bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor eradication by triplet therapy with BRAF inhibitor, TLR 7 agonist, and PD‐1 antibody for BRAF‐mutated melanoma
Authors: Nakamura Kenta , Yaguchi Tomonori , Murata Masashi , Ota Yosuke , Mikoshiba Asuka , Kiniwa Yukiko , Okuyama Ryuhei , Kawakami Yutaka 
Published: June 2024

AbstractProgrammed death 1 (PD‐1)/programmed death‐ligand 1 inhibitors are commonly used to treat various cancers, including melanoma. However, their efficacy as monotherapy is limited, and combination immunotherapies are being explored to improve outcomes. In this study, we investigated a combination immunotherapy involving an anti‐PD‐1 antibody that blocks the major adaptive immune‐resistant mechanisms, a BRAF inhibitor that inhibits melanoma cell proliferation, and multiple primary immune‐resistant mechanisms, such as cancer cell‐derived immunosuppressive cytokines, and a Toll‐like receptor 7 agonist that enhances innate immune responses that promote antitumor T‐cell induction and functions. Using a xenogeneic nude mouse model implanted with human BRAF‐mutated melanoma, a BRAF inhibitor vemurafenib was found to restore T‐cell‐stimulatory activity in conventional dendritic cells by reducing immunosuppressive cytokines, including interleukin 6, produced by human melanoma. Additionally, intravenous administration of the Toll‐like receptor 7 agonist DSR6434 enhanced tumor growth inhibition by vemurafenib through stimulating the plasmacytoid dendritic cells/interferon‐α/natural killer cell pathways and augmenting the T‐cell‐stimulatory activity of conventional dendritic cells. In a syngeneic mouse model implanted with murine BRAF‐mutated melanoma, the vemurafenib and DSR6434 combination synergistically augmented the induction of melanoma antigen gp100‐specific T cells and inhibited tumor growth. Notably, only triplet therapy with vemurafenib, DSR6434, and the anti‐PD‐1 antibody resulted in complete regression of SIY antigen‐transduced BRAF‐mutated melanoma in a CD8 T‐cell‐dependent manner. These findings indicate that a triple‐combination strategy targeting adaptive and primary resistant mechanisms while enhancing innate immune responses that promote tumor‐specific T cells may be crucial for effective tumor eradication.
Uncovering the Challenges and Needs of Chinese Adoptive Parents in Hong Kong
Authors: Chan Anita Kit‐Wa , Fang Tevin Shuhan , Kwok Diana Kan 
Published: June 2024

ABSTRACTAdoptive parenting is a lifelong process. Adoptive parents face unique challenges at different stages of parenting, which require proper recognition, specialised support and sustained services. However, social stigma against infertility and adoption in Asian societies, including Hong Kong, has rendered the lived experiences of adoptive parents almost invisible. To address this knowledge gap, the current qualitative study drew on in‐depth interviews with 23 Chinese parents from 14 families (including nine couples, three wives, one single mother and one divorced mother) with school‐age adoptees aged 6–17. Adopting a biographical approach, we collected their experiences from their adoption decision to their current stage of parenting. Their narratives revealed that Chinese adoptive parents in Hong Kong, despite their resourcefulness and commitment, encounter challenges throughout the adoption process, including family misunderstandings, lack of adoption leave, struggles related to discipline, difficulties with adoptees with special learning needs and the prevalence of cultural devaluation. Our findings contribute to and have implications for research and adoption services and policies.
Unraveling GRIA1 neurodevelopmental disorders: Lessons learned from the p.(Ala636Thr) variant
Authors: Tvergaard Nicolai Kohring , Tkemaladze Tinatin , Stödberg Tommy , Kvarnung Malin , Tatton‐Brown Katrina , Baralle Diana , Tümer Zeynep , Bayat Allan 
Published: June 2024

AbstractIonotropic glutamate receptors (iGluRs), specifically α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptors (AMPARs), play a crucial role in orchestrating excitatory neurotransmission in the brain. AMPARs are intricate assemblies of subunits encoded by four paralogous genes: GRIA1‐4. Functional studies have established that rare GRIA variants can alter AMPAR currents leading to a loss‐ or gain‐of‐function. Patients affected by rare heterozygous GRIA variants tend to have family specific variants and only few recurrent variants have been reported. We deep‐phenotyped a cohort comprising eight unrelated children and adults, harboring a recurrent and well‐established disease‐causing GRIA1 variant (NM_001114183.1: c.1906G>A, p.(Ala636Thr)). Recurrent symptoms included motor and/or language delay, mild–severe intellectual disability, behavioral and psychiatric comorbidities, hypotonia and epilepsy. We also report challenges in social skills, autonomy, living and work situation, and occupational levels. Furthermore, we compared their clinical manifestations in relation to those documented in patients presenting with rare heterozygous variants at analogous positions within paralogous genes. This study provides unprecedented details on the neurodevelopmental outcomes, cognitive abilities, seizure profiles, and behavioral abnormalities associated with p.(Ala636Thr) refining and broadening the clinical phenotype.
New kinase‐deficient PAK2 variants associated with Knobloch syndrome type 2
Authors: Schnur Rhonda E. , Dvořáček Lukáš , Kalsner Louisa , Shapiro Faye L. , Grebeňová Dana , Yanni Diana , Wasserman Barry N. ,   VIGOR, Dyer Lisa M. , Antonarakis Stylianos E. , Kuželová Kateřina 
Published: June 2024

AbstractThe p21‐activated kinase (PAK) family of proteins regulates various processes requiring dynamic cytoskeleton organization such as cell adhesion, migration, proliferation, and apoptosis. Among the six members of the protein family, PAK2 is specifically involved in apoptosis, angiogenesis, or the development of endothelial cells. We report a novel de novo heterozygous missense PAK2 variant, p.(Thr406Met), found in a newborn with clinical manifestations of Knobloch syndrome. In vitro experiments indicated that this and another reported variant, p.(Asp425Asn), result in substantially impaired protein kinase activity. Similar findings were described previously for the PAK2 p.(Glu435Lys) variant found in two siblings with proposed Knobloch syndrome type 2 (KNO2). These new variants support the association of PAK2 kinase deficiency with a second, autosomal dominant form of Knobloch syndrome: KNO2.
Exploring patients' needs and expectations for information on sexual dysfunction after rectal cancer treatment: A qualitative study
Authors: Brissette Vincent , Monton Olivia , Demian Marie , Al Busaidi Nasra , Moon Jeongyoon , Sabboobeh Sarah , Vasilevsky Carol‐Ann , Rajabiyazdi Fateme , Boutros Marylise 
Published: June 2024

AbstractAimSexual dysfunction is an important, and often overlooked, sequela of rectal cancer treatment with significant implications for patients' quality of life. The aim of this study was to explore patients' information needs regarding sexual health after rectal cancer treatment and their experiences accessing information on sexual dysfunction throughout the cancer care continuum. The secondary aim was to explore surgeons' perspectives on patients' information needs and gain insight into their experiences providing information on sexual health following rectal cancer surgery.MethodA qualitative study was conducted using semistructured interviews with 10 rectal cancer survivors and six colorectal surgeons from a Canadian tertiary care institution. Transcribed interviews were coded independently by two researchers and thematic analysis was performed.ResultsAnalysis of patient interviews revealed that patients had limited knowledge of sexual dysfunction symptoms following rectal cancer treatment and received inadequate information on sexual dysfunction from their treating medical team. Patients expressed the desire to receive information on sexual dysfunction in different formats, especially before the start of treatment. The surgeon interviews revealed that colorectal surgeons faced challenges when informing patients about sexual dysfunction. Surgeons did not routinely provide information on sexual dysfunction to all patients; however, they felt that patients should receive high‐quality information on sexual dysfunction, both before and after treatment.ConclusionPatients' information needs related to sexual dysfunction after rectal cancer treatment were inadequately met. High‐quality informational resources are needed to facilitate communication between patients and physicians and improve patients' understanding of sexual dysfunction.
A novel feature integration method for named entity recognition model in product titles
Authors: Sun Shiqi , Li Jingyuan , Zhang Kun , Sun Xinghang , Cen Jianhe , Wang Yuanzhuo 
Published: June 2024

AbstractEntity recognition of product titles is essential for retrieving and recommending product information. Due to the irregularity of product title text, such as informal sentence structure, a large number of professional attribute words, a large number of unrelated independent entities of various combinations, the existing general named entity recognition model is limited in the e‐commerce field of product title entity recognition. Most of the current studies focus on only one of the two challenges instead of considering the two challenges together. Our approach proposes NEZHA‐CNN‐GlobalPointer architecture with the addition of label semantic network, and uses multigranularity contextual and label semantic information to fully capture the internal structure and category information of words and texts to improve the entity recognition accuracy. Through a series of experiments, we proved the efficiency of our approach over a dataset of Chinese product titles from JD.com, improving the F1‐value by 5.98%, when compared to the BERT‐LSTM‐CRF model on the product title corpus.
Molecular identification of HLA‐B75 serotype markers by qPCR: A more inclusive pharmacogenetic approach before carbamazepine prescription
Authors: Jaruthamsophon Kanoot , Sangmanee Pornsiri , Plong‐on Oradawan , Charalsawadi Chariyawan , Sukasem Chonlaphat , Hnoonual Areerat 
Published: June 2024

AbstractGenetic screening for HLA‐B*15:02 before prescribing carbamazepine is standard practice to prevent severe cutaneous adverse reactions in Asian populations. These reactions are associated not only with this allele but also with closely related HLA‐B75 serotype markers—HLA‐B*15:11 and HLA‐B*15:21—which are prevalent in several Asian countries. However, a reliable method for identifying HLA‐B75 serotype markers is still not available. We developed an in‐house quantitative PCR (qPCR) for HLA‐B75 screening and validated it using 303 anonymized DNA samples. Due to inadequate quality control, the qPCR results for 11 samples were excluded. We analyzed the sensitivity and specificity of the test using 93 HLA‐typed samples. The concordance between the qPCR method and an established screening method was assessed using 199 HLA‐screened samples tested for HLA‐B*15:02 at Songklanagarind Hospital, Songkhla, Thailand. All discordant results were confirmed by Sanger sequencing. The qPCR method demonstrated a sensitivity of 100% (95% confidence interval = 83.16%–100.00%) and a specificity of 100% (95% confidence interval = 95.07%–100.00%). Concordance analysis revealed a 96.5% agreement between methods (192/199; 44 positive and 148 negative results). All discordant results were due to HLA‐B75 markers not being HLA‐B*15:02 (two samples with HLA‐B*15:11 and five samples with HLA‐B*15:21). In conclusion, this qPCR method could be useful for identifying HLA‐B75 carriers at risk of carbamazepine‐induced reactions in Asian populations where carriers of HLA‐B*15:02, HLA‐B*15:11, or HLA‐B*15:21 are common.
Rotation from methadone to buprenorphine using a micro‐dosing regime in patients with opioid use disorder and serious mental illness: A case series
Authors: Praeger Vivian C. , Frei Matthew Y. , Pham Dan , Praeger Adrian J. , Lubman Dan I. , Arunogiri Shalini 
Published: June 2024

AbstractIntroductionInducting buprenorphine from methadone has traditionally involved initial opioid withdrawal, with risk of mental state deterioration in patients with serious mental illness (SMI). Micro‐dosing of buprenorphine, with small incremental doses, is a novel off‐label approach to transitioning from methadone and does not require a period of methadone abstinence. Given the limited literature about buprenorphine microdosing, we aimed to evaluate the feasibility and safety of inducting buprenorphine in a series of patients on methadone with SMI.MethodsFor this retrospective case series, we reviewed the records of 16 patients with SMI at a Melbourne addiction treatment centre, from January 2021 to July 2022, who transitioned via micro‐dosing, from high‐dose methadone (>30 mg) to buprenorphine and depot‐buprenorphine. Psychiatric diagnoses, mental state, other substance withdrawal, transfer success, transition time, opioid withdrawal symptoms and overall patient experience were collected via objective and subjective reporting.ResultsMethadone to buprenorphine transfer was completed by 88% of patients. Mental health measures remained stable with the exception of mildly increased anxiety. Median transfer time was 6.5 days for inpatients, 9 days for mixed setting and 10 days for outpatients. Most patients (93%) rated their experience ‘manageable’ reporting mild withdrawal symptoms. One patient met study criteria for precipitated withdrawal.Discussion and ConclusionsThis retrospective case series provides evidence that the use of a micro‐dosing buprenorphine induction for methadone to buprenorphine transitions, including to depot‐buprenorphine, has negligible risk, is tolerated by patients with SMI and is unlikely to precipitate an exacerbation of their mental illness.
The Parkinson's Puzzle Box
Authors: Hussain‐Ali Shafaq , Alty Jane , Callisaya Michele 
Published: June 2024

ABSTRACTIntroductionWomen and those with younger onset Parkinson's Disease (YOPD) are typically diagnosed later and face unique situations and challenges. This essay aims to raise awareness of the difficulties in diagnosing YOPD and the need for a personalised approach to care for women with YOPD.MethodsTwo professional women with YOPD (academic physiotherapist and practicing dentist) and a female neurologist (clinician academic) came together to write a narrative essay on their personal experience and perspectives in relation to women and YOPD.ResultsThe essay outlines how the experience of diagnosis is likened to a complex puzzle box with many interlocking components that are hidden and difficult to solve. The concerns of the women about their identity, work, family and the future, with most supports targeting those that are older and retired are outlined.ConclusionIt is concluded that YOPD is a complex puzzle to solve, but can be done by understanding all the intricate interlocking components of the puzzle and combined with greater awareness could lead to earlier diagnosis and the delivery of successful person‐centred care.Patient or Public ContributionPeople with lived experience were involved in the essay conception and writing.
Acceptability of Using a Decision Aid to Support Family Carers of People With Dementia Towards the End of Life: A Qualitative Study
Authors: Davies Nathan , Aker Narin , West Emily , Rait Greta , Sampson Elizabeth L. 
Published: June 2024

AbstractObjectivesTo explore the experiences, acceptability and utility of a decision aid for family carers of people with dementia towards the end of life.MethodsWe conducted semi‐structured interviews with a sample of family carers enroled into a 6‐month feasibility study in England, sampling to gain a range of experiences and views, based on relationship to person they cared for (e.g., spouse, adult child), age, gender, and self‐reported use of the decision aid during the feasibility study. Interviews were conducted in March 2021–July 2021 and analysed using reflexive thematic analysis. We used COREQ checklist to report our methods and results.ResultsFamily carers found the decision aid acceptable, describing it as comprehensive, accessible with relevant information and its presentation enabled good engagement. Experiences of the decision aid covered four main themes which demonstrated the perceived acceptability and utility: 1. A source of support and reassurance; 2. Empowering conversations and confidence; 3. Including the person living with dementia; and 4. Breaking down complexity.ConclusionsAn aid focussing on decisions about dementia end of life care supported family carers break down complex and emotive decisions, not only with making decisions in the moment but also in future planning.Patient or Public ContributionOur three Patient and Public Involvement (PPI) members (all former family carers) were crucial throughout the wider study. PPI supported development of the topic guides, supported trialling the topic guide and interview procedures and finally supported the development of themes as part of the analysis.
The spectrum of oestrogen receptor expression in endometrial carcinomas of no specific molecular profile
Authors: Alafraidi Mona , Hoang Lynn , Howitt Brooke E. , Longacre Teri A. , McAlpine Jessica N. , Jamieson Amy , Singh Naveena , Gilks C Blake , Pors Jennifer 
Published: June 2024

AimsDecreased oestrogen receptor (ER) expression is a marker of poor prognosis in endometrial carcinomas (EC) of no specific molecular profile (NSMP), but the optimal cut‐off to separate high‐risk ‘low ER’ versus low‐risk ‘high ER’ expression has not been defined. Here we characterised the distribution of ER staining in a cohort of ECs.Methods and resultsBiopsy specimens from 120 cases of NSMP EC were stained for ER and assigned an Allred score. In 66 additional cases ER staining of matched biopsy and hysterectomy were compared. Twelve of 120 tumours had an Allred score of 0–3, including three endometrioid carcinomas (EEA) (one G1, two G3), four clear cell carcinomas (CCC), two mesonephric‐like adenocarcinoma (MLA) and one each of: gastric‐type adenocarcinoma, carcinosarcoma and endometrial carcinoma NOS. Three had Allred scores of 4–5: two MLA and one high‐grade carcinoma with yolk sac differentiation. Five had Allred scores of 6: four EEA (one G1, one G2, two G3) and one mixed clear cell and endometrioid carcinoma. The remaining 100 tumours with Allred scores ≥ 7 were all EEA (66 G1, 28 G2, five G3 and one grade unknown). Comparing the biopsy versus hysterectomy ER staining (n = 66), the results were within a single Allred score point, except two cases with strong diffuse expression in the biopsy (Allred 8) and moderate expression in the hysterectomy (Allred 5).ConclusionsMost NSMP ECs (> 80%) show high ER expression (Allred score ≥ 7). All non‐endometrioid carcinomas and a few endometrioid carcinomas had lower ER expression (Allred score ≤ 6) or were completely negative.
Morphoea presenting histopathologically as mycosis fungoides: an illustrative series of four cases
Authors: Kazmi Ahmed , Feuerhake Teo , Zidan Anoud , Frewen John , Carmichael Andrew , Ross Janet , Orteu Catherine H , Calonje Eduardo 
Published: June 2024

AimsThere have been exceptional reports of morphoea presenting with epidermal changes overlapping histopathologically with cutaneous T cell lymphoma of the mycosis fungoides type (MF). This phenomenon gives rise to an ambiguous clinicopathological scenario in which distinguishing these conditions may be challenging. The aim of this study is to characterise the clinical, histopathological and molecular findings of this phenomenon through a case series.Methods and resultsFour patients with classical clinical presentation of morphoea but unusual histopathology displaying typical findings of morphoea, together with intra‐epidermal CD8 positive lymphocytes indistinguishable from MF, were identified. The clinical phenotypes of morphoea were varied, and they all presented early in the active phase of the disease. They all exhibited intra‐epidermal lymphocytes with tagging and cytological atypia. Pautrier‐like microabscesses were also seen. Using molecular analysis, two cases showed clonal TCR gene rearrangement. Follow‐up of all cases has been consistent with classical morphoea.ConclusionEarly morphoea can seldom present with atypical clonal intra‐epidermal lymphocytes indistinguishable from MF. The fact that these changes can occur in several different clinical subtypes of morphoea raises the possibility that this could be a pattern of inflammation in early disease more common than currently appreciated.
Long‐term clinical impact of early recurrence of atrial tachyarrhythmia after cryoballoon ablation in patients with atrial fibrillation
Authors: Park Jinsun , Cha Myung‐Jin , Kwon Chang Hee , Cho Min Soo , Nam Gi‐Byoung , Oh Il‐Young , Lee So‐Ryoung , Kim Ju Youn , Lee Sung Ho , Park Junbeom , Kim Ki‐Hun , Yang Pil‐Sung , Kim Jun Hyung , Shim Jaemin , Lim Hong Euy 
Published: June 2024

AbstractIntroductionThe impact of early recurrence of atrial tachyarrhythmia (ERAT) within the 90‐day blanking period on long‐term outcomes in atrial fibrillation (AF) patients undergoing cryoballoon ablation (CBA) is controversial. This study aimed to assess the relationship between ERAT and late recurrence of atrial tachyarrhythmia (LRAT) post‐CBA.MethodsUtilizing data from a multicenter registry in Korea (May 2018 to June 2022), we analyzed the presence and timing of ERAT (<30, 30–60, and 60–90 days) and its association with LRAT risk after CBA. LRAT was defined as any recurrence of AF, atrial flutter, or atrial tachycardia lasting more than 30 s beyond the 90 days.ResultsOut of 2636 patients, 745 (28.2%) experienced ERAT post‐CBA. Over an average follow‐up period of 21.2 ± 10.3 months, LRAT was observed in 874 (33.1%) patients. Patients with ERAT had significantly lower 1‐year LRAT freedom compared to those without ERAT (42.6% vs. 85.5%, p < .001). Multivariate analysis identified ERAT as a potential predictor of LRAT, with a hazard ratio (HR) of 3.98 (95% confidence interval [CI], 3.47–4.57). Significant associations were noted across all examined time frames (HR, 3.84; 95% CI, 3.32–4.45 in <30 days, HR, 5.53; 95% CI, 4.13–7.42 in 30–60 days, and HR, 4.29; 95% CI, 3.12–5.89 in 60–90 days). This finding was consistently observed across all types of AF.ConclusionERAT during the 90‐day blanking period strongly predicts LRAT in AF patients undergoing CBA, indicating a need to reconsider the clinical significance of this period.