Establishment of a trastuzumab-resistant extramammary Paget disease model: loss of PTEN as a potential mechanism.

BACKGROUND/OBJECTIVES: Extramammary Paget disease (EMPD) is a rare, cutaneous intraepithelial adenocarcinoma typically treated with wide local excision. Unfortunately, a number of patients with metastases show poor responses to chemotherapy. While some studies have explored trastuzumab's effectiveness against EMPD positive for human epidermal growth factor receptor 2 (HER2), trastuzumab resistance (TR) may emerge after anti-HER2 therapy. METHODS/SUBJECTS: In this study, we established TR EMPD patient-derived xenografts (PDX) that replicated the histological and HER2 expression traits of naive EMPD tumours. RESULTS: Cancer gene analyses revealed a loss of the PTEN gene in TR tumours, which was further confirmed by immunohistochemical staining and immunoblotting to test for protein expression levels. Reduced PTEN levels correlated with increased protein kinase B (Akt) phosphorylation and p27 downregulation, suggesting a potential mechanism for trastuzumab resistance in EMPD cells. In the trastuzumab-sensitive EMPD-PDX mouse model, PTEN inhibitors partially restored trastuzumab-mediated tumour regression. The TR EMPD-PDX responded favourably to targeted therapy (lapatinib, abemaciclib, palbociclib) and chemotherapy (eribulin, docetaxel, trastuzumab deruxtecan). CONCLUSIONS: This study demonstrates an innovative TR EMPD-PDX model and introduces promising antineoplastic effects with various treatments for TR EMPD tumours.

The disaster liaison for pediatric and perinatal medicine: A new system in Japan.

BACKGROUND: Worldwide, children, newborns, and pregnant or postpartum women are vulnerable to disasters and emergency situations, and providing support to this population is of great concern. Japan is located in a disaster-prone area, so disaster response and risk reduction strategies are important priorities. METHODS: We introduce a system called the Disaster Liaison for Pediatric and Perinatal Medicine (DLPPM). This was created with a specific focus on perinatal children and pregnant women in Japan. We report the details of its activities, discuss its challenges, and draw on lessons learned for the further development of perinatal support systems, particularly for children. RESULTS: The lessons learned from the activities of the DLPPM include the following: (1) establish a support system for emergency specialists beyond those with pediatric and perinatal specialties; (2) mitigate the risk of indirect damage caused by primary disasters; and (3) establish a networking function linked to existing pediatric and perinatal medicine facilities. CONCLUSIONS: By establishing similar systems, we believe that it will be feasible to address pediatric and perinatal care needs in disaster response contexts in other countries and regions around the world.

Challenges and solutions for discharge support of elderly people in the acute care ward: Interviews with community-based integrated care supporters and patients in Tokyo, Japan.

Japan, which has become the country with the longest-living people in the world due to rapid population aging, has an insurer function for each local government and socialized long-term care under a public system. Japan aims to build a Community-based Integrated Care System (CICS) for each municipality with the goal of integrating medical care and long-term care. However, despite the policy and management studies, the challenges and solutions for discharge support by the parties have not yet been clarified. This study aimed to obtain suggestions on challenges and solutions for discharge support in the acute care wards for the elderly for community-based integrated care support providers and patients in Kita Ward, Tokyo. Semi-structured interviews were conducted, and the obtained data were a priori analyzed by a deductive thematic analysis using a conceptual framework for integrated care based on the integrative functions of primary care. The challenges were found to include: i) disparity between medical and lifestyle perspectives, ii) competencies of medical and care workers at homes, iii) discharge support challenges related to the elderly themselves, iv) nursing care dependent on family; and v) the impact of payment of medical service in the health insurance system and payment of long-term care services. The solution that can be applied at the local government level was community connection. While aiming to build a CICS for each local government, there was a contradiction in that the challenges and solutions required examination at the national and prefectural levels.

Simultaneous measurement of nascent transcriptome and translatome using 4-thiouridine metabolic RNA labeling and translating ribosome affinity purification.

Regulation of gene expression in response to various biological processes, including extracellular stimulation and environmental adaptation requires nascent RNA synthesis and translation. Analysis of the coordinated regulation of dynamic RNA synthesis and translation is required to determine functional protein production. However, reliable methods for the simultaneous measurement of nascent RNA synthesis and translation at the gene level are limited. Here, we developed a novel method for the simultaneous assessment of nascent RNA synthesis and translation by combining 4-thiouridine (4sU) metabolic RNA labeling and translating ribosome affinity purification (TRAP) using a monoclonal antibody against evolutionarily conserved ribosomal P-stalk proteins. The P-stalk-mediated TRAP (P-TRAP) technique recovered endogenous translating ribosomes, allowing easy translatome analysis of various eukaryotes. We validated this method in mammalian cells by demonstrating that acute unfolded protein response (UPR) in the endoplasmic reticulum (ER) induces dynamic reprogramming of nascent RNA synthesis and translation. Our nascent P-TRAP (nP-TRAP) method may serve as a simple and powerful tool for analyzing the coordinated regulation of transcription and translation of individual genes in various eukaryotes.

Real-world safety and effectiveness of adalimumab in patients with hidradenitis suppurativa: A 52-week analysis of a postmarketing surveillance study in Japan.

Adalimumab is a human monoclonal antibody against tumor necrosis factor-α that was approved in Japan for the treatment of hidradenitis suppurativa (HS), a chronic recurrent inflammatory skin disease. We report the results of the final analysis of the postmarketing surveillance (PMS) study (ClinicalTrials.gov: NCT03894956), which evaluated the 52-week safety and efficacy of adalimumab for HS treatment in real-world clinical practice in Japan. This multicenter, prospective, open-label, observational study (March 2019 to May 2021) included patients with HS treated with subcutaneous adalimumab at doses following the package insert. The primary endpoint was safety, and the secondary endpoints were effectiveness, including HS clinical response (HiSCR), C-reactive protein (CRP), skin pain, and Dermatology Life Quality Index (DLQI). Of the 84 patients registered at 65 sites, 83 patients were included in the analyses. Adverse drug reactions (ADRs) were reported by 10 (12.0%) patients; two patients reported a serious ADR, including one patient with serious infection. Other safety events of special interest reported were liver disorder and dermatitis psoriasiform (one patient each). Almost all patients with ADRs were recovering or had recovered, except for one patient who experienced a serious ADR of liver disorder and died. At 12 weeks, 55.4% of patients achieved HiSCR; this increased to 60.5% and 62.8% at 24 and 52 weeks of adalimumab treatment, respectively. Significant reductions from baseline in CRP (P < 0.05), skin pain (P < 0.0001), and DLQI (P < 0.0001) were observed at all time points. The results from this PMS study demonstrated that long-term adalimumab treatment is well tolerated and effective in patients with HS in real-world clinical practice in Japan.

Association of systemic adverse reaction patterns with long-term dynamics of humoral and cellular immunity after coronavirus disease 2019 third vaccination.

The objective of this study was to clarify the impact of adverse reactions on immune dynamics. We investigated the pattern of systemic adverse reactions after the second and third coronavirus disease 2019 (COVID-19) vaccinations and their relationship with immunoglobulin G against severe acute respiratory syndrome coronavirus 2 spike 1 protein titers, neutralizing antibody levels, peak cellular responses, and the rate of decrease after the third vaccination in a large-scale community-based cohort in Japan. Participants who received a third vaccination with BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna), had two blood samples, had not had COVID-19, and had information on adverse reactions after the second and third vaccinations (n = 2198) were enrolled. We collected data on sex, age, adverse reactions, comorbidities, and daily medicine using a questionnaire survey. Participants with many systemic adverse reactions after the second and third vaccinations had significantly higher humoral and cellular immunity in the peak phase. Participants with multiple systemic adverse reactions after the third vaccination had small changes in the geometric values of humoral immunity and had the largest geometric mean of cellar immunity in the decay phase. Systemic adverse reactions after the third vaccination helped achieve high peak values and maintain humoral and cellular immunity. This information may help promote uptake of a third vaccination, even among those who hesitate due to adverse reactions.

Difficulties experienced by health care professionals who performed home visits to screen for postpartum depression during the COVID-19 pandemic: a qualitative study in Japan.

BACKGROUND: Postpartum depression is a risk factor for suicide and maltreatment of children, and its early detection and appropriate intervention are issues to be resolved. In Japan, local governments are working to detect postpartum depression early by conducting home visits to families with infants within 4 months postpartum, but home-visit professionals have faced new difficulties due to the coronavirus disease 2019 (COVID-19) pandemic that started in 2020. The purpose of this study was to clarify the difficulties experienced by health care professionals who perform home visits to screen for postpartum depression. METHODS: Focus-group interviews were conducted during the COVID-19 pandemic with health care professionals (n = 13) who make postpartum home visits to families with infants within 4 months. Data were analyzed using thematic analysis. RESULTS: Four main categories were identified that describe the difficulties experienced by health care professionals: "Lack of support for partners," "Difficulty in talking face-to-face," "Inability to offer family assistance," and "Anxiety about being a source of infection." CONCLUSIONS: This study shed light on the difficulties faced by professionals in supporting mothers and children in the community during the COVID-19 pandemic. Although these difficulties were considered to have become apparent during the pandemic, the results may offer an important perspective for postpartum mental health support even after the pandemic ends. Accordingly, it may be necessary for these professionals to receive supported through multidisciplinary collaboration in order to improve postpartum care in the community.

English version of Japanese guidance for the use of oral Janus kinase inhibitors (JAK1 and TYK2 inhibitors) in the treatments of psoriasis.

This is the English version of Japanese guidance for the use of oral Janus kinase (JAK) inhibitors (JAK1 and tyrosine kinase 2 [TYK2] inhibitors) in the treatments of psoriasis. Several cytokines, such as interleukin (IL)-6, IL-7, IL-12, IL-21, IL-22, IL-23, interferon (IFN)-α, and IFN-γ, are involved in the pathogenesis of psoriasis (including psoriatic arthritis). As oral JAK inhibitors hinder the JAK-signal transducers and activators of transcription signal transduction routes involved in the signal transduction of these cytokines, they may be effective for the treatment of psoriasis. JAK has four types: JAK1, JAK2, JAK3, and TYK2. Regarding the use of oral JAK inhibitors for the treatment of psoriasis in Japan, indications of the JAK1 inhibitor upadacitinib were extended also to psoriatic arthritis in 2021, and the use of the TYK2 inhibitor deucravacitinib for plaque-type psoriasis, pustular psoriasis, and erythrodermic psoriasis became covered by health insurance in 2022. This guidance was developed for board-certified dermatologists who specialize in the treatment of psoriasis and to promote the proper use of oral JAK inhibitors. In the package inserts and guides for appropriate use, upadacitinib and deucravacitinib are classified as a "JAK inhibitor" and a "TYK2 inhibitor", respectively, and it is possible that there may be differences in safety between the two drugs. The safety of these drugs will be evaluated for the future by the postmarketing surveillance for molecularly targeted drugs for psoriasis of the Japanese Dermatological Association.

Current findings and gaps in early initiation of breastfeeding practices in sub-Saharan African countries: A scoping review.

Background: Early initiation of breastfeeding (EIBF) plays an important role in reducing neonatal and infant mortality. Sub-Saharan African countries have high rates of neonatal and infant mortality, as well as a low prevalence of EIBF. By conducting a scoping review, we aimed to determine the gaps and current understandings of EIBF in Sub-Saharan Africa. Methods: We conducted this scoping review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) reporting guidelines, focusing on primary studies published from 2008 to 2021. We reviewed their titles and abstracts against the eligibility criteria, selecting the relevant ones to this study's criteria for a further full-text review. Results: The identified determinants can be categorized into household, maternal, and health service characteristics. Regarding health service characteristics, many studies reported that cesarean section was strongly associated with the delayed initiation of breastfeeding. Institutional delivery and delivery by skilled birth attendants were also reported to be associated with the early initiation of breastfeeding. Others pointed out that place of residence and wealth index as two household characteristics that were strongly associated with EIBF, as well as maternal characteristics such as older maternal age and higher education status. Conclusions: We found that only eleven studies on the early initiation of breastfeeding have been conducted in Central and West Africa. Household, maternal, and health service factors have been reported to be associated with the early initiation of breastfeeding across many countries. More studies are needed to fill the current geographic gaps and investigate determinants that have not been examined. Future research should also cover interventions that have been effective in improving EIBF for women after caesarean sections in sub-Saharan Africa. Interventions that promote institutional delivery and deliveries by skilled attendants have the potential to improve the practice.

The safety of plasma apheresis from donors recovering from COVID-19 infection in Japan.

PURPOSE: Since 2020, the novel coronavirus infection (COVID-19) has spread globally. A few studies have investigated the safety of COVID-19 convalescent plasma (CCP) apheresis from COVID-19. This study was the first retrospective observational study of CCP in Japan. METHODS: We recruit donors from April 2020 to November 2021 and plasmapheresis in our center (NCGM: national center for global health and medicine). We set the primary endpoint as the Donors Adverse Event (DAE) occurrence at the time of the CCP collection. Variable selection was used to explore the determinants of DAE. RESULTS: Mean and SD age was 50.5 (10.6) years old. Seventy-three (42.2 %) were female, and 87 (33.3 %) were multiple-times donors. Twelve (6.97 % by donors and 4.6 % in total collections) adverse events occurred. The DAEs were VVR (Vaso Vagal Reaction), paresthesia, hypotension, agitation, dizziness, malaise, and hearing impairment/paresthesia. Half of them were VVR during apheresis. DAE occurred only in first-time donors and more in severe illnesses such as using ventilation and ECMO. From the donor characteristics and variable selection, the risk factors are as follows: younger age, female, the severity of disease at the time of the disease, and lower SBP before initiation. Our DAE incidence did not differ from previous studies. DAEs were more likely to occur in CCP apheresis than in healthy donors. CONCLUSION: We confirm the safety of CCP apheresis in this study, although DAEs were more than healthy donors. More caution should be exercised in the plasma collection for future outbreaks of emerging infectious diseases.