 2015–2016. The cohort included HIV-negative and HIV-positive persons aged 50 years and older recruited from multiple rural and peri-urban sites in Uganda. Data were collected using interviewer-administered questionnaire. Time-dependent ART data were collected from medical records using a data-abstraction form. This study was conducted before the universal test and treat policy came into effect. We fitted Cox survival models to estimate hazard ratios to compare the risk of death between groups, adjusted for age, sex, marital status and hypertension.

Results

Of 623 participants, 517 (82.9%) of respondents had follow-up data and were included in this analysis. We observed 1571 person-years of follow-up from 274 people who were HIV-negative, and 1252 from 243 who were HIV-positive. The estimated mortality adjusted hazard ratio (aHR) was 1.89 (95% CI 1.0–3.4; p = 0.04) among people living with HIV compared to HIV-negative people. The aHR for mortality among people receiving ART compared with HIV-negative people was 1.75 (95% CI 0.9–3.5). People who were HIV-positive and not receiving ART had the greatest risk of death (aHR = 2.09, 95% CI 1.0–4.4 compared with HIV negative participants). The aHR for HIV-positive people not receiving ART, compared to those who were on treatment, was 1.19 (95% CI 0.6–2.5).

Conclusion

Older adults living with HIV on ART had a risk of mortality that was nearly twice as high as HIV-negative adults. Further analyses of longitudinal data should be done to understand factors that affect the survival of older adults on ART.
Impact of WHO guidelines on trends in HIV testing and ART initiation among children living with HIV in Zambia
Authors: Munthali Tendai , Michelo Charles , Mee Paul , Moyo Crispin , Kashoka Andrew , Liswaniso Liswaniso , Chiboma Innocent , Todd Jim
Published: May 2020

Background

About 13 years since the introduction of antiretroviral therapy (ART) for children living with HIV (CLHIV) in Zambia, HIV/AIDS testing and treatment guidelines for children have evolved over the years with limited documentation of long-term trends in the numbers testing HIV positive and initiating ART. We examined trends in HIV testing and ART initiation in Zambia.

Methods

We conducted a retrospective cohort study using routinely collected patient level data from 496 health facilities across Zambia. We used Poisson regression to derive incident rate ratios and 95% confidence intervals (95% CI) for background characteristics and used a Cuzick non-parametric test for trends to test the 13-year trends. Median time from testing to ART initiation in days and incidence rates were derived using life tables in survival analysis. We used multi-level random effects Poisson regression model to determine variations in time from HIV testing to ART initiation by facility.

Results

Overall, the cumulative proportion of the children who tested positive and initiated antiretroviral therapy (ART for HIV) from 2004 to 2017 was 69% (n = 99 592). During the period under review proportions of ART initiation increased from 52% in 2004–2006 to 97% in 2016–2017 (P < 0.001) and time from testing to ART initiation reduced from a median of 17 days IQR (1–161) in 2004 to one day IQR (1–14), P < 0.001 in 2016–2017. CLHIV were 15 times more likely to be initiated on ART in 2016-17 compared to period 2004-6 (IRR = 15.2, 95% CI 14.7–15.7). Time to ART initiation increased with age and was higher in rural health facilities compared to urban facilities. About 11% of the variability in time to ART initiation in children could be attributed to differences between facilities.

Conclusions

The substantial increase in ART initiation and reduction in time to ART initiation among CLHIV identified in this study, reflects improvements in the paediatric HIV programme in Zambia in relation to health care delivery and adherence to national testing and treatment guidelines that were adapted from WHO guidelines. However, age-related differentials in rates of ART initiation suggests that urgent interventions are needed to sustain and further improve programme performance.
Intraoperative radiotherapy with low energy x-rays for primary and recurrent soft-tissue sarcomas
Authors: Sarria Gustavo R. , Petrova Vera , Wenz Frederik , Abo-Madyan Yasser , Sperk Elena , Giordano Frank A.
Published: May 2020

Background

Soft tissue sarcomas (STS) treatment remains a therapeutic challenge. Intraoperative radiotherapy (IORT) resembles a safe and efficient for STS treatment. The first data on electronic-IORT (eIORT) using low-energy photons is herein presented.

Methods

Thirty-one patients with newly and recurrent STS were retrospectively assessed. EIORT was applied with low-energy photons during surgery. The dose was either prescribed to the applicator surface (spherical applicators) or 5 mm depth (flat applicators). Overall progression-free survival (O-PFS), local progression-free survival (L-PFS), overall survival (OS) and adverse events were evaluated.

Results

Median follow-up was 4.88 (1.0–8.95) years. Twenty-five patients (80.6%) had recurrent STS with prior treatment. The resection status was R1 in 25.8% and R2 in 6.5%. The distribution was 51.7% for extremities, 35.5% for abdomen and pelvis, 9.7% for thorax and 3.2% for head and neck tumors. The median O-PFS was 11.0 months, with 42.6% 5-year estimated O-PFS. The only local recurrence in the primary setting occurred after 22 months. Median L-PFS in recurrent STS was 12.5 months, with 65.5% 5-year estimated L-PFS. The 5-year OS estimated rate was 94.7% (3 events after 7 years). No G3 toxicity related to eIORT was observed. Two patients exhibited G2 acute neuropathic pain. Late neuropathic pain was seen in 6 patients being 3 graded as G1 and 3 as G2. No wound-related toxicity was found.

Conclusion

Electronic IORT with low-energy photons is a safe treatment option for STS, yielding similar outcomes as historical series reporting IORT with electrons or HDR brachytherapy.
Augmented reality-based navigation increases precision of pedicle screw insertion
Authors: Dennler Cyrill , Jaberg Laurenz , Spirig José , Agten Christoph , Götschi Tobias , Fürnstahl Philipp , Farshad Mazda
Published: May 2020

Background

Precise insertion of pedicle screws is important to avoid injury to closely adjacent neurovascular structures. The standard method for the insertion of pedicle screws is based on anatomical landmarks (free-hand technique). Head-mounted augmented reality (AR) devices can be used to guide instrumentation and implant placement in spinal surgery. This study evaluates the feasibility and precision of AR technology to improve precision of pedicle screw insertion compared to the current standard technique.

Methods

Two board-certified orthopedic surgeons specialized in spine surgery and two novice surgeons were each instructed to drill pilot holes for 40 pedicle screws in eighty lumbar vertebra sawbones models in an agar-based gel. One hundred and sixty pedicles were randomized into two groups: the standard free-hand technique (FH) and augmented reality technique (AR). A 3D model of the vertebral body was superimposed over the AR headset. Half of the pedicles were drilled using the FH method, and the other half using the AR method.

Results

The average minimal distance of the drill axis to the pedicle wall (MAPW) was similar in both groups for expert surgeons (FH 4.8 ± 1.0 mm vs. AR 5.0 ± 1.4 mm, p = 0.389) but for novice surgeons (FH 3.4 mm ± 1.8 mm, AR 4.2 ± 1.8 mm, p = 0.044).

Expert surgeons showed 0 primary drill pedicle perforations (PDPP) in both the FH and AR groups. Novices showed 3 (7.5%) PDPP in the FH group and one perforation (2.5%) in the AR group, respectively (p > 0.005).

Experts showed no statistically significant difference in average secondary screw pedicle perforations (SSPP) between the AR and the FH set 6-, 7-, and 8-mm screws (p > 0.05). Novices showed significant differences of SSPP between most groups: 6-mm screws, 18 (45%) vs. 7 (17.5%), p = 0.006; 7-mm screws, 20 (50%) vs. 10 (25%), p = 0.013; and 8-mm screws, 22 (55%) vs. 15 (37.5%), p = 0.053, in the FH and AR group, respectively. In novices, the average optimal medio-lateral convergent angle (oMLCA) was 3.23° (STD 4.90) and 0.62° (STD 4.56) for the FH and AR set screws (p = 0.017), respectively. Novices drilled with a higher precision with respect to the cranio-caudal inclination angle (CCIA) category (p = 0.04) with AR.

Conclusion

In this study, the additional anatomical information provided by the AR headset superimposed to real-world anatomy improved the precision of drilling pilot holes for pedicle screws in a laboratory setting and decreases the effect of surgeon’s experience. Further technical development and validations studies are currently being performed to investigate potential clinical benefits of the herein described AR-based navigation approach.
Variability and uncertainty in forest biomass estimates from the tree to landscape scale: the role of allometric equations
Authors: Vorster Anthony G. , Evangelista Paul H. , Stovall Atticus E. L. , Ex Seth
Published: May 2020

Background

Biomass maps are valuable tools for estimating forest carbon and forest planning. Individual-tree biomass estimates made using allometric equations are the foundation for these maps, yet the potentially-high uncertainty and bias associated with individual-tree estimates is commonly ignored in biomass map error. We developed allometric equations for lodgepole pine (Pinus contorta), ponderosa pine (P. ponderosa), and Douglas-fir (Pseudotsuga menziesii) in northern Colorado. Plot-level biomass estimates were combined with Landsat imagery and geomorphometric and climate layers to map aboveground tree biomass. We compared biomass estimates for individual trees, plots, and at the landscape-scale using our locally-developed allometric equations, nationwide equations applied across the U.S., and the Forest Inventory and Analysis Component Ratio Method (FIA-CRM). Total biomass map uncertainty was calculated by propagating errors from allometric equations and remote sensing model predictions. Two evaluation methods for the allometric equations were compared in the error propagation—errors calculated from the equation fit (equation-derived) and errors from an independent dataset of destructively-sampled trees (n = 285).

Results

Tree-scale error and bias of allometric equations varied dramatically between species, but local equations were generally most accurate. Depending on allometric equation and evaluation method, allometric uncertainty contributed 30–75% of total uncertainty, while remote sensing model prediction uncertainty contributed 25–70%. When using equation-derived allometric error, local equations had the lowest total uncertainty (root mean square error percent of the mean [% RMSE] = 50%). This is likely due to low-sample size (10–20 trees sampled per species) allometric equations and evaluation not representing true variability in tree growth forms. When independently evaluated, allometric uncertainty outsized remote sensing model prediction uncertainty. Biomass across the 1.56 million ha study area and uncertainties were similar for local (2.1 billion Mg; % RMSE = 97%) and nationwide (2.2 billion Mg;  % RMSE = 94%) equations, while FIA-CRM estimates were lower and more uncertain (1.5 billion Mg;  % RMSE = 165%).

Conclusions

Allometric equations should be selected carefully since they drive substantial differences in bias and uncertainty. Biomass quantification efforts should consider contributions of allometric uncertainty to total uncertainty, at a minimum, and independently evaluate allometric equations when suitable data are available.
Promotion of ubiquitination-dependent survivin destruction contributes to xanthohumol-mediated tumor suppression and overcomes radioresistance in human oral squamous cell carcinoma
Authors: Li Ming , Gao Feng , Yu Xinfang , Zhao Qing , Zhou Li , Liu Wenbin , Li Wei
Published: May 2020

Background

Overexpression of survivin plays a crucial role in tumorigenesis and correlates with poor prognosis in human malignancies. Thus, survivin has been proposed as an attractive target for new anti-tumor interventions.

Methods

A natural product library was used for natural compound screening through MTS assay. The expression of survivin in oral squamous cell carcinoma (OSCC) and the inhibitory effect of xanthohumol (XN) on OSCC were examined by anchorage-dependent and -independent growth assays, immunoblot, immunofluorescence, immunohistochemical staining, ubiquitination analysis, co-immunoprecipitation assay, CRISPR-Cas9-based gene knockout, and xenograft experiment.

Results

Survivin is highly expressed in OSCC patient-derived tissues and cell lines. Knockout of survivin reduced the tumorigenic properties of OSCC cells in vitro and in vivo. With a natural compound screening, we identified that xanthohumol inhibited OSCC cells by reducing survivin protein level and activating mitochondrial apoptotic signaling. Xanthohumol inhibited the Akt-Wee1-CDK1 signaling, which in turn decreased survivin phosphorylation on Thr34, and facilitated E3 ligase Fbxl7-mediated survivin ubiquitination and degradation. Xanthohumol alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors.

Conclusion

Our findings indicate that targeting survivin for degradation might a promising strategy for OSCC treatment.
Association of TILs with clinical parameters, Recurrence Score® results, and prognosis in patients with early HER2-negative breast cancer (BC)—a translational analysis of the prospective WSG PlanB trial
Authors: Kolberg-Liedtke Cornelia , Gluz Oleg , Heinisch Fred , Feuerhake Friedrich , Kreipe Hans , Clemens Michael , Nuding Benno , Malter Wolfram , Reimer Toralf , Wuerstlein Rachel , Graeser Monika , Shak Steve , Nitz Ulrike , Kates Ronald , Christgen Matthias , Harbeck Nadia
Published: May 2020

Background

The presence of tumor-infiltrating lymphocytes has been associated with prognosis and chemotherapy response, particularly in high-risk breast cancer subtypes. There is limited data so far as to (i) how tumor-infiltrating lymphocyte (TIL) measurements correlate with genomic measurements such as the Oncotype DX Recurrence Score® and (ii) whether the survival impact of TIL measurements varies according to different adjuvant systemic therapies.

Methods

The WSG PlanB trial compared an anthracycline-free chemotherapy regimen (6x docetaxel/cyclophosphamide, TC) to an anthracycline-taxane sequence (4xEC followed by 4x docetaxel) in patients with intermediate-risk, HER2-negative early breast cancer (EBC). Patients with HR-positive HER2-negative EBC were further stratified to receive endocrine therapy alone vs. chemotherapy followed by endocrine therapy based on Recurrence Score results and nodal status. In this analysis, three independent observers quantified and categorized the presence of TILs among tumor samples from patients in PlanB. TIL measurements were correlated with clinical/pathological parameters and treatment outcome overall and according to the treatment arm.

Results

Disease-free survival (DFS) rates were significantly better (p = .04) in HR-negative patients with high vs. intermediate TIL levels and were higher in low vs. intermediate TIL patients, however with borderline significance only (p = .06). There were no significant differences among TIL categories in HR+ patients. High RS categories, HR-negative status, and high KI67 were independently and significantly associated with high TIL categories. There was no significant impact of TIL category on DFS in patients treated by endocrine therapy only; however, in patients receiving chemotherapy, DFS in the intermediate TIL category was lower than that in the other categories.

Conclusion

Although the presence of high TILs is associated with negative prognostic parameters such as high KI67 and HR-negative status among patients with HR-positive HER2-negative EBC, patients with high TILs show a favorable 5-year DFS in both HR-positive/HER2-negative and triple-negative breast cancer.
Comparison of the clinical and cost effectiveness of two management strategies (rehabilitation versus surgical reconstruction) for non-acute anterior cruciate ligament (ACL) injury: study protocol for the ACL SNNAP randomised controlled trial
Authors: Davies Loretta , Cook Jonathan , Leal Jose , Areia Carlos Morgado , Shirkey Beverly , Jackson William , Campbell Helen , Fletcher Heidi , Carr Andrew , Barker Karen , Lamb Sarah E. , Monk Paul , O’Leary Sean , Haddad Fares , Wilson Chris , Price Andrew , Beard David
Published: May 2020

Background

Anterior cruciate ligament (ACL) rupture is a common knee injury that can lead to poor quality of life, decreased activity and increased risk of secondary osteoarthritis of the knee. Management of patients with a non-acute ACL injury can include a non-surgical (rehabilitation) or surgical (reconstruction) approach. However, insufficient evidence to guide treatment selection has led to high variation in treatment choice for patients with non-acute presentation of ACL injury.

The objective of the ACL SNNAP trial is to determine in patients with non-acute anterior cruciate ligament deficiency (ACLD) whether a strategy of non-surgical management (rehabilitation) (with option for later ACL reconstruction only if required) is more clinically effective and cost effective than a strategy of surgical management (reconstruction) without prior rehabilitation with all patients followed up at 18 months.

Methods

The study is a pragmatic, multi-centre, superiority, randomised controlled trial with two-arm parallel groups and 1:1 allocation. Patients with a symptomatic non-acute ACL deficient knee will be randomised to either non-surgical management (rehabilitation) or surgical management (reconstruction). We aim to recruit 320 patients from approximately 30 secondary care orthopaedic units from across the United Kingdom. Randomisation will occur using a web-based randomisation system. Blinding of patients and clinicians to treatment allocation will not be possible because of the nature of the interventions. Participants will be followed up via self-reported questionnaires at 6, 12 and 18 months. The primary outcome is the Knee injury and Osteoarthritis Outcome Score (KOOS) at 18 months post randomisation. Secondary outcomes will include a return to sport/activity, intervention-related complications, patient satisfaction, expectations of activity, generic health quality of life, knee specific quality of life and resource usage.

Discussion

At present, no evidence-based treatment of non-acute ACL deficiency exists, particularly in the NHS. Moreover, little consensus exists on the management approach for these patients. The proposed trial will address this gap in knowledge regarding the clinical and cost effectiveness of ACL treatment and inform future standards of care for this condition.

Trial registration

ISRCTN:10110685. Registered on 16 November 2016. ClinicalTrials.gov:NCT02980367. Registered in December 2016.
Xiaochaihu decorction relieves liver fibrosis caused by Schistosoma japonicum infection via the HSP47/TGF-β pathway
Authors: Huang Yuzheng , Lu Jin , Xu Yongliang , Xiong Chunrong , Tong Deshen , Hu Nannan , Yang Haitao
Published: May 2020

Background

Hepatic fibrosis caused by chronic infection with Schistosoma japonica remains a serious public health problem in the world. Symptoms include inflammation, liver granuloma and fibrosis, whilst treatment options are still limited. This study aims to investigate whether and how traditional Chinese medicine Xiaochaihu decoction (XCH) could mitigate liver fibrosis caused by S. japonicum infection.

Methods

BALB/c mice were infected with S. japonicum cercariae and treated with XCH for 16 weeks. Liver pathological changes were assessed by H&E and Masson staining. NIH3T3 and Raw264.7 cells were treated with S. japonicum egg antigens with or without XCH treatment. Quantitative real-time PCR, western blot, immunfluorescence and ELISA were performed to determine the changes of levels of fibrogenic markers.

Results

XCH protected mouse liver from injuries and fibrosis caused by S. japonicum infection and considerably reduced egg burden in a dose-dependent manner. Infection with S. japonicum caused elevation of serum ALT, AST, ALP, HA and PIIINP levels and reduction of ALB and GLOB levels, which was markedly suppressed by XCH. The upregulation of TGF-β1, Hsp47, α-SMA, Col1A1 and Col3A1 in S. japonicum-infected mouse liver was also significantly inhibited by XCH. Schistosoma japonicum egg antigens promoted the expression of Hsp47, TGF-β1, Timp-1, α-SMA, Col1A1 and Col3A1 in NIH3T3 cells, and TGF-β1, CTGF, IL-13, IL-17 and IL-6 in Raw264.7 cells, which was inhibited by XCH, LY2157299 and shRNA-Hsp47.

Conclusions

These results demonstrated that the hepatic protective effects of Xiaochaihu decoction were mediated by HSP47/TGF-β axis.
Slight temperature changes cause rapid transcriptomic responses in Trypanosoma cruzi metacyclic trypomastigotes
Authors: Cruz-Saavedra Lissa , Muñoz Marina , Patiño Luz Helena , Vallejo Gustavo A. , Guhl Felipe , Ramírez Juan David
Published: May 2020

Background

Severe changes in temperature can affect the behavior and ecology of some infectious agents. Trypanosoma cruzi is a protozoan that causes Chagas disease. This parasite has high genetic variability and can be divided into six discrete typing units (DTUs). Trypanosoma cruzi also has a complex life-cycle, which includes the process of metacyclogenesis when non-infective epimastigote forms are differentiated into infective metacyclic trypomastigotes (MT). Studies in triatomines have shown that changes in temperature also affect the number and viability of MT.

Methods

The objective of this study was to evaluate how temperature affects the transcriptional profiles of T. cruzi I and II (TcI and TcII) MT by exposing parasites to two temperatures (27 °C and 28 °C) and comparing those to normal culture conditions at 26 °C. Subsequently, RNA-seq was conducted and differentially expressed genes were quantified and associated to metabolic pathways.

Results

A statistically significant difference was observed in the number of MT between the temperatures evaluated and the control, TcII DTU was not strongly affected to exposure to high temperatures compared to TcI. Similar results were found when we analyzed gene expression in this DTU, with the greatest number of differentially expressed genes being observed at 28 °C, which could indicate a dysregulation of different signaling pathways under this temperature. Chromosome analysis indicated that chromosome 1 harbored the highest number of changes for both DTUs for all thermal treatments. Finally, gene ontology (GO) analyses showed a decrease in the coding RNAs involved in the regulation of processes related to the metabolism of lipids and carbohydrates, the evasion of oxidative stress, and proteolysis and phosphorylation processes, and a decrease in RNAs coding to ribosomal proteins in TcI and TcII, along with an increase in the expression of surface metalloprotease GP63 in TcII.

Conclusions

Slight temperature shifts lead to increased cell death of metacyclic trypomastigotes because of the deregulation of gene expression of different processes essential for the TcI and TcII DTUs of T. cruzi.
Toxoplasma gondii and Neospora caninum infections in South American camelids in Switzerland and assessment of serological tests for diagnosis
Authors: Basso Walter , Sollberger Elena , Schares Gereon , Küker Susanne , Ardüser Flurin , Moore-Jones Gaia , Zanolari Patrik
Published: May 2020

Background

Little is known about the epidemiology of Toxoplasma gondii and Neospora caninum infections in alpacas (Vicugna pacos) and llamas (Lama glama) outside South America. The study aimed to estimate the seroprevalence of T. gondii and N. caninum infections in South American camelids (SAC) in Switzerland, to optimize serological tests for SAC and to identify risk factors, which may favour infection.

Methods

A total of 571 sera from 132 Swiss farms (374 alpacas and 197 llamas, mean 4.3 animals/farm) were obtained. Four commercial enzyme-linked immunosorbent assays (ELISA) for detecting antibodies against T. gondii (ID Screen® Toxoplasmosis Indirect (TOXO-MS)) or N. caninum (i.e. ID Screen® Neospora caninum Indirect Multi-species (NCS-MS); ID Screen® Neospora caninum Competition (NCC) and ID Screen® Neospora caninum Indirect (NCS)) were first assessed for their use on SAC comparing their results with those in immunoblot, and optimizing cut-offs. Subsequently, two kits (TOXO-MS and NCS-MS) were selected for seroprevalence estimation. Additionally, a risk factor analysis for infection was performed on 41 farms, which agreed to participate in a web-based survey.

Results

Three kits (TOXO-MS, NCS-MS and NCC) showed almost perfect agreement (kappa > 0.901) with immunoblot results when the cut-offs were optimized, and one kit (NCS) proved not to be useful for detecting N. caninum seropositive SAC. By TOXO-MS ELISA, 82.3% (308/374) of the alpacas and 84.8% (167/197) of the llamas were seropositive for T. gondii, and 131/132 (99.2%) farms had seropositive animals. By NCS-MS ELISA, 3.5% (13/374) of the alpacas and 2.5% (5/197) of the llamas evidenced antibodies against N. caninum, and 9.1% (12/132) of the farms had seropositive animals. The variables “age” and “female sex” were identified as risk factors for T. gondii infection and “absence of cats in the farm during the last two years” as a protective factor. No risk or protective factors for N. caninum infection could be identified.

Conclusions

This nationwide cross-sectional study demonstrated for the first time the presence of antibodies against T. gondii and N. caninum in the Swiss SAC population, highlighting a high seroprevalence for T. gondii, the presence of cats as a risk factor and suggesting that SAC meat might represent an additional infection source for humans.