bluuebunny/crossref_metadata_2025 huggingface dataset:
UK poSt Arthroplasty Follow-up rEcommendations (UK SAFE): what does analysis of linked, routinely collected national datasets tell us about mid–late term revision risk after knee replacement?
Authors: Smith Lindsay K , Garriga Cesar , Kingsbury Sarah R , Pinedo-Villanueva Rafael , Delmestri Antonella , Arden Nigel K , Stone Martin , Conaghan Philip G , Judge Andrew
Published: March 2022

Objective

To identify patients at risk of mid-late term revision of knee replacement (KR) to inform targeted follow-up.

Design

Analysis of linked national datasets from primary and secondary care (Clinical Practice Research Datalink (CPRD GOLD), National Joint Registry (NJR), English Hospital Episode Statistics (HES) and Patient Reported Outcome Measures (PROMs)).

Participants

Primary elective KRs aged ≥18 years.

Event of interest

Revision surgery ≥5 years (mid–late term) postprimary KR.

Statistical methods

Cox regression modelling to ascertain risk factors of mid–late term revision. HRs and 95% CIs assessed association of sociodemographic factors, comorbidities, medication, surgical variables and PROMs with mid–late term revision.

Results

NJR-HES-PROMs data were available from 2008 to 2011 on 188 509 KR. CPRD GOLD-HES data covered 1995–2011 on 17 378 KR. Patients had minimum 5 years postprimary surgery to end 2016. Age and gender distribution were similar across datasets; mean age 70 years, 57% female. In NJR, there were 8607 (4.6%) revisions, median time-to-revision postprimary surgery 1.8 years (range 0–8.8), with 1055 (0.6%) mid–late term revisions; in CPRD GOLD, 877 (5.1%) revisions, median time-to-revision 4.2 years (range 0.02–18.3), with 352 (2.0%) mid–late term revisions.

Reduced risk of revision after 5 years was associated with older age (HR: 0.95; 95% CI 0.95 to 0.96), obesity (0.70; 0.56 to 0.88), living in deprived areas (0.71; 0.58 to 0.87), non-white ethnicity (0.58; 0.43 to 0.78), better preoperative pain and functional limitation (0.42; 0.33 to 0.53), better 6-month postoperative pain and function (0.33; 0.26 to 0.41) or moderate anxiety/depression (0.73; 0.63 to 0.83) at primary surgery.

Increased risk was associated with male gender (1.32; 1.04 to 1.67); when anticonvulsants (gabapentin and pregabalin) (1.58; 1.01 to 2.47) or opioids (1.36; 1.08 to 1.71) were required prior to primary surgery.

No implant factors were identified.

Conclusion

The risk of mid–late term KR revision is very low. Increased risk of revision is associated with patient case-mix factors, and there is evidence of sociodemographic inequality.
Internet-based cognitive-behavioural writing therapy for reducing post-traumatic stress after severe sepsis in patients and their spouses (REPAIR): results of a randomised-controlled trial
Authors: Gawlytta Romina , Kesselmeier Miriam , Scherag Andre , Niemeyer Helen , Böttche Maria , Knaevelsrud Christine , Rosendahl Jenny
Published: March 2022

Objectives

To investigate the efficacy, safety and applicability of internet-based, therapist-led partner-assisted cognitive-behavioural writing therapy (iCBT) for post-traumatic stress disorder (PTSD) symptoms after intensive care for sepsis in patients and their spouses compared with a waitlist (WL) control group.

Design

Randomised-controlled, parallel group, open-label, superiority trial with concealed allocation.

Setting

Internet-based intervention in Germany; location-independent via web-portal.

Participants

Patients after intensive care for sepsis and their spouses of whom at least one had a presumptive PTSD diagnosis (PTSD-Checklist (PCL-5)≥33). Initially planned sample size: 98 dyads.

Interventions

ICBT group: 10 writing assignments over a 5-week period; WL control group: 5-week waiting period.

Primary and secondary outcome measures

Primary outcome: pre–post change in PTSD symptom severity (PCL-5). Secondary outcomes: remission of PTSD, depression, anxiety and somatisation, relationship satisfaction, health-related quality of life, premature termination of treatment. Outcomes measures were applied pre and post treatment and at 3, 6 and 12 months follow-up.

Results

Twenty-five dyads representing 34 participants with a presumptive PTSD diagnosis were randomised and analysed (ITT principle). There was no evidence for a difference in PCL-5 pre–post change for iCBT compared with WL (mean difference −0.96, 95% CI (−5.88 to 3.97), p=0.703). No adverse events were reported. Participants confirmed the applicability of iCBT.

Conclusions

ICBT was applied to reduce PTSD symptoms after intensive care for sepsis, for the first time addressing both patients and their spouses. It was applicable and safe in the given population. There was no evidence for the efficacy of iCBT on PTSD symptom severity. Due to the small sample size our findings remain preliminary but can guide further research, which is needed to determine if modified approaches to post-intensive care PTSD may be more effective.

Trial registration number

DRKS00010676.
Comparative effectiveness of different surgical procedures for traumatic acute epidural haematoma: study protocol for Prospective, Observational Real-world Treatments of AEDH in Large-scale Surgical Cases (PORTALS-AEDH)
Authors: Yang Chun , Hui Jiyuan , Xie Li , Feng Junfeng , Jiang Jiyao
Published: March 2022

Introduction

Controversy and variation exist in surgical management for acute epidural haematoma (AEDH). Although craniotomy for AEDH is conventionally employed, no specific evaluation on the necessity of decompressive craniectomy (DC) followed by AEDH evacuation has been performed.

Methods and analysis

This is a multicentre prospective, phase III observational study that evaluates different surgical managements for the AEDH. Patients of both genders, aged 18–65 years, presenting to the emergency room with a clinical and radiological diagnosis of AEDH, complying with other inclusion and exclusion criteria, are enrolled. Clinical information, including diagnosis of AEDH, radiological information, treatment procedures and follow-up data of 1, 3 and 6 months post-injury, is collected on 2000 eligible patients among 263 hospitals in China. Recruitment for the study started in April 2021, and inclusion will be continued until the sample size is obtained, expected is an inclusion period of 24 months. The interventions of concern are surgical treatments for AEDH, including craniotomy and DC. The primary outcome is the Glasgow Outcome Score-Extended 6 months post-injury. Secondary outcomes include the incidence of postoperative cerebral infarction, the incidence of additional craniocerebral surgery and other evaluation indicators within 6 months post-injury.

Ethics and dissemination

The study protocol has been approved by the ethics committee and institutional review board of Renji Hospital, School of Medicine, Shanghai Jiao Tong University. All study investigators strictly follow the Declaration of Helsinki and Human Biomedical Research Ethical Issues. Signed written informed consent will be obtained from all enrolled patients. The trial results will be disseminated through academic conferences and published in peer-reviewed journals.

Trial registration number

NCT04229966.
Effectiveness of a workplace intervention to reduce workplace bullying and violence at work: study protocol for a two-wave quasi-experimental intervention study
Authors: Ervasti Jenni , Seppälä Piia , Olin Nina , Kalavainen Susanna , Heikkilä Heli , Aalto Ville , Kivimäki Mika
Published: March 2022

Introduction

Bullying and violence at work are relatively common in Finnish public sector workplaces. Previous research has demonstrated their association with increased risk of poor health and well-being, but only few intervention studies exist. The aim of this protocol paper is to describe the development and assessment of the effectiveness of a workplace intervention aimed at reducing these harmful phenomena.

Methods and analysis

This protocol describes a two-wave quasi-experimental intervention. Each of the three participating Finnish public sector organisations (cities) will select four work units (a total of 450–500 employees) to participate in an intervention including 2–3 workshops for the work unit, 2–3 consultative meetings with the supervisor of the work unit, a follow-up meeting for the entire work unit (a maximum of 6-month time lag) and online meetings with the supervisor to monitor achievements and discuss about difficult cases, if any. Three age-matched, sex-matched and occupation-matched controls for each participants of the intervention group will be randomly selected, a total 1350–1500 individuals in the control group. For intervention and control groups, premeasurement is based on responses to a survey that was conducted in 2020. Postintervention measurement will be based on survey responses in 2022. Data will be analysed using latent change score modelling or difference-in-difference analysis.

Ethics and dissemination

Ethics approvals are from the Ethics committees of the Helsinki and Uusimaa hospital district and the Finnish institute of Occupational Health. Results will be made available to participating organisations and their employees, the funder and other researchers via open access article in a peer-reviewed journal and subsequent reporting of the results via social media channels and press release to the public.
Intrapleural fibrinolysis and DNase versus video-assisted thoracic surgery (VATS) for the treatment of pleural empyema (FIVERVATS): protocol for a randomised, controlled trial – surgery as first-line treatment
Authors: Christensen Thomas Decker , Bendixen Morten , Skaarup Søren Helbo , Jensen Jens-Ulrik , Petersen Rene Horsleben , Christensen Merete , Licht Peter , Neckelmann Kirsten , Bibby Bo Martin , Møller Lars B , Bodtger Uffe , Borg Morten Hornemann , Saghir Zaigham , Langfeldt Sten , Harders Stefan M W , Bedawi Eihab O , Naidu Babu , Rahman Najib , Laursen Christian B
Published: March 2022

Introduction

Pleural empyema is a frequent disease with a high morbidity and mortality. Current standard treatment includes antibiotics and thoracic ultrasound (TUS)-guided pigtail drainage. Simultaneously with drainage, an intrapleural fibrinolyticum can be given. A potential better alternative is surgery in terms of video-assisted thoracoscopic surgery (VATS) as first-line treatment. The aim of this study is to determine the difference in outcome in patients diagnosed with complex parapneumonic effusion (stage II) and pleural empyema (stage III) who are treated with either VATS surgery or TUS-guided drainage and intrapleural therapy (fibrinolytic (Alteplase) with DNase (Pulmozyme)) as first-line treatment.

Methods and analysis

A national, multicentre randomised, controlled study. Totally, 184 patients with a newly diagnosed community acquired complicated parapneumonic effusion or pleural empyema are randomised to either (1) VATS procedure with drainage or (2) TUS-guided pigtail catheter placement and intrapleural therapy with Actilyse and DNase. The total follow-up period is 12 months. The primary endpoint is length of hospital stay and secondary endpoints include for example, mortality, need for additional interventions, consumption of analgesia and quality of life.

Ethics and dissemination

All patients provide informed consent before randomisation. The research project is carried out in accordance with the Helsinki II Declaration, European regulations and Good Clinical Practice Guidelines. The Scientific Ethics Committees for Denmark and the Danish Data Protection Agency have provided permission. Information about the subjects is protected under the Personal Data Processing Act and the Health Act. The trial is registered at www.clinicaltrials.gov, and monitored by the regional Good clinical practice monitoring unit. The results of this study will be published in peer-reviewed journals and presented at various national and international conferences.

Trial registration number

NCT04095676.
Prevalence and predictors of drug-related hospitalisation among patients visiting emergency departments of Addis Ababa city hospitals in Ethiopia: a multicentre prospective observational study
Authors: Demessie Mulate Belete , Berha Alemseged Beyene
Published: March 2022

Objectives

This study aimed to determine the prevalence, categories and predictors of drug-related hospitalisation (DRH) among patients visiting emergency departments of Addis Ababa city hospitals, Ethiopia.

Design

A multicentre prospective observational study was conducted through patients’ interview and chart review.

Settings

The study was undertaken in three tertiary care hospitals in Addis Ababa, Ethiopia.

Participants

A total of 423 patients fulfilling the inclusion criteria were included.

Outcome measures

Prevalence and preventability of DRH, categories of drug-related problems causing DRH, medications and diseases involved in DRH, and factors significantly associated with DRH.

Result

More than half of the patients (216, 51.1%) were female. The mean age (SD) was 47.50 (±17.21) years. The mean length of hospital stay (SD) was 10.29 (±8.99) days. Nearly 60% (249) of them were hospitalised due to drug-related problems, of which 87.8% were preventable. The cause for hospitalisation for more than half (130, 53%) of them was a failure to receive drugs, and 37.85 (94) patients were categorised as untreated indications. Age ≥65 years (adjusted OR (AOR)=7.451, 95% CI: 1.889 to 29.397), tertiary educational level (AOR=0.360, 95% CI: 0.141 to 0.923), participants who did not have any occupation (AOR=3.409, 95% CI: 1.120 to 10.374) and presence of comorbid conditions (AOR=2.004, 95% CI: 1.095 to 3.668) were predictors of DRH.

Conclusion

Nearly 90% of DRH was deemed to be preventable in the study settings. Older age, lower educational level, unemployment and presence of comorbid conditions in hospital as an inpatient were predictors of DRH.
Preventing type 2 diabetes, overweight and obesity in the Norwegian primary healthcare: a longitudinal design with 60 months follow-up results and a cross-sectional design with comparison of dropouts versus completers
Authors: Følling Ingrid Sørdal , Klöckner Christian , Devle Monica Tømmervold , Kulseng Bård
Published: March 2022

Objectives

Studies have demonstrated that it is possible to prevent type 2 diabetes for individuals at high risk, but long-term results in the primary healthcare are limited and high dropout rates have been reported.

Design

A longitudinal design was used to study changes in participants’ diabetes risk and anthropometrics from baseline to 60 months follow-up. A cross-sectional design was applied to investigate differences between dropouts and completers of the 60 months follow-up.

Setting

Healthy Life Centres in the Norwegian primary healthcare.

Participants

189 individuals aged >18 years with a Finnish Diabetes Risk Score ≥12 and/or a body mass index (BMI) ≥25 kg/m2 were included and offered to attend Healthy Life Centre programmes for 12 months. Measurements were performed annually up to 60 months after inclusion.

Interventions

Healthy Life Centres arrange behavioural programmes including physical activity offers and dietary courses as part of the primary healthcare. This study offered individuals to attend Healthy Life Centre programmes and followed them for 60 months.

Primary outcome

Assess changes in participants’ diabetes risk, cardiovascular measures and anthropometrics from baseline to 60 months.

Secondary outcome

Investigate characteristics of dropouts compared with completers of 60 months follow-up.

Results

For participants at 60 months follow-up, diabetes risk and anthropometrics decreased (p<0.001). Out of 65 participants classified as high risk for diabetes at baseline, 27 (42%) changed to being at moderate risk at 60 months follow-up. Remission of diabetes was seen for six of nine participants. Of 189 participants enrolled in the programme, 54 (31%) dropped out at any given point before 60 months follow-up. Dropouts were younger with higher, BMI, weight and waist circumference compared with the completers (p<0.001).

Conclusions

Having a long-term commitment for participants in primary healthcare interventions could be beneficial for the reduction of diabetes risk and improvement of anthropometrics as shown at the 60 months follow-up.

Trial registration number

NCT01135901.
Behavioural approaches to recruitment and retention in clinical trials: a systematic mapping review
Authors: Coffey Taylor , Duncan Eilidh M , Morgan Heather , Lawrie Louisa , Gillies Katie
Published: March 2022

Objectives

To identify studies that applied behavioural approaches to issues of recruitment and/or retention to trials; to describe these approaches; and to identify gaps for future research.

Design

Systematic mapping review of research undertaken in clinical trials within peer-reviewed sources. Review participants were individuals involved in clinical trials, including trial staff, participants, potential participants and former participants.

Data sources

MEDLINE, EMBASE, CINAHL, ERIC, PsycINFO, Web of Science and ASSIA from inception to 15 January 2020 with no date or language restrictions.

Eligibility criteria

Studies within the context of clinical trials reporting the barriers/facilitators to recruitment and retention, or developing/evaluating solutions to said barriers/facilitators, using a behavioural approach.

Results

31 articles were included. Recruitment-focused studies (n=22, 71%) represented the majority. Studies tended to focus on participant behaviours (n=22, 71%). Underserved populations (n=11, 35%) were a notable subset of studies. Most studies (n=23, 74%) were exploratory but those that evaluated interventions (n=8, 26%) often did so within underserved populations (n=6). A majority of studies (n=30, 97%) did not specify their behaviours consistent with guidelines from behavioural scientists. The most used approaches were social cognitive theory (n=8, 26%), the theory of planned behaviour (n=6, 19%) and the theoretical domains framework (n=5, 16%).

Conclusions

A range of behavioural approaches have been applied to recruitment and retention to trials. The multitude of recruitment research here is consistent with trials research generally and emphasises the need for research into retention. Authors report target behaviours minimally, which is not conducive to replication. Further research should build on lessons here, such as clearly specifying behaviours. Increased methodological rigour and transparency will lead to robust evidence bases and less research waste in poor recruitment and retention. Overall, trials informed by behavioural approaches promises to be efficient and more participant focused.
What is the definition of acute episodic and chronic pain in critically ill neonates and infants? A global, four-stage consensus and validation study
Authors: Ilhan Emre , Pacey Verity , Brown Laura , Spence Kaye , van Ganzewinkel Christ-jan , Pillai Riddell Rebecca , Campbell-Yeo Marsha , Stevens Bonnie J , Eriksson Mats , Shah Vibhuti , Anand Kanwaljeet J S , Bellieni Carlo , Daly Mandy , Johnston Celeste , Hush Julia
Published: March 2022

Objectives

To define and validate types of pain in critically ill neonates and infants by researchers and clinicians working in the neonatal intensive care unit (NICU) and high dependency unit (HDU).

Design

A qualitative descriptive mixed-methods design.

Procedure/s

Each stage of the study was built on and confirmed the previous stages. Stage 1 was an expert panel to develop definitions; stage 2 was a different expert panel made up of neonatal clinicians to propose clinical characteristics associated with the definitions from stage 1; stage 3 was a focus group of neonatal clinicians to provide clinical case scenarios associated with each definition and clinical characteristics; and stage 4 was a survey administered to neonatal clinicians internationally to test the validity of the definitions using the clinical case scenarios.

Results

In stage 1, the panel (n=10) developed consensus definitions for acute episodic pain and chronic pain in neonates and infants. In stage 2, a panel (n=8) established clinical characteristics that may be associated with each definition. In stage 3, a focus group (n=11) created clinical case scenarios of neonates and infants with acute episodic pain, chronic pain and no pain using the definitions and clinical characteristics. In stage 4, the survey (n=182) revealed that the definitions allowed an excellent level of discrimination between case scenarios that described neonates and infants with acute episodic pain and chronic pain (area under the receiver operating characteristic=0.87 and 0.89, respectively).

Conclusions

This four-stage study enabled the development of consensus-based and clinically valid definitions of acute episodic pain and chronic pain. There is a need to define and validate other pain types to inform a taxonomy of pain experienced by neonates and infants in the NICU and HDU.
What is the healthcare utilisation and out-of-pocket expenditure associated with osteoarthritis? A cross-sectional study
Authors: Sibbritt David , Sundberg Tobias , Ward Lesley , Broom Alex , Frawley Jane , Bayes Jessica , Adams Jon
Published: March 2022

Objective

To examine the use and out-of-pocket expenses resulting from consultations, products and practices across conventional, self-care, and complementary medicine (CM) treatments for osteoarthritis (OA) among Australian women.

Design, setting and participants

A cross-sectional survey of 800 women from the 45 and Up Study who had reported a clinical diagnosis of OA.

Outcome measures

Women’s use of conventional, CM and self-prescribed treatments for OA and the associated out-of-pocket cost.

Results

Completed questionnaires were returned by 403 women (50.4%). Their average time since the first diagnosis of OA was 15.4 years, and self-rated severity of OA was 5.1 (out of 10) over the past 12 months. During the previous year, 67.0% of the women consulted a doctor, 39.2% consulted an allied health practitioner and 34.7% consulted a CM practitioner for their OA. Some women (19%) consulted with practitioner(s) from all three practitioner groups, 27% consulted with practitioner(s) from two of the three practitioner groups, while 6% consulted with a CM practitioner only. Women with a greater time since diagnosis had more consultations, as did women who rated their OA as more severe. Women’s average combined out-of-pocket expenditure for OA-related healthcare consultations, prescription medications, products, and practices was $673 per annum. Extrapolated to all Australian women with OA, aged 50 years and over, the total out-of-pocket expenditure for this condition is estimated to be $873 million per annum.

Conclusions

Australian women with OA use a range of conventional and CM consultations, self-care, products and practices to manage their condition, incurring significant out-of-pocket expenses. Given the high individual and societal burden of OA, there is a need for further research into the concurrent use of different healthcare resources with a view to providing safe, cost-effective management of OA across the healthcare system and the wider community.
Psychological stress; knowledge, attitude and practice and acceptance of antiviral therapy in pregnant women with hepatitis B in Zhejiang, China: a case comparison study
Authors: Liu Xiaoxiao , Chen Can , Jiang Daixi , Yan Danying , Zhou Yuqing , Ding Cheng , Lan Lei , Huang Chenyang , Zhang Xiaobao , Li Lanjuan , Yang Shigui
Published: March 2022

Objectives

To determine knowledge, attitude and practice (KAP) and antiviral therapy’s acceptance during pregnancy of pregnant women with hepatitis B and influencing factors.

Design

Case-comparison study.

Setting

The study was conducted in Zhejiang province, China, from September 2019 to December 2020.

Participants

Pregnant and postpartum women with chronic hepatitis B.

Primary and secondary outcome measures

The stress scores, self-assessed health score, KAP, antiviral therapy’s acceptance rate during pregnancy and influencing factors were analysed. The Perceived Stress Scale-10 was used to assess stress. Logistic regression was used to analyse influencing factors on antiviral therapy.

Results

The self-assessed health score of pregnant women without liver diseases (82.4±9.3) was significantly higher than that of pregnant women with chronic hepatitis B (75.5±9.5) and postpartum (75.1±14.1). Psychological stress of pregnant women with chronic hepatitis B was significantly high with a 14.9±3.6 score, but there was no significant difference between hepatitis B postpartum and non-liver disease women (12.7±3.5 vs 12.9±3.5, p=0.75). The acceptance rate of pregnant women with hepatitis B for antiviral therapy was 84.2%, while that of postpartum women was even higher. Logistic regression analysis showed that patients with positive hepatitis B e antigen (HBeAg) (OR, 3.35; 95% CI, 1.21 to 9.26) and higher scores on hepatitis B-related knowledge (OR, 3.52, 95% CI, 2.18 to 5.69) were more likely to accept antiviral therapy during pregnancy.

Conclusions

Pregnant women with hepatitis B in Zhejiang have heavy psychological stress and a high antiviral therapy acceptance rate during pregnancy. Acceptance is related to HBeAg status and level of understanding of hepatitis B during pregnancy. It is necessary to provide education on hepatitis B to reduce psychological stress and increase acceptance of antiviral therapy during pregnancy.
Does left atrial epicardial conduction time reflect atrial fibrosis and the risk of atrial fibrillation recurrence after thoracoscopic ablation? Post hoc analysis of the AFACT trial
Authors: Wesselink R , Neefs J , van den Berg N W E , Meulendijks E R , Terpstra M M , Kawasaki M , Nariswari F A , Piersma F R , van Boven W J P , Driessen A H G , de Groot J R
Published: March 2022

Objectives

To determine the association between left atrial epicardial conduction time (LAECT), fibrosis and atrial fibrillation (AF) recurrence after thoracoscopic surgical ablation of persistent AF.

Setting

Single tertiary care centre in the Netherlands.

Participants

Patients with persistent AF from the randomised Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery (AFACT)-trial were included. Patients eligible for thoracoscopic AF ablation were included, full inclusion and exclusion criteria were previously published. All patients underwent thoracoscopic ablation, encompassing pulmonary vein isolation with an additional roof and trigone lesion. In patients with conduction block across the roof and trigone lesion, LAECT was measured. LAECT was defined as the time to local activation at one side of the roofline on pacing from the opposite side. Collagen fibre density was quantified from left atrial appendage histology.

Outcome measures

Primary outcome: AF recurrence during 2 years of follow-up.

Results

121 patients were included, of whom 35(29%) were women, age was 60.4±7.8 and 51% (62) had at least one AF recurrence during 2 years of follow-up. LAECT was longer in patients with versus without AF recurrence (182±43 ms vs 147±29 ms, p<0.001). LAECT was longer in older patients, in patients with a higher body mass index (BMI) and in patients using class IC antiarrhythmic drugs. LAECT was shorter in patients with higher collagen fibre density. A previously failed catheter ablation, LAECT and BMI were independently associated with AF recurrence.

Conclusion

LAECT is correlated with collagen fibre density and BMI and is independently associated with AF recurrence in patients with persistent AF. In these patients, LAECT appears to reflect substrate characteristics beyond clinical AF type and left atrial volume.

Trial registration number

NCT01091389.
Understanding ethnic inequalities in stillbirth rates: a UK population-based cohort study
Authors: Matthews Ruth J , Draper Elizabeth S , Manktelow Bradley N , Kurinczuk Jennifer J , Fenton Alan C , Dunkley-Bent Jacqueline , Gallimore Ian , Smith Lucy K
Published: March 2022

Objectives

To investigate inequalities in stillbirth rates by ethnicity to facilitate development of initiatives to target those at highest risk.

Design

Population-based perinatal mortality surveillance linked to national birth and death registration (Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK).

Setting

UK.

Participants

4 391 569 singleton births at ≥24+0 weeks gestation between 2014 and 2019.

Main outcome measures

Stillbirth rate difference per 1000 total births by ethnicity.

Results

Adjusted absolute differences in stillbirth rates were higher for babies of black African (3.83, 95% CI 3.35 to 4.32), black Caribbean (3.60, 95% CI 2.65 to 4.55) and Pakistani (2.99, 95% CI 2.58 to 3.40) ethnicities compared with white ethnicities. Higher proportions of babies of Bangladeshi (42%), black African (39%), other black (39%) and black Caribbean (37%) ethnicities were from most deprived areas, which were associated with an additional risk of 1.50 stillbirths per 1000 births (95% CI 1.32 to 1.67). Exploring primary cause of death, higher stillbirth rates due to congenital anomalies were observed in babies of Pakistani, Bangladeshi and black African ethnicities (range 0.63–1.05 per 1000 births) and more placental causes in black ethnicities (range 1.97 to 2.24 per 1000 births). For the whole population, over 40% of stillbirths were of unknown cause; however, this was particularly high for babies of other Asian (60%), Bangladeshi (58%) and Indian (52%) ethnicities.

Conclusions

Stillbirth rates declined in the UK, but substantial excess risk of stillbirth persists among babies of black and Asian ethnicities. The combined disadvantage for black, Pakistani and Bangladeshi ethnicities who are more likely to live in most deprived areas is associated with considerably higher rates. Key causes of death were congenital anomalies and placental causes. Improved strategies for investigation of stillbirth causes are needed to reduce unexplained deaths so that interventions can be targeted to reduce stillbirths.
Enablers and barriers to newborn screening for sickle cell disease in Africa: results from a qualitative study involving programmes in six countries
Authors: Archer Natasha M , Inusa Baba , Makani Julie , Nkya Siana , Tshilolo Léon , Tubman Venee N , McGann Patrick T , Ambrose Emmanuela Eusebio , Henrich Natalie , Spector Jonathan , Ohene-Frempong Kwaku
Published: March 2022

Objectives

Given the fundamental role of newborn bloodspot screening (NBS) to enable prompt diagnosis and optimal clinical management of individuals with sickle cell disease (SCD), we sought to systematically assess enablers and barriers to implementation of NBS programmes for SCD in Africa using established qualitative research methods.

Setting

Childbirth centres and NBS laboratories from six countries in East, West and Southern Africa.

Participants

Eight programme leaders involved with establishing and operating NBS programmes for SCD in Angola, Democratic Republic of Congo, Ghana, Liberia, Nigeria and Tanzania.

Primary and secondary outcome measures

Data obtained through a structured, phased interview approach were analysed using a combination of inductive and deductive codes and used to determine primary themes related to the implementation and sustainability of SCD NBS programmes.

Results

Four primary themes emerged from the analysis relating to governance (eg, pragmatic considerations when deploying overcommitted clinical staff to perform NBS), technical (eg, design and execution of operational processes), cultural (eg, variability of knowledge and perceptions of community-based staff) and financial (eg, issues that can arise when external funding may effectively preclude government inputs) aspects. Key learnings included perceived factors that contribute to long-term NBS programme sustainability.

Conclusions

The establishment of enduring NBS programmes is a proven approach to improving the health of populations with SCD. Organising such programmes in Africa is feasible, but initial implementation does not assure sustainability. Our analysis suggests that future programmes should prioritise government partner participation and funding from the earliest stages of programme development.
Early mobilisation using a mobile patient lift in the intensive care unit: protocol for a randomised controlled trial
Authors: Suzuki Ginga , Kanayama Hiromi , Ichibayashi Ryo , Arai Yoshiaki , Iwanami Yuji , Masuyama Yuka , Yamamoto Saki , Serizawa Hibiki , Nakamichi Yoshimi , Watanabe Masayuki , Honda Mitsuru , Ebihara Satoru
Published: March 2022

Introduction

It is important to prevent the deterioration of activities of daily living to improve the long-term prognoses of patients in the intensive care unit (ICU). The patients’ conditions, along with the lack of human and technical resources, often become barriers to achieving early mobilisation after the introduction of mechanical ventilation. We plan to verify the usefulness of a mobile patient lift for early mobilisation.

Methods and analysis

We will conduct a single-centre, open-label, randomised controlled trial. The inclusion criteria are as follows: age ≥18 years, independent walking before admission and expected mechanical ventilation for at least 48 hours. The participants will be randomly divided into groups with (intervention group) or without (control group) a mobile lift protocol. A mobile lift will be used in the intervention group. The primary endpoint will be the number of days required to achieve an ICU mobility scale of ≥4 (standing position). The results of the two groups will be analysed using the Student’s t-test.

Ethics and dissemination

This study will be conducted in accordance with the Declaration of Helsinki and with the approval of the Toho University Omori Medical Center Ethics Committee (approval number M20259). The results of this study will be presented internationally at academic conferences and published in the literature.

Trial registration number

UMIN000044965.
Sex differences in clinical outcomes for obstructive hypertrophic cardiomyopathy in the USA: a retrospective observational study of administrative claims data
Authors: Butzner Michael , Leslie Douglas , Cuffee Yendelela , Hollenbeak Christopher S , Sciamanna Christopher , Abraham Theodore P
Published: March 2022

Objectives

To evaluate sex differences in demographic and clinical characteristics, treatments and outcomes for patients with diagnosed obstructive hypertrophic cardiomyopathy (oHCM) in the USA.

Setting

Retrospective observational study of administrative claims data from MarketScan Commercial Claims and Encounters Database from IBM Watson Health.

Participants

Of the 28 million covered employees and family members in MarketScan, 9306 patients with oHCM were included in this analysis.

Main outcome measures

oHCM-related outcomes included heart failure, atrial fibrillation, ventricular tachycardia/ fibrillation, sudden cardiac death, septal myectomy, alcohol septal ablation (ASA) and heart transplant.

Results

Among 9306 patients with oHCM, the majority were male (60.5%, p<0.001) and women were of comparable age to men (50±15 vs 49±15 years, p<0.001). Women were less likely to be prescribed beta blockers (42.7% vs 45.2%, p=0.017) and undergo an implantable cardioverter-defibrillator (1.7% vs 2.6%, p=0.005). Septal reduction therapy was performed slightly more frequently in women (ASA: 0.08% vs 0.05%, p=0.600; SM: 0.35% vs 0.18%, p=0.096), although not statistically significant. Women were less likely to have atrial fibrillation (6.7% vs 9.9%, p<0.001).

Conclusion

Women were less likely to be prescribed beta blockers, ACE inhibitors, anticoagulants, undergo implantable cardioverter-defibrillator and have ventricular tachycardia/fibrillation. Men were more likely to have atrial fibrillation. Future research using large, clinical real-world data are warranted to understand the root cause of these potential treatment disparities in women with oHCM.
Factors associated with female genital mutilation: a systematic review and synthesis of national, regional and community-based studies
Authors: El-Dirani Zeinab , Farouki Leen , Akl Christelle , Ali Ubah , Akik Chaza , McCall Stephen J
Published: March 2022

Background

This systematic review aimed to identify and describe the factors that influence female genital mutilation/cutting (FGM/C).

Methods

Searches were conducted in Medline, PsycInfo, Web of Science, Embase and the grey literature from 2009 to March 2020 with no language restrictions, using related MESH terms and keywords. Studies were included if they were quantitative and examined factors associated with FGM/C. Two researchers independently screened studies for inclusion, extracted data and assessed study quality. The direction, strength and consistency of the association were evaluated for determinants, presented as a descriptive summary, and were disaggregated by age and region.

Results

Of 2230 studies identified, 54 published articles were included. The majority of studies were from the African Region (n=29) followed by the Eastern Mediterranean Region (n=18). A lower level of maternal education, family history of FGM/C, or belonging to the Muslim religion (in certain contexts) increased the likelihood of FGM/C. The majority of studies that examined higher paternal education (for girls only) and living in an urban region showed a reduced likelihood of FGM/C, while conflicting evidence remained for wealth. Several studies reported that FGM/C literacy, and low community FGM/C prevalence were associated with a reduced likelihood of FGM/C.

Conclusions

There were several characteristics that appear to be associated with FGM/C, and these will better enable the targeting of policies and interventions. Importantly, parental education may be instrumental in enabling communities and countries to meet the Sustainable Development Goals.
PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment
Authors: Collins Natalie B , Al Abosy Rose , Miller Brian C , Bi Kevin , Zhao Qihong , Quigley Michael , Ishizuka Jeffrey J , Yates Kathleen B , Pope Hans W , Manguso Robert T , Shrestha Yashaswi , Wadsworth Marc , Hughes Travis , Shalek Alex K , Boehm Jesse S , Hahn William C , Doench John G , Haining W Nicholas
Published: March 2022

Background

Oncogenes act in a cell-intrinsic way to promote tumorigenesis. Whether oncogenes also have a cell-extrinsic effect on suppressing the immune response to cancer is less well understood.

Methods

We use anin vivoexpression screen of known cancer-associated somatic mutations in mouse syngeneic tumor models treated with checkpoint blockade to identify oncogenes that promote immune evasion. We then validated candidates from this screenin vivoand analyzed the tumor immune microenvironment of tumors expressing mutant protein to identify mechanisms of immune evasion.

Results

We found that expression of a catalytically active mutation in phospho-inositol 3 kinase (PI3K),PIK3CAc.3140A>G (H1047R) confers a selective growth advantage to tumors treated with immunotherapy that is reversed by pharmacological PI3K inhibition. PIK3CA H1047R-expression in tumors decreased the number of CD8+T cells but increased the number of inhibitory myeloid cells following immunotherapy. Inhibition of myeloid infiltration by pharmacological or genetic modulation of Ccl2 in PIK3CA H1047R tumors restored sensitivity to programmed cell death protein 1 (PD-1) checkpoint blockade.

Conclusions

PI3K activation enables tumor immune evasion by promoting an inhibitory myeloid microenvironment. Activating mutations in PI3K may be useful as a biomarker of poor response to immunotherapy. Our data suggest that some oncogenes promote tumorigenesis by enabling tumor cells to avoid clearance by the immune system. Identification of those mechanisms can advance rational combination strategies to increase the efficacy of immunotherapy.
Enhanced antigen cross-presentation in human colorectal cancer-associated fibroblasts through upregulation of the lysosomal protease cathepsin S
Authors: Harryvan Tom J , Visser Marten , de Bruin Linda , Plug Léonie , Griffioen Lisa , Mulder Arend , van Veelen Peter A , van der Heden van Noort Gerbrand J , Jongsma Marlieke LM , Meeuwsen Miranda H , Wiertz Emmanuel JHJ , Santegoets Saskia J , Hardwick James CH , Van Hall Thorbald , Neefjes Jacques , Van der Burg Sjoerd H , Hawinkels Lukas JAC , Verdegaal Els ME
Published: March 2022

Background

Cross-presentation of exogenous antigens in HLA-class I molecules by professional antigen presenting cells (APCs) is crucial for CD8+ T cell function. Recent murine studies show that several non-professional APCs, including cancer-associated fibroblasts (CAFs) also possess this capacity. Whether human CAFs are able to cross-present exogenous antigen, which molecular pathways are involved in this process and how this ultimately affects tumor-specific CD8+ T cell function is unknown.

Methods

In this study, we investigated the ability of human colorectal cancer (CRC)-derived CAFs to cross-present neoantigen-derived synthetic long peptides (SLPs), corresponding to tumor-derived mutant peptides, and how this affects tumor-specific T-cell function. Processing of the SLP was studied by targeting components of the cross-presentation machinery through CRISPR/Cas9 and siRNA-mediated genetic ablation to identify the key molecules involved in fibroblast-mediated cross-presentation. Multispectral flow cytometry and killing assays were performed to study the effect of fibroblast cross-presentation on T cell function.

Results

Here, we show that human CRC-derived CAFs display an enhanced capacity to cross-present neoantigen-derived SLPs when compared with normal colonic fibroblasts. Cross-presentation of antigens by fibroblasts involved the lysosomal protease cathepsin S. Cathepsin S expression by CAFs was detected in situ in human CRC tissue, was upregulated in ex vivo cultured CRC-derived CAFs and showed increased expression in normal fibroblasts after exposure to CRC-conditioned medium. Cognate interaction between CD8+ T cells and cross-presenting CAFs suppressed T cell function, reflected by decreased cytotoxicity, reduced activation (CD137) and increased exhaustion (TIM3, LAG3 and CD39) marker expression.

Conclusion

These data indicate that CAFs may directly suppress tumor-specific T cell function in an antigen-dependent fashion in human CRC.
Necroptosis-driving genesRIPK1, RIPK3andMLKL-pare associated with intratumoral CD3+and CD8+T cell density and predict prognosis in hepatocellular carcinoma
Authors: Nicolè Lorenzo , Sanavia Tiziana , Cappellesso Rocco , Maffeis Valeria , Akiba Jun , Kawahara Akihiko , Naito Yoshiki , Radu Claudia Maria , Simioni Paolo , Serafin Davide , Cortese Giuliana , Guido Maria , Zanus Giacomo , Yano Hirohisa , Fassina Ambrogio
Published: March 2022

Background

Hepatocellular carcinoma (HCC) is a highly lethal cancer and the second leading cause of cancer-related deaths worldwide. As demonstrated in other solid neoplasms and HCC, infiltrating CD8+T cells seem to be related to a better prognosis, but the mechanisms affecting the immune landscape in HCC are still mostly unknown. Necroptosis is a programmed, caspase-independent cell death that, unlike apoptosis, evokes immune response by releasing damage-associated molecular factors. However, in HCC, the relationship between the necroptotic machinery and the tumor-infiltrating lymphocytes has not been fully investigated so far.

Methods

We investigated the association between the main necroptosis-related genes, that is,RIPK1,RIPK3, MLKL-p, and CD3+/CD8+tumor-infiltrating T cell by RNA-seq data analysis in 371 patients with primary HCC from The Cancer Genome Atlas and then by immunohistochemistry in two independent cohorts of HCC patients from Italy (82) and Japan (86).

Results

Our findings highlighted the immunogenetic role of necroptosis and its potential prognostic role in HCC: RIPK1, RIPK3 and MLKL-p were found significantly associated with intratumoral CD3+and CD8+T cells. In addition, multivariate survival analysis showed that the expression of RIPK1, RIPK3 and MLKL-p was associated with better overall survival in the two independent cohorts.

Conclusions

Our results confirmed the immunogenetic properties of necroptosis (NCP) in human HCC, showing that tumor-infiltrating lymphocytes (TILs) and, specifically, CD8+ T cells accumulate in tumors with higher expression of the necroptosis-related genes. These results suggest the importance of further studies to better assess the specific composition, as well as the functional features of the immune environment associated with a necroptotic signature in order to explore new possible diagnostic and immunotherapeutic scenarios.
Spatial profiling reveals association between WNT pathway activation and T-cell exclusion in acquired resistance of synovial sarcoma to NY-ESO-1 transgenic T-cell therapy
Authors: Campbell Katie M , Thaker Maneesha , Medina Egmidio , Kalbasi Anusha , Singh Arun , Ribas Antoni , Nowicki Theodore Scott
Published: March 2022

Background

Genetically engineered T-cell immunotherapies for adoptive cell transfer (ACT) have emerged as a promising form of cancer treatment, but many of these patients develop recurrent disease. Furthermore, delineating mechanisms of resistance may be challenging since the analysis of bulk tumor profiling can be complicated by spatial heterogeneity.

Methods

Tumor samples were collected from a patient with synovial sarcoma who developed acquired resistance to ACT targeting NY-ESO-1. Biopsies (primary, progressive metastasis, and recurrence) were subjected to bulk tumor DNA and RNA sequencing, as well as high-dimensional spatial profiling of RNA and protein targets. Untreated and progressive lesions were compared with identified patterns associated with acquired resistance to ACT.

Results

Gene expression patterns due to immune activity and infiltration were diluted in bulk tumor sequencing. The metastasis was enriched for tumor regions with increasedCTNNB1(encoding beta-catenin), which were negatively associated with the expression of T-cell surface proteins and antigen presentation machinery. Spatial profiling was most highly concordant with bulk sequencing in the lesions with decreased spatial heterogeneity.

Conclusions

Complementary use of bulk and spatial profiling enables more accurate interrogation of tumor specimens, particularly to address complex questions regarding immunotherapeutic mechanisms. Our study uses this approach to demonstrate a mechanism of T-cell exclusion and resistance to cellular immunotherapy in synovial sarcoma.