bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementing structured follow-up of neonatal and paediatric patients: an evaluation of three university hospital case studies using the functional resonance analysis method
Authors: Bos Véronique , Roorda Daniëlle , de Sonnaville Eleonore , van Boven Menne , Oosterlaan Jaap , van Goudoever Johannes , Klazinga Niek , Kringos Dionne
Published: February 2022

Background

In complex critical neonatal and paediatric clinical practice, little is known about long-term patient outcomes and what follow-up care is most valuable for patients. Emma Children’s Hospital, Amsterdam UMC (Netherlands), implemented a follow-up programme called Follow Me for neonatal and paediatric patient groups, to gain more insight into long-term outcomes and to use such outcomes to implement a learning cycle for clinical practice, improve follow-up care and facilitate research. Three departments initiated re-engineering and change processes. Each introduced multidisciplinary approaches to long-term follow-up, including regular standardised check-ups for defined age groups, based on medical indicators, developmental progress, and psychosocial outcomes in patients and their families. This research evaluates the implementation of the three follow-up programmes, comparing predefined procedures (work-as-imagined) with how the programmes were implemented in practice (work-as-done).

Methods

This study was conducted in 2019–2020 in the outpatient settings of the neonatal intensive care, paediatric intensive care and paediatric surgery departments of Emma Children’s Hospital. It focused on the organisational structure of the follow-up care. The functional resonance analysis method (FRAM) was applied, using documentary analysis, semi-structured interviews, observations and feedback sessions.

Results

One work-as-imagined model and four work-as-done models were described. The results showed vast data collection on medical, developmental and psychosocial indicators in all work-as-done models; however, process indicators for programme effectiveness and performance were missing. In practice there was a diverse allocation of roles and responsibilities and their interrelations to create a multidisciplinary team; there was no one-size-fits-all across the different departments. Although control and feedback loops for long-term outcomes were specified with respect to the follow-up groups within the programmes, they were found to overlap and misalign with other internal and external long-term outcome monitoring practices.

Conclusion

Implementing structured long-term follow-up may provide insights for improving daily practice and follow-up care, with the precondition of standardised measurements. Lessons learned from practice are (1) to address fragmentation in data collection and storage, (2) to incorporate the diverse ways to create a multidisciplinary team in practice, and (3) to include timely actionable indicators on programme effectiveness and performance, alongside medical, developmental and psychosocial indicators.
Treatment pathways and associated costs of metastatic colorectal cancer in Greece
Authors: Sougklakos Ioannis , Athanasiadis Elias , Boukovinas Ioannis , Karamouzis Michalis , Koutras Aggelos , Papakotoulas Paulos , Latsou Dimitra , Hatzikou Magda , Stamuli Eugena , Balasopoulos Athanasios , Sideris Aggelos
Published: February 2022

Objectives

Colorectal cancer (CRC) is the second leading cause of cancer in Europe, with 1.931.590 people newly diagnosed in 2020. The purpose of this study is the investigation of treatment options and healthcare resource metastatic CRC (mCRC) in Greece.

Methods

This study is based on the information collected in November 2020 by an expert panel comprising of 6 medical oncologists from major public and private centers around Greece. A 3-round survey was undertaken, according to Delphi method. The treatment phases studied were: pre-progression; disease progression and terminal care. Pharmaceutical costs and resource utilization data were considered from the perspective of the Greek National Services Organization (EOPYY). RESULTS: Experts agreed that the anticipated prevalence of RAS mutation in mCRC is 47% (30% RAS/BRAF WT Left, 17% RAS/BRAF WT Right); 8% BRAF while, MSI-H/dMMR are found in 5% of mCRC tumors. Based on mutational status, 74.8% of patients receive biological targeted therapies in combination with fluoropyrimidine/based combination chemotherapy, as 1st line treatment, and 25.2% combination chemotherapy alone. At 2nd line, 58.6% of patients receive biological targeted therapies in combination with chemotherapy, 25.4% immunotherapy, 11% combination chemotherapy and 5% biological targeted therapies. At 3rd line 56% of patients receive combination chemotherapy, 28% biological targeted therapies, 10% biological targeted therapies in combination with chemotherapy and 6% immunotherapy. The weighted annual cost (pharmaceuticals and resource use cost) in 1st line per mCRC patient was calculated at €28,407, in 2nd line €33,568, in 3rd line €25,550. The annual cost beyond 3rd line per patient regardless mutation was €19,501 per mCRC patient.

Conclusions

mCRC is a societal challenge for healthcare systems as the treatment is more prolonged but expand patients’ survival. Thus, reimbursement decisions should be based not just on the cost of the treatment, but on the magnitude of the benefit of its treatment on patients’ survival and quality of life.
Primary antiphospholipid syndrome in pediatrics: beyond thrombosis. Report of 32 cases and review of the evidence
Authors: Torres-Jimenez Alfonso-Ragnar , Ramirez-Nova Virginia , Cespedes-Cruz Adriana Ivonne , Sanchez-Jara Berenice , Velazquez-Cruz Alejandra , Bekker-Méndez Vilma Carolina , Guerra-Castillo Francisco Xavier
Published: February 2022

Objective

Describe the frequency of thrombotic and non-thrombotic clinical manifestations, laboratory, treatment and prognosis in patients with pediatric primary antiphospholipid syndrome.

Material and methods

A retrospective study was carried out in patients with a diagnosis of primary antiphospholipid antibody syndrome, under 16 years of age, under follow-up by the pediatric rheumatology service of the General Hospital, National Medical Center, La Raza, from January 2013 to December 2020. The antiphospholipid syndrome was defined when it met the laboratory criteria of the Sidney criteria and the presence of thrombosis or non-criteria manifestations of the disease (hematological, neurological, cutaneous, renal, cardiac or pulmonary). Demographic, clinical, laboratory, treatment, and prognosis data were collected.

Results

We report 32 patients, 21 female (65%) and 11 male (35%), mean age 11.75 years, evolution time 16 weeks. Thrombosis 9 patients (28%), 1 arterial and 8 venous. Non-thrombotic manifestations; Hematologic: thrombocytopenia 22 patients (69%), autoimmune hemolytic anemia 13 (40%), Fisher-Evans syndrome 6 (19%), lupus anticoagulant with hypoprothrombinemia syndrome 2 (6%). Dermatological: livedo reticularis 20 (62%), skin ulcers 2 (6%), Raynaud's phenomenon 8 (25%). Neurological: epilepsy 1 (3%), migraine 3 (9%), chorea 1 (3%) and cognitive impairment 3 (9%). Renal in 4 (13%). Laboratory: prolonged aPTT 30 (93%), lupus anticoagulant 32 (100%), positive IgG anticardiolipin 20 (62%), positive IgM anticardiolipin 19 (60%). AntiB2GPI was performed in only 3 patients, being positive in all. Treatment: anticoagulation in patients with thrombosis, antiplatelet in 23 (72%), steroid 30 (94%), immunosuppressant 30 (94%) and rituximab 4 (12.5%). No deaths were reported.

Conclusions

The clinical characteristics of patients with pediatric primary antiphospholipid syndrome differ from those presented in adults, since non-thrombotic manifestations are more frequent in children, for which classification criteria that include these manifestations are necessary for a better characterization of the disease in pediatric population.
Exploring the intersection of adverse childhood experiences, pediatric chronic pain, and rheumatic disease
Authors: Sonagra Maitry , Jones Jeremy , McGill Mackenzie , Gmuca Sabrina
Published: February 2022

Background

While the general relationship between ACEs and the development of chronic pain has become increasingly clear, how ACEs may shape a child’s clinical presentation with regards to chronic pain has yet to be fully expounded. We aimed to determine the association between ACEs and clinical manifestations of pediatric chronic pain and explore the interaction of ACEs and pediatric rheumatic disease among youth with chronic pain on health-related outcomes.

Methods

We conducted a cross-sectional cohort study of patients aged ≤18 years with chronic pain seen in a pediatric rheumatology amplified pain clinic between August 2018 and July 2020. We stratified subjects into three groups: no ACEs, one ACE, and ≥ 2 ACEs. We assessed clinical signs and symptoms associated with the presence of ACEs using Chi-square or Wilcoxon-rank test. The association between ACEs as well as other variables of interest with functional impairment was tested using simple and multivariable linear regression.

Results

Of the 412 patients included, more than 75% of patients reported at least one ACE. Most frequent included history of mental illness in a first degree relative (56%) and parental divorce or separation (20%). Those with ≥2 ACEs had more somatic symptoms, worse functional disability, and a higher proportion of mental health conditions. There appeared to be a dose dependent interaction between ACEs and functional disability from co-morbid rheumatologic disease. In multivariable regression, higher verbal pain score, symptom severity score (SSS), and presence of autonomic changes were associated with estimated average increase in FDI score (β = 1.05, 1.95 and 4.76 respectively; all p < 0.01).

Conclusion

Children with chronic pain and/or rheumatologic diseases who are exposed to ACEs are at increased risk of greater symptomatology, functional disability, and somatization of symptoms. Our findings indicate an ongoing need for systemic evaluation of ACEs in children with chronic pain and/or rheumatic disease and incorporation of trauma-based care.
Higher levels of neurofilament light chain and total tau in CSF are associated with negative outcome after shunt surgery in patients with normal pressure hydrocephalus
Authors: Braun Madelene , Bjurnemark Caroline , Seo Woosung , Freyhult Eva , Nyholm Dag , Niemelä Valter , Blennow Kaj , Zetterberg Henrik , Fällmar David , Kultima Kim , Virhammar Johan
Published: February 2022

Background

Lumbar punctures are a common examination in the work-up of patients with idiopathic normal pressure hydrocephalus (iNPH) and cerebrospinal fluid (CSF) biomarkers should therefore be available for use in selection of shunt candidates. The aim of this study was to investigate if CSF biomarkers are associated with outcome after shunt surgery alone or in combination with comorbidity and imaging markers, and investigate associations between CSF biomarkers and symptoms.

Methods

Preoperative CSF biomarkers were analyzed in 455 patients operated with shunt surgery for iNPH at a single center during 2011–2018. Symptoms before and 12 months after shunt surgery were graded with the Swedish iNPH scale. Neurofilament light chain protein (NfL), total tau (T-tau), phosphorylated tau (P-tau) and amyloid beta1-42 (Aβ1-42) CSF levels were measured. Evans’ index and disproportionately enlarged subarachnoid space hydrocephalus were measured on preoperative CT-scans. Preoperative evaluation and follow-up 12 months after shunt surgery were available in 376 patients.

Results

Higher levels of NfL and T-tau were associated with less improvement after shunt surgery (β = − 3.10, p = 0.016 and β = − 2.45, p = 0.012, respectively). Patients whose symptoms deteriorated after shunt surgery had higher preoperative levels of NfL (1250 ng/L [IQR:1020–2220] vs. 1020 [770–1649], p < 0.001) and T-tau (221 ng/L [IQR: 159–346] vs. 190 [135–261], p = 0.0039) than patients with postoperative improvement on the iNPH scale. Among the patients who improved ≥ 5 levels on the iNPH scale (55%), NfL was abnormal in 22%, T-tau in 14%, P-tau in 6% and Aβ1-42 in 45%, compared with normal reference limits. The inclusion of CSF biomarkers, imaging markers and comorbidity in multivariate predictive Orthogonal Projections to Latent Structures (OPLS) models to did not improve predictability in outcome after shunt surgery.

Conclusions

Higher levels of T-tau and NfL were associated with a less favorable response to shunt surgery, suggesting a more active neurodegeneration in this group of patients. However, CSF levels of these biomarkers can be elevated also in patients who respond to shunt surgery. Thus, none of these CSF biomarkers, alone or used in combination, are suitable for excluding patients from surgery.
Development of digital diagnostic templates by cluster analysis based on 2249 lateral cephalograms of Chinese Han population
Authors: Su Hong , Lu Wenhsuan , Deng Jingjing , Chen Gui , Jiang Ruoping , Wei Yan , Zhang Xiaoyun , Xu Tianmin , Han Bing
Published: February 2022

Background

To establish the digital diagnostic templates by cluster analysis based on a set of cephalometric films and evaluate the outcome of the different treatment methods in the patients affiliated to the same cephalometric morphology template (CMT). These templates could be used for the automatic diagnosis of dentofacial deformities and prediction of treatment outcomes in the future.

Methods

In this study, we assessed the coordinates of 60 different landmarks on the cephalograms of 2249 patients (14.35 ± 4.99 years, range from 7 to 62) with dentofacial deformities. The cephalometric data were subjected to dentist for clustering without a priori pattern definitions to generate biologically informative CMTs. Three templates were selected to evaluate the treatment outcome of patients affiliated to the same CMT.

Results

The cluster analysis yielded 21 distinct groups. The total discriminant accuracy was 89.1%, while the cross-validation accuracy was 85.0%, showing that the clusters were robust. All CMTs were automatically created and drawn using a computer, based on the average coordinates of each cluster. Individuals affiliated to the same CMT showed similar dentofacial features. We also evaluated differences in the outcomes of patients affiliated to the same CMT.

Conclusions

Our results demonstrated the utility of clustering methods for grouping dentofacial deformities with similar dentofacial features. Clustering methods can be used to evaluate the differences in the outcomes of patients affiliated to the same CMT, which has good clinical application value.
An updated view on the centrosome as a cell cycle regulator
Authors: Lin Muyang , Xie Shuang Shuang , Chan Kuan Yoow
Published: February 2022

The centrosome is a multifunctional organelle that is known primarily for its microtubule organising function. Centrosomal defects caused by changes in centrosomal structure or number have been associated with human diseases ranging from congenital defects to cancer. We are only beginning to appreciate how the non-microtubule organising roles of the centrosome are related to these clinical conditions. In this review, we will discuss the historical evidence that led to the proposal that the centrosome participates in cell cycle regulation. We then summarize the body of work that describes the involvement of the mammalian centrosome in triggering cell cycle progression and checkpoint signalling. Then we will highlight work from the fission yeast model organism, revealing the molecular details that explain how the spindle pole body (SPB, the yeast functional equivalent of the centrosome), participates in these cell cycle transitions. Importantly, we will discuss some of the emerging questions from recent discoveries related to the role of the centrosome as a cell cycle regulator.
Clusters, lines and webs—so does my patient have psychosis? reflections on the use of psychiatric conceptual frameworks from a clinical vantage point
Authors: Kovacs Tibor Zoltan , Hill Reece William , Watson Stuart , Turkington Douglas
Published: February 2022

Mental health professionals working in hospitals or community clinics inevitably face the realisation that we possess imperfect conceptual means to understand mental disorders. In this paper the authors bring together ideas from the fields of Philosophy, Psychiatry, Cognitive Psychology and Linguistics to reflect on the ways we represent phenomena of high practical importance that we often take for granted, but are nevertheless difficult to define in ontological terms. The paper follows through the development of the concept of psychosis over the last two centuries in the interplay of three different conceptual orientations: the categorical, dimensional and network approaches. Each of these represent the available knowledge and dominant thinking styles of the era in which they emerged and take markedly different stances regarding the nature of mental phenomena. Without particular commitment to any ontological positions or models described, the authors invite the reader into a thinking process about the strengths and weaknesses of these models, and how they can be reconciled in multidisciplinary settings to benefit the process of patient care.
Development of models of care coordination for rare conditions: a qualitative study
Authors: Walton Holly , Simpson Amy , Ramsay Angus I. G. , Hunter Amy , Jones Jennifer , Ng Pei Li , Leeson-Beevers Kerry , Bloom Lara , Kai Joe , Kokocinska Maria , Sutcliffe Alastair G. , Morris Stephen , Fulop Naomi J.
Published: February 2022

Introduction

Improving care coordination for people with rare conditions may help to reduce burden on patients and carers and improve the care that patients receive. We recently developed a taxonomy of different ways of coordinating care for rare conditions. It is not yet known which models of care coordination are appropriate in different situations. This study aimed to: (1) explore what types of care coordination may be appropriate in different situations, and (2) use these findings to develop hypothetical models of care coordination for rare conditions.

Methods

To explore appropriateness of different types of care coordination, we conducted interviews (n = 30), four focus groups (n = 22) and two workshops (n = 27) with patients, carers, healthcare professionals, commissioners, and charity representatives. Participants were asked about preferences, benefits and challenges, and the factors influencing coordination. Thematic analysis was used to develop hypothetical models of care coordination. Models were refined following feedback from workshop participants.

Results

Stakeholders prefer models of care that: are nationally centralised or a hybrid of national and local care, involve professionals collaborating to deliver care, have clear roles and responsibilities outlined (including administrative, coordinator, clinical and charity roles), provide access to records and offer flexible appointments (in terms of timing and mode). Many factors influenced coordination, including those relating to the patient (e.g., condition complexity, patient’s location and ability to coordinate their own care), the healthcare professional (e.g., knowledge and time), the healthcare environment (e.g., resources) and societal factors (e.g., availability of funding). We developed and refined ten illustrative hypothetical models of care coordination for rare conditions.

Conclusion

Findings underline that different models of care coordination may be appropriate in different situations. It is possible to develop models of care coordination which are tailored to the individual in context. Findings may be used to facilitate planning around which models of care coordination may be appropriate in different services or circumstances. Findings may also be used by key stakeholders (e.g. patient organisations, clinicians and service planners) as a decision-making tool.
Clinical measurement of cellular DNA damage hypersensitivity in patients with DNA repair defects
Authors: Hammarsten Ola , Lyytikäinen Anna , Thunström Sofia , Ek Torben , Fasth Anders , Ekwall Olov , Cajander Sara , Borgström Emilie Wahren , Smith C. I. Edvard , Johansson Pegah
Published: February 2022

Background

DNA repair deficiency disorders are rare inherited diseases arising from pathogenic (disease-causing) variants in genes involved in DNA repair. There are no standardized diagnostic assays for the investigation of pathological significance of unknown variants in DNA repair genes. We hypothesized that our assays for measuring in vitro patient blood cell hypersensitivity to DNA-damaging agents can be used to establish the pathological significance of unknown variants in DNA repair genes. Six patients with variants in the DNA repair genes PRKDC (two siblings), DCLRE1C (two siblings), NBN, and MSH6 were included. Here, we used the cell division assay (CDA) and the γ-H2AX assay, which were both developed and clinically validated by us, to measure patient cell hypersensitivity in response to ionizing radiation, mitomycin C, cytarabine and doxorubicin.

Results

Radiation hypersensitivity was detected in the two patients with variants in the PRKDC gene (p < 0.0001 for both at 3.5 Gy), and the two patients with DCLRE1C variants (p < 0.0001 at 3.5 Gy for sibling 1 and p < 0.0001 at 1 Gy for sibling 2). The cells from the patients with the PRKDC variant were also deficient in removing γ-H2AX (p < 0.001). The cells from the patient with variants in the NBN gene were hypersensitive to mitomycin C (p = 0.0008) and deficient in both induction and removal of γ-H2AX in response to radiation.

Conclusions

The combination of the CDA and the γ-H2AX assay is useful in investigating the significance of unknown variants in some DNA repair genes.
A mediation analysis of the role of girl child marriage in the relationship between proximity to conflict and past-year intimate partner violence in post-conflict Sri Lanka
Authors: Fonseka Ruvani W. , McDougal Lotus , Raj Anita , Reed Elizabeth , Lundgren Rebecka , Urada Lianne , Silverman Jay G.
Published: February 2022

Background

Studies from many contexts indicate that proximity to conflict is associated with increased likelihood of intimate partner violence (IPV), and girl child marriage is associated with both proximity to conflict and increased IPV. In this study, we consider whether girl child marriage acts as a mediator of the association between proximity to conflict and IPV in the context of Sri Lanka, which sustained long-term conflict until 2009.

Methods

We analyzed responses of currently partnered women between ages 18 and 49 in the 2016 Sri Lankan Demographic and Health Survey (N = 13,691). Using logistic regression analyses, we measured associations between proximity to conflict (residence in districts which were central, proximal, or distal to the regions where the war occurred) and the outcomes of IPV and girl child marriage, and secondarily assessed girl child marriage as a possible mediator of the association between proximity to conflict and past year IPV.

Results

Women residing in districts central to conflict, as compared to districts distal to conflict, had increased odds of past year sexual, physical, and emotional IPV, with the odds of sexual IPV increasing the most (adjusted odds ratio/aOR 4.19, 95% confidence interval/CI 2.08–8.41). Residing in districts proximal to conflict compared to those distal to conflict was associated with lower odds of past year physical and emotional IPV, with the greatest decrease in emotional IPV (aOR 0.31, CI 0.18–0.54). Girl child marriage was more likely in districts central to conflict as opposed to those distal to conflict (aOR 1.89, CI 1.22–2.93), and partially mediated the relationship between centrality to conflict and IPV.

Conclusions

Our findings demonstrate that residing in districts central to conflict compared to those distal to conflict is associated with greater odds of IPV and girl child marriage in post-conflict Sri Lanka, with girl child marriage partially mediating the association between centrality to conflict and IPV. Residence in districts proximal to conflict appears protective against IPV. Future research should investigate what factors are responsible for decreased IPV in districts proximal to violence, and whether these factors can be reproduced to mitigate the increased prevalence of IPV in districts central to conflict.
What if children with psychiatric problems disagree with their clinicians on the need for care? Factors explaining discordance and clinical directions
Authors: Vijverberg Richard , Ferdinand Robert , Beekman Aartjan , van Meijel Berno
Published: February 2022

Background

Children and adolescents in mental healthcare often perceive their care needs and necessary treatment differently from their clinicians. As such discordance between young patients and clinicians may obstruct treatment adherence and compromise treatment outcomes, it is important to understand the factors associated with it. We therefore investigated the factors associated with patient–clinician discordance with regard to care needs in various areas of functioning.

Methods

A cross-sectional study involving 244 children/adolescents aged 6–18 participating with their clinicians in treatment at a specialized mental healthcare center. As a previous study conducted by our research group had found the greatest patient–clinician discordance in three CANSAS care needs—“mental health problems,” “information regarding diagnosis and/or treatment,” and “making and/or keeping friends”—we used univariable and multivariable statistics to investigate the factors associated with discordance regarding these three care needs.

Results

patient–clinician discordance on the three CANSAS items was associated with child, parent, and family/social-context factors. Three variables were significant in each of the three final multivariable models: dangerous behavior towards self (child level); severity of psychiatric problems of the parent (parent level); and growing up in a single-parent household (family/social-context level).

Conclusions

To deliver treatment most effectively and to prevent drop-out, it is important during diagnostic assessment and treatment planning to address the patient’s care needs at all three levels: child, parent and family/social context.
Influenza, dengue and common cold detection using LSTM with fully connected neural network and keywords selection
Authors: Nadda Wanchaloem , Boonchieng Waraporn , Boonchieng Ekkarat
Published: February 2022

Symptom-based machine learning models for disease detection are a way to reduce the workload of doctors when they have too many patients. Currently, there are many research studies on machine learning or deep learning for disease detection or clinical departments classification, using text of patient’s symptoms and vital signs. In this study, we used the Long Short-term Memory (LSTM) with a fully connected neural network model for classification, where the LSTM model was used to receive the patient’s symptoms text as input data. The fully connected neural network was used to receive other input data from the patients, including body temperature, age, gender, and the month the patients received care in. In this research, a data preprocessing algorithm was improved by using keyword selection to reduce the complexity of input data for overfitting problem prevention. The results showed that the LSTM with fully connected neural network model performed better than the LSTM model. The keyword selection method also increases model performance.
A boy with blistering of sun-exposed skin and finger shortening: the first case of Variegate Porphyria with a novel mutation in protoporphyrinogen oxidase (PPOX) gene in Iran: a case report and literature review
Authors: Vafaee-Shahi Mohammad , Ghasemi Saeide , Riahi Aina , Sadr Zahra
Published: February 2022

Variegate Porphyria (VP) is an inherited rare disorder that is caused by mutations in the protoporphyrinogen oxidase (PPOX) gene. This deficiency is associated with the accumulation of porphyrins and porphyrin precursors in the body, which, in turn, can potentially result in a variety of skin and neurological symptoms. Here, we reported a 7-year-old boy with homozygous VP and novel mutation on PPOX gene. He was admitted with three episodes of generalized tonic-clonic seizure in the last 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin. The weakness of limbs and brachydactyly were observed. In the follow-up, he had aggressive behavior, learning disability and abdominal pain, particularly around the navel. Eventually, the whole exome sequencing (WES) result reported a novel homozygous pathogenic variant (c.1072G > A p.G358R) in PPOX gene which confirmed the VP. He had been advised to be away from the sun and use sunscreen regularly.
Comparison of erector spinae plane and paravertebral nerve blocks for postoperative analgesia in children after the Nuss procedure: study protocol for a randomized controlled non-inferiority clinical trial
Authors: Xu Min , Zhang Guangchao , Gong Jingxuan , Yang Jing
Published: February 2022

Background

Thoracic paravertebral block (TPVB) is a widely advocated regional technique for alleviating postoperative pain in children undergoing elective pectus excavatum repair. However, this technique is associated with some undesirable adverse events. Recently, the erector spinae plane block (ESPB) has been introduced as a practical alternative to the TPVB in thoracic surgery. This interfascial regional anesthesia technique interrupts pain sensation by injecting local anesthetics between the muscular layers of the thoracic wall. Several case series described it as an effective pain management technique following pectus excavatum repair. Therefore, this trial is designed to test the hypothesis that ESPB is non-inferior to TPVB in postoperative pain control after pectus excavatum repair.

Methods

This is a prospective randomized double-blind non-inferiority trial. A total of 40 patients aged 4 to 18 years undergoing Nuss surgery will be randomly assigned to receive pain treatment with either ESPB or TPVB. All patients will receive additional systemic multimodal analgesia with an intravenous patient-controlled analgesia pump and acetaminophen. The primary outcome is the pain intensity at rest, 24 h postoperatively. Secondary outcomes include accumulated morphine-equivalent consumption, postoperative pain scores, emergence agitation incidence, time of the first mobilization, time to first rescue analgesia, complications related to pain treatment, and morphine-related adverse events.

Discussion

This will the first randomized controlled trial to compare ESPB with TPVB for analgesia after pectus excavatum repair. This trial aims to provide important clinical evidence to elaborate on the analgesic mechanism of ESPB in children.

Trial registration

ClinicalTrials.govNCT05034601. This trial was prospectively registered.
Review of the recruitment process for a large investigator-initiated trial in early Parkinson’s disease
Authors: Verschuur C. V. M. , Donovan J. L. , de Bie R. M. A.
Published: February 2022

Introduction

Organizing and executing a large clinical trial is a complex process, and often recruitment targets are not met. We describe the organization of the Levodopa in the Early Parkinson’s disease (LEAP) trial and the results of an external assessment of the recruitment process.

Methods

Several strategies were used to ensure that recruitment for the trial was effective and efficient. We analyzed the patterns in referrals, inclusions, and non-inclusions to investigate whether there were bottlenecks in the referral and inclusion process. For the external assessment of the recruitment process, the QuinteT Recruitment Intervention (QRI-Two) was used retrospectively, focusing on finding possible issues impeding recruitment that are less easily recognized.

Results

Recruitment took 57 months, which was 27 months longer than initially expected. 6.8% of the estimated eligible patients in the Netherlands were included. The number of referrals differed widely between participating centers and regions in the Netherlands, with the region of the principal study center having the most referrals. Reasons of exclusion varied across regions, as in some regions more patients already started, wanted to start, or did not want to start with Parkinson medication compared to other regions.

Discussion

Executing a large, investigator-initiated clinical trial on a limited budget still remains possible by focusing on minimizing administrative and organizational procedures. Our study suggests that centers with closer institutional ties to a principal study center tend to have a higher referral rate. The review of the LEAP trial recruitment strategies and data using the QRI-Two suggested that the variations in referrals and reasons of non-inclusion could indicate the presence of issues related to clinical equipoise, patient eligibility, or study presentation. Integrating a recruitment intervention could have explored issues with study presentation and equipoise that might have increased recruitment efficiency.

Trial registration

ISRCTN ISRCTN30518857. The registration was initiated on 02/08/2011 and finalized on 25/08/2011. Recruitment started on 17/08/2011, after the initiation of public registration.
Recruitment to a large scale randomised controlled clinical trial in primary care: the Helicobacter Eradication Aspirin Trial (HEAT)
Authors: Stevenson Diane J. , Avery Anthony J. , Coupland Carol , Hobbs F. D. Richard , Kendrick Denise , Moore Michael V. , Morris Clive , Rubin Greg P. , Smith Murray D. , Hawkey Christopher J. , Dumbleton Jennifer S.
Published: February 2022

Background

The Helicobacter Eradication Aspirin Trial (HEAT) is a multicentre, double blind, randomised controlled trial investigating whether Helicobacter (H.) pylori eradication reduces hospitalisation for peptic ulcer bleeding. Recruited participants were aged 60 and over and taking aspirin (≤325 mg daily) for at least four months prior to consent. Based on results of a pilot study, a sample size calculation predicted 6600 H. pylori-positive randomised participants would be required, from 33,000 volunteers, recruited from 170,000 invited patients. Methodology was therefore designed for recruitment of large numbers of patients from primary care using a novel electronic search tool, automated mail-out and electronic follow-up. Recruitment started in 2012 and completed in 2017.

Methods

All participants were recruited from GP practices, with assistance from the UK Clinical Research Network (UKCRN). H. pylori-positive participants were randomised to one week of eradication treatment or placebo. Recruitment was managed using a bespoke web-based database that communicated directly with a programmed search tool downloaded at participating practices. The primary endpoint is hospitalisation due to peptic ulcer bleeding. The trial will end when 87 adjudicated events have occurred, identified from searches of GP databases, review of secondary care admission data and mortality data, and reported events from randomised participants and GPs.

Results

HEAT has recruited participants from 1208 GP practices across the UK. Of the 188,875 invitation letters sent, 38,771 returned expressions of interest. Of these, 30,166 patients were consented to the trial, of whom 5355 H. pylori-positive participants (17.8% of those consented) were randomised.

Mean age at consent was 73.1 ± 6.9 (SD) years and 72.2% of participants were male. Of the randomised (H. pylori-positive) participants, 531 have died (as of 17 Sep 2020); none of the deaths was due to trial treatment.

Conclusion

The HEAT trial methodology has demonstrated that recruitment of large numbers of patients from primary care is attainable, with the assistance of the UKCRN, and could be applied to other clinical outcomes studies.

Trial registration

ClinicalTrials.gov; registration number NCT01506986. Registered on 10 Jan 2012.
Distribution of acetylcholinesterase (Ace-1R) target-site G119S mutation and resistance to carbamates and organophosphates in Anopheles gambiae sensu lato populations from Cameroon
Authors: Binyang Achille Jerome , Elanga-Ndille Emmanuel , Tene-Fossog Billy , Ndo Cyrille , Nouage Lynda , Assatse Tatiane , Fotso-Toguem Yvan , Tabue Raymond , Zeukeng Francis , Nguiffo Daniel Nguete , Etang Josiane , Njiokou Flobert , Wondji Charles S.
Published: February 2022

Background

Cameroon is considering the implementation of indoor residual spraying (IRS) as a complementary measure to control malaria in the context of high pyrethroid resistance in major malaria vectors. Non-pyrethroid insecticide classes such as organophosphates and carbamates may be utilized in IRS due to widespread pyrethroid resistance. However, the success of this strategy depends on good knowledge of the resistance status of malaria vectors to carbamates and organophosphates. Here, we assessed the susceptibility profile of Anopheles gambiae sensu lato with respect to carbamates and organophosphate and the distribution of the molecular mechanism underlying resistance to these insecticides.

Methods

Anopheles gambiae s.l. mosquitoes were collected from nine settings across the country and bio-assayed with bendiocarb, propoxur and pirimiphos-methyl. The Ace-1 target-site G119S mutation was genotyped using a TaqMan assay. To investigate the polymorphism in the Ace-1 gene, a region of 924 base pairs in a sequence of the gene was amplified from both live and dead females of An. gambiae exposed to bendiocarb.

Results

Pirimiphos-methyl induced full mortality in An. gambiae s.l. from all study sites, whereas for carbamates, resistance was observed in four localities, with the lowest mortality rate recorded in Mangoum (17.78 ± 5.02% for bendiocarb and 18.61 ± 3.86% for propoxur) in the southern part of Cameroon. Anopheles coluzzii was found to be the predominant species in the northern tropical part of the country where it is sympatric with Anopheles arabiensis. In the localities situated in southern equatorial regions, this species was predominant in urban settings, while An. gambiae was the most abundant species in rural areas. The G119S Ace-1 target-site mutation was detected only in An. gambiae and only in the sites located in southern Cameroon. Phylogenetic analyses showed a clustering according to the phenotype.

Conclusion

The occurrence of the Ace-1 target-site substitution G119S in An. gambiae s.l. populations highlights the challenge associated with the impending deployment of IRS in Cameroon using carbamates or organophosphates. It is therefore important to think about a resistance management plan including the use of other insecticide classes such as neonicotinoids or pyrrole to guarantee the implementation of IRS in Cameroon.

Graphical Abstract
Seasonality and transmissibility of Plasmodium ovale in Bagamoyo District, Tanzania
Authors: Tarimo Brian B. , Nyasembe Vincent O. , Ngasala Billy , Basham Christopher , Rutagi Isaack J. , Muller Meredith , Chhetri Srijana B. , Rubinstein Rebecca , Juliano Jonathan J. , Loya Mwajabu , Dinglasan Rhoel R. , Lin Jessica T. , Mathias Derrick K.
Published: February 2022

Background

Plasmodium ovale is a neglected malarial parasite that can form latent hypnozoites in the human liver. Over the last decade, molecular surveillance studies of non-falciparum malaria in Africa have highlighted that P. ovale is circulating below the radar, including areas where Plasmodium falciparum is in decline. To eliminate malaria where P. ovale is endemic, a better understanding of its epidemiology, asymptomatic carriage, and transmission biology is needed.

Methods

We performed a pilot study on P. ovale transmission as part of an ongoing study of human-to-mosquito transmission of P. falciparum from asymptomatic carriers. To characterize the malaria asymptomatic reservoir, cross-sectional qPCR surveys were conducted in Bagamoyo, Tanzania, over three transmission seasons. Positive individuals were enrolled in transmission studies of P. falciparum using direct skin feeding assays (DFAs) with Anopheles gambiae s.s. (IFAKARA strain) mosquitoes. For a subset of participants who screened positive for P. ovale on the day of DFA, we incubated blood-fed mosquitoes for 14 days to assess sporozoite development.

Results

Molecular surveillance of asymptomatic individuals revealed a P. ovale prevalence of 11% (300/2718), compared to 29% (780/2718) for P. falciparum. Prevalence for P. ovale was highest at the beginning of the long rainy season (15.5%, 128/826) in contrast to P. falciparum, which peaked later in both the long and short rainy seasons. Considering that these early-season P. ovale infections were low-density mono-infections (127/128), we speculate many were due to hypnozoite-induced relapse. Six of eight P. ovale-infected asymptomatic individuals who underwent DFAs successfully transmitted P. ovale parasites to A. gambiae.

Conclusions

Plasmodium ovale is circulating at 4–15% prevalence among asymptomatic individuals in coastal Tanzania, largely invisible to field diagnostics. A different seasonal peak from co-endemic P. falciparum, the capacity to relapse, and efficient transmission to Anopheles vectors likely contribute to its persistence amid control efforts focused on P. falciparum.

Graphical Abstract
Association of DNA repair genes polymorphisms with childhood acute lymphoblastic leukemia: a high-resolution melting analysis
Authors: Zehtab Shahrzad , Sattarzadeh Bardsiri Mahla , Mirzaee Khalilabadi Roohollah , Ehsan Mohsen , Fatemi Ahmad
Published: February 2022

Objective

Acute lymphoblastic leukemia (ALL) is one of the most common cancers in children for which the exact pathogenesis is not yet known. Single-nucleotide variants (SNVs) in different DNA repair genes are reported to be associated with ALL risk. This study aimed to determine the association between XRCC1 (rs1799782) and NBN (rs1805794, rs709816) SNVs and childhood ALL risk in a sample of the Iranian population. Fifty children with ALL and 50 age- and sex-matched healthy children were included in this case–control study. Genotyping of the mentioned SNVs was done by high-resolution melting (HRM) analysis.

Results

The prevalence of all three SNVs in XRCC1 and NBN genes did not differ between the patient and control groups, and these polymorphisms were not associated with childhood ALL risk (P > 0.05). HRM was a practical method for the detection of SNVs in XRCC1 and NBN genes. We found no significant association between XRCC1 (rs1799782) and NBN (rs1805794, rs709816) SNVs and childhood ALL risk.
Nivolumab-related myasthenia gravis with myositis requiring prolonged mechanical ventilation: a case report
Authors: Saishu Yumi , Yoshida Takuya , Seino Yusuke , Nomura Takeshi
Published: February 2022

Background

Nivolumab is an immune checkpoint inhibitor that blocks inhibitors of T-cell activation and blunts antitumor immunity and is used in the treatment of various cancers. However, immune checkpoint inhibitors have immune-related adverse effects on various organs due to promoting T-cell activity against host tissues by blocking inhibition of T-cell function. Although immune-related adverse effects including hepatitis, colitis, pneumonitis, dermatitis, nephritis, endocrinopathies, and hypophysitis are well recognized with established treatment guidelines, neuromuscular immune-related adverse effects are rare phenomena.

Case presentation

A 55-year-old Asian (Japanese) woman was diagnosed with nivolumab-related myasthenia gravis with myositis and myocarditis. She had a past history of thymectomy for large thymoma with a high anti-acetylcholine receptor antibody level without any symptoms. Nivolumab was administered for the treatment of malignant melanoma. Creatine kinase levels began to rise 2 weeks after the administration, and abnormal neurological findings appeared 3 weeks after the administration. Ventricular arrhythmia, wide QRS complex, and dyssynchrony of the left ventricle also appeared. Intravenous immunoglobulin and corticosteroids were administered, and plasma exchange was performed. The patient required intensive care and prolonged mechanical ventilation with tracheostomy owing to weakness of the diaphragm; she was eventually weaned from the ventilator and discharged. Diaphragm ultrasound was used for the decision-making of the weaning strategy and evaluation of the diaphragmatic function.

Conclusions

Nivolumab-induced severe myasthenia gravis with myositis and myocarditis required intensive care and prolonged mechanical ventilation. Although immune checkpoint inhibitor-related myasthenia gravis is a rare adverse event, appropriate and prompt treatment is required because of its severity and rapid progression. Diaphragm ultrasound was useful not only in diagnosing diaphragm dysfunction and deciding the strategy for weaning from mechanical ventilation but also in evaluating the recovery of the diaphragmatic function.
Antemortem detection of Parkinson’s disease pathology in peripheral biopsies using artificial intelligence
Authors: Signaevsky Maxim , Marami Bahram , Prastawa Marcel , Tabish Nabil , Iida Megan A. , Zhang Xiang Fu , Sawyer Mary , Duran Israel , Koenigsberg Daniel G. , Bryce Clare H. , Chahine Lana M. , Mollenhauer Brit , Mosovsky Sherri , Riley Lindsey , Dave Kuldip D. , Eberling Jamie , Coffey Chris S. , Adler Charles H. , Serrano Geidy E. , White Charles L. , Koll John , Fernandez Gerardo , Zeineh Jack , Cordon-Cardo Carlos , Beach Thomas G. , Crary John F.
Published: February 2022

The diagnosis of Parkinson’s disease (PD) is challenging at all stages due to variable symptomatology, comorbidities, and mimicking conditions. Postmortem assessment remains the gold standard for a definitive diagnosis. While it is well recognized that PD manifests pathologically in the central nervous system with aggregation of α-synuclein as Lewy bodies and neurites, similar Lewy-type synucleinopathy (LTS) is additionally found in the peripheral nervous system that may be useful as an antemortem biomarker. We have previously found that detection of LTS in submandibular gland (SMG) biopsies is sensitive and specific for advanced PD; however, the sensitivity is suboptimal especially for early-stage disease. Further, visual microscopic assessment of biopsies by a neuropathologist to identify LTS is impractical for large-scale adoption. Here, we trained and validated a convolutional neural network (CNN) for detection of LTS on 283 digital whole slide images (WSI) from 95 unique SMG biopsies. A total of 8,450 LTS and 35,066 background objects were annotated following an inter-rater reliability study with Fleiss Kappa = 0.72. We used transfer learning to train a CNN model to classify image patches (151 × 151 pixels at 20× magnification) with and without the presence of LTS objects. The trained CNN model showed the following performance on image patches: sensitivity: 0.99, specificity: 0.99, precision: 0.81, accuracy: 0.99, and F-1 score: 0.89. We further tested the trained network on 1230 naïve WSI from the same cohort of research subjects comprising 42 PD patients and 14 controls. Logistic regression models trained on features engineered from the CNN predictions on the WSI resulted in sensitivity: 0.71, specificity: 0.65, precision: 0.86, accuracy: 0.69, and F-1 score: 0.76 in predicting clinical PD status, and 0.64 accuracy in predicting PD stage, outperforming expert neuropathologist LTS density scoring in terms of sensitivity but not specificity. These findings demonstrate the practical utility of a CNN detector in screening for LTS, which can translate into a computational tool to facilitate the antemortem tissue-based diagnosis of PD in clinical settings.