bluuebunny/crossref_metadata_2025 huggingface dataset:
Classification of sleep‐related sudden unexpected death in infancy: A national survey
Authors: Garstang Joanna , Cohen Marta , Mitchell Edwin A. , Sidebotham Peter
Published: July 2020

Aim

To identify how British Child Death Overview Panels (CDOPs) and paediatric pathologists classify cause of death for sleep‐related Sudden Unexpected Death in Infancy (SUDI). To determine compliance with national requirements for SUDI investigation.

Methods

Electronic survey of CDOPs and pathologists using three vignettes of SUDI cases illustrating: accidental asphyxia, typical Sudden Infant Death Syndrome (SIDS) and SIDS with co‐sleeping.

Results

Thirty‐eight (41%) of 92 CDOPs returned questionnaires, and 32 were complete. Thirteen (14%) of 90 pathologists returned complete questionnaires. Thirty‐one (97%) CDOPs and 7 (53%) pathologists agreed with the cause of death in the accidental asphyxia case; 24 (75%) CDOPs and 9 (69%) pathologists in the typical SIDS case; and 11 (34%) CDOPs and 1 (8%) pathologist in the co‐sleeping SIDS case. Pathologists used the terms SUDI or unascertained as the cause of death for the accidental asphyxia case (46%) and the co‐sleeping SIDS case (77%). These terms were used by CDOPs for the typical SIDS case (25%) and the co‐sleeping SIDS case (41%). Seventeen (46%) CDOPs reported compliance with guidelines for investigation in more than 75% of cases.

Conclusion

There is wide variation in classification of deaths, with only limited agreement between CDOPs and pathologists. The terms SIDS and accidental asphyxia are underused, even in typical cases.
Symptoms of problematic feeding in infants under 1 year of age undergoing frenotomy: A review article
Authors: Hill Rebecca R. , Pados Britt F.
Published: July 2020

Aim

The aims of this systematic review were to first identify and summarise original research that compared symptoms of problematic feeding in infants with tongue tie before and after frenotomy and then evaluate the quality of measures used to assess problematic feeding.

Methods

CINAHL and PubMed were searched for ((tongue‐tie) or (ankyloglossia)) and ((feeding) or (breastfeeding) or (bottle‐feeding)) and ((frenotomy) or (frenectomy) or (frenulectomy) or (frenulotomy)). Original research reporting on feeding before and after frenotomy in infants under 1 year old was included.

Results

Maternal nipple pain, breastfeeding self‐efficacy and LATCH scores improved after frenotomy. Few data are available on the effect of frenotomy on infant feeding. The measures used to assess infant feeding were not comprehensive and did not possess strong psychometric properties.

Conclusion

Literature suggests that maternal nipple pain, self‐efficacy and LATCH scores improve in breastfeeding mother‐infant dyads after frenotomy. However, current literature does not provide adequate data regarding the effect of frenotomy on the infant's ability to feed or which infants benefit from the procedure. Future research should utilise comprehensive, psychometrically sound measures to assess infants for tongue tie and to evaluate infant feeding to provide stronger evidence for the effect of frenotomy on feeding in infants with tongue tie.
Swedish references for weight, weight‐for‐height and body mass index: The GrowUp 1990 Gothenburg study
Authors: Albertsson‐Wikland Kerstin , Niklasson Aimon , Gelander Lars , Holmgren Anton , Sjöberg Agneta , Aronson A. Stefan , Nierop Andreas F. M.
Published: July 2020

Aim

To update the Swedish references for weight, weight‐for‐height and body mass index (BMI) considering the secular trend for height but not including that for weight.

Methods

Longitudinal measures of height and weight were obtained (0‐18 years) from 1418 (698 girls) healthy children from the GrowUp 1990 Gothenburg cohort born at term to non‐smoking mothers and Nordic parents. A total of 145 individuals with extreme BMI value vs GrowUp 1974 BMI SDS reference were excluded (0‐2 years: ±4SDS, 2 < years: −3SDS, +2.3SDS). References were constructed using the LMS method.

Results

The updated weight reference became similar to the GrowUp 1974 Gothenburg reference: BMI increased rapidly up to lower levels in the 1990 cohort during infancy/early childhood, similar in both groups in late childhood/adolescence, despite lower values at +2SDS. Compared with the WHO weight standard, median and −2SDS weight values were higher for the 1990 cohort, whereas +2SDS values were lower, resulting in narrower normal range. Median values were greater and ±2SDS narrower for the 1990 vs the WHO weight‐for‐height reference. International Obesity Task force (IOTF) BMI lines for definitions for over‐ and underweight were added.

Conclusion

We present updated references for weight, weight‐for‐height and BMI, providing a healthy goal for weight development when monitoring growth within healthcare settings.
Impact of rotavirus vaccine on admissions due to acute gastroenteritis and rotavirus gastroenteritis in Israel
Authors: Klivitsky Amir , Algabria Salam , Paret Gideon , Michaan Nadav , Goldberg Lior , Halutz Ora , Grisaru‐Soen Galia
Published: July 2020

Aim

We examined the impact of insertion of the Rotavirus vaccine (RVV) into the Israeli National Immunisation Programme (NIP) on hospitalisations due to both acute gastroenteritis (AGE) and Rotavirus gastroenteritis (RVGE) in children.

Methods

We retrospectively analysed the medical records of children aged <5 years admitted with a diagnosis of AGE between 2008 and 2016 in two children's hospitals in central Israel. Clinical, laboratory, microbiological data and RV immunisation status were retrieved. Data were compared before and after the introduction of the RVV into the NIP.

Results

A total of 2042 children were admitted with AGE. Hospitalisations due to AGE and RVGE decreased from 3310 to 1950 and from 1027 to 585 per 100 000 admissions, respectively, after the RVV (relative risk reduction (RRR) of 41% and 43%, respectively). RV remained the most common pathogen in both study periods. There was no significant difference in the clinical course between immunised and non‐immunised children admitted with RVGE.

Conclusion

The introduction of the RVV to the NIP significantly reduced the admissions due to both AGE and RVGE in children <5 years. However, RV is still the most common agent for admissions due to AGE in this age group.
The geographers in the cupboard: Narrating the history of Geography using undergraduate dissertations
Authors: Bruinsma Mette
Published: July 2020

This paper explores the possibilities of examining undergraduate dissertations as sources. By means of archival research on a collection of Geography undergraduate dissertations at the University of Glasgow, comprising over 2,600 dissertations from 1954 to 2014, this paper argues for the epistemological value of both these “small” knowledge productions and the experiences of becoming a geographer for studying the history of Geography. A sustained study of the collection reveals that the dissertations comprise three kinds of sources: intellectual sources, seeing the dissertations as original pieces of academic research; cultural sources, examining the role of this “rites of passage” in becoming a geographer; and lastly, as social sources, whereby the dissertations illuminate a diverse, personal network within and beyond the university. The vastness of the archival collection of undergraduate Geography dissertations and the opportunities offered for a longitudinal examining of shifts within them over the years, revealing notable overall trends and traditions, ultimately discloses their own importance as exciting and striking original knowledge productions.
The influence of borderline personality traits on clinical outcomes in bipolar disorder
Authors: Saunders Kate E. A. , Jones Tomos , Perry Amy , Di Florio Arianna , Craddock Nick , Jones Ian , Gordon‐Smith Katherine , Jones Lisa
Published: July 2020

Objectives

Systematic reviews suggest comorbid borderline personality disorder is present in approximately 20% of individuals who have bipolar disorder, but current diagnostic systems demonstrate a move towards dimensional rather than categorical approaches to classifying personality pathology. We aimed to examine the presence and severity of borderline personality traits in bipolar I and bipolar II disorder, and to explore associations between the presence/severity of borderline personality traits and clinical outcomes in bipolar disorder.

Methods

Borderline personality traits were measured in 1447 individuals with DSM‐IV bipolar disorder (1008 bipolar I disorder and 439 bipolar II disorder) using the Borderline Evaluation of Severity over Time (BEST) questionnaire. Lifetime clinical outcomes were assessed via Schedules for Clinical Assessment in Neuropsychiatry (SCAN) semi‐structured interview and clinical case notes.

Results

Borderline personality traits were common in both bipolar disorder groups, with 86.2% participants reporting at least one trait. These included traits that overlap with (eg mood instability) and those that are distinct from the symptoms of bipolar disorder (eg fear of abandonment). Borderline personality traits were significantly more frequent and more severe in bipolar II disorder compared to bipolar I disorder. More severe borderline traits, and even the presence of a single borderline personality trait, were significantly associated with younger age of bipolar disorder onset and higher prevalence of lifetime alcohol misuse in both bipolar disorder groups.

Conclusions

The presence of comorbid borderline personality traits should be considered in the management of all patients with bipolar disorder irrespective of whether criteria for a categorical borderline personality disorder diagnosis are met.
Randomised Phase II study comparing alternating cycles of sunitinib and everolimus vs standard sequential administration in first‐line metastatic renal carcinoma (SUNRISES study)
Authors: Rodriguez‐Vida Alejo , Bamias Aristotelis , Esteban Emilio , Saez Maria Isabel , Lopez‐Brea Marta , Castellano Daniel , Caballero Cristina , Gonzalez‐Larriba Jose Luis , Calvo Emiliano , Macia Sonia , Ravaud Alain , Bellmunt Joaquim
Published: July 2020

Objective

To investigate the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus in first‐line metastatic renal cell carcinoma (mRCC), as alternating blockade of vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) pathways could potentially prevent the occurrence of resistance to anti‐VEGFR therapy in mRCC.

Patients and Methods

SUNRISES, a randomised open‐label Phase II study, investigated the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus upon progression. Treatment‐naïve patients with clear‐cell mRCC were included. Alternating treatment consisted on 12 weeks of sunitinib, followed by 12 weeks of everolimus. The primary endpoint was the progression‐free survival (PFS) rate at 1 year. The secondary endpoints included the median PFS, overall survival (OS), response rate, and safety.

Results

Accrual was low due to the advent of new‐generation therapies, and the study was stopped prematurely. Only 41 patients out of the planned 102 patients were accrued, and randomised in a 2:1 ratio (15 patients to the control arm, 26 to the experimental arm). In all, 60.9% of patients had performance status (PS) 0 and 39% PS 1; 63% had a favourable prognostic risk profile, while 36% were intermediate risk. The primary endpoint was not met. The 1‐year PFS rate was 49.7% (experimental arm) vs 84.62% (control arm; P = 0.11). There was a trend towards fewer Grade ≥3 adverse events with the alternating approach (50% vs 73.3%; P = 0.14). The median OS was similar in both treatment arms. The other secondary endpoints favoured the control arm.

Conclusions

The study failed to show any benefit of alternating cycles of sunitinib and everolimus in patients with mRCC. The alternating approach using an mTOR inhibitor does not seem to prevent the occurrence of resistance to VEGFR blockade.
Complications after open and robot‐assisted radical prostatectomy and association with postoperative opioid use: an analysis of data from the PREVENTER trial
Authors: Huang Mitchell M. , Su Zhuo T. , Becker Russell E.N. , Pavlovich Christian P. , Partin Alan W. , Allaf Mohamad E. , Patel Hiten D.
Published: July 2020

Objective

To evaluate perioperative complications for open radical prostatectomy (ORP) and robot‐assisted RP (RARP) for patients enrolled in the PREvention of VENous ThromboEmbolism Following Radical Prostatectomy (PREVENTER; ClinicalTrials.gov Identifier: NCT03006562) trial, to determine predictors and impact on opioid consumption.

Patients and Methods

A prospective cohort of 500 patients undergoing ORP and RARP was followed to determine rates of complications and opioid use. Complications were classified 30 days after RP using the Clavien–Dindo system. Patient characteristics and outcomes were compared using appropriate statistical tests. Logistic and linear regressions were performed to identify predictors of complications and evaluate the relationship between complications and postoperative opioid use.

Results

A total of 124 (24.8%) men underwent ORP and 376 (75.2%) RARP, with 418 (83.6%) receiving pelvic lymph node dissection (PLND). While 83 patients (16.6%) had complications, only 19 (3.8%) were major (Clavien–Dindo Grade ≥III), with no differences by surgical approach. PLND (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.25–8.71; P = 0.03) and Stage pT3b (OR 2.76, 95% CI 1.23–6.00;P = 0.01) were the only predictors of complications after controlling for potential confounders. Patients who had complications had greater inpatient (P = 0.02) and outpatient (P = 0.005) opioid use, which persisted after controlling for patient‐reported pain, attending surgeon variation, surgical approach, and undergoing PLND (inpatient β:77.2, 95% CI 17.9–136.5,P = 0.03; and outpatient β:21.9, 95% CI 4.7–39.1,P = 0.01).

Conclusion

In an analysis of prospectively collected data, overall and major complications rates did not differ by surgical approach. Patients receiving PLND and with Stage pT3b disease had more complications. Complications were independently associated with higher inpatient and outpatient postoperative opioid use.
Effect of low‐energy shock wave therapy on intravesical epirubicin delivery in a rat model of bladder cancer
Authors: Elkashef Ahmed , Barakat Nashwa , Khater Sherry M. , Awadalla Amira , Belal Fathallah , El‐Assmy Ahmed M. , Sheir Khaled Z. , Shokeir Ahmed A.
Published: July 2020

Objectives

To study the efficacy of low‐energy shock wave therapy (LESW) on enhancing intravesical epirubicin (EPI) delivery in a rat model of bladder cancer (BCa).

Materials and Methods

A total of 100 female Fischer rats were randomly allocated into five groups: control; BCa; LESW; EPI; and EPI plus LESW. After BCa induction by N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine, EPI (0.6 mg/0.3 mL of EPI diluted in 0.3 mL saline) or saline (0.6 mL) was administered and retained in the bladders for 1 h with or without LESW treatment (300 pulses at 0.12 mJ/mm2). This was repeated weekly for 6 weeks. Survival was then calculated, rats were weighed and their bladders were harvested for bladder/body ratio estimation, histopathological examination, p53 immunostaining, miR‐210, hypoxia‐inducible factor (HIF)‐1α, tumour necrosis factor (TNF)‐α and interleukin (IL)‐6 relative gene expression and fluorescence spectrophotometric drug quantification. Heart and blood samples were also collected for assessment of the safety profile and toxicity.

Results

The EPI plus LESW group had significantly lower mortality rates, loss of body weight and bladder/body ratio. Histopathological results in terms of grossly visible bladder lesions, mucosal thickness, dysplasia formation and tumour invasion were significantly better in the combined treatment group. The EPI plus LESW group also had statistically significant lower expression levels of p53, miR‐210, HIF‐1α, TNF‐α and IL‐6. LESW increased urothelial concentration of EPI by 5.7‐fold (P < 0.001). No laboratory variable exceeded the reference ranges in any of the groups. There was an improvement of the indicators of EPI‐induced cardiomyopathy in terms of congestion, hyalinization and microvesicular steatosis of cardiomyocytes (P = 0.068, 0.003 and 0.046, respectively) in the EPI plus LESW group.

Conclusions

The combined use of intravesical EPI and LESW results in less BCa invasion and less dysplasia formation, as LESW increases urothelial permeability of EPI and enhances its delivery into tumour tissues, without subsequent toxicity.
Neonatal apneic phenotype in a murine congenital central hypoventilation syndrome model is induced through non‐cell autonomous developmental mechanisms
Authors: Alzate‐Correa Diego , Mei‐ling Liu Jillian , Jones Mikayla , Silva Talita M. , Alves Michele Joana , Burke Elizabeth , Zuñiga Jessica , Kaya Behiye , Zaza Giuliana , Aslan Mehmet Tahir , Blackburn Jessica , Shimada Marina Y. , Fernandes‐Junior Silvio A. , Baer Lisa A. , Stanford Kristin I. , Kempton Amber , Smith Sakima , Szujewski Caroline C. , Silbaugh Abby , Viemari Jean‐Charles , Takakura Ana C. , Garcia Alfredo J. , Moreira Thiago S. , Czeisler Catherine M. , Otero José J.
Published: July 2020

Congenital central hypoventilation syndrome (CCHS) represents a rare genetic disorder usually caused by mutations in the homeodomain transcription factor PHOX2B. Some CCHS patients suffer mainly from deficiencies in CO2 and/or O2 respiratory chemoreflex, whereas other patients present with full apnea shortly after birth. Our goal was to identify the neuropathological mechanisms of apneic presentations in CCHS. In the developing murine neuroepithelium, Phox2b is expressed in three discrete progenitor domains across the dorsal‐ventral axis, with different domains responsible for producing unique autonomic or visceral motor neurons. Restricting the expression of mutant Phox2b to the ventral visceral motor neuron domain induces marked newborn apnea together with a significant loss of visceral motor neurons, RTN ablation, and preBötzinger complex dysfunction. This finding suggests that the observed apnea develops through non‐cell autonomous developmental mechanisms. Mutant Phox2b expression in dorsal rhombencephalic neurons did not generate significant respiratory dysfunction, but did result in subtle metabolic thermoregulatory deficiencies. We confirm the expression of a novel murine Phox2b splice variant which shares exons 1 and 2 with the more widely studied Phox2b splice variant, but which differs in exon 3 where most CCHS mutations occur. We also show that mutant Phox2b expression in the visceral motor neuron progenitor domain increases cell proliferation at the expense of visceral motor neuron development. We propose that visceral motor neurons may function as organizers of brainstem respiratory neuron development, and that disruptions in their development result in secondary/non‐cell autonomous maldevelopment of key brainstem respiratory neurons.
Considerations for integrative multi‐omic approaches to explore Alzheimer's disease mechanisms
Authors: Ma Yiyi , Klein Hans‐Ulrich , De Jager Philip L.
Published: July 2020

The past decade has seen the maturation of multiple different forms of high‐dimensional molecular profiling to the point that these methods could be deployed in initially hundreds and more recently thousands of human samples. In the field of Alzheimer's disease (AD), these profiles have been applied to the target organ: the aging brain. In a growing number of cases, the same samples were profiled with multiple different approaches, yielding genetic, transcriptomic, epigenomic and proteomic data. Here, we review lessons learned so far as we move beyond quantitative trait locus (QTL) analyses which map the effect of genetic variation on molecular features to integrate multiple levels of “omic” data in an effort to identify the molecular drivers of AD. One thing is clear: no single layer of molecular or “omic” data is sufficient to capture the variance of AD or aging‐related cognitive decline. Nonetheless, reproducible findings are emerging from current efforts, and there is evidence of convergence using different approaches. Thus, we are on the cusp of an acceleration of truly integrative studies as the availability of large numbers of well‐characterized brain samples profiled in three or more dimensions enables the testing, comparison and refinement of analytic methods with which to dissect the molecular architecture of the aging brain.
Applying gene‐editing technology to elucidate the functional consequence of genetic and epigenetic variation in Alzheimer’s disease
Authors: Schrauben Michael , Dempster Emma , Lunnon Katie
Published: July 2020

Recent studies have highlighted a potential role of genetic and epigenetic variation in the development of Alzheimer’s disease. Application of the CRISPR‐Cas genome‐editing platform has enabled investigation of the functional impact that Alzheimer’s disease‐associated gene mutations have on gene expression. Moreover, recent advances in the technology have led to the generation of CRISPR‐Cas–based tools that allow for high‐throughput interrogation of different risk variants to elucidate the interplay between genomic regulatory features, epigenetic modifications, and chromatin structure. In this review, we examine the various iterations of the CRISPR‐Cas system and their potential application for exploring the complex interactions and disruptions in gene regulatory circuits that contribute to Alzheimer’s disease.
Controls of pre‐existing structures on clinoform architecture and the associated progradational system elements
Authors: Clairmont Roberto , Kolawole Folarin , Omale Abah P. , Bedle Heather
Published: July 2020

There remains a limited understanding of the controls of pre‐existing structures on the architecture of deep‐water progradational sequences. In the Northern Taranaki Basin (NTB), New Zealand, Pliocene post‐extensional sedimentary sequences overlie Miocene back‐arc volcaniclastic units. We utilize seismic reflection datasets to investigate the relationships between the buried back‐arc mound‐shaped structures, and the spatio‐temporal changes in clinoform architecture and the associated progradational system elements within the overlying continental slope margin sequences. Our results reveal the following: (a) buried mound‐shaped structures in the northern domain of the study area, overlain by younging progression of shelf‐to‐basin prograding clinoforms; (b) folding of the deeper clinoforms that systematically decrease in magnitude with shallowing depth from the top of the seamounts; (c) overall, the N‐S‐trending continental slope margin evolves from a highly curvilinear/angular trend in the deeper clinoforms (Units 1 and 2) into a rectilinear geometry within the shallower post‐extensional intervals (Unit 3 and shallower); (d) Units 1 and 2 characterized by dominance of stacked offlap breaks and over‐steepened (7–10°) clinoform foreset slopes in the northern domain, and dominance of gently dipping foreset slopes (<6°) in the south; (e) Unit 3 shows very low (<5°) and intermediate (5–7°) foreset slopes across the entire survey; (f) in the northern domain, differential loading by prograding sequences about the buried seamounts and horst–graben structures induced a differential compaction of the deeper units, which influenced a temporal pinning of the prograding slope margin in pre‐Unit 2 times and (g) wide, closely spaced channel incision into over‐steepened slopes dominate the deeper prograding sequence in the northern domain, whereas narrower, straighter channels dominate the south. We show that the buried pre‐existing structures constitute rigid buttresses that modulated the syn‐depositional topography and post‐depositional architecture of the prograding sequences in the NTB. Our findings present a distinction in the controls on progradational sedimentation patterns between magmatic and non‐magmatic continental margins.
Debate: COVID‐19 and psychological well‐being of children and adolescents in Italy
Authors: Caffo Ernesto , Scandroglio Francesca , Asta Lisa
Published: July 2020

Italy was the first country in Europe to deal with COVID‐19. Measures taken by the government to contain the spread of the virus were based mainly on quarantine and social distancing, with dramatic economic, social and psychological consequences. Since March, Italian children and adolescents are facing school closures, which have caused a disruption in the daily lives of millions of young people and their families. To date, despite the slow reopening, the government has decided to maintain school closures for the entire academic year, leaving the future of young people in uncertainty. There is already some evidence that quarantine and social isolation are having negative impact on children's and adolescents' psychological well‐being. Moreover, this situation will mainly affect those children and adolescents with pre‐existing vulnerabilities and those suffering of mental disorders. It is imperative to keep young people’s needs at the core of reconstruction plans, allowing them to return to school safely, and providing them with some strategies to heal and dealing with this stressful and potentially traumatic situation.
Relapse‐related molecular signature in early‐stage lung adenocarcinomas based on base excision repair, stimulator of interferon genes pathway and tumor‐infiltrating lymphocytes
Authors: Yang Bo , Rao Wen , Luo Hao , Zhang Liang , Wang Dong
Published: July 2020

Approximately 30% of patients with early‐stage non–small cell lung cancer (NSCLC) relapse within 5 years after surgery. Therefore, it is necessary to identify a robust and reliable prognostic signature for early‐stage NSCLC. Immunohistochemistry data from 147 patients with stage I lung adenocarcinoma (stage I‐LUAD) were analyzed for the protein expression of base excision repair (BER), stimulator of interferon genes (STING) and tumor‐infiltrating lymphocytes (TIL) to explore the relationship between protein expression and prognosis. A prediction model was further established by nomogram and externally verified using The Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases. XRCC1 and H2AX are negative prognostic markers for relapse‐free survival (RFS), while CD8, CD20 and STING are positive prognostic markers for RFS. Nomograms for RFS share common prognostic markers, including XRCC1, H2AX, STING, CD8 and CD20. The c‐index was 0.724 and 0.698 in the training cohort and the internal validation cohort, respectively. It was externally verified that the nomogram model had a good prediction for recurrence of stage I‐LUAD. Correlation analysis showed that APE1 and H2AX were negatively correlated with STING, while STING was positively correlated with TIL. BER, the STING pathway and TIL were associated with early recurrence and were correlated with the tissue expression of stage I‐LUAD. Our nomogram model was a good predictor for recurrence of stage I‐LUAD.
Cancer‐associated mutations in normal human endometrium: Surprise or expected?
Authors: Kyo Satoru , Sato Seiya , Nakayama Kentaro
Published: July 2020

The human endometrium is an essential component in human reproduction that has the unique characteristic of undergoing cyclic regeneration during each menstrual cycle. Vigorous regeneration after shedding may be sustained by stem/progenitor cells, for which molecular markers have not been fully identified. Although clonality analysis using X chromosome inactivation patterns has shown that normal human endometrial glands are composed of a monoclonal cell population, whether clonal expansion is derived from stem/progenitor cells remains unclear. Remarkable advances in next‐generation sequencing technology over the past decade have enabled somatic mutations to be detected in not only cancers, but also normal solid tissues. Unexpectedly frequent cancer‐associated mutations have been detected in a variety of normal tissues, and recent studies have clarified the mutational landscape of normal human endometrium. In epithelial glandular cells, representative cancer‐associated mutations are frequently observed in an age‐dependent manner, presumably leading to growth advantage. However, the extremely high mutation loads attributed to DNA mismatch repair deficiency and POLE mutations, as well as structural and copy number alterations, are specific to endometrial cancer, not to normal epithelial cells. The malignant conversion of normal epithelial cells requires these additional genetic hits, which are presumably accumulated during aging, and may therefore be a rare life event. These discoveries could be expected to shed light on the physiology and pathogenesis of the human endometrium and urge caution against the application of genetic screening for the early detection of endometrial cancer.
The recent challenges of highly contagious COVID‐19, causing respiratory infections: Symptoms, diagnosis, transmission, possible vaccines, animal models, and immunotherapy
Authors: Mohapatra Ranjan K. , Pintilie Lucia , Kandi Venkataramana , Sarangi Ashish K. , Das Debadutta , Sahu Raghaba , Perekhoda Lina
Published: July 2020

COVID‐19 is highly contagious pathogenic viral infection initiated from Wuhan seafood wholesale market of China on December 2019 and spread rapidly around the whole world due to onward transmission. This recent outbreak of novel coronavirus (CoV) was believed to be originated from bats and causing respiratory infections such as common cold, dry cough, fever, headache, dyspnea, pneumonia, and finally Severe Acute Respiratory Syndrome (SARS) in humans. For this widespread zoonotic virus, human‐to‐human transmission has resulted in nearly 83 lakh cases in 213 countries and territories with 4,50,686 deaths as on 19 June 2020. This review presents a report on the origin, transmission, symptoms, diagnosis, possible vaccines, animal models, and immunotherapy for this novel virus and will provide ample references for the researchers toward the ongoing development of therapeutic agents and vaccines and also preventing the spread of this disease.
Icaritin activates Nrf2/Keap1 signaling to protect neuronal cells from oxidative stress
Authors: Xu Yuyu , Lu Xiaoyan , Zhang Li , Wang Lijuan , Zhang Guimin , Yao Jingchun , Sun Chenghong
Published: July 2020

Our earlier study indicated that icaritin (ICT) protected mice from cerebral ischemic injury by inhibiting oxidative stress, and this study aimed to investigate its mechanism using a H2O2‐treated SH‐SY5Y cells model. Cell viability was assessed by cell counting kit 8 (CCK‐8). Oxidative stress parameters were detected by flow cytometry, and signaling pathways were analyzed by immunoblotting. We found that ICT alleviated apoptosis and intracellular and mitochondrial reactive oxygen species (ROS) levels, decreased the expressions of Bax and cleaved caspase‐3, and increased the expressions of Bcl‐2 compared to H2O2 group. ICT increased mitochondrial membrane potential (ΔΨm) and blocked the opening of mitochondrial membrane permeability transporter (MPT), and increased the activity of glutathione peroxidase (GSH‐px), catalase (CAT), and superoxide dismutase (SOD), meanwhile, decreased the activity of malondialdehyde (MDA) compared to H2O2 group. Further investigation revealed that ICT significantly up‐regulated the expressions of nuclear factor erythroid 2‐related factor 2 (Nrf2), heme oxygenase 1 (HO‐1) and NAD(P)H‐quinone oxidoreductase 1 (NQO‐1). The anti‐apoptosis and antioxidative effects of ICT were blocked bay ML385, a Nrf2/Keap1 signaling pathway inhibitor. These results indicate that ICT can play a neuroprotective role against oxidative stress injury by activating Nrf2/Keap1 signaling pathway.
Comprehensive flow cytometric reference intervals of leukocyte subsets from six study centers across Europe
Authors: Oras A , Quirant-Sanchez B , Popadic D , Thunberg S , Winqvist O , Heck S , Cwikowski M , Riemann D , Seliger B , Martinez Caceres E , Uibo R , Giese T
Published: July 2020

A group of European FOCIS Centers of Excellence adapted panels of the Human Immunophenotyping Consortium (HIPC) for whole blood analysis. Using four core panels [T/regulatory T cell/B/natural killer (T/Treg/B/NK) and myeloid cells] the main leukocyte populations were analyzed in a clinical–diagnostic setting in a harmonized manner across different platforms. As a first step, the consortium presents here the absolute and relative frequencies of the leukocyte subpopulations in the peripheral blood of more than 300 healthy volunteers across six different European centers.
Static computer‐aided, partially guided, and free‐handed implant placement: A systematic review and meta‐analysis of randomized controlled trials
Authors: Tattan Mustafa , Chambrone Leandro , González‐Martín Oscar , Avila‐Ortiz Gustavo
Published: July 2020

Objective

To analyze the outcomes of static computer‐aided implant placement (sCAIP) compared to partially guided (PGIP) and free‐handed (FHIP) implant placement.

Material and Methods

This study was registered in PROSPERO (CRD42019131397). A comprehensive literature search was performed by two independent examiners. Only randomized controlled trials (RCTs) were selected. Treatment modalities included sCAIP, PGIP, and FHIP. Data pertaining to the outcomes of interest were extracted. Random‐effects meta‐analyses were feasible for a subset of outcomes.

Results

From an initial list of 2,870 records, fourteen articles for a total of ten RCTs were selected. Data from 7 of these studies allowed for the conduction of three meta‐analyses comparing accuracy of implant placement across modalities. Survival rate up to 12 months post‐loading was high (>98%) and comparable between treatments (low‐quality evidence). No tangible differences in terms of patient perception of intra‐ or postoperative discomfort were observed (low‐quality evidence). Quantitative analyses revealed significantly lower angular (MD = 4.41°, 95% CI 3.99–4.83, p < .00001), coronal (MD = 0.65 mm, 95% CI 0.50–0.79, p < .00001), and apical (MD = 1.13 mm, 95% CI 0.92–1.34, p < .00001) deviation values for sCAIP as compared to FHIP (8 studies, 383 patients, 878 implants, high‐quality evidence). A similar discrepancy, in favor of sCAIP, was observed for angular deviation only as compared to PGIP (MD = 2.11°, 95% CI 1.06–3.16, p < .00001).

Conclusions

sCAIP is associated with superior accuracy compared to PGIP and FHIP.
Long‐term functional and clinical outcomes following transanal advancement flap for complex anal fistula repair: are there predictors of recurrence and incontinence?
Authors: Uribe N. , Balciscueta Z. , Cuneo B. , Martín M.C. , Tabet J. , Torrijo I. , López M.
Published: July 2020

Aim

Transanal flap is an attractive technique for complex fistulas. The aim of this study was to identify factors associated with poor outcome, recurrence and incontinence.

Method

All patients who underwent an advancement flap for the treatment of a complex anal fistula between 1995 and 2019 were prospectively enrolled. The patient data obtained included age, sex, body mass index, comorbid conditions and smoking history. The fistula characteristics analysed included previous anal surgery, anatomy of the fistula according to Park's classification, horseshoe or supralevator extension and preoperative seton drainage. The postoperative data registered included complications, postoperative stay, recurrence and incontinence. Predictive factors for recurrence and incontinence were identified using univariate and multivariate analysis.

Results

One hundred and ninety patients were included; 134 (70.5%) were men and the mean patient age was 50 years. The median length of follow‐up was 44.6 months. The fistula recurred in 14 patients (7.3%). Before surgery, 20 patients (10.5%) reported incontinence symptoms. In the continent patients a Wexner postoperative score of 0 was identified in 79.4%. Wexner scores between 1 and 3 were observed in 17% and scores of 4 or more in five patients (3%). Factors associated with recurrence included age < 50 years (OR = 4.8, P = 0.02, 95% CI 1.2–19), smoking (OR = 4.1, P = 0.03, 95% CI 1–16.5) and suprasphincteric fistula (OR = 0.5, P = 0.01, 95% CI 0.2–0.8) in multivariate log regression analysis. Major incontinence was influenced by female sex and previous anal surgery (OR = 7.5, P = 0.003, 95% CI 1.6–34 and OR = 0.1, P = 0.007, 95% CI 0.1–0.7, respectively).

Conclusion

Full‐thickness transanal advancement flap is a good treatment for complex anal fistula repair. This study provides relevant information on risk factors for failure of therapy and incontinence, which can help in advising patients before surgery and planning a good treatment strategy.
Minimally invasive organ‐preserving approaches in the management of mesh erosion after laparoscopic ventral mesh rectopexy
Authors: Ratnatunga K. , Singh S. , Bolckmans R. , Goodbrand S. , Gorissen K. , Jones O. , Lindsey I. , Cunningham C.
Published: July 2020

Aim

This is a systematic approach for minimally invasive methods in the management of mesh erosion after laparoscopic ventral mesh rectopexy.

Methods

All patients managed with organ‐preserving techniques for mesh erosion were identified from a prospective database and clinical records were reviewed. Each patient was contacted via telephone and a structured questionnaire was applied. A Likert score was used to assess patient symptoms and overall satisfaction with management. One or more of the following techniques were used: (i) transanal or transvaginal trimming/excision of exposed mesh and sutures, with or without using transanal endoscopic micro surgery or transanal minimally invasive surgery; (ii) laparoscopic pelvic assessment and detachment of mesh from the sacral promontory.

Results

Eleven patients were managed for mesh erosion with organ‐preserving techniques. All were women with a median age of 60 years [interquartile range (IQR) 53.5–68.5]. Vaginal, rectal, perineal erosion and recto‐vaginal fistulation occurred in five, four, one and one patient respectively. Vaginal erosions presented at a median of 51 months (IQR 36–56) after index laparoscopic ventral mesh rectopexy compared to 17.5 months (IQR 14.5–27.25) for the rectal erosions. Median follow‐up time was 24 months (IQR 19–49). Four of the meshes (36%) were removed completely whereas seven (63%) were partially removed. Vaginal erosions required a median of two procedures to achieve resolution as opposed to five for rectal. Out of 11 patients, eight were satisfied with the outcome of their management, whereas two were not and one remained ambivalent.

Conclusion

An organ‐sparing minimally invasive approach is feasible in managing mesh erosions but requires multiple procedures and months to complete.
Sonographic detection of physiological lower leg oedema in the late afternoon in healthy young women
Authors: Shibasaki Shohei , Kishino Tomonori , Yokoyama Tomomi , Sunahara Sakura , Harashima Keiichiro , Nakajima Satoshi , Ohnishi Hiroaki , Watanabe Takashi
Published: July 2020

Lower leg oedema occurs physiologically in the evening after daytime activity. Various oedema‐related sonographic findings have recently been reported, but this physiological oedema has not been evaluated quantitatively using imaging examinations. The present study investigated whether sonography could detect physiological lower leg oedema, comparing measured values between the morning and late afternoon. Diameters of leg veins were also measured as a possible source of leg oedema. Subjects comprised 55 healthy young women (mean age, 21 ± 1 years). Oedema‐related findings such as papillary dermis thickness, subcutaneous adipose tissue thickness and echogenicity (as estimated in grey‐scale using image analysis software) increased in the late afternoon when compared with those in the morning (1.4 [1.1–1.7] mm vs. 1.4 [1.1–1.8] mm, p < .01; 7.3 [6.0–8.1] mm vs. 7.3 [6.1–8.3] mm, p < .05; and 37.3 [31.5–39.4] vs. 39.8 [35.7–44.1], p < .01, respectively). Diameters of leg veins such as the great saphenous vein, small saphenous vein and dorsal vein of the foot were all reduced towards late afternoon (p < .01 each). Sonography quantitatively and precisely detected physical changes associated with physiological lower leg oedema after daytime activity in healthy young women.
National survey of physicians’ perspectives on pharmacogenetic testing in solid organ transplantation
Authors: Deininger Kimberly M. , Tsunoda Shirley M. , Hirsch Jan D. , Anderson Heather , Lee Yee Ming , McIlvennan Colleen K. , Page Robert L. , Tran Jacinda N. , Aquilante Christina L.
Published: July 2020

Introduction

Our objective was to evaluate physicians' perspectives on the clinical utility of pharmacogenetic (PGx) testing in kidney, liver, heart, and lung transplantation (KLHL‐Tx).

Methods

A 36‐question web‐based survey was developed and administered to medical and surgical directors of US KLHL‐Tx centers.

Results

There were 82 respondents (10% response rate). The majority were men (78%), non‐Hispanic whites (70%), medical directors (72%), and kidney transplant physicians (35%). Although 78% of respondents reported having some PGx education, most reported lack of confidence in their PGx knowledge and ability to apply a PGx test. Participants reported mixed views about the clinical utility of PGx testing—most agreed with the efficacy of PGx testing, but not the benefits relative to the risks or standard of care. While 55% reported that testing was available at their institution, only 38% ordered a PGx test in the past year, most commonly thiopurine‐S‐methyltransferase. Physician‐reported barriers to PGx implementation included uncertainty about the clinical value of PGx testing and patient financial burden.

Conclusion

Together, our findings suggest prospective PGx research and pilot implementation programs are needed to elucidate the clinical utility and value of PGx in KLHL‐Tx. These initiatives should include educational efforts to inform the use of PGx testing.
Incorporating patient and caregiver feedback into lung transplant referral guidelines for individuals with cystic fibrosis—Preliminary findings from a novel paradigm
Authors: Smith Patrick J. , Dunitz Jordan M. , Lucy Amy , Hempstead Sarah E. , Tallarico Erin , Faro Albert , Pilewski Joseph M. , Ramos Kathleen J.
Published: July 2020

Background

Lung transplantation is a common therapeutic option for individuals with cystic fibrosis (CF) and advanced lung disease, yet many individuals with CF are not appropriately referred for evaluation. The present study sought to enhance CF transplant referral guidelines by integrating patient‐centered input to identify possible psychosocial barriers contributing to suboptimal referral for appropriate CF transplant candidates.

Methods

As a component of developing the Cystic Fibrosis Foundation (CFF) Lung Transplant Referral Consensus Guidelines, we convened a focus group of lung transplant recipients with CF and two spouses of CF recipients. Each session involved standardized approaches to elicit qualitative, thematic content.

Results

CF patients and caregivers characterized five areas for improvement, which were integrated into formal CFF referral guidelines. These included (a) timing of transplant discussion with CF providers, (b) accuracy of transplant‐related knowledge and expectations, (c) stigma associated with the need for transplantation, (d) treatment team transition issues, and (e) social support and mental health concerns. Earlier introduction of transplant, greater details regarding manageable aspects of treatment, and greater provision of social support were all associated with better psychosocial experiences.

Conclusions

Integrating patient‐centered input into guideline development yielded important and previously unknown psychosocial barriers contributing to suboptimal transplant referral.
Impact of warm ischemia time on outcomes for kidneys donated after cardiac death Post‐KAS
Authors: Brennan Corey , Sandoval Pedro Rodrigo , Husain Syed Ali , King Kristen L. , Dube Geoffrey K. , Tsapepas Demetra , Mohan Sumit , Ratner Lloyd E.
Published: July 2020

Prolonged warm (WIT) and cold (CIT) ischemia times are often important considerations in the discard of DCD kidneys, but their impact on post‐transplant outcomes in the post‐KAS era is unclear. We examined the association of ischemia time on delayed graft function (DGF) and death‐censored graft failure for DCD kidneys. The 2018 SRTR SAF was utilized to identify post‐KAS DCD kidney transplants occurring from 2015 to 2018. Relative risk and Cox regression were used to calculate risk of delayed graft function and hazard of death‐censored graft failure, respectively. We identified 4,680 kidneys from DCD donors transplanted from 2015 to 2018 with recorded WIT and CIT times. Median WIT was 21.0 minutes (IQR 14.0‐28.0), and CIT was 18.5 hours (IQR 13.9‐23.5). The overall incidence of DGF was 42.7%. In a univariable relative risk regression model, extended CIT (24‐30 hours:RR 1.37, 95% CI 1.15‐1.77; >30 hours:RR 1.47, 95% CI 1.22‐1.77) and WIT (20‐40 minutes:RR 1.10, 95% CI 1.03‐1.17) were associated with increased risk of DGF. When included in a multivariable model, neither prolonged CIT nor WIT were significantly associated with death‐censored graft failure. Prolonged WIT and CIT are associated with increased DGF but not death‐censored graft failure in recipients of DCD kidney transplants in the post‐KAS era. Extended ischemia alone should not be used as a basis for discard or non‐utilization of these organs.
Conversion to belatacept maintenance immunosuppression in HIV‐positive kidney transplant recipients
Authors: Santeusanio Andrew , Bhansali Arjun , De Boccardo Graciela , Sehgal Vinita , Delaney Veronica , Florman Sander , Shapiro Ron
Published: July 2020

There are only scattered case reports documenting belatacept use in HIV + kidney transplant recipients. We performed a retrospective review to describe short‐term outcomes following conversion to belatacept in a cohort of HIV + patients. Patients were included if they were converted to belatacept between May 2015 and May 2019, had an HIV‐ donor, and received ≥4 doses of belatacept. All patients were treated with non‐depleting induction and triple maintenance immunosuppression. Allograft and HIV‐related outcomes were collected from the date of belatacept infusion until May 2020. Ten HIV + kidney transplant recipients were identified, who were converted to belatacept a median of 364 days post‐transplant. At last follow‐up (median 3.3 years), 8 patients remained on belatacept therapy, and all patients were alive with functioning allografts. Mean estimated glomerular filtration rates (eGFR) improved from 31.6 mL/min at baseline to 42.8 mL/min at 1 year (P = .03). Two patients developed acute rejection, with one necessitating conversion back to tacrolimus. All patients maintained undetectable HIV‐1 viral loads at last follow‐up. One patient each developed pneumocystis pneumonia and Kaposi sarcoma following conversion, which were responsive to standard medical therapy. In our cohort of stable HIV + kidney transplant recipients, conversion to belatacept was associated with excellent early patient and allograft survival and improved eGFR at 1 year.