bluuebunny/crossref_metadata_2025 huggingface dataset:
Associated factors, inequalities, and spatial distribution of the use of modern contraceptive methods among women of reproductive age in Peru: a population-based cross-sectional study
Authors: Díaz-Alvites Ana Lucía , Yrala-Castillo Gonzalo , Al-kassab-Córdova Ali , Munayco César V.
Published: December 2022

Background

The use of contraceptive methods in Peru has remarkably increased in recent decades. Nevertheless, despite the completeness and accessibility of family planning methods, modern contraceptive methods utilization in Peru remains below the South American average. Thus, this study aimed to elucidate the factors associated with modern contraceptive use, as well as the presence of inequalities and the spatial distribution in Peruvian women aged 15–49 years in 2019.

Methods

A secondary data analysis was conducted using information from the 2019 Peruvian Demographic and Health Survey. We performed descriptive statistics, bivariate analysis, and Poisson multiple regression. Inequalities were estimated through concentration curves and Erreygers’ normalized concentration index. Spatial analysis included choropleth map, Global Moran’s I, Kriging interpolation and Getis-Ord-Gi* statistic.

Results

The prevalence of modern contraceptive use was 39.3% among Peruvian women of reproductive age. Modern contraceptive use was directly associated with youth (aPR 1.39), women having their first sexual intercourse before the age of 18 (aPR 1.41), and being married but not together (aPR 1.87). In addition, speaking Quechua or Aymara (aPR 0.87) and having no children (aPR 0.59) were inversely associated with utilization of modern contraceptives. We found the presence of inequalities in the use of contraceptive methods (pro-rich distribution), although the magnitude was low. Spatial analysis unveiled the presence of a clustered distribution pattern (Moran’s Index = 0,009); however, there was inter-departmental and intra-departmental heterogeneity in the predicted prevalence of the use of modern contraceptives. In addition, significant hot and cold spots were found in Peru.

Conclusion

Two out of five Peruvian women of reproductive age used modern contraceptives. It was associated with younger women’s age, younger age at first sexual intercourse, being married or cohabitant, among others. No substantial inequality was found in modern contraceptive use. The prevalence was heterogeneous at the intra- and inter-departmental level. Those departments located in the south, south-east, and north-east had the lowest prevalence. Therefore, nonfinancial barriers must be tackled through multi- and cross-sectoral efforts and continue to universally provide modern contraceptives.
The mental health and well-being effects of wildfire smoke: a scoping review
Authors: Eisenman David P. , Galway Lindsay P.
Published: December 2022

Background

Smoke from wildfires is a growing public health risk due to the enormous amount of smoke-related pollution that is produced and can travel thousands of kilometers from its source. While many studies have documented the physical health harms of wildfire smoke, less is known about the effects on mental health and well-being. Understanding the effects of wildfire smoke on mental health and well-being is crucial as the world enters a time in which wildfire smoke events become more frequent and severe. We conducted a scoping review of the existing information on wildfire smoke’s impact on mental health and well-being and developed a model for understanding the pathways in which wildfire smoke may contribute to mental health distress.

Methods

We conducted searches using PubMed, Medline, Embase, Google, Scopus, and ProQuest for 1990–2022. These searches yielded 200 articles. Sixteen publications met inclusion criteria following screening and eligibility assessment. Three more publications from the bibliographies of these articles were included for a total of 19 publications.

Results

Our review suggests that exposure to wildfire smoke may have mental health impacts, particularly in episodes of chronic and persistent smoke events, but the evidence is inconsistent and limited. Qualitative studies disclose a wider range of impacts across multiple mental health and well-being domains. The potential pathways connecting wildfire smoke with mental health and well-being operate at multiple interacting levels including individual, social and community networks, living and working conditions, and ecological levels.

Conclusions

Priorities for future research include: 1) applying more rigorous methods; 2) differentiating between mental illness and emotional well-being; 3) studying chronic, persistent or repeated smoke events; 4) identifying the contextual factors that set the stage for mental health and well-being effects, and 5) identifying the causal processes that link wildfire smoke to mental health and well-being effects. The pathways model can serve as a basis for further research and knowledge synthesis on this topic. Also, it helps public health, community mental health, and emergency management practitioners mitigate the mental health and well-being harms of wildfire smoke.
Physician and patient perceptions of surgical procedures for osteoarthritis of the knee in the United States, Europe, and Japan: results of a real-world study
Authors: Fukui N , Conaghan PG , Togo K , Ebata N , Abraham L , Jackson J , Berry M , Cappelleri JC , Pandit H
Published: December 2022

Background

Osteoarthritis (OA) is the most common form of arthritis, with the knee being the joint most frequently affected, and symptomatic knee OA affecting around one quarter of the general population. For patients who do not respond to non-pharmacologic or pharmacologic treatment, surgery is a recommended option. The objectives of this study were to compare the willingness of patients with knee OA to undergo surgery, together with reasons for delaying surgery, and factors affecting successful outcomes.

Methods

A point-in-time survey was conducted in 729 primary care physicians, rheumatologists, orthopedic surgeons, and 2,316 patients with knee OA across three geographical regions: Japan, the United States (US), and Europe (EUR: France, Spain, Italy, Germany, and the United Kingdom), in order to garner their perceptions of knee surgery. Regression models were used to identify factors that might affect patients’ and physicians’ perceptions of surgery, including severity of OA (mild/moderate/severe), number of affected joints, surgery status, and willingness to undergo or delay surgery.

Results

Baseline demographics were similar between US and EUR, although patients in Japan were more likely to be female, older, and only 7% in fulltime employment. We found that few patients with end-stage knee OA, across all regions, but particularly Japan, were willing to undergo surgery (Japan 17%, US 32%, EUR 38%), either through fear, or the lack of awareness of the risk/benefits. Moreover, surgeons are prepared to delay surgery in elderly or unwilling patients, due to their dissatisfaction with the outcome, and may defer surgery in younger patients due to the need for future revision. We also identified a disconnect between physicians, of whom over 80% consider improved functioning to be the most important outcome of surgery, and patients, who seek pain relief (Japan 60%, US 35%, EUR 14%). Since physicians across all regions considered pain reduction to be an indication of surgery success (Japan 27%, US 47%, EUR 43%), this may indicate a need for improved communication to patients on the potential benefits of surgery.

Conclusion

Managing the expectations of patients undergoing surgery remains an important goal in the treatment of knee OA and may help guide physician choice.
Clinical outcome and healing rate after meniscal bucket handle tear repair
Authors: Muench Lukas N. , Achtnich Andrea , Krivec Lukas , Diermeier Theresa , Woertler Klaus , Braun Sepp , Imhoff Andreas B. , Willinger Lukas
Published: December 2022

Background

Reports combining patient-reported outcome measures, clinical evaluation, and radiographic assessment of postoperative healing after arthroscopic repair of bucket-handle meniscal tears (BHMT) are scarce.

Methods

Patients who underwent arthroscopic repair for acute traumatic BHMTs between October 2011 and March 2016 with a minimum follow-up of two years were included. Postoperative outcome scores comprised the International Knee Documentation Society Score (IKDC), Lysholm score, Tegner activity score (TAS), and visual analog scale (VAS) for pain. Clinical meniscal healing failure was assessed according to Barrett’s criteria. Side-to-side difference in knee laxity was measured using KT-2000. Radiographic healing was assessed by 3-Tesla magnetic resonance imaging (MRI) and classified according to Henning’s criteria at final follow-up.

Results

Forty patients with a mean age of 32.0 ± 11.5 years were available for follow-up after 51.8 ± 14.3 months. Revision surgery by means of arthroscopic partial meniscectomy was performed in four patients (10%) prior to the follow-up visit. The clinical healing rate was 83.3% at final follow-up. Mean IKDC score was 82.8 ± 13.8 and Lysholm score was 77.4 ± 24.8. Of all patients, 87.5% reached or exceeded the patient-acceptable symptomatic state (PASS) criteria for the IKDC score at final follow-up. The median TAS was 6 and VAS for pain was 0.46 ± 0.9. Side-to-side difference in knee laxity was higher in patients with concomitant ACL reconstruction (2.1 ± 2.7 mm) compared to isolated BHMTs (1.0 ± 2.0 mm). MR examination showed 69.4% healed, 25.0% partially healed, and 5.6% unhealed menisci.

Conclusion

Patients who underwent repair for acute traumatic BHMTs achieved good to excellent clinical outcome along with a high rate of meniscal healing at a minimum follow-up of two years. Clinical and radiological healing rates were similarly satisfactory and most patients exceeded the PASS criteria for the IKDC score. Patients were able to reach a high postoperative activity level.

Level of evidence

Case Series; IV.
Children as an afterthought during COVID-19: defining a child-inclusive ethical framework for pandemic policymaking
Authors: Campbell Sydney , Carnevale Franco A.
Published: December 2022

Background

Following the SARS pandemic, jurisdictions around the world began developing ethical resource allocation frameworks for future pandemics—one such framework was developed by Thompson and colleagues. While this framework offers a solid backbone upon which decision-makers can rest assured that their work is driven by rigorous ethical processes and principles, it fails to take into account the nuanced experiences and interests of children and youth (i.e., young people) in a pandemic context. The current COVID-19 pandemic offers an opportunity to re-examine this framework from young people’s perspectives, informed by advances in childhood ethics and children’s rights.

Main body

In this paper, we revisit the Thompson et al. framework and propose adaptations to the ethical processes and values outlined therein. This work is informed by expertise in clinical ethics and literature related to impacts of COVID-19 and other pandemics on the health and well-being of children around the world, though with particular attention to Canada. During the processes of drafting this work, stakeholders were consulted—aligned with the approach used by Thompson and colleagues—to validate the interpretations provided. We also propose a new principle, namely practicability, to indicate the complex balance between what is possible and what is convenient that is required in ethically sound decisions in the context of services affecting young people. We outline and discuss the strengths and limitations of our work and indicate next steps for scholars in the areas of childhood studies and child health.

Conclusion

Efforts to ensure frameworks are truly child-inclusive should be the status-quo, so pandemic impacts and policy implications can be considered in advance of emergency preparedness contexts.
Equity assessment of the distribution of mental health beds in China: based on longitudinal data from 2011 to 2020
Authors: Fan Xin , Zhang Weibo , Guo Yanping , Cai Jun , Xie Bin
Published: December 2022

Background

Mental health problems have become a public health problem that needs to be solved in China. However, medical resources for mental healthcare remain insufficient and unevenly distributed. The Chinese central government has taken many measures to address this issue over the last decade. This study aimed to evaluate the changes in equity in mental health bed allocation from 2011 to 2020.

Methods

The data of this study came from the China Health Statistical Yearbook (2012–2021) and the China National Administrative Division Information Platform. The annual growth rate was used to evaluate the time trends of mental health beds. The Lorenz curve, Gini coefficient and Theil index were used to assess equity in the demographic and geographical dimensions. The distribution of mental health beds was visualized on a map using geographic information system (GIS) software.

Results

The total number of mental health beds in China increased steadily from 2011 to 2020. At the national level, the Gini coefficient and Theil index all exhibited downward trends over time. The mental health bed allocation in terms of the demographic dimension was relatively equitable, with Gini values all less than 0.3; however, the Gini coefficients by geographical area were all more than 0.6, indicating inequity. Intraregional contribution rates were higher than interregional contribution rates, which were all above 60%.

Conclusion

The overall distribution equity of mental health beds improved from 2011 to 2020. The equity of mental health beds in terms of population size is superior to that in terms of geographical area. Intraregional differences are the main source of inequity. In particular, differences within the western region need to be given attention. Thus, the findings from this study emphasize that the demographic and geographical distributions and all influencing factors should be considered when the government makes mental health resource allocation policies.
The cost of implementing the Systems Analysis and Improvement Approach for a cluster randomized trial integrating HIV testing into family planning services in Mombasa County, Kenya
Authors: Thomas Dorothy , Wanje George , Eastment McKenna C. , McClelland R. Scott , Mwaringa Emily , Patta Shem , Jaoko Walter , Kinuthia John , Abubakar Aisha , Sherr Kenneth , Barnabas Ruanne V.
Published: December 2022

Background

Although HIV testing in family planning (FP) clinics is a promising approach for engaging women in HIV treatment and prevention services, HIV testing rates are low in FP clinics in Kenya. In 2018, a cluster randomized trial was implemented in Mombasa, Kenya applying the Systems Analysis and Improvement Approach (SAIA) to integrate HIV testing into FP services (1K24HD088229-01). We estimated the incremental costs and explored cost drivers of the FP HIV SAIA implementation in Mombasa, Kenya.

Methods

We conducted a costing evaluation from the payer perspective for the FP HIV SAIA randomized control trial. We identified relevant activities for the intervention including start-up, training, research and FP HIV SAIA. We estimated activity time burden using a time-and motion study. We derived unit costs through staff interviews and programmatic budgets. We present cost estimates for two different scenarios: as-implemented including research and projected costs for a Ministry of Health-supported intervention. All costs are reported in 2018 USD.

Results

For an annual program output of 36,086 HIV tests administered to new FP clients, we estimated the total annual program cost to be $91,994 with an average cost per new FP client served of $2.55. Personnel and HIV rapid testing kits comprised 55% and 21% of programmatic costs, respectively. Assuming no changes to program outputs and with efficiency gains under the MOH scenario, the estimated cost per new FP client served decreased to $1.30 with a programmatic cost reduction of 49%.

Conclusion

FP HIV SAIA is a low-cost and flexible implementation strategy for facilitating integrated delivery of HIV testing alongside FP services. Although cost implications of the FP HIV SAIA intervention must continue to be evaluated over time, these findings provide context-specific cost data useful for budget planning and decision-making regarding intervention delivery and expansion.

Trial registration

The trial was registered
on December 15, 2016, with clinicaltrials.gov (NCT02994355).
Laboratory evaluation of a new integrative assay to phenotype plasma fibrinolytic system
Authors: Bareille Marion , Hardy Michael , Chatelain Bernard , Lecompte Thomas , Mullier François
Published: December 2022

Background

There is currently no universal and standardized test available to phenotype plasma fibrinolytic system.

Aims

Our main aims were to evaluate the performances of the ‘global fibrinolysis capacity’ assay (GFC) performed with the Lysis Timer® instrument, and to study the influence of some preanalytical conditions.

Method

Euglobulin clot lysis time (ECLT) and GFC were performed under several preanalytical conditions.

Results

GFC showed satisfactory intra- and inter-run precision. Frozen controls and reagents showed stability over the studied period.

There was no statistically significant difference between GFC assessed in plasma samples processed at 4 °C or at 20 °C. GFC assessed with frozen-thawed plasma samples was prolonged when compared to fresh samples (p = 0.014). The centrifugation scheme had no influence on PAI-1 activity levels, GFC and ECLT.

Reference interval for GFC ranges from 29.3 (C I90% = 26.9–31.9) to 49.5 (90% CI = 45.9–52.2) minutes.

In addition, a preliminary study in 40 healthy volunteers and 43 adult patients referred for investigation of a bleeding disorder was conducted to compare GFC and ECLT assays in their ability to classify samples with shortened or prolonged clot lysis times. Disagreements between ECLT and GFC were observed for 23 samples (out of 83), most of them minor.

Conclusion

GFC is suitable and convenient for a broad clinical use and can be performed with frozen-thawed plasma samples.

Unlike ECLT, GFC is designed to take into account the balance between inhibitors and activators of the fibrinolytic system and could detect both hypo- and hyperfibrinolytic states. Whether it is as suitable as or even better than ECLT to detect a bleeding tendency due to a hyperactive fibrinolytic system deserves to be properly investigated.
Discontinuation of biologic DMARDs in non-systemic JIA patients: a scoping review of relapse rates and associated factors
Authors: Gieling Job , van den Bemt Bart , Hoppenreijs Esther , Schatorjé Ellen
Published: December 2022

Background

Biologic disease-modifying antirheumatic drugs (bDMARDs) have changed the treatment of juvenile idiopathic arthritis (JIA) patients notably, as bDMARDs enable substantially more patients to achieve remission. When sustained remission is achieved, tapering or even discontinuation of the bDMARD is advocated, to reduce side effects and costs. However, when and how to discontinue bDMARD therapy and what happens afterwards, is less known.

Objectives

With this scoping review we aim to collect available data in current literature on relapse rate, time to relapse (TTR) and possible flare associated variables (such as time spent in remission and method of discontinuation) after discontinuing bDMARDs in non-systemic JIA patients.

Methods

We performed a literature search until July 2022 using the Pubmed database. All original studies reporting on bDMARD discontinuation in non-systemic JIA patients were eligible. Data on patient- and study characteristics, the applied discontinuation strategy, relapse rates and time to relapse were extracted in a standardized template.

Results

Of the 680 records screened, 28 articles were included in this review with 456 non-systemic JIA patients who tapered and/or stopped bDMARD therapy. Relapse rate after discontinuation of bDMARDs, either abruptly or following tapering, were 40–48%, 36.8–45.0% and 60–78% at 6, 8 and 12 months respectively. Total relapse rate ranged from 26.3% to 100%, with mean time to relapse (TTR) of 2 to 8.4 months, median TTR 3 to 10 months. All studies stated a good response after restart of therapy after flare.

JIA subtype, type of bDMARD, concomitant methotrexate use, treatment duration, tapering method, age, sex, and time in remission could not conclusively be related to relapse rate or TTR. However, some studies reported a positive correlation between flare and antinuclear antibodies positivity, younger age at disease onset, male sex, disease duration and delayed remission, which were not confirmed in other studies.

Conclusion

Flares seem to be common after bDMARD discontinuation, but little is known about which factors influence these flares in JIA patients. Follow up after discontinuation with careful registration of patient variables, information about tapering methods and flare rates are required to better guide tapering and/or stopping of bDMARDs in JIA patients in the future.
p53 immunostaining pattern is a useful surrogate marker for TP53 gene mutations
Authors: Sung You-Na , Kim Deokhoon , Kim Jihun
Published: December 2022

Background

TP53 is the most frequently mutated gene in the human cancer, and the awareness of its mutational status is useful in the diagnosis and treatment of cancer patients. In the present study, we investigated the association between TP53 gene mutations and p53 immunohistochemical staining (IHC) patterns and non-genetic effect of MDM2 as a negative regulator of p53.

Methods

A total of 135 solid cancer cases with next generation sequencing data were subjected to p53 IHC and classified as overexpression, null type or usual pattern.

Results

TP53 mutation was observed in 104 out of 135 cases (77.0%). When the TP53 mutations were annotated into DISRUPTED (truncations, frameshifts, splice site mutations, and deep deletions) and IF-DBD (in-frame mutations in the DNA binding domain), the null type p53 IHC pattern was associated with DISRUPTED mutations (sensitivity 86.2%, specificity 97.2%) while the overexpression pattern was associated with IF-DBD mutations (sensitivity 100%, specificity 81.7%). The specificity of p53 IHC usual pattern predicting wild type TP53 was also as high as 100%. Regardless of MDM2 amplification, p53 IHC pattern showed a perfect association with TP53 mutation pattern.

Conclusions

p53 IHC pattern (overexpression, null type, usual) reasonably predicted TP53 mutational status (DISRUPTED, IF-DBD), and MDM2 amplification status did not have any impact on the p53 IHC pattern.
Accuracy of acetabular cup placement during anterolateral supine total hip arthroplasty using intraoperative fluoroscopy: a retrospective study
Authors: Cho Eiji , Hisatome Takashi , Oda Shuhei , Fujimaki Hirohisa , Nakanishi Kazuyoshi
Published: December 2022

Background

In our institution, total hip arthroplasty (THA) is performed using the anterolateral supine (ALS) approach with intraoperative fluoroscopy. This study aimed to investigate and review the accuracy of acetabular cup placement in ALS-THA using intraoperative fluoroscopy.

Methods

A total of 142 patients with 154 joints (mean age 64.3 years, 30 males and 112 females) underwent ALS-THA with intraoperative fluoroscopy at the same institution. The target angle of the cup position was set at 40° for radiographic inclination (RI) and 5°–25° for radiographic anteversion (RA) based on the functional pelvic plane according to the pelvic motion during individual postural changes. The cup position angle was measured using postoperative computed tomography, and the error in the target angle was investigated.

Results

The target angle of RI was 40°, and the postoperative RI was 39.3° ± 4.3°. The target angle of the RA was 17° ± 2.6°, and the postoperative RA was 20.6° ± 3.7°. The absolute values of the error from the target angle were 3.6° ± 2.5° for RI and 4.2° ± 3.3° for RA.

For RI and RA, 67.5% (104/154 joints) were within ± 5° of the target and 96.1% (148/154 joints) were within ± 10°.

Conclusions

The accuracy of cup positioning in ALS-THA using intraoperative fluoroscopy was good and appeared comparable to that of various navigation systems.
Successful management of hemodynamic instability secondary to saddle pulmonary embolism-induced cardiac arrest using VA-ECMO in advanced malignancy with brain metastases
Authors: Pan Jianneng , Zhou Xiaoyang , Xu Zhaojun , Chen Bixin
Published: December 2022

Background

Saddle pulmonary embolism (SPE) represents a rare type of venous thromboembolism that frequently causes circulation collapse and sudden death. While venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been well established as a salvage treatment for SPE-induced circulatory shock, it is infrequently administered in patients with advanced malignancy, especially those with brain metastases, given the potential bleeding complications and an uncertain prognosis. As far, there are rare case reports regarding the successful management of hemodynamic instability secondary to SPE-induced cardiac arrest using VA-ECMO in advanced malignancy patients with brain metastases.

Case presentation

A 65-year-old woman presenting with cough and waist discomfort who had a history of lung cancer with brain metastases was admitted to the hospital to receive chemoradiotherapy. She suffered sudden cardiac arrest during hospitalization and returned to spontaneous circulation after receiving a 10-min high-quality cardiopulmonary resuscitation. Pulmonary embolism was suspected due to the collapsed hemodynamics and a distended right ventricle identified by echocardiography. Subsequent computed tomographic pulmonary angiography revealed a massive saddle thrombus straddling the bifurcation of the pulmonary trunk. VA-ECMO with adjusted-dose systemic heparinization was initiated to rescue the unstable hemodynamics despite receiving thrombolytic therapy with alteplase. Immediately afterward, the hemodynamic status of the patient stabilized rapidly. VA-ECMO was successfully discontinued within 72 h of initiation without any clotting or bleeding complications. She was weaned off invasive mechanical ventilation on the 6th day of intensive care unit (ICU) admission and discharged from the ICU 3 days later with good neurological function.

Conclusion

VA-ECMO may be a ‘bridging’ therapy to circulation recovery during reperfusion therapy for SPE-induced hemodynamic collapse in malignancy patients with brain metastases.
Systemic amyloidosis journey from diagnosis to outcomes: a twelve-year real-world experience of a single center in a middle-income country
Authors: Szor Roberta Shcolnik , Fernandes Fabio , Lino Angelina Maria Martins , Mendonça Leonardo Oliveira , Seguro Fernanda Salles , Feitosa Valkercyo Araujo , Castelli Jussara Bianchi , Jorge Lecticia Barbosa , de Oliveira Alves Lucas Bassolli , de Menezes Neves Precil Diego Miranda , de Oliveira Souza Evandro , Cavalcante Livia Barreira , Malheiros Denise , Kalil Jorge , Martinez Gracia Aparecida , Rocha Vanderson
Published: December 2022

Background

Systemic amyloidosis is caused by the deposition of misfolded protein aggregates in tissues, leading to progressive organ dysfunction and death. Epidemiological studies originate predominantly from high-income countries, with few data from Latin America. Due to the non-specific clinical manifestations, diagnosing amyloidosis is often challenging and patients experience a long journey and delay in diagnosis. This study aimed to assess clinical and laboratory characteristics, the diagnostic journey, and outcomes of patients with biopsy-proven systemic amyloidosis diagnosed between 2009 and 2020 at a university referral center in a middle-income Latin American country. Patients´ medical records were retrospectively reviewed.

Results

One hundred and forty-three patients were included. The median age at diagnosis was 60 years and 54% were male. Until the diagnosis, most of the patients (52%) were seen by at least 3 specialists, the main ones being: general practitioners (57%), nephrologists (45%), and cardiologists (38%). The most common manifestations were renal (54%) and cardiac (41%) disorders, and cachexia was seen in 36% of patients. In 72% of the cases, ≥ 2 biopsies were required until the final diagnosis. The median time from symptoms onset to diagnosis was 10.9 months, and most patients (75%) had ≥ 2 organs involved. The following subtypes were identified: AL (68%), ATTR (13%), AA (8%), AFib (4%), and inconclusive (7%). Median OS was 74.3 months in the non-AL subgroup and 18.5 months in AL. Among AL patients, those with advanced cardiac stage had the worst outcome [median OS 8.6 months versus 52.3 for stage III versus I–II, respectively (p < 0.001)]. AL subtype, cardiac involvement, and ECOG ≥ 2 were identified as independent risk factors for reduced survival.

Conclusions

Systemic amyloidosis is still an underdiagnosed condition and the delay in its recognition leads to poor outcomes. Medical education, better diagnostic tools, improvement in access to therapies, and establishment of referral centers may improve patient outcomes in middle-income countries.
Cortical pain induced by optogenetic cortical spreading depression: from whole brain activity mapping
Authors: Pi Chenghui , Tang Wenjing , Li Zhishuai , Liu Yang , Jing Qi , Dai Wei , Wang Tao , Yang Chunxiao , Yu Shengyuan
Published: December 2022

Background

Cortical spreading depression (CSD) is an electrophysiological event underlying migraine aura. Traditional CSD models are invasive and often cause injuries. The aim of the study was to establish a minimally invasive optogenetic CSD model and identify the active networks after CSD using whole-brain activity mapping.

Methods

CSD was induced in mice by light illumination, and their periorbital thresholds and behaviours in the open field, elevated plus-maze and light-aversion were recorded. Using c-fos, we mapped the brain activity after CSD. The whole brain was imaged, reconstructed and analyzed using the Volumetric Imaging with Synchronized on-the-fly-scan and Readout technique. To ensure the accuracy of the results, the immunofluorescence staining method was used to verify the imaging results.

Results

The optogenetic CSD model showed significantly decreased periorbital thresholds, increased facial grooming and freezing behaviours and prominent light-aversion behaviours. Brain activity mapping revealed that the somatosensory, primary sensory, olfactory, basal ganglia and default mode networks were activated. However, the thalamus and trigeminal nucleus caudalis were not activated.

Conclusions

Optogenetic CSD model could mimic the behaviours of headache and photophobia. Moreover, the optogenetic CSD could activate multiple sensory cortical regions without the thalamus or trigeminal nucleus caudalis to induce cortical pain.
Complexity of progranulin mechanisms of action in mesothelioma
Authors: Ventura Elisa , Xie Christopher , Buraschi Simone , Belfiore Antonino , Iozzo Renato V. , Giordano Antonio , Morrione Andrea
Published: December 2022

Background

Mesothelioma is an aggressive disease with limited therapeutic options. The growth factor progranulin plays a critical role in several cancer models, where it regulates tumor initiation and progression. Recent data from our laboratories have demonstrated that progranulin and its receptor, EphA2, constitute an oncogenic pathway in bladder cancer by promoting motility, invasion and in vivo tumor formation. Progranulin and EphA2 are expressed in mesothelioma cells but their mechanisms of action are not well defined. In addition, there are no data establishing whether the progranulin/EphA2 axis is tumorigenic for mesothelioma cells.

Methods

The expression of progranulin in various mesothelioma cell lines derived from all major mesothelioma subtypes was examined by western blots on cell lysates, conditioned media and ELISA assays. The biological roles of progranulin, EphA2, EGFR, RYK and FAK were assessed in vitro by immunoblots, human phospho-RTK antibody arrays, pharmacological (specific inhibitors) and genetic (siRNAs, shRNAs, CRISPR/Cas9) approaches, motility, invasion and adhesion assays. In vivo tumorigenesis was determined by xenograft models. Focal adhesion turnover was evaluated biochemically using focal adhesion assembly/disassembly assays and immunofluorescence analysis with focal adhesion-specific markers.

Results

In the present study we show that progranulin is upregulated in various mesothelioma cell lines covering all mesothelioma subtypes and is an important regulator of motility, invasion, adhesion and in vivo tumor formation. However, our results indicate that EphA2 is not the major functional receptor for progranulin in mesothelioma cells, where progranulin activates a complex signaling network including EGFR and RYK. We further characterized progranulin mechanisms of action and demonstrated that progranulin, by modulating FAK activity, regulates the kinetic of focal adhesion disassembly, a critical step for cell motility.

Conclusion

Collectively, our results highlight the complexity of progranulin oncogenic signaling in mesothelioma, where progranulin modulate functional cross-talks between multiple RTKs, thereby suggesting the need for combinatorial therapeutic approaches to improve treatments of this aggressive disease.
Associations between quantitative measures of TDLU involution and breast tumor molecular subtypes among breast cancer cases in the Black Women’s Health Study: a case–case analysis
Authors: Davis Lynn Brittny C. , Lord Brittany D. , Cora Renata , Pfeiffer Ruth M. , Lawrence Scott , Zirpoli Gary , Bethea Traci N. , Palmer Julie R. , Gierach Gretchen L.
Published: December 2022

Background

Terminal duct lobular units (TDLUs) are the structures in the breast that give rise to most breast cancers. Previous work has shown that TDLU involution is inversely associated with TDLU metrics, such as TDLU count/100mm2, TDLU span (µm), and number of acini/TDLU, and that these metrics may be elevated in the normal breast tissue of women diagnosed with triple-negative (TN) compared with luminal A breast tumors. It is unknown whether this relationship exists in Black women, who have the highest incidence of TN breast cancer and the highest overall breast cancer mortality rate. We examined relationships between TDLU metrics and breast cancer molecular subtype among breast cancer cases in the Black Women’s Health Study (BWHS).

Methods

We assessed quantitative TDLU metrics (TDLU count/100mm2, TDLU span (µm), and number of acini/TDLU) in digitized 247 hematoxylin and eosin-stained adjacent normal tissue sections from 223 BWHS breast cancer cases, including 65 triple negative (TN) cancers (estrogen receptor (ER) negative, progesterone receptor (PR) negative, human epidermal growth factor-2 (HER2) negative) and 158 luminal A cancers (ER positive, HER2 negative). We evaluated associations of least square mean TDLU metrics adjusted for age and body mass index (BMI) with patient and clinical characteristics. In logistic regression models, we evaluated associations between TDLU metrics and breast cancer subtype, adjusting for age, BMI, and tumor size.

Results

Older age and higher BMI were associated with lower TDLU metrics and larger tumor size and lymph node invasion with higher TDLU metrics. The odds of TN compared with luminal A breast cancer increased with increasing tertiles of TDLU metrics, with odds ratios (95% confidence intervals) for tertile 3 versus tertile 1 of 2.18 (0.99, 4.79), 2.77 (1.07, 7.16), and 1.77 (0.79, 3.98) for TDLU count, TDLU span, and acini count/TDLU, respectively.

Conclusion

Associations of TDLU metrics with breast cancer subtypes in the BWHS are consistent with previous studies of White and Asian women, demonstrating reduced TDLU involution in TN compared with luminal A breast cancers. Further investigation is needed to understand the factors that influence TDLU involution and the mechanisms that mediate TDLU involution and breast cancer subtype.
Testing an attachment- and trauma-informed intervention approach for parents and young children after interparental violence: protocol for a randomized controlled trial
Authors: van der Asdonk Sabine , Kesarlal Ashwina R. , Schuengel Carlo , Draaisma Nina , de Roos Carlijn , Zuidgeest Karine , Rippe Ralph C. A. , Alink Lenneke R. A.
Published: December 2022

Background

Interparental violence has persistent adverse effects on victimized parents and children. Young children, including infants and toddlers, are at particular risk to develop long-lasting negative outcomes, and yet specific evidence on effective intervention approaches for this vulnerable group is still lacking. This study will test the effectiveness of an attachment- and trauma-informed intervention approach in a sample of parent-child dyads who have experienced severe interparental violence. We test the individual and combined effects of two interventions: (1) “Nederlandse Interventie Kortdurend op Atypisch oudergedrag” (NIKA; Dutch, short-term intervention focused on atypical parenting behavior) aimed at improving the attachment relationship and (2) eye movement desensitization and reprocessing (EMDR) therapy aimed at reducing parental post-traumatic stress disorder (PTSD) symptoms.

Methods

This study uses a multicenter randomized controlled design across multiple domestic violence shelters in the Netherlands. We aim to recruit 150 parent-child dyads with children aged between 0.5 and 6 years old. The study design consists of two phases. During the first phase for testing the effect of NIKA only, eligible dyads are randomly allocated to either NIKA or a waitlist usual care group. A pre-test is conducted prior to the treatment period and a post-test takes place directly afterwards (6 weeks after the pre-test). Phase 2 follows directly for testing the effects of EMDR and the combination of NIKA and EMDR. Parents who report clinical PTSD symptoms are randomly allocated to either EMDR therapy or a waitlist usual care group. Parents who do not report clinical PTSD symptoms only receive care as usual. Six weeks later, a post-test of phase 2 is conducted for all participating dyads. Primary study outcomes are disrupted parenting behavior, sensitive parenting behavior, and parental PTSD symptoms. Secondary study outcomes include PTSD symptoms and behavioral and emotional problems of the child.

Discussion

This study will inform and enhance the clinical field by providing new insights regarding effective treatment combinations for traumatized parents and their young children after interparental violence.

Trial registration

Netherlands Trial Register (NTR) NL9179. Registered 7 January 2021
A novel Bayesian adaptive design incorporating both primary and secondary endpoints for randomized IIB chemoprevention study of women at increased risk for breast cancer
Authors: Gajewski Byron J. , Kimler Bruce F. , Koestler Devin C. , Mudaranthakam Dinesh Pal , Young Kate , Fabian Carol J.
Published: December 2022

Background

Our randomized controlled clinical trial will explore the potential of bazedoxifene plus conjugated estrogen to modulate breast tissue-based risk biomarkers as a surrogate for breast cancer risk reduction. This paper investigates the statistical design features of the trial and the rationale for the final choice of its design. Group sequential designs are a popular design approach to allow a trial to stop early for success or futility, potentially saving time and money over a fixed trial design. While Bayesian adaptive designs enjoy the same properties as group sequential designs, they have the added benefit of using prior information as well as inferential interpretation conditional on the data. Whether a frequentist or Bayesian trial, most adaptive designs have interim analyses that allow for early stopping, typically utilizing only the primary endpoint. A drawback to this approach is that the study may not have enough data for adequate comparisons of a single, key secondary endpoint. This can happen, for example, if the secondary endpoint has a smaller effect than the primary endpoint.

Methods

In this paper, we investigate a trial design called two-endpoint adaptive, which stops early only if a criterion is met for primary and secondary endpoints. The approach focuses the final analysis on the primary endpoint but ensures adequate data for the secondary analysis. Our study has two arms with a primary (change in mammographic fibroglandular volume) and secondary endpoint (change in mammary tissue Ki-67).

Results

We present operating characteristics including power, trial duration, and type I error rate and discuss the value and risks of modeling Bayesian group sequential designs with primary and secondary endpoints, comparing against alternative designs. The results indicate that the two-endpoint adaptive design has better operating characteristics than competing designs if one is concerned about having adequate information for a key secondary endpoint.

Discussion

Our approach balances trial speed and the need for information on the single, key secondary endpoint.
Cardio-pulmonary parasites of the European wildcat (Felis silvestris) in Germany
Authors: Bisterfeld Katrin , Raulf Marie-Kristin , Waindok Patrick , Springer Andrea , Lang Johannes , Lierz Michael , Siebert Ursula , Strube Christina
Published: December 2022

Background

In the last years, research on feline cardio-pulmonary parasites has considerably increased in Europe. Not only domestic cats (Felis catus), but also European wildcats (Felis silvestris) can serve as definitive hosts for these nematodes. The F. silvestris population in Germany has been growing rapidly within the last decades; therefore, the assessment of its cardio-pulmonary parasite status is of importance to unravel whether the wildcat population serves as a substantial reservoir for these nematodes and might pose a health threat to domestic cats.

Methods

As part of a nature conservation project for European wildcats in the German federal state Rhineland-Palatinate, lungs (n = 128) and hearts (n = 111) of 128 F. silvestris found dead were examined for cardio-pulmonary parasites. All isolated parasites were identified morphologically, and results were confirmed by molecular analysis of a total of 3–11 specimens of each worm species.

Results

A total of 70.3% (90/128) wildcats were positive for at least one lungworm species. Angiostrongylus chabaudi was most common (53.1% [68/128]), followed by Aelurostrongylus abstrusus (42.2% [54/128]), Troglostrongylus brevior (31.3% [40/128]) and Capillaria spp. (3.1% [4/128]). Of note, about two-thirds of the infected wildcats harboured coinfections. Infection intensities ranged from 1 to 167 nematodes per wildcat. Generalised linear models revealed a strong correlation between A. chabaudi and A. abstrusus infection, and prevalences were higher in adult than in younger wildcats, except for T. brevior. Moreover, the T. brevior prevalence varied significantly with nutritional status.

Conclusions

This study shows that feline cardio-pulmonary nematodes are common parasites in European wildcats in Germany but do not appear to have a serious impact on the overall health of the population. Due to presumed spillover events via prey, cardio-pulmonary nematodes may circulate between the wildcat population and domestic cats and might therefore pose a health risk to individual domestic cats.

Graphical abstract
Quantification of DNA methylation for carcinogenic risk estimation in patients with non-alcoholic steatohepatitis
Authors: Kuramoto Junko , Arai Eri , Fujimoto Mao , Tian Ying , Yamada Yuriko , Yotani Takuya , Makiuchi Satomi , Tsuda Noboru , Ojima Hidenori , Fukai Moto , Seki Yosuke , Kasama Kazunori , Funahashi Nobuaki , Udagawa Haruhide , Nammo Takao , Yasuda Kazuki , Taketomi Akinobu , Kanto Tatsuya , Kanai Yae
Published: December 2022

Background

In recent years, non-alcoholic steatohepatitis (NASH) has become the main cause of hepatocellular carcinoma (HCC). As a means of improving the treatment of NASH-related HCCs based on early detection, this study investigated the feasibility of carcinogenic risk estimation in patients with NASH.

Results

Normal liver tissue (NLT), non-cancerous liver tissue showing histological findings compatible with non-alcoholic fatty liver from patients without HCC (NAFL-O), non-cancerous liver tissue showing NASH from patients without HCC (NASH-O), non-cancerous liver tissue showing non-alcoholic fatty liver from patients with HCC (NAFL-W), non-cancerous liver tissue showing NASH from patients with HCC (NASH-W) and NASH-related HCC were analyzed. An initial cohort of 171 tissue samples and a validation cohort of 55 tissue samples were used. Genome-wide DNA methylation screening using the Infinium HumanMethylation450 BeadChip and DNA methylation quantification using high-performance liquid chromatography (HPLC) with a newly developed anion-exchange column were performed. Based on the Infinium assay, 4050 CpG sites showed alterations of DNA methylation in NASH-W samples relative to NLT samples. Such alterations at the precancerous NASH stage were inherited by or strengthened in HCC samples. Receiver operating characteristic curve analysis identified 415 CpG sites discriminating NASH-W from NLT samples with area under the curve values of more than 0.95. Among them, we focused on 21 CpG sites showing more than 85% specificity, even for discrimination of NASH-W from NASH-O samples. The DNA methylation status of these 21 CpG sites was able to predict the coincidence of HCC independently from histopathological findings such as ballooning and fibrosis stage. The methylation status of 5 candidate marker CpG sites was assessed using a HPLC-based system, and for 3 of them sufficient sensitivity and specificity were successfully validated in the validation cohort. By combining these 3 CpG sites including the ZC3H3 gene, NAFL-W and NASH-W samples from which HCCs had already arisen were confirmed to show carcinogenic risk with 95% sensitivity in the validation cohort.

Conclusions

After a further prospective validation study using a larger cohort, carcinogenic risk estimation in liver biopsy specimens of patients with NASH may become clinically applicable using this HPLC-based system for quantification of DNA methylation.