bluuebunny/crossref_metadata_2025 huggingface dataset:
28 Assessment of Pain and Provision of Non-Pharmacologic Analgesia to Children by Prehospital Providers in Southwestern Ontario: A Cross-Sectional Study
Authors: Burke Karina , Vujcic Branka , Hamilton Jonathan , Mace Charlotte , Teefy John , Poonai Naveen
Published: October 2021

Primary Subject area

Emergency Medicine - Paediatric

Background

There is abundant evidence that provision of pharmacologic analgesia by prehospital providers to children is suboptimal. Most paediatric calls are performed by primary care paramedics (PCPs) who are unable to administer pharmacologic analgesia to children but can administer non-pharmacologic therapies.

Objectives

Our objective was to describe the provision of non-pharmacologic analgesia to children by prehospital providers.

Design/Methods

We reviewed all ambulance call reports (ACRs) of children 0-17 years with acutely painful conditions (headache, abdominal pain, injury, head/ears/eyes/nose/throat pain, and back pain) who were transported to a paediatric tertiary referral centre serving a catchment of > 1 million from 2017-2019. Data collection was recorded by two blinded assessors using a study-specific Excel™ sheet. The primary outcome was the proportion of children offered non-pharmacologic analgesia. We performed a stepwise logistic regression on the primary outcome using covariates defined a priori: age, sex, visible deformity, type of crew, complaint, pain score, call time, and prior analgesia.

Results

All 11,084 ACRs from January 1, 2017 to December 31, 2019 were reviewed. The sample included 5887/11084 (53.1%) males, ranging from 1 month to 17 years, with a mean (SD) age of 10.5 (5.6) years. Calls involved mainly PCPs [8576/11084 (77.4%)]. Non-trauma-related musculoskeletal injuries were most common, comprising 2743/11,084 (24.7%) of calls. Pain scores were documented in 6947/11084 (62.7%) of calls. The verbal numeric rating scale (0-10) was used in 5022/6947 (72.3%) of calls, with a mean (SD) score of 5.2 (3.2). Non-pharmacologic analgesia was provided in 2926/11084 (26.4%) of calls, most commonly splint (1115/2926, 38.1%) and ice (931/2926, 31.8%). Pharmacologic analgesia was provided in 458/11084 (4.1%) of calls. In the multivariate model, mild (OR: 3.2; 95% CI 2.3-4.4; p < 0 .001) and moderate pain (OR: 1.7; 95% CI 1.3-2.2) (versus no pain) were significant predictors of non-pharmacologic analgesia, whereas visible deformity (OR: 0.5; 95% CI 0.3-0.6; p < 0 .001) was a significant negative predictor.

Conclusion

The provision of non-pharmacologic analgesia to children in Southwestern Ontario by prehospital providers is suboptimal, despite moderate to severe pain. There is a clear need for education surrounding approaches to non-pharmacologic analgesia in children among prehospital providers.
38 Clinical features and echocardiographic parameters of relative adrenal insufficiency (RAI) among preterm infants: A five-year review
Authors: Grewal Gurpreet , Ting Joseph , Lam Carol , Yadav Krishan , Kuan Mimi
Published: October 2021

Primary Subject area

Neonatal-Perinatal Medicine

Background

Infants born at low gestational age (GA) often present with a septic shock-like picture in the neonatal intensive care unit (NICU). Some of these premature infants are noticed to exhibit inadequate cortisol levels at such a time of stress, an entity termed ‘relative adrenal insufficiency’ (RAI), which is postulated to compromise the compensatory mechanisms and further circulatory collapse.

Objectives

To review the clinical features and echocardiographic parameters of RAI in preterm infants, and their correlation with adrenocorticotropic hormone (ACTH) stimulation tests in a quaternary NICU over 5 years.

Design/Methods

This is a single centre retrospective study. Infants born at < 32 weeks GA between January 2015 to June 2019, admitted to the British Columbia Women’s Hospital NICU (Vancouver, British Columbia), were reviewed. Infants who presented with a shock-like picture with a cortisol level at this time of stress of < 250 nmol/L were included. Infants who have received corticosteroid prior to cortisol collection were excluded.

Results

There were 798 infants < 32 weeks admitted to the BCWH NICU over a 5 year period, of which 284 had a spot cortisol drawn. We identified 45 eligible infants in our study (5.6% of NICU admissions). Their median (IQR) for GA, birth weight, cortisol level, and age of onset of RAI were 25 weeks (24, 26), 690 g (590, 815), 83 (58, 127), and 13 days of life (8, 24), respectively. Among these infants, 73% developed significant hypotension or respiratory failure (Table 1). 13 infants (28.9%) had echocardiogram performed at the time of cardiopulmonary deterioration, and all had normal left ventricular (LV) fractioning shortening (median [IQR]: 42% [38-49%]) and LV output (median [IQR]: 242 mL/kg/min [155-330 mL/kg/min]). Only 19 infants (42.2%) received hydrocortisone, with a median [range] treatment duration of 2 days [1–8]. Lower cortisol level was associated with lower GA at the presentation of RAI (p=0.049), but not predictive of adverse clinical and laboratory outcomes (Table 2). ACTH stimulation tests were performed in 20 (44.5%) infants and 3 (15%) were found to be abnormal, and results were not correlated with clinical features.

Conclusion

In our cohort, we identified 5% of NICU admission with RAI, based on the cut-off of cortisol < 250 nmol/L at the time of shock-like presentation. Lower cortisol level was associated with lower GA at the presentation of RAI. Further prospective study with a well-defined protocol is needed to understand the use of cortisol and its clinical implications.
46 Impact of early versus late medical treatment of a hemodynamically significant patent ductus arteriosus on time to reach full feeds in preterm neonates
Authors: Yadav Krishan , Ting Joseph , Castaldo Michael , Grewal Gurpreet , Kuan Mimi
Published: October 2021

Primary Subject area

Neonatal-Perinatal Medicine

Background

Prolonged exposure to a hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants has been associated with an increase in neonatal morbidities.

Objectives

To examine the effect of timing of medical treatment (within first 7 days of life versus after 7 days of life) for a hsPDA on the duration to achieve full feeds in infants born at <30 weeks of gestation.

Design/Methods

This was a retrospective cohort study in a quaternary neonatal intensive care unit (NICU) with a targeted neonatal echocardiography service. Infants admitted between July 2015 – June 2019 who received medical treatment for an hsPDA were included and grouped based on those who received first medical therapy within 7 days of life (early treatment) and after 7 days of life (late treatment). An hsPDA was defined using both clinical (worsening ventilation, pulmonary hemorrhage/edema, or hypotension requiring inotrope or hydrocortisone) and echocardiographic findings (LA/Ao ratio >1.4; LVO >350 mL/kg/min, PDA >1.4 mm, IVRT < 35 ms). Duration to reach full feeds was calculated based on number of days to reach a total enteral feed ≥ 120 mL/kg/day with no parenteral source of nutrition.

Results

Forty-six infants met the inclusion criteria. Of the 46 infants, 24 were identified as receiving early treatment and 22 received late treatment. Infants in the early treatment group had lower median birth weight than the late treatment group (802 g vs. 1016 g, p=0.022). All other clinical characteristics were not significantly different. No significant difference was found in the use of indomethacin, ibuprofen, or acetaminophen as the initial medical treatment (Table 1). The late treatment group had elevated left ventricular output (median: 286 vs. 369 mL/kg/min, p=0.013) and tricuspid annular plane systolic excursion (median: 6 vs. 8 mm, p=0.002) (Table 2). Infants in the early treatment group reached full feeds earlier than those in the late treatment group (19 vs. 30 days, p=0.042) (Table 1).

Conclusion

Early medical treatment of hsPDA was associated with shorter duration to reach full feeds in our cohort of preterm infants. Further larger scale study is needed to understand the association between the timing of medical therapy and prolonged exposure of splanchnic circulation to hemodynamically significant ductus.
50 Poractant alfa versus bovine lipid extract surfactant for respiratory distress syndrome in preterm infants: A prospective comparative effectiveness cohort study
Authors: Lemyre Brigitte , Lacaze-Masmonteil Thierry , Shah Prakesh , Bodani Jaya , Doucette Stefanie , Dunn Michael , Louis Deepak , Monterrosa Luis , Mukerji Amit , Schmolzer Georg , Singh Balpreet , Wong Jonathan , Ye Xiang Y , Offringa Martin
Published: October 2021

Primary Subject area

Neonatal-Perinatal Medicine

Background

There is a paucity of comparative effectiveness data for bovine lipid extract surfactant (BLES) and poractant alfa (Curosurf).

Objectives

To compare duration of respiratory support and short-term outcomes in very preterm infants treated with bovine lipid extract surfactant and poractant alfa.

Design/Methods

We performed a prospective, multicentre, comparative effectiveness study. Thirteen Canadian level III neonatal intensive care units (NICUs) provided bovine lipid extract surfactant to infants born <32 weeks’ gestational age (GA) for a set period of time in the year 2019 (3 to 9 months), then changed to poractant alfa for the remainder of the year. The primary outcome was total duration of respiratory support (invasive and non-invasive). We utilized the Canadian Neonatal Network database for all study data.

Results

A total of 968 eligible infants (530 infants < 28 weeks’ GA and 438 infants 280-316weeks’ GA) were included, of which 494 received bovine lipid extract surfactant and 474 received poractant alfa. In unadjusted analysis, no difference was observed in total duration of any respiratory support (median 38 vs. 40.5 days). After adjusting for baseline characteristics and accounting for cluster effects, infants treated with poractant alfa spent a median of 4.16 fewer days on respiratory support (95% CI 0.05, 8.28 days). This reduction was observed in the subgroup of infants 280-316 weeks’ GA, but not in those < 28 weeks’ GA, and was explained by their shorter time on non-invasive respiratory support. No differences were observed in the need to re-dose surfactant, hospital mortality, bronchopulmonary dysplasia, or length of stay in NICU.

Conclusion

Administration of poractant alfa was associated with shorter median duration of respiratory support compared to bovine lipid extract surfactant in preterm neonates < 32 weeks’ GA.
53 Health Outcomes of Siblings of Children with Chronic Health Conditions: A Systematic Review and Meta-Analysis
Authors: Martinez Benjamin , Pechlivanoglou Petros , Meng Dorisa , Traubici Benjamin , Mahood Quenby , Korczak Daphne , Colasanto Marlena , Mahant Sanjay , Orkin Julia , Cohen Eyal
Published: October 2021

Primary Subject area

Mental Health

Background

Chronic childhood health conditions are known to have an impact on the well-being of family members. Parental caregivers face well-defined adverse health outcomes, though less is known about the health impacts on siblings.

Objectives

To assess clinical health outcomes in siblings of children with chronic health condition(s) compared to siblings of healthy children or normative data.

Design/Methods

We searched Ovid MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, PsycInfo, and CINAHL through June 4, 2020. We included English-language studies that: (1) reported clinically diagnosable mental or physical health outcomes of siblings of children (0-18 years old) diagnosed with any childhood chronic health condition; (2) included a comparison group; and (3) used an experimental or observational study design. Risk of bias was assessed using the Newcastle-Ottawa Scale.

Results

We included 28 studies of the 9053 screened, comprising 10 cohort studies and 18 cross-sectional studies. Studies from 11 different countries reported most commonly on siblings of children with disabilities (12 studies), cancer (8 studies), or psychiatric disorders (4 studies). Siblings of children with chronic conditions had greater depression rating scale scores than their comparison groups (standardized mean difference 0.49; 95% CI 0.33-0.65; P < .001 [5 studies]) (Fig. 1), whereas anxiety scores did not differ significantly (standardized mean difference 0.24; 95% CI -0.03-0.52; P = .08 [6 studies]) (Fig. 2). Studies that reported on prevalence of psychiatric diagnoses, rather than rating scale scores, had mixed results, either indicating increased risk (3 studies) or no increased risk (4 studies) among exposed siblings. We did not meta-analyze effects for mortality (3 studies) or physical health outcomes (dental caries [1 study], traumatic brain injury [1 study], sexually transmitted infection [1 study], overweightness/obesity [1 study]) given the limited number of studies and between-study heterogeneity. Included studies were rated as high quality (12 studies) or of moderate quality (16 studies).

Conclusion

Siblings of children with chronic health conditions may be at an increased risk of depression. Our findings suggest the need for targeted interventions to support the psychological well-being of siblings of children with chronic health conditions.
60 Impact of sequential implementation of a standardized feeding protocol and donor breastmilk on necrotizing enterocolitis among preterm infants born <31 weeks gestation
Authors: Ng Laura Li Ching , Beltempo Marc , Patel Sharina , Paquette Katryn , Filion-Ouellet Emilie , Plourde Hugues , Besner Marie-Eve
Published: October 2021

Primary Subject area

Neonatal-Perinatal Medicine

Background

Necrotizing enterocolitis (NEC) is the leading cause of gastrointestinal morbidity and mortality among preterm infants born <31 weeks. Nutritional interventions such as a standardized feeding protocol (SFP) and donor breastmilk (DBM) are recommended to reduce NEC.

Objectives

Our objective was to assess the impact of implementing a feeding protocol and pasteurized donor breastmilk protocol on NEC among preterm infants born < 31 weeks GA.

Design/Methods

Retrospective cohort study including 682 infants born < 31 weeks, who survived ≥ 14 days and were admitted to two tertiary NICUs from 2009-2018. Data was obtained from the local Canadian Neonatal Network database. Infants were classified into epochs, based on the timing of interventions: Epoch 1, baseline (2009-2012); Epoch 2, SFP (2013-2015); Epoch 3, SFP + DBM (2016-2018). The primary outcome was NEC stage ≥ 2. Multivariable logistic regression models were used to assess associations between epochs and outcomes and were adjusted for confounders.

Results

Among 682 infants, 46 (7%) had NEC and 74 (11%) had mortality/NEC. Rates of NEC decreased with each epoch: 10% (25/246) Epoch 1 (baseline); 5% (8/163) Epoch 2 (SFP); and 5% (13/273) Epoch 3 (SFP+DBM), (p<0.01) (Table1). SFP alone was associated with significantly lower odds of NEC compared to baseline (Epoch 2 vs 1, AOR 0.42, 95% CI 0.17-0.93) (Table 2). Implementation of DBM was not associated with lower odds of NEC compared to SFP alone (Epoch 3 vs 2, AOR 0.94, 95% CI 0.38-2.42) (Table2). Number of NPO days prior to the initiation of enteric feeds after birth decreased in Epoch 3 (Epoch 1&2: 2 days versus Epoch 3: 1 day; p<0.01). Exclusive human breastmilk feeds during the first 3 weeks increased from 62% in Epoch 2 to 82% in Epoch 3 (p<0.01). A significant decrease in number of total parenteral nutrition and central venous line (CVL) days was observed from Epoch 1 to 3 (25 to 15 days and 26 to 15 days respectively; p<0.01) (Table 1), this was reflected in the decrease in late onset sepsis (Epoch 3 vs 1, AOR 0.55, 95% CI 0.35-0.86).

Conclusion

Implementation of SFP was associated with a significant decrease in NEC among infants born < 31 weeks. Combining the SFP and DBM did not further decrease NEC, but was associated with shorter NPO days, higher exclusive human breastmilk exposure, and significant decrease in number of central venous line (CVL) days.
91 Health care needs and missed care among youth in care in British Columbia: A population study
Authors: Wang James , Marshall Sheila K , Poon Colleen S
Published: October 2021

Primary Subject area

Adolescent Medicine

Background

Youth in care (YIC), including those living in foster care, kinship care, group homes, and youth agreements, are a vulnerable population with many risk factors leading to a high prevalence of mental and physical health needs. YIC are recommended to have more frequent health care encounters than the general adolescent population, though it is unknown how Canadian YIC perceive whether their health care needs are sufficiently met.

Objectives

To assess YIC's perception of their health care needs and frequency of missed care, defined as not having received needed health care.

Design/Methods

A representative sample of 38,015 students in Grades 7 to 12 across British Columbia was surveyed in the 2018 BC Adolescent Health Survey (McCreary Centre Society). Questionnaire items on demographics, mental and physical health, and health care access in the past year were examined. Frequencies and cross-tabulations were performed using IBM SPSS® Complex Samples module software.

Results

In the past year, 1.9% of respondents reported living in government care. YIC had a mean age of 14.76 years and were 50.9% female. YIC reported worse mental health (46.5% vs. 27.6% poor/fair rating, p < 0.01) and physical health (36.4% vs. 19.1% poor/fair rating, p < 0.01) compared to non-YIC, with female and non-binary YIC most severely impacted. YIC were less likely to report not needing health care (15.6% vs. 21.3%, p < 0.01) and more likely to report missed care (11.2% vs. 3.1%, p < 0.01) compared to non-YIC. Although the rate of any health care usage was not significantly different between the groups, nearly one-quarter (23.7%) of YIC accessed health care at 3 or more locations, compared to only 16.4% of non-YIC (p < 0.01), with YIC accessing counsellors/psychologists and youth clinics more frequently. YIC reported more missed mental health care (32.9% vs. 18.4%, p < 0.01) and physical health care (21.6% vs. 7.8%, p < 0.01) than non-YIC, with female YIC reporting more missed care than male YIC. Non-binary YIC also reported more missed mental health care than male YIC. YIC were more likely than non-YIC to have missed mental health care due to reasons such as prior negative experiences and lack of transportation.

Conclusion

YIC reported worse mental and physical health and greater frequencies of missed care compared to non-YIC, especially female and non-binary YIC. Further attention is needed in addressing systemic and individual barriers to health care in this vulnerable population.
116 Canadian Community Paediatricians' Perspectives of Sport Medicine in Residency and in Practice
Authors: Purcell Laura , Campos Sarah , Dickinson Mike , Thompson Graham
Published: October 2021

Primary Subject area

Community Paediatrics

Background

Participation by children and adolescents in organized sports and recreational sporting activities is increasingly popular in Canada. Although the health and psychosocial benefits of sports for children are significant, participation in sports confers an increased risk of injury, resulting in a considerable burden of visits to emergency departments and primary care offices. Despite the frequency of sport-related injuries, there are documented gaps in sport and exercise medicine (SEM) education in paediatric training, leading to many practicing paediatricians feeling uncomfortable in managing these issues.

Objectives

We sought to describe Canadian community paediatricians’ perspectives about SEM in training and practice. This descriptive, cross-sectional cohort study of practicing Canadian community paediatricians was designed to assess: i) self-reported practice profiles with respect to sport issues; ii) perceptions of SEM training during paediatric residency; and iii) comfort level with management of sport injuries.

Design/Methods

To address these questions, a cross-sectional electronic survey of Canadian community paediatricians was conducted between February and March 2020. A survey was emailed to full members of the community paediatrics section of the Canadian Paediatric Society (CPS) (n=370) by CPS administrative staff. Participants were asked about musculoskeletal (MSK)/sport issues seen, how they manage these cases, their comfort level with diagnosis and management of sport injuries (on a 5-point Likert scale), and their perceptions of MSK/SEM training during paediatric residency.

Results

The response rate was 23.0% (85/370). A quarter of respondents (20/85; 23.4%) reported seeing MSK/sport issues very often; a third (27/85; 31.7%) were comfortable managing these patients on their own. Almost all respondents did not feel that they had received adequate SEM training during paediatric residency (81/85; 95.3%). Respondents were most comfortable managing concussion, rating their comfort 4.17/5 on a 5-point scale (95% CI=3.96-4.38), and Osgood-Schlatter’s disease 3.86/5 (95% CI=3.60-4.11). Participants were uncomfortable managing acromioclavicular joint separations 1.81/5 (95% CI=1.58-20.6) and elbow pain 2.65/5 (95% CI=2.40-2.90). Regression analysis indicated that only the frequency of MSK/sport-related visits was associated with provider comfort level (p < 0 .001).

Conclusion

Most Canadian community paediatricians do not manage many patients with sport-related issues and are not comfortable managing these patients on their own. They feel that SEM training during their paediatric residency inadequately prepared them for practice. Incorporating more SEM training into paediatric residency programs may increase comfort level with MSK/sport issues and change referral patterns and practice patterns amongst community paediatricians.
128 Evaluation of a Secure Messaging System for Children with Medical Complexity
Authors: Parpia Camilla , Miranda Susan , Beatty Madison , Moore Clara , Adams Sherri , Stinson Jennifer , Desai Arti , Bartlett Leah , Culbert Erin , Orkin Julia , Cohen Eyal
Published: October 2021

Primary Subject area

Complex Care

Background

The Connecting2gether (C2) platform is a secure online information-sharing tool that aims to improve care for Children with Medical Complexity (CMC) and their families. A key feature of C2 is secure messaging that enables parents to communicate with their child’s healthcare providers (HCPs) in an easy and timely manner.

Objectives

The objectives of this project are to (1) describe the usage of the secure messaging system; and (2) conduct a thematic comparative evaluation of the secure messaging tool, and email and phone calls.

Design/Methods

This study is a sub-component of a larger project investigating the overall feasibility and acceptability of the C2 platform. Parents of CMC were recruited from a tertiary level Complex Care program to use the C2 platform for a period of 6 months. Messaging data was extracted from C2 usage reports, and phone and email documentation was extracted from the patient’s electronic medical record. Codes were developed iteratively through comprehensive review of the C2 messages. Message, phone, and email data were then coded by two investigators using thematic analysis. Quantitative data from C2 usage reports were analyzed using descriptive statistics.

Results

Thirty-four parents and 90 care team members, including HCPs, family, and patient information coordinators were registered on the platform. 4027 messages were exchanged on C2. On average, parents sent 33.4 messages and received 66.4 messages on C2. Of all messages on C2, 32.6% were related to comments, questions, and concerns about the platform itself and its features. Figure 1 demonstrates the thematic content of messages related to care, and highlights the differences in messaging content between the 3 forms of communication. Email and phone content focused primarily on clinical care whereas C2 messaging content also emphasized other aspects of care including education, provision of resources, and personal support.

Conclusion

This study demonstrates the role that a secure messaging system can have for parents of CMC in being active members of their child’s care. Phone and email were mostly used to discuss medications or clinical issues, whereas C2 enabled the discussion of the patient as a whole. The use of secure messaging can therefore complement other forms of communication between providers and families, instead of replacing them. Further research is needed to understand clinical outcomes associated with the use of secure messaging in order to understand its role in improving patient care and overall caregiver and provider experience.
Patient-Reported Experience Measures in outpatient rheumatology care: a systematic review
Authors: Bryant Madeleine J , Schubert Jonathon P , Black Rachel J , Hill Catherine L
Published: October 2021

Objectives

There is a growing acceptance of the need for routine implementation of patient-reported experience measures (PREMs) in health care. Rheumatology patients, as frequent and long-term users of care, stand to benefit from collection of experience-related data. The aim of this study was to perform a systematic review to identify and critically appraise the development and psychometric validation of PREMs in rheumatology.

Methods

Six databases were searched systematically from inception to 14 December 2020: MEDLINE, EMBASE, PsycINFO, SCOPUS, Cochrane and Google Scholar. We included articles in English that described the use or development of PREMs, with results of psychometric testing, in an adult outpatient rheumatology context. This study is registered with PROSPERO (CRD42021233819). Articles were appraised using the COnsensus Based Standards for the selection of health status Measurement Instruments (COSMIN) (i) Risk of Bias checklist and (ii) criteria for good measurement properties.

Results

The search yielded 3809 publications, and six studies met inclusion criteria. All the included studies on PREM development fulfilled COSMIN standards for ‘doubtful’ or ‘inadequate’ quality of instrument development. One study fulfilled a ‘sufficient’ rating for content validity, and the remainder fulfilled ‘inconsistent’ ratings. During validity testing, studies fulfilled between one and four of the eight COSMIN checklist criteria for good measurement properties.

Conclusion

Methodological concerns regarding instrument development and validation limit the generalizability of the existing six validated PREMs in use in rheumatology contexts. There is a need for further well-designed studies to validate existing and new PREMs in this area.
High-throughput visual assessment of sleep stages in mice using machine learning
Authors: Geuther Brian , Chen Mandy , Galante Raymond J , Han Owen , Lian Jie , George Joshy , Pack Allan I , Kumar Vivek
Published: October 2021

Study Objectives

Sleep is an important biological process that is perturbed in numerous diseases, and assessment of its substages currently requires implantation of electrodes to carry out electroencephalogram/electromyogram (EEG/EMG) analysis. Although accurate, this method comes at a high cost of invasive surgery and experts trained to score EEG/EMG data. Here, we leverage modern computer vision methods to directly classify sleep substages from video data. This bypasses the need for surgery and expert scoring, provides a path to high-throughput studies of sleep in mice.

Methods

We collected synchronized high-resolution video and EEG/EMG data in 16 male C57BL/6J mice. We extracted features from the video that are time and frequency-based and used the human expert-scored EEG/EMG data to train a visual classifier. We investigated several classifiers and data augmentation methods.

Results

Our visual sleep classifier proved to be highly accurate in classifying wake, non-rapid eye movement sleep (NREM), and rapid eye movement sleep (REM) states, and achieves an overall accuracy of 0.92 ± 0.05 (mean ± SD). We discover and genetically validate video features that correlate with breathing rates, and show low and high variability in NREM and REM sleep, respectively. Finally, we apply our methods to noninvasively detect that sleep stage disturbances induced by amphetamine administration.

Conclusions

We conclude that machine learning-based visual classification of sleep is a viable alternative to EEG/EMG based scoring. Our results will enable noninvasive high-throughput sleep studies and will greatly reduce the barrier to screening mutant mice for abnormalities in sleep.
Use of low dosage amino acid blends to prevent stress-related piglet diarrhea
Authors: Wessels Anna G , Chalvon-Demersey Tristan , Zentek Jürgen
Published: October 2021

Weaning is a challenging period for piglets associated with reduced feed intake, impairment of gut integrity, and diarrhea. Previous studies demonstrate that supplementation with single functional amino acids (AA) promote piglets’ performance due to the improvement of intestinal health. Thus, we hypothesized that a combination of functional AA provided beyond the postulated requirement for growth could facilitate the weaning transition. Ninety piglets, initially stressed after weaning by 100 min overland transport, received a control diet or the same diet supplemented with a low-dosed (0.3%) mixture of AA (AAB-1: L-arginine, L-leucine, L-valine, L-isoleucine, L-cystine; AAB-2: L-arginine, L-leucine, L-valine, L-isoleucine, L-cystine, and L-tryptophan) for 28 days. Fecal consistency was ranked daily, growth performance was assessed weekly. On days 1 and 14 of the trial, blood samples were collected from a subset of 10 piglets per group to assess concentrations of insulin-like growth factor 1. After 28 days of feeding, tissues were obtained from the same piglets to analyze gut morphology and relative mRNA expression of genes related to gut function. Even if the stress response as indicated by rectal temperature was not different between the groups, pigs supplemented with AAB-2 showed firmer feces after weaning and less days with diarrhea compared to control. Furthermore, the jejunal expression of the MUC-2 gene was reduced (P < 0.05) in group AAB-2. Both AA mixtures increased crypt depth in the duodenum. Collectively, the given results indicate that 0.3% extra AA supplementation might alleviate postweaning diarrhea but did not alter growth performance of weanling piglets.
COVID-19 vaccine brand hesitancy and other challenges to vaccination in the Philippines
Authors: Amit Arianna Maever L. , Pepito Veincent Christian F. , Sumpaico-Tanchanco Lourdes , Dayrit Manuel M.
Published: October 2021

Background

COVID-19 vaccines have been developed at a rapid and unprecedented pace to control the spread of the virus, and prevent hospitalisations and deaths. However, there are a series of events and factors that create barriers to vaccination. In this paper, we explore vaccination narratives and challenges experienced and observed by Filipinos during the early vaccination period in the Philippines.

Material and methods

We conducted 35 interviews from a subsample of 1,599 survey respondents ages 18 and older in the Philippines. The interviews were conducted in Filipino, Cebuano, and/or English via online platforms such as Zoom or via phone call. All interviews were recorded, transcribed verbatim, translated, and analysed using inductive content analysis. To highlight the complex reasons for delaying and/or refusing COVID-19 vaccines, we embedded our findings within the social ecological model.

Results

Our analysis showed that individual perceptions play a major role on the decision to vaccinate. Such perceptions are shaped by exposure to (mis)information amplified by the media, the community, and the health system. Social networks may either positively or negatively impact vaccination uptake, depending on their views on vaccines. Political issues contribute to vaccine brand hesitancy, resulting to vaccination delays and refusals. Perceived inefficiencies and inflexibility of the system also create additional barriers to the vaccine rollout in the country, especially among vulnerable and marginalised groups.

Conclusions

Challenges to COVID-19 vaccination may be individual, interpersonal, and structural, which work individually and collectively. Among these barriers, our results suggest that many concerns regarding vaccination operate at the individual level. Vaccine brand hesitancy and misinformation are growing public health challenges in the country that need to be addressed. Recognising and addressing concerns at all levels are critical to solutions aimed at improving COVID-19 vaccination uptake and reach.
Accuracy of computer-aided chest X-ray screening in the Kenya National Tuberculosis Prevalence Survey
Authors: Mungai Brenda , Ong‘angò Jane , Ku Chu Chang , Henrion Marc YR , Morton Ben , Joekes Elizabeth , Onyango Elizabeth , Kiplimo Richard , Kirathe Dickson , Masini Enos , Sitienei Joseph , Manduku Veronica , Mugi Beatrice ,   The IMPALA Consortium, Squire Stephen Bertel , MacPherson Peter
Published: October 2021

Background

Community-based screening for tuberculosis (TB) could improve detection but is resource intensive. We set out to evaluate the accuracy of computer-aided TB screening using digital chest X-ray (CXR) to determine if this approach met target product profiles (TPP) for community-based screening.

Methods

CXR images from participants in the 2016 Kenya National TB Prevalence Survey were evaluated using CAD4TBv6 (Delft Imaging), giving a probabilistic score for pulmonary TB ranging from 0 (low probability) to 99 (high probability). We constructed a Bayesian latent class model to estimate the accuracy of CAD4TBv6 screening compared to bacteriologically-confirmed TB across CAD4TBv6 threshold cut-offs, incorporating data on Clinical Officer CXR interpretation, participant demographics (age, sex, TB symptoms, previous TB history), and sputum results. We compared model-estimated sensitivity and specificity of CAD4TBv6 to optimum and minimum TPPs.

Results

Of 63,050 prevalence survey participants, 61,848 (98%) had analysable CXR images, and 8,966 (14.5%) underwent sputum bacteriological testing; 298 had bacteriologically-confirmed pulmonary TB. Median CAD4TBv6 scores for participants with bacteriologically-confirmed TB were significantly higher (72, IQR: 58-82.75) compared to participants with bacteriologically-negative sputum results (49, IQR: 44-57, p<0.0001). CAD4TBv6 met the optimum TPP; with the threshold set to achieve a mean sensitivity of 95% (optimum TPP), specificity was 83.3%, (95% credible interval [CrI]: 83.0%—83.7%, CAD4TBv6 threshold: 55). There was considerable variation in accuracy by participant characteristics, with older individuals and those with previous TB having lowest specificity.

Conclusions

CAD4TBv6 met the optimal TPP for TB community screening. To optimise screening accuracy and efficiency of confirmatory sputum testing, we recommend that an adaptive approach to threshold setting is adopted based on participant characteristics.

Take home message

CAD4TBv6 met the optimal WHO target product profile for a community TB screening tool. Specificity was lower in adults with previous TB and those aged 41 years or older; an adaptive approach to setting CAD thresholds will likely be required to optimize use.
mTOR inhibition via Rapamycin treatment partially reverts the deficit in energy metabolism caused by FH loss in RPE cells
Authors: Merle David A. , Provenzano Francesca , Jarboui Mohamed Ali , Kilger Ellen , Clark Simon J. , Deleidi Michela , Armento Angela , Ueffing Marius
Published: October 2021

Age-related macular degeneration (AMD) is a complex degenerative disease of the retina with multiple risk-modifying factors, including ageing, genetics and lifestyle choices. The combination of these factors leads to oxidative stress, inflammation and metabolic failure in the retinal pigment epithelium (RPE) with subsequent degeneration of photoreceptors in the retina. The alternative complement pathway is tightly linked to AMD. In particular, the genetic variant in the complement factor H gene (CFH), that leads to the Y402H polymorphism in the factor H protein (FH), confers the second highest risk for the development and progression of AMD. While the association between the FH Y402H variant and increased complement system activation is known, recent studies have uncovered novel FH functions not tied to this activity and highlighted functional relevance for intracellular FH. In our previous studies, we show that loss of CFH expression in RPE cells causes profound disturbances in cellular metabolism, increases the vulnerability towards oxidative stress and modulates the activation of pro-inflammatory signaling pathways, most importantly the NF-kB pathway. Here, we silenced CFH in hTERT-RPE1 cells to investigate the mechanism by which intracellular FH regulates RPE cell homeostasis. We found that silencing of CFH results in hyperactivation of mTOR signaling along with decreased mitochondrial respiration and that mTOR inhibition via rapamycin can partially rescue these metabolic defects. To obtain mechanistic insight into the function of intracellular FH in hTERT-RPE1 cells, we analyzed the interactome of FH via immunoprecipitation followed by Mass spectrometry-based analysis. We found that FH interacts with essential components of the ubiquitin-proteasomal pathway (UPS) as well as with factors associated with RB1/E2F signalling in a complement-pathway independent manner. Moreover, we found, that FH silencing affects mRNA levels of the E3 Ubiquitin-Protein Ligase Parkin and PTEN induced putative kinase (Pink1), both of them are associated with UPS. As inhibition of mTORC1 has been previoulsy shown to result in increased overall protein degradation via UPS and as FH mRNA and protein levels were shown to be affected by inhibition of UPS, our data stress a potential regulatory link between endogenous FH activity and the UPS.
Transcription disrupts DNA-scaffolded bacteriophage repressor complexes
Authors: Lu Yue , Voros Zsuzsanna , Borjas Gustavo , Hendrickson Cristin , Shearwin Keith , Dunlap David , Finzi Laura
Published: October 2021

DNA can act as a scaffold for the cooperative binding of protein oligomers. For example, the phage 186 CI repressor forms a wheel of seven dimers wrapped in DNA carrying specific binding sites, while the phage λ CI repressor binds in units of dimers to two well-separated sets of operators, forming a DNA loop. Atomic force microscopy was used to measure transcription elongation by E. coli RNA polymerase through these protein complexes. 186 CI or λ CI bound along unlooped DNA negligibly interfered with transcription by RNAP. More complex topologies induced by scaffolded, cooperatively bound repressor oligomers did not form significantly better roadblocks to transcription. Thus, despite binding with rather high affinity, these repressors are not effective roadblocks to transcription.
Lipid phase separation in vesicles enhances TRAIL-mediated cytotoxicity
Authors: Vu Timothy , Peruzzi Justin A. , Sant’Anna Lucas E. , Kamat Neha P.
Published: October 2021

Ligand spatial presentation and density play important roles in many signaling pathways mediated by cell receptors and are critical parameters when designing protein-conjugated therapeutic nanoparticles. Currently, Janus particles are most often used to spatially control ligand conjugation, but the technological challenge of manufacturing Janus particles limits adoption for translational applications. Here, we demonstrate that lipid phase separation can be used to spatially control protein presentation onto lipid vesicles. We used this system to study the density dependence of TNF-related apoptosis inducing ligand (TRAIL), a model therapeutic protein that exhibits greater cytotoxicity to cancer cells when conjugated onto a vesicle surface than when administered as a soluble protein. Using assays for apoptosis and caspase activity, we show that phase separated TRAIL vesicles induced higher cytotoxicity to Jurkat cancer cells than uniformly-conjugated TRAIL vesicles, and enhanced cytotoxicity was dependent on the TRAIL domain density. We then assessed this relationship in other cancer cell lines and demonstrated that phase separated TRAIL vesicles only enhanced cytotoxicity through one TRAIL receptor, DR5, while another TRAIL receptor, DR4, was unaffected by the TRAIL density. These results indicate unique signaling requirements for each TRAIL receptor and how TRAIL therapy could be tailored depending on the relative levels of expression for cancer receptors of interest. Overall, this work demonstrates a readily adoptable method to control protein conjugation and density on bilayer vesicles that can be easily adopted to other therapeutic nanoparticle systems to improve receptor signaling of nanoparticles targeted to cancer and diseased cells.
CTCF blocks anti-sense transcription initiation at divergent gene promoters
Authors: Luan Jing , Syrett Camille M. , Vermunt Marit W. , Coté Allison , Tome Jacob M. , Zhang Haoyue , Huang Anran , Luppino Jennifer M. , Keller Cheryl A. , Giardine Belinda M. , Zhang Shiping , Dunagin Margaret C. , Zhang Zhe , Joyce Eric F. , Lis John T. , Raj Arjun , Hardison Ross C. , Blobel Gerd A.
Published: October 2021

Transcription at most promoters is divergent, initiating at closely spaced oppositely oriented core promoters to produce sense transcripts along with often unstable upstream antisense (uasTrx). How antisense transcription is regulated and to what extent it is coordinated with sense transcription is largely unknown. Here by combining acute degradation of the multi-functional transcription factor CTCF and nascent transcription measurements, we find that CTCF specifically suppresses antisense but not sense transcription at hundreds of divergent promoters, the great majority of which bear proximal CTCF binding sites. Genome editing, chromatin conformation studies, and high-resolution transcript mapping revealed that precisely positioned CTCF directly suppresses the initiation of uasTrx, in a manner independent of its chromatin architectural function. Primary transcript RNA FISH revealed co-bursting of sense and anti-sense transcripts is disfavored, suggesting CTCF-regulated competition for transcription initiation. In sum, CTCF shapes the transcriptional landscape in part by suppressing upstream antisense transcription.
Identification, Characterization and Synthesis of Natural Parasitic Cysteine Protease Inhibitors – More Potent Falcitidin Analogs
Authors: Brinkmann Stephan , Semmler Sandra , Kersten Christian , Patras Maria A. , Kurz Michael , Fuchs Natalie , Hammerschmidt Stefan J. , Legac Jennifer , Hammann Peter E. , Vilcinskas Andreas , Rosenthal Philip. J. , Schirmeister Tanja , Bauer Armin , Schäberle Till F.
Published: October 2021

Protease inhibitors represent a promising therapeutic option for the treatment of parasitic diseases such as malaria and human African trypanosomiasis. Falcitidin was the first member of a new class of inhibitors of falcipain-2, a cysteine protease of the malaria parasite Plasmodium falciparum. Using a metabolomics dataset of 25 Chitinophaga strains for molecular networking enabled identification of over 30 natural analogs of falcitidin. Based on MS/MS spectra, they vary in their amino acid chain length, sequence, acyl residue, and C-terminal functionalization; therefore, they were grouped into the four falcitidin peptide families A-D. The isolation, characterization and absolute structure elucidation of two falcitidin-related pentapeptide aldehyde analogs by extensive MS/MS spectrometry and NMR spectroscopy in combination with advanced Marfey’s analysis was in agreement with the in silico analysis of the corresponding biosynthetic gene cluster. Total synthesis of chosen pentapeptide analogs followed by in vitro testing against a panel of proteases revealed selective parasitic cysteine protease inhibition and additionally low-micromolar inhibition of α-chymotrypsin. The pentapeptides investigated here showed superior inhibitory activity compared to falcitidin.
Evaluation of small non-coding RNAs as a possible epigenetic mechanism mediating the transition from biotrophy to necrotrophy in the life cycle of Phytophthora infestans
Authors: González-Tobón Juliana , Rodríguez-Jaramillo Alejandra , Forero Laura Milena , González Laura Natalia , Danies Giovanna , Restrepo Silvia
Published: October 2021

Phytophthora infestans, causal agent of late blight disease of potatoes, causes billion-dollar losses worldwide each year. This plant pathogen is a hemibiotroph, first feeding on the host and later killing it. Even though the transcription dynamics of this transition are characterized, the role that small non-coding RNAs (sRNAs) might have is still unknown. Furthermore, a bioinformatic pipeline to search and analyze sRNAs in P. infestans, is needed. Using our proposed pipeline, 146 sRNAs were found to be significantly differentially expressed between the evaluated stages of the pathogen’s life cycle. One hundred of these sRNAs were successfully annotated and classified into nine functional categories. The expression of the genes associated to ten of these sRNAs was validated via qRT-PCR. Among these, the expression levels of genes encoding for effectors were inversely correlated to that of the sRNAs aligning to them, which is expected if sRNAs are indeed regulating their expression. This correlation was not clear for sRNAs in other functional categories and should not be confused with strict causality. This study works as a starting point for considering sRNAs as role players in the transition from biotrophy to necrotrophy in P. infestans when infecting Solanum tuberosum.
Biological Flora of the British Isles: Salvia pratensis
Authors: Moughan Joseph , McGinn Kevin J. , Jones Laura , Rich Tim C. G. , Waters Elliot , de Vere Natasha
Published: October 2021

This account presents information on all aspects of the biology of Salvia pratensis L. (Meadow Clary) that are relevant to understanding its ecological characteristics and behaviour. The main topics are presented within the standard framework of the Biological Flora of the British Isles: distribution, habitat, communities, responses to biotic factors, responses to environment, structure and physiology, phenology, floral and seed characters, herbivores and disease, history and conservation.

Salvia pratensis is an erect, rosette‐forming, perennial herb with a broad native distribution covering much of Europe—from the British Isles, Spain and Morocco in the west, across Europe into Asia, as far east as the Urals. In the British Isles, the species is nationally scarce, confined to a few south‐ to west‐facing sites with calcareous soils in Southern England and one site in Wales. It is predominately found in unimproved pasture, hay meadows and grassy verges, but can occur on the fringes of scrub or woodland. Although the species is abundant in central Europe, changes to land management since the mid‐20th century have resulted in fragmented and threatened populations in several European countries. It is cultivated as an ornamental, as is S. × sylvestris, the hybrid with S. nemorosa.

Populations are typically gynodioecious, having both female (male‐sterile) and hermaphrodite individuals at variable proportions. The species has a mixed mating system and is self‐compatible via insect pollination, but predominantly outcrosses. Honeybees and bumblebees are abundant pollinators, but a diverse range of bee species and other insect species visit S. pratensis flowers. Inbreeding depression has been documented, presenting a conservation concern for small, fragmented populations.

The species is the focus of conservation efforts and has been reintroduced to sites where it had become locally extinct in Britain. To sustain favourable habitat, site management should maintain low soil nutrient levels, and prevent scrub encroachment and the dominance of coarse grasses. The removal of sward by hay cutting or grazing after plants have flowered and set seed is advised, in addition to maintaining a degree of disturbance to provide bare patches of soil for seedling recruitment.