bluuebunny/crossref_metadata_2025 huggingface dataset:
Behavioral factors associated with multiple-type HPV genital infections: data from a cross-sectional study in young women in Brazil
Authors: Kops Natália Luiza , Caierão Juliana , Bessel Marina , Horvath Jaqueline Driemeyer Correia , Domingues Carla Magda , Benzaken Adele Schwartz , Villa Luisa Lina , de Souza Flávia Moreno Alves , Pereira Gerson Fernando Mendes , Wendland Eliana Marcia
Published: October 2021

Objectives

To investigate the pattern of multiple human papillomavirus (HPV) infections and associated factors in young women who access the Brazilian public health care system to better understand the characteristics of multiple HPV infections, a critical issue in this era of multivalent vaccines.

Methods

This was a cross-sectional, multicenter study with sexually active unvaccinated women (16–25 years old) from 119 primary Brazilian healthcare centers between September 2016 and November 2017. Cervical samples were collected by trained health professionals, and HPV detection was performed in a central laboratory by Linear Array.

Results

Of the 5268 women, 33.00% (95% CI 31.07–34.92) had multiple infections. At least one type of high-risk HPV was present in 85.50% of all multiple infections. All HPV types were detected more frequently in association with other types than alone. Young individuals who were single or in a casual relationship and those who had more than one sexual partner in the past year were more likely to have multiple infections.

Conclusions

In this work, a high rate of multiple HPV infections among unvaccinated young adults tended to increase due to certain risk factors. Such data can provide insight for decision makers in the development of public policies regarding HPV prevention.
Analysis of the levels of hope and influencing factors in infertile women with first-time and repeated IVF-ET cycles
Authors: Ni Ying , Huang Limin , Tong Chenye , Qian Wen , Fang Qiong
Published: October 2021

Purpose

To explore the hope levels and influencing factors in infertile women undergoing first-time and repeated in vitro fertilization-embryo transfer (IVF-ET) cycles.

Methods

This study was a cross-sectional and convenient sampling study conducted among patients undergoing IVF-ET from January to June 2019. Patients were divided into first-time and repeated groups by the number of IVF-ET cycles, and then a questionnaire survey was administered. The questionnaire included demographic information, Herth hope index (HHI) scale, Locke-Wallace short marital-adjustment test scale and social support rating scale. Multiple linear regression was used to analyse the influencing factors associated with hope levels.

Results

A total of 298 IVF-ET patients were recruited for the study, including 150 (50.3%) in the first-time cycle group and 148 (49.7%) in the repeated cycle group. The HHI score of the repeated cycle group was significantly lower than that of the first-time cycle group (34.4 ± 3.5 vs. 37.5 ± 3.7, P < 0.001). Multiple linear regression analysis indicated that repeated IVF-ET and age were independently negatively correlated with HHI, with standardized coefficient β values of − 0.895 and − 0.223, respectively (both P < 0.001). High education level (P = 0.002), high monthly income (P = 0.020), high degree of short marital-adjustment test (P < 0.001) and social support rating (P < 0.001) were independently positively correlated with HHI.

Conclusion

Infertile women undergoing repeated IVF-ET have low hope levels. Maintaining a good marriage adjustment and establishing a good social support and relationship network could effectively improve their hope levels.
Determinants of viral suppression among adolescents on antiretroviral treatment in Ehlanzeni district, South Africa: a cross-sectional analysis
Authors: Okonji Emeka F. , van Wyk Brian , Mukumbang Ferdinand C. , Hughes Gail D.
Published: October 2021

Background

Achieving undetectable viral load is crucial for the reduction of HIV transmissions, AIDS-related illnesses and death. Adolescents (10 to19 years) living with HIV (ALHIV) on antiretroviral treatment (ART) have worse treatment adherence and lower viral suppression rates compared to adults. We report on the clinical factors associated with viral suppression among ALHIV in the Ehlanzeni district, Mpumalanga in South Africa.

Methods

A cross-sectional analysis was conducted with 9386 ALHIV, aged 10 to 19 years, who were enrolled in 136 ART clinics in the Ehlanzeni district. Clinical and immunological data were obtained from electronic medical records (Tier.net). ALHIV were categorised as having achieved viral suppression if their latest viral load count was < 1000 ribonucleic acid (RNA) copies/mL. Using a backward stepwise approach, a multivariate logistic regression analysis was performed to identify factors independently associated with viral suppression.

Results

The mean age of the participants was 14.75 years (SD = 2.9), and 55.43% were female. Mean duration on ART was 72.26 (SD = 42.3) months. Of the 9386 adolescents with viral load results recorded, 74% had achieved viral suppression. After adjusting for other covariates, the likelihood of achieving viral suppression remained significantly higher among ALHIV who were: female (AOR = 1.21, 95% CI 1.05–1.39), and had most recent CD4 count > 200 (AOR = 2.53, 95% CI 2.06–3.11). Furthermore, the likelihood of having viral suppression was lower among adolescents with CD4 count > 200 at baseline (AOR = 0.73, 95% CI 0.61–0.87), and who were switched to second line regimen (AOR = 0.41, 95% CI 0.34–0.49).

Conclusions

Viral suppression amongst ALHIV at 74% is considerably lower than the WHO target of 95%. Of particular concern for intervention is the lower rates of viral suppression amongst male ALHIV. Greater emphasis should be placed to early enrolment of ALHIV on ART and keeping them engaged in care (beyond 6 months). Furthermore, improved and regular viral load monitoring will help to adequately identify and manage ALHIV with unsuppressed viral load and subsequently switching to second line treatment.
Acute fibrinous and organizing pneumonia: two case reports and literature review
Authors: Chen Haihong , Kuang Yukun , Huang Xinyan , Ye Ziyin , Liu Yangli , Xie Canmao , Tang Ke-Jing
Published: October 2021

Background

Acute fibrinous and organizing pneumonia (AFOP) is a rare histologic interstitial pneumonia pattern characterized by the intra-alveolar fibrin deposition and organizing pneumonia. Its clinical characteristics are still not well known and there is no consensus on treatment yet.

Case presentation

We report two female cases in their fifties diagnosed with AFOP confirmed by a second lung biopsy. Case 1 was idiopathic AFOP with manifestation of 6-week fever, dyspnea, and cough, while case 2 was secondary to systemic lupus erythematosus and fever was the major symptom. Their chest CT scans revealed bilateral multiple consolidations, predominantly in the lower lobes. Both cases were initially diagnosed with pneumonia, but did not improve after treatment with broad-spectrum antibiotics. In both cases, transbronchial biopsy and bronchoalveolar lavage fluid examination were inconclusive and the pathological diagnosis was confirmed by percutaneous lung biopsy. Both patients had a good clinical response to prednisone.

Conclusions

We report two rare AFOP cases to highlight the importance of awareness of this disease. We further perform the most comprehensive review to date in AFOP, including 150 patients since 2002. Consolidation was the most common imaging pattern, followed by ground-glass opacity and nodules. A lung biopsy is required for a definitive diagnosis. Corticosteroids is recommended as the most effective therapy, but treatment options should depend on the etiology and disease severity.
Secretory breast carcinoma in a female adult with liver metastsis: a case report and literature review
Authors: Lian Jing , Wang Li-Xia , Guo Jiang-hong , Bu Peng , Xi Yan-feng , Yun Ke-ming
Published: October 2021

Background

Secretory breast carcinoma is an uncommon subset of breast cancer that usually has a favorable outcome. Although initially described in children, it also occurs in adults where it may metastasize, possibly resulting in death. To date, only 20 cases of secretory breast carcinoma with distant metastases have been described.

Case presentation

A 42-year-old female presented with liver metastasis after modified radical mastectomy of the left breast in 2008 at 34 years of age. The liver metastasis was morphologically similar to the primary tumor. Pan-TRK and Fluorescence in situ hybridization showed a rearrangement in the ETV6 gene. She subsequently underwent adjuvant chemotherapy with a fatal outcome.

Conclusions

Although secretory breast carcinoma is usually associated with favorable outcomes, our study and reviews provide a novel insight into the genetic spectrum and treatment of secretory breast carcinoma showing reduced expression of hormone receptors, abnormal genomic profiles, and possible poor prognosis. Targeted therapy may curb clinically aggressive cases. Additional molecular investigations are needed to determine the links between specific mutations and poor prognosis.
Preserving for the future the — once widespread but now vanishing — knowledge on traditional pig grazing in forests and marshes (Sava-Bosut floodplain, Serbia)
Authors: Molnár Zsolt , Szabados Klára , Kiš Alen , Marinkov Jelena , Demeter László , Biró Marianna , Öllerer Kinga , Katona Krisztián , Đapić Marko , Perić Ranko , Ulicsni Viktor , Babai Dániel
Published: October 2021

Background

Traditional knowledge is key for sustainability, but it is rapidly disappearing. Pig keeping in forests and marshes is an ancient, once widespread, now vanishing practice, with a major economic and ecological potential. The knowledge of pig keepers and the foraging activity of pigs are hardly documented.

Methods

We studied the knowledge of traditional pig keepers (svinjars) on wild plants and pig foraging on the Sava-Bosut forest-marsh complex in Serbia. We conducted picture-based interviews about 234 locally common and/or salient plant species, and participatory fieldwork (11 days) and visual observation (21 days) on pig foraging.

Results

181 wild plant species were known bysvinjars and 106 taxa were consumed by pigs.Svinjars knew well and could name most regularly foraged species. 98 species were reported bysvinjars as foraged and 56 as not eaten. 28 species were observed by the authors as eaten regularly, while 21 were nibbled and 17 avoided. Contradictory information on foraging was rare both amongsvinjars (8 species) and betweensvinjars and researchers (7 species); several of these species were rare. Leaves of 92, fruits or seeds of 21 and ‘roots’ of 20 species were reported or observed as eaten, usually with high seasonality.Svinjars were overall observant, but knew little about some less salient species (e.g.Veronica,Circaea). The most common forages (reported and/or observed) were fruits (Quercus, fleshy fruits), grasses (Agrostis,Glyceria), herbs (Ranunculus ficaria,Circaea), nutritious ‘roots’ (Carexspp.,Iris), young shrub leaves (Crataegus,Carpinus) and ‘tame’ plants growing in the sun (Persicaria dubia,Erigeron annuus). Traditional, now extinct pig breeds were reported as less selective and more ‘knowledgeable’ about plants, as they received less additional fodder.Svinjars learnt their knowledge since childhood, from community members, but long-term personal observations and everyday encounters with pigs were also important sources of knowledge.

Conclusions

A deeper understanding of pig foraging could contribute to using pigs in nature conservation management, resource management and organic farming, and to a better understanding of wild boar foraging. The knowledge ofsvinjars is a disappearing intangible cultural heritage of European importance. Knowledge holders deserve recognition, and legal and financial support to continue this tradition.
Validation and refinement of the Stakeholder-driven Community Diffusion Survey for childhood obesity prevention
Authors: Korn Ariella R. , Appel Julia , Hammond Ross A. , Hennessy Erin , Mâsse Louise C. , Must Aviva , Economos Christina D.
Published: October 2021

Background

Whole-of-community interventions hold promise in addressing childhood obesity. The COMPACT Stakeholder-driven Community Diffusion theory posits that stakeholders’ knowledge of childhood obesity prevention efforts and engagement with the issue contribute to successful intervention implementation. Building on completed formative research and pilot testing, we describe the validation and refinement of knowledge and engagement measures.

Methods

We assessed content validity using a modified Delphi process with science (n=18) and practice-based (n=16) experts. Next, we refined the survey based on input from science- and practice-based experts, cognitive response testing, and item analysis of extant survey data. Field testing of the refined survey involved community stakeholders in Greenville County, South Carolina (n=50), East Boston, Massachusetts (n=30), and Tucson, Arizona (n=84) between 2019 and 2020. Construct validity was assessed with confirmatory factor analysis (CFA). Two-week test-retest reliability was assessed among a subsample of 14 paired respondents in South Carolina.

Results

Experts rated existing knowledge domains (intervention factors, roles, sustainability, problem, resources) and engagement domains (dialogue/mutual learning, flexibility, influence/power, leadership/stewardship, trust) highly for their importance in addressing childhood obesity. Expert input resulted in 11 new knowledge items and 7 new engagement items that mapped onto existing domains. Correspondingly, two domain names were modified: implementation/sustainability and trust/trustworthiness. We also eliminated 8 extant items (4 knowledge and 4 engagement) and adapted item language for comprehension and consistency. Further modifications based on CFA results and item analyses resulted in 23 knowledge items across four domains (roles and resources merged) and 23 engagement items across five domains. Modified knowledge and engagement scales had adequate fit and strong item factor loadings (most >0.7 and all >0.5). Knowledge (α=0.86–0.87) and engagement (α=0.75–0.90) subscales had high internal scale consistency. Knowledge intraclass correlation coefficients (ICCs) for test-retest agreement of subscale scores ranged from 0.50 for intervention factors to 0.86 for roles/resources. For engagement subscale scores, ICCs ranged from 0.70 for trust/trustworthiness to 0.96 for leadership/stewardship.

Conclusions

Findings from this multi-method survey development process increase our confidence of the knowledge and engagement measures’ content validity, construct validity, and reliability.
Reduction of inter-observer differences in the delineation of the target in spinal metastases SBRT using an automatic contouring dedicated system
Authors: Giaj-Levra Niccolò , Figlia Vanessa , Cuccia Francesco , Mazzola Rosario , Nicosia Luca , Ricchetti Francesco , Rigo Michele , Attinà Giorgio , Vitale Claudio , Sicignano Gianluisa , De Simone Antonio , Naccarato Stefania , Ruggieri Ruggero , Alongi Filippo
Published: October 2021

Background

Approximately one third of cancer patients will develop spinal metastases, that can be associated with back pain, neurological symptoms and deterioration in performance status. Stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT) have been offered in clinical practice mainly for the management of oligometastatic and oligoprogressive patients, allowing the prescription of high total dose delivered in one or few sessions to small target volumes, minimizing the dose exposure of normal tissues. Due to the high delivered doses and the proximity of critical organs at risk (OAR) such as the spinal cord, the correct definition of the treatment volume becomes even more important in SBRT treatment, thus making it necessary to standardize the method of target definition and contouring, through the adoption of specific guidelines and specific automatic contouring tools. An automatic target contouring system for spine SBRT is useful to reduce inter-observer differences in target definition. In this study, an automatic contouring tool was evaluated.

Methods

Simulation CT scans and MRI data of 20 patients with spinal metastases were evaluated. To evaluate the advantage of the automatic target contouring tool (Elements SmartBrush Spine), which uses the identification of different densities within the target vertebra, we evaluated the agreement of the contours of 20 spinal target (2 cervical, 9 dorsal and 9 lumbar column), outlined by three independent observers using the automatic tool compared to the contours obtained manually, and measured by DICE similarity coefficient.

Results

The agreement of GTV contours outlined by independent operators was superior with the use of the automatic contour tool compared to manually outlined contours (mean DICE coefficient 0.75 vs 0.57, p = 0.048).

Conclusions

The dedicated contouring tool allows greater precision and reduction of inter-observer differences in the delineation of the target in SBRT spines. Thus, the evaluated system could be useful in the setting of spinal SBRT to reduce uncertainties of contouring increasing the level of precision on target delivered doses.
Pulmonary nodular lymphoid hyperplasia in a 53-year-old man with malignant sign: a case report
Authors: Yang Zhen , Wei Lianshuang , Li Xu , Liu Xin
Published: October 2021

Background

Pulmonary nodular lymphoid hyperplasia (PNLH) is a rare benign illness. Due to atypical clinical and radiographic presentations, diagnosis largely depends on postoperative pathological examination. Thus, preoperative misdiagnosis is often occurred.

Case presentation

We present a case of asymptomatic PNLH that was seen as ground-glass opacity (GGO) on computed tomography (CT). After 3-year observation, the diagnosis tends to adenocarcinoma owing to increasing density of the node and vessel convergence sign, which were signs of malignancy. Video-assisted segmentectomy (S10) was carried out. Histopathologic examination of postoperative specimen showed follicular lymphoid hyperplasia with interfollicular lymphoplasmacytosis, consistent with PNLH. The follow-up chest CT images showed no recurrence or metastasis.

Conclusion

Although it is a benign disease, PNLH can exhibit malignant signs in the imaging examinations, which could lead to misdiagnosis. This reminds us of the uncertainty between imaging findings and diagnosis. The diagnosis depends on postoperative pathological examination. Volume doubling time is a potential parameter to differentiate PNLH from lung cancer.
Hepatic dysfunction in patients who received acute DeBakey type I aortic dissection repair surgery: incidence, risk factors, and long-term outcomes
Authors: Wang Zhigang , Ge Min , Chen Cheng , Lu Lichong , Zhang Lifang , Wang Dongjin
Published: October 2021

Background

Hepatic dysfunction (HD) increases the morbidity and mortality rates after cardiac surgery. However, few studies have investigated the association between HD and acute DeBakey type I aortic dissection (ADIAD) surgery. This retrospective study aimed to identify risk factors for developing HD in patients who received acute type I aortic dissection repair and its consequences.

Methods

A total of 830 consecutive patients who received ADIAD surgery from January 2014 to December 2019 at our center were screened for this study. The End-Stage Liver Disease (MELD) score more than 14 was applied to identify postoperative HD. Logistic regression model was applied to identify risk factors for postoperative HD, Kaplan–Meier survival analysis and Cox proportional hazards regression assay were conducted to analyze the association between HD and postoperative long-term survival.

Results

Among 634 patients who eventually enrolled in this study, 401 (63.2%) experienced postoperative HD with a 30-Day mortality of 15.5%. Preoperative plasma fibrinogen level (PFL) [odds ratio (OR): 0.581, 95% confidence interval (CI): 0.362–0.933, P = 0.025], serum creatinine (sCr) on admission (OR: 1.050, 95% CI 1.022–1.079, P < 0.001), cardiopulmonary bypass (CPB) time (OR: 1.017, 95% CI 1.010–1.033, P = 0.039), and postoperative mechanical ventilation (MV) duration (OR: 1.019, 95% CI 1.003–1.035, P = 0.020) were identified as independent risk factors for developing postoperative HD by multivariate analyses. In addition, the Kaplan–Meier analysis indicated that the long-term survival rate was significantly different between patients with or without postoperative HD. However, the hazard ratios of long-term survival for these two groups were not significantly different.

Conclusions

HD was a common complication after ADIAD surgery and associated with an increasing 30-Day mortality rate. Decreased PFL, elevated sCr, prolonged CPB duration, and longer postoperative MV time were independent risk factors for postoperative HD.
Integrated Chinese and western medicine interventions for atopic dermatitis: a systematic review and meta-analysis
Authors: Sum Chi Him , Ching Jessica , Zhang Hongwei , Loo Steven , Lo Cho Wing , Lai Mei Kwan , Cheong Pui Kuan , Yu Chau Leung , Lin Zhi-xiu
Published: October 2021

Background

Atopic dermatitis (AD) is a chronic relapsing skin disease characterized by recurring episodes of itchiness with skin erythema and surface damages. Chinese medicine (CM) is widely used for the management of AD in China not only by its own, but also used in combination with conventional therapy (integrated Chinese-Western medicine, ICWM). Although many clinical trials on the effectiveness of ICWM on AD have been conducted, however, up to date, no sound evidence has been established on the clinical effectiveness and safety of ICWM for AD.

Objectives

To systematically review the currently available clinical evidence on the clinical effectiveness and safety of ICWM for AD.

Methods

Randomised and quasi-randomised controlled trials, which investigated ICWM interventions with at least one control group using the same conventional interventions, no treatment or placebo treatment, were included. Four English (CENTRAL, MEDLINE, EMBASE, AMED) and three Chinese (CNKI, CBM, WanFang Med) databases were searched. Risk of bias was assessed according to the Cochrane’s tool. Meta-analysis was performed to pool the data.

Results

From 1473 entries, 55 studies were included, involving 5953 participants aged between 35 days and 67 years old. Duration of treatment ranged from 1 to 24 weeks. Only 2 studies were judged to have low risk of bias, 3 studies had unclear risk of bias, and the other 50 studies were with high risk of bias. ICWM was found to be superior over WM alone in improving clinical severity of AD (measured by EASI, SCORAD), health-related quality of life (measured by CDLQI, DLQI), long term control of AD (recurrence rate), patients/investigator global score (clinical effectiveness rate), and serum IgE level. Adverse events associated with ICWM were found to be comparable with WM alone.

Conclusion

ICWM seems to produce superior treatment response than WM alone in managing AD without increased risk of adverse events. However, the current available evidence remains too weak to make a conclusive decision.
Clinical, imaging, biochemical and molecular features in Leigh syndrome: a study from the Italian network of mitochondrial diseases
Authors: Ardissone Anna , Bruno Claudio , Diodato Daria , Donati Alice , Ghezzi Daniele , Lamantea Eleonora , Lamperti Costanza , Mancuso Michelangelo , Martinelli Diego , Primiano Guido , Procopio Elena , Rubegni Anna , Santorelli Filippo , Schiaffino Maria Cristina , Servidei Serenella , Tubili Flavia , Bertini Enrico , Moroni Isabella
Published: October 2021

Background

Leigh syndrome (LS) is a progressive neurodegenerative disorder associated with primary or secondary dysfunction of mitochondrial oxidative phosphorylation and is the most common mitochondrial disease in childhood. Numerous reports on the biochemical and molecular profiles of LS have been published, but there are limited studies on genetically confirmed large series. We reviewed the clinical, imaging, biochemical and molecular data of 122 patients with a diagnosis of LS collected in the Italian Collaborative Network of Mitochondrial Diseases database.

Results

Clinical picture was characterized by early onset of several neurological signs dominated by central nervous system involvement associated with both supra- and sub-tentorial grey matter at MRI in the majority of cases. Extraneurological organ involvement is less frequent in LS than expected for a mitochondrial disorder. Complex I and IV deficiencies were the most common biochemical diagnoses, mostly associated with mutations in SURF1 or mitochondrial-DNA genes encoding complex I subunits. Our data showed SURF1 as the genotype with the most unfavorable prognosis, differently from other cohorts reported to date.

Conclusion

We report on a large genetically defined LS cohort, adding new data on phenotype-genotype correlation, prognostic factors and possible suggestions to diagnostic workup.
Development of symptom-focused outcome measures for advanced and indolent systemic mastocytosis: the AdvSM-SAF and ISM-SAF©
Authors: Taylor Fiona , Akin Cem , Lamoureux Roger E. , Padilla Brad , Green Tanya , Boral Anthony L. , Mazar Iyar , Mar Brenton , Shields Alan L. , Siebenhaar Frank
Published: October 2021

Background

Advanced systemic mastocytosis (AdvSM), indolent systemic mastocytosis (ISM), and smoldering systemic mastocytosis (SSM) are rare diseases characterized by neoplastic mast cell infiltration of more than one organ. A content-valid patient-reported outcome (PRO) questionnaire that assesses relevant signs and symptoms that are important and understandable to individuals with a condition is critical for assessing new treatment benefit as well as supporting product labeling claims. Notably, no such PRO questionnaire has been developed in accordance with regulatory and scientific guidelines for use in AdvSM, ISM, and SSM patient populations. To fill that gap, this study documents the development and content validity of instruments evaluating signs and symptoms of systemic mastocytosis.

Methods

A review of peer-reviewed literature, advice meetings with clinical therapeutic area experts, patient concept elicitation interviews, concept selection and questionnaire construction meetings, and patient cognitive debriefing interviews were conducted, and regulatory feedback was incorporated.

Results

For AdvSM, 26 sign- and symptom-level concepts were identified in literature, 39 by clinicians, and 33 by patients. For ISM/SSM, 38 sign- and symptom-level concepts were identified in the literature, 39 by clinicians, and 57 by patients. Two patient-reported instruments, the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF) and Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF)(©Blueprint Medicines Corporation), were developed based on consolidated findings. Cognitive debriefing interviews with AdvSM and ISM patients showed the AdvSM-SAF and ISM-SAF were understood and interpreted as intended by the majority of patients.

Conclusion

The AdvSM-SAF and ISM-SAF are content-valid tools measuring symptoms from AdvSM and ISM patients’ perspective.
Confounding factors in the diagnosis and clinical course of rare congenital hemolytic anemias
Authors: Fattizzo Bruno , Giannotta Juri Alessandro , Cecchi Nicola , Barcellini Wilma
Published: October 2021

Congenital hemolytic anemias (CHAs) comprise defects of the erythrocyte membrane proteins and of red blood cell enzymes metabolism, along with alterations of erythropoiesis. These rare and heterogeneous conditions may generate several difficulties from the diagnostic point of view. Membrane defects include hereditary spherocytosis and elliptocytosis, and the group of hereditary stomatocytosis; glucose-6-phosphate dehydrogenase and pyruvate kinase, are the most common enzyme deficiencies. Among ultra-rare forms, it is worth reminding other enzyme defects (glucosephosphate isomerase, phosphofructokinase, adenylate kinase, triosephosphate isomerase, phosphoglycerate kinase, hexokinase, and pyrimidine 5′-nucleotidase), and congenital dyserythropoietic anemias. Family history, clinical findings (anemia, hemolysis, splenomegaly, gallstones, and iron overload), red cells morphology, and biochemical tests are well recognized diagnostic tools. Molecular findings are increasingly used, particularly in recessive and de novo cases, and may be fundamental in unraveling the diagnosis. Notably, several confounders may further challenge the diagnostic workup, including concomitant blood loss, nutrients deficiency, alterations of hemolytic markers due to other causes (alloimmunization, infectious agents, rare metabolic disorders), coexistence of other hemolytic disorders (autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, etc.). Additional factors to be considered are the possible association with bone marrow, renal or hepatic diseases, other causes of iron overload (hereditary hemochromatosis, hemoglobinopathies, metabolic diseases), and the presence of extra-hematological signs/symptoms. In this review we provide some instructive clinical vignettes that highlight the difficulties and confounders encountered in the diagnosis and clinical management of CHAs.
Nintedanib in idiopathic and secondary pleuroparenchymal fibroelastosis
Authors: Nasser Mouhamad , Si-Mohamed Salim , Turquier Ségolène , Traclet Julie , Ahmad Kaïs , Philit François , Bonniaud Philippe , Chalabreysse Lara , Thivolet-Béjui Françoise , Cottin Vincent
Published: October 2021

Background

Pleuroparenchymal fibroelastosis (PPFE) has a variable disease course with dismal prognosis in the majority of patients with no validated drug therapy. This study is to evaluate the effect of nintedanib in patients with idiopathic and secondary PPFE. Patients admitted to a tertiary care center (2010–2019) were included into this retrospective analysis if they had a multidisciplinary diagnosis of PPFE, had been followed-up for 3 months or more, and had lung function tests and chest CTs available for review. Changes in pulmonary function tests were assessed using non-parametric tests and linear mixed effect model. Lung volumes were measured with lobar segmentation using chest CT.

Results

Out of 21 patients with PPFE, nine had received nintedanib, six had received another treatment and another six patients were monitored without drug therapy. Annual FVC (% of predicted) relative decline was − 13.6 ± 13.4%/year before nintedanib and − 1.6 ± 6.02%/year during nintedanib treatment (p = 0.014), whereas no significant change in FVC% relative decline was found in patients receiving another treatment (− 13.25 ± 34 before vs − 16.61 ± 36.2%/year during treatment; p = 0.343). Using linear mixed effect model, the slope in FVC was − 0.97%/month (95% CI: − 1.42; − 0.52) before treatment and − 0.50%/month (95% CI: − 0.88; 0.13) on nintedanib, with a difference between groups of + 0.47%/month (95% CI: 0.16; 0.78), p = 0.004. The decline in the upper lung volumes measured by CT was − 233 mL/year ± 387 mL/year before nintedanib and − 149 mL/year ± 173 mL/year on nintedanib (p = 0.327). Nintedanib tolerability was unremarkable.

Conclusion

In patients with PPFE, nintedanib treatment might be associated with slower decline in lung function, paving the way for prospective, controlled studies.
Executive functions and quality of life in children with neurofibromatosis type 1
Authors: Roy Arnaud , Roulin Jean-Luc , Gras-Le Guen Christèle , Corbat Marie-Laure , Barbarot Sébastien
Published: October 2021

Background

To examine the impact of executive function disorders on health-related quality of life (QoL) in children with neurofibromatosis type 1 (NF1), we conducted a prospective single-center study among 40 children with NF1 aged 8–12 years (mean = 9.7,SD = 1.4) and their parents, comparing them with 56 healthy control children matched for age, sex, parental education level, and handedness. We collected children’s self-reports and parents’ proxy reports of QoL with the Kidscreen-52 questionnaire, and measured executive functions by combining seven performance-based tests and a daily life questionnaire completed by parents and teachers.

Results

Several QoL domains were significantly impaired in the children with NF1, compared with healthy controls, mainly according to their parents’ reports (3 out of 9 scales; Cohen’sd: 0.57–0.76), with particularly low scores in the social support and peers and school environment domains. Executive function difficulties (Cohen’sd: 0.64–1.72) significantly predicted the impairment of QoL domains as perceived by the children or their parents, regardless of the indirect indicators of learning disabilities.

Conclusions

Both performance-based executive function scores and behavioral ratings of executive functions in daily life by parents and teachers were associated with low QoL levels in the children with NF1. The school environment and social integration appear to be particularly affected and should therefore be targeted in the management of the disease.
Postsynaptic structure formation of human iPS cell-derived neurons takes longer than presynaptic formation during neural differentiation in vitro
Authors: Togo Kazuyuki , Fukusumi Hayato , Shofuda Tomoko , Ohnishi Hiroshi , Yamazaki Hiroyuki , Hayashi Mariko Kato , Kawasaki Nana , Takei Nobuyuki , Nakazawa Takanobu , Saito Yumiko , Baba Kousuke , Hashimoto Hitoshi , Sekino Yuko , Shirao Tomoaki , Mochizuki Hideki , Kanemura Yonehiro
Published: October 2021

The generation of mature synaptic structures using neurons differentiated from human-induced pluripotent stem cells (hiPSC-neurons) is expected to be applied to physiological studies of synapses in human cells and to pathological studies of diseases that cause abnormal synaptic function. Although it has been reported that synapses themselves change from an immature to a mature state as neurons mature, there are few reports that clearly show when and how human stem cell-derived neurons change to mature synaptic structures. This study was designed to elucidate the synapse formation process of hiPSC-neurons. We propagated hiPSC-derived neural progenitor cells (hiPSC-NPCs) that expressed localized markers of the ventral hindbrain as neurospheres by dual SMAD inhibition and then differentiated them into hiPSC-neurons in vitro. After 49 days of in vitro differentiation, hiPSC-neurons significantly expressed pre- and postsynaptic markers at both the transcript and protein levels. However, the expression of postsynaptic markers was lower than in normal human or normal rat brain tissues, and immunostaining analysis showed that it was relatively modest and was lower than that of presynaptic markers and that its localization in synaptic structures was insufficient. Neurophysiological analysis using a microelectrode array also revealed that no synaptic activity was generated on hiPSC-neurons at 49 days of differentiation. Analysis of subtype markers by immunostaining revealed that most hiPSC-neurons expressed vesicular glutamate transporter 2 (VGLUT2). The presence or absence of NGF, which is required for the survival of cholinergic neurons, had no effect on their cell fractionation. These results suggest that during the synaptogenesis of hiPSC-neurons, the formation of presynaptic structures is not the only requirement for the formation of postsynaptic structures and that the mRNA expression of postsynaptic markers does not correlate with the formation of their mature structures. Technically, we also confirmed a certain level of robustness and reproducibility of our neuronal differentiation method in a multicenter setting, which will be helpful for future research. Synapse formation with mature postsynaptic structures will remain an interesting issue for stem cell-derived neurons, and the present method can be used to obtain early and stable quality neuronal cultures from hiPSC-NPCs.
A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma
Authors: Mei Heng , Li Chenggong , Jiang Huiwen , Zhao Xinying , Huang Zhiping , Jin Dan , Guo Tao , Kou Haiming , Liu Lin , Tang Lu , Yin Ping , Wang Zhihui , Ai Lisha , Ke Sha , Xia Yimeng , Deng Jun , Chen Lei , Cai Li , Sun Chunyan , Xia Linghui , Hua Gaoquan , Hu Yu
Published: October 2021

Background

BCMA-specific chimeric antigen receptor-T cells (CAR-Ts) have exhibited remarkable efficacy in refractory or relapsed multiple myeloma (RRMM); however, primary resistance and relapse exist with single-target immunotherapy. Bispecific CARs are proposed to mitigate these limitations.

Methods

We constructed a humanized bispecific BM38 CAR targeting BCMA and CD38 and tested the antimyeloma activity of BM38 CAR-Ts in vitro and in vivo. Twenty-three patients with RRMM received infusions of BM38 CAR-Ts in a phase I trial.

Results

BM38 CAR-Ts showed stronger in vitro cytotoxicity to heterogeneous MM cells than did T cells expressing an individual BCMA or CD38 CAR. BM38 CAR-Ts also exhibited potent antimyeloma activity in xenograft mouse models. In the phase I trial, cytokine release syndrome occurred in 20 patients (87%) and was mostly grade 1–2 (65%). Neurotoxicity was not observed. Hematologic toxicities were common, including neutropenia in 96% of the patients, leukopenia in 87%, anemia in 43% and thrombocytopenia in 61%. At a median follow-up of 9.0 months (range 0.5 to 18.5), 20 patients (87%) attained a clinical response and minimal residual disease-negativity (≤ 10–4 nucleated cells), with 12 (52%) achieving a stringent complete response. Extramedullary plasmacytoma was eliminated completely in 56% and partially in 33% and of 9 patients. The median progression-free survival was 17.2 months. Two relapsed patients maintained BCMA and CD38 expression on MM cells. Notably, BM38 CAR-Ts cells were detectable in 77.8% of evaluable patients at 9 months and 62.2% at 12 months.

Conclusion

Bispecific BM38 CAR-Ts were feasible, safe and significantly effective in patient with RRMM.

Trial registration: Chictr.org.cn ChiCTR1800018143.
CAR T cells targeting CD99 as an approach to eradicate T-cell acute lymphoblastic leukemia without normal blood cells toxicity
Authors: Shi Jiangzhou , Zhang Zijian , Cen Hong , Wu Han , Zhang Shangkun , Liu Jiaxing , Leng Yingqi , Ren Anqi , Liu Xiyu , Zhang Zhijie , Tong Xiqin , Liang Jinjue , Li Zhe , Zhou Fuling , Huang Liang , Qin You , Yang Kunyu , Zhang Tongcun , Zhu Haichuan
Published: October 2021

CAR T cell therapy has shown dramatic clinical success in relapsed or refractory B-ALL and other hematological malignancies. However, the loss of specific antigens, cell fratricide, T cell aplasia, and normal T cell separation are challenges in treating T cell leukemia/lymphoma with CAR T therapy. CD99 is a promising antigen to target T-ALL and AML as it is strongly expressed on the majority of T-ALL and AML. Here, we isolated a low-affinity CD99 (12E7) antibody, which specifically recognizes leukemia cells over normal blood cells. Moreover, T cells transduced with an anti-CD99-specific CAR that contained the 12E7 scFv expanded with minor fratricide and without normal blood cells toxicity. We observed that our anti-CD99 CAR T cells showed robust cytotoxicity specifically against CD99+ T-ALL cell lines and primary tumor cells in vitro and significantly prolonged cell line-derived xenografts (CDXs) or patient-derived xenografts (PDXs) models survival in vivo. Together, our results demonstrate that anti-CD99 CAR T cells could specifically recognize and efficiently eliminate CD99+ leukemia cells.
Alloantigen-activated (AAA) CD4+ T cells reinvigorate host endogenous T cell immunity to eliminate pre-established tumors in mice
Authors: Mochizuki Kazuhiro , Kobayashi Shogo , Takahashi Nobuhisa , Sugimoto Kotaro , Sano Hideki , Ohara Yoshihiro , Mineishi Shin , Zhang Yi , Kikuta Atsushi
Published: October 2021

Background

Cancer vaccines that induce endogenous antitumor immunity represent an ideal strategy to overcome intractable cancers. However, doing this against a pre-established cancer using autologous immune cells has proven to be challenging. “Allogeneic effects” refers to the induction of an endogenous immune response upon adoptive transfer of allogeneic lymphocytes without utilizing hematopoietic stem cell transplantation. While allogeneic lymphocytes have a potent ability to activate host immunity as a cell adjuvant, novel strategies that can activate endogenous antitumor activity in cancer patients remain an unmet need. In this study, we established a new method to destroy pre-developed tumors and confer potent antitumor immunity in mice using alloantigen-activated CD4+ (named AAA-CD4+) T cells.

Methods

AAA-CD4+ T cells were generated from CD4+ T cells isolated from BALB/c mice in cultures with dendritic cells (DCs) induced from C57BL/6 (B6) mice. In this culture, allogeneic CD4+ T cells that recognize and react to B6 mouse-derived alloantigens are preferentially activated. These AAA-CD4+ T cells were directly injected into the pre-established melanoma in B6 mice to assess their ability to elicit antitumor immunity in vivo.

Results

Upon intratumoral injection, these AAA-CD4+ T cells underwent a dramatic expansion in the tumor and secreted high levels of IFN-γ and IL-2. This was accompanied by markedly increased infiltration of host-derived CD8+ T cells, CD4+ T cells, natural killer (NK) cells, DCs, and type-1 like macrophages. Selective depletion of host CD8+ T cells, rather than NK cells, abrogated this therapeutic effect. Thus, intratumoral administration of AAA-CD4+ T cells results in a robust endogenous CD8+ T cell response that destroys pre-established melanoma. This locally induced antitumor immunity elicited systemic protection to eliminate tumors at distal sites, persisted over 6 months in vivo, and protected the animals from tumor re-challenge. Notably, the injected AAA-CD4+ T cells disappeared within 7 days and caused no adverse reactions.

Conclusions

Our findings indicate that AAA-CD4+ T cells reinvigorate endogenous cytotoxic T cells to eradicate pre-established melanoma and induce long-term protective antitumor immunity. This approach can be immediately applied to patients with advanced melanoma and may have broad implications in the treatment of other types of solid tumors.
Mechanistic and therapeutic insight into the effects of cinnamon in polycystic ovary syndrome: a systematic review
Authors: Maleki Vahid , Faghfouri Amir Hossein , Tabrizi Fatemeh Pourteymour Fard , Moludi Jalal , Saleh-Ghadimi Sevda , Jafari-Vayghan Hamed , Qaisar Shaimaa A.
Published: October 2021

Polycystic
ovary syndrome (PCOS) is one of the most common endocrine diseases in the women at their reproductive age. Nowadays, the use of herbal compounds for lesser side effects, as compared to drug treatments, has become popular for the prevention and reduction of the complications of this disease. Evidence suggests that cinnamon, given its antioxidant and anti-inflammatory properties, can be associated with reduced metabolic complications from chronic non-communicable diseases. This systematic review aimed to determine the potential effect of cinnamon on the metabolic status in the PCOS. PICO framework for current systematic review was Population (P): subjects with PCOS; Intervention (I): oral cinnamon supplement; Comparison (C): the group as control or administered placebo; and Outcome (O): changed inflammatory, oxidative stress, lipid profile, glycemic, hormonal and anthropometric parameters and ovarian function. PubMed, Scopus, EMBASE, ProQuest and Google Scholar were searched from their very inception until January, 2020, considering specific keywords to explore the related studies. Out of 266 studies retrieved by the search strategy, only nine were eligible for evaluation. All clinical trials, animal studies, and published English-language journal studies were eligible for this review. The results showed that increased high-density lipoprotein and insulin sensitivity were increased by the cinnamon supplementation while low-density lipoprotein, triglyceride, and blood glucose were decreased in patients with PCOS. However, the results related to the potential effects of cinnamon on body weight and body mass index were inconsistent, thus calling for further studies. Also, despite improved results regarding the effect of cinnamon on oxidative stress and ovarian function, further studies are required to explore the precise mechanisms. Overall, the effects of cinnamon on the improvement of metabolic status in PCOS were promising. However, to observe clinical changes following cinnamon supplementation in PCOS, more clinical trials with higher doses of cinnamon and a longer duration of intervention are needed.
Evolving outcomes of extracorporeal membrane oxygenation support for severe COVID-19 ARDS in Sorbonne hospitals, Paris
Authors: Schmidt Matthieu , Langouet Elise , Hajage David , James Sarah Aissi , Chommeloux Juliette , Bréchot Nicolas , Barhoum Petra , Lefèvre Lucie , Troger Antoine , de Chambrun Marc Pineton , Hékimian Guillaume , Luyt Charles-Edouard , Dres Martin , Constantin Jean-Michel , Fartoukh Muriel , Leprince Pascal , Lebreton Guillaume , Combes Alain ,   for the GRC RESPIRE Sorbonne Université
Published: October 2021

Background

Extracorporeal membrane oxygenation (ECMO) was frequently used to treat patients with severe coronavirus disease-2019 (COVID-19)-associated acute respiratory distress (ARDS) during the initial outbreak. Care of COVID-19 patients evolved markedly during the second part of 2020. Our objective was to compare the characteristics and outcomes of patients who received ECMO for severe COVID-19 ARDS before or after July 1, 2020.

Methods

We included consecutive adults diagnosed with COVID-19 in Paris–Sorbonne University Hospital Network ICUs, who received ECMO for severe ARDS until January 28, 2021. Characteristics and survival probabilities over time were estimated during the first and second waves. Pre-ECMO risk factors predicting 90-day mortality were assessed using multivariate Cox regression.

Results

Characteristics of the 88 and 71 patients admitted, respectively, before and after July 1, 2020, were comparable except for older age, more frequent use of dexamethasone (18% vs. 82%), high-flow nasal oxygenation (19% vs. 82%) and/or non-invasive ventilation (7% vs. 37%) after July 1. Respective estimated probabilities (95% confidence intervals) of 90-day mortality were 36% (27–47%) and 48% (37–60%) during the first and the second periods. After adjusting for confounders, probability of 90-day mortality was significantly higher for patients treated after July 1 (HR 2.27, 95% CI 1.02–5.07). ECMO-related complications did not differ between study periods.

Conclusions

90-day mortality of ECMO-supported COVID-19–ARDS patients increased significantly after July 1, 2020, and was no longer comparable to that of non-COVID ECMO-treated patients. Failure of prolonged non-invasive oxygenation strategies before intubation and increased lung damage may partly explain this outcome.