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Abstract Aim The present study aimed to describe in detail the changes to and assess the risk factors for poor long‐term outcomes of psychiatric disorders in families of COVID‐19 patients. Methods A single‐center, retrospective study using questionnaires. Family members of patients admitted to the intensive care unit (ICU) with severe COVID‐19 participated. Psychiatric disorders refer to the psychological distress such as anxiety, depression, and posttraumatic stress disorder (PTSD) experienced by the patient's family. Results Forty‐six family members completed the survey and were analyzed. Anxiety, depression, and PTSD occurred in 24%, 33%, and 2% of family members, respectively, and psychiatric disorders occurred in 39%. On multivariable analysis, living in the same house with the patient was independently associated with a lower risk of psychiatric disorders in families of COVID‐19 patients (OR, 0.180; 95% CI, 0.036–0.908; p = 0.038). Furthermore, four family members overcame psychiatric disorders, and six family members newly developed psychiatric disorders during the one‐year follow‐up period. Conclusion Approximately 40% of family members had long‐term psychiatric disorders, and some of them overcame the psychiatric disorders, and some newly developed psychiatric disorders over the one‐year follow‐up. Living in the same house with the patient was possibly significantly associated with the reduction of long‐term symptoms of psychiatric disorders, but this result must be interpreted with care. Further large studies are needed to examine the factors associated with the long‐term mental status of family members.

Abstract After disasters, people are often forced to reconstruct or move to new residences. This study aimed to reveal the association between the types of reconstructed residences and psychosocial or psychiatric conditions among the population. A total of 1071 adult residents in a coastal town, whose houses were destroyed by the tsunami caused by the Great East Japan Earthquake, enrolled in the study five years after the disaster. The type of reconstructed post-disaster residences (reconstructed on the same site/disaster-recovery public condominium/mass-translocation to higher ground/privately moving to remote areas) and the current psychosocial indicators were investigated. The results revealed that individuals living in public condominiums showed significantly worse scores on the Lubben Social Network Scale-6 (p

Abstract Background Few studies exploring the actual practices implemented for long-term mental health and psychosocial support after a natural disaster have been published. This study aimed to reveal (1) the types of activities that were actually provided as mental health and psychosocial support (MHPSS) in the long-term phase after the Great East Japan Earthquake (GEJE) and (2) the problems that must be addressed to provide post-disaster MHPSS activities. Methods An open-ended questionnaire was sent to organizations in the Iwate, Miyagi and Fukushima prefectures that were potentially involved in providing MHPSS to communities affected by the GEJE. The organizations were asked to describe their activities and the problems that needed to be addressed to provide these support activities. The collected statements were analysed using content analysis with NVivo11. Results The support activities conducted to provide MHPSS in the long-term phase after the catastrophe were diverse and classified into 7 major categories, namely, (1) one-on-one support for individuals in need of assistance, (2) support for collective activities, (3) support around living conditions and income, (4) increasing public awareness about mental health, (5) human resource development to improve response capabilities for MHPSS, (6) support for MHPSS providers, and (7) facilitating collaborations among the MHPSS activities provided to affected communities. Problems with human resources and funding were the most frequently mentioned concerns among the organizations participating in the survey. Conclusions The establishment of systems to collect and share sufficient and relevant knowledge and to coordinate organizations for long-term post-disaster postventions would be desirable.

Background: Our aim was to investigate oral health in newly diagnosed head and neck squamous cell carcinoma (HNSCC) patients in relation to long-term survival. We assessed whether the level of alveolar bone loss due to periodontitis at diagnosis, measured from orthopantomogram (OPG), and reported dental health-related quality of life (HRQoL) scores obtained at diagnosis contain prognostic information for HNSCC patients., Methods: A total of 79 patients from a consecutive cohort of 106 diagnosed with HNSCC between November 2002 and June 2005 were included. All patients reported dental HRQoL, OPG-determined alveolar bone loss were measured in 79 patients at diagnosis. Reduced alveolar bone loss (≥ 4 mm) from cement-enamel junction on at least two molars or premolars registered both horizontally and vertically served as indicator of periodontal disease., Results: With alveolar bone loss, we determined increased mortality by univariate analysis (RR = 2.28, CI: 1.22-4.28, p = 0.01) and a strong trend by multivariate analyses adjusted for standard clinical information (RR = 1.95, CI: 0.98-3.87, p = 0.056). Reported lowered dental HRQoL scores predicted long-term survival in both univariate (RR = 3.58, CI: 1.99-6.45, p < 0.001) and multivariate adjusted for standard clinical information (RR = 2.17, CI: 1.17-4.01, p = 0.014). When analyzed with Cox regression, including alveolar bone loss and dental HRQoL, both factors, adjusted by clinical variables, were significant predictors of long-term survival: dental HRQoL (p = 0.007) and present alveolar bone loss (p = 0.034). Non-HNSCC disease-specific long-term survival predicted was also predicted when alveolar bone loss and dental HRQoL were analyzed simultaneously and adjusted for standard clinical information., Conclusions: The degree of alveolar bone loss, as determined by OPG, and dental HRQoL both obtained at the time of HNSCC diagnosis, predicted long-term survival. When analyzed simultaneously, both factors remained significant in both univariate and multivariate analyses, adjusted by pertinent clinical variables, highlighting their unique prognostic value., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the Norwegian regional ethics committee (REK VEST 2011 − 125) and performed in accordance with the Declaration of Helsinki. Informed consent to participate was obtained from all the participants in the study. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Somatic TP53 mutations are frequent in head and neck squamous cell carcinoma (HNSCC) and are important pathogenic factors., Objective: To study TP53 mutations relative to the presence of human papillomavirus (HPV) in tumors in HNSCC patients., Methods: Using a custom-made next-generation sequencing (NGS) panel on formalin-fixed, paraffin-embedded tumor tissue, we analyzed somatic TP53 mutations and the TP53 single-nucleotide polymorphism (SNP) codon 72 (P72R; rs1042522) (proline → arginine) from 104 patients with HNSCC., Results: Only 2 of 44 patients with HPV-positive (HPV(+)) HNSCC had a TP53 somatic mutation, as opposed to 42/60 HPV-negative (HPV(-)) HNSCC patients ( p < 0.001). Forty-five different TP53 somatic mutations were detected. Furthermore, in HPV(-) patients, we determined an 80% prevalence of somatic TP53 mutations in the TP53 R72 polymorphism cohort versus 40% in the TP53 P72 cohort ( p = 0.001). A higher percentage of patients with oral cavity SCC had TP53 mutations than HPV(-) oropharyngeal (OP) SCC patients ( p = 0.012). Furthermore, 39/44 HPV(+) tumor patients harbored the TP53 R72 polymorphism in contrast to 42/60 patients in the HPV(-) group ( p = 0.024)., Conclusions: Our observations show that TP53 R72 polymorphism is associated with a tumor being HPV(+). We also report a higher percentage of somatic TP53 mutations with R72 than P72 in HPV(-) HNSCC patients.

Oropharynx squamous cell carcinoma (OPSCC) is of special interest because human papilloma virus (HPV) and/or smoking cause this disease. Influxes of inflammatory cells into such tumors are known to vary with prognoses., Aims: To study whether the density of tumor-infiltrating T lymphocytes and tumor-infiltrating macrophages predicted general 20-year overall survival (OS), as well as OS with only disease-specific survival (DSS) patients included., Methods: Biopsies from patients treated for OPSCC ( n = 180) were stained by immunohistochemistry and the tumor cell macrophage (CD68), pan T lymphocytes (CD3), and regulatory T lymphocytes (Foxp3) densities were determined. The HE-determined percentage of matured tumor cells and the rate of invasion were calculated, and stromal desmoplasia were performed. Tumor HPV presence was studied by PCR. Twenty-year OS and five-year DSS patients were determined., Results: Tumor HPV status strongly predicted survival. High tumor infiltration of CD3, Foxp3 and CD68-positive cells predicted better twenty-year OS, with and without HPV stratification. Foxp3 and CD68 levels predicted OS, and 20-year among DSS patients, primarily among HPV(+) patients. Tumor HE-derived variables did not predict such survival., Conclusions: Tumor HPV status, level of Foxp3 tumor-infiltrating lymphocytes and CD68 tumor-infiltrating macrophages predicted up to 20-year OS of both all patients and disease-specific survived patients.

Objective: There is limited knowledge on the relative impact of lupus nephritis (LN) on morbidity and mortality in population-based systemic lupus erythematous (SLE) cohorts. Here, the primary aim was to compare mortality rates between patients with and without LN in a population-based SLE cohort., Methods: The study cohort included all SLE patients resident in the city of Oslo during 1999-2008. Follow-up time was median 14 (0-15) years. Presence of LN was defined according to the 1987 American College of Rheumatology classification criteria for SLE. LN class was determined by renal biopsy. Data on kidney function, including presence of end-stage renal disease (ESRD), were obtained from patient charts. Standardized mortality ratios (SMRs) were estimated by comparing deaths in the SLE cohort with age- and gender-matched population controls., Results: We found that 98/325 SLE patients (30%) developed LN, 92% of whom had occurrence within the first five years from disease onset. Incidence rate of ESRD was 2.3 per 1000 patient-years. A total of 56 deaths occurred during the study period, corresponding to an overall SMR in the SLE cohort of 2.1 (95% confidence interval (CI) 1.2-3.4). Estimated SMR for LN patients was 3.8 (95% CI 2.1-6.2), and for SLE patients without LN it was 1.7 (95% CI 0.9-2.7)., Conclusion: In this population-based SLE cohort, we found that LN was associated with increased morbidity and mortality, whereas SLE patients who did not develop LN had good overall prognoses regarding survival.

Aquaporin-4 (AQP4) is a water channel found at high concentrations around blood vessels in the brain and is organized into elaborate assemblies called square arrays. The natural functions of AQP4 and the square arrays remain unknown, but under pathophysiological conditions, AQP4 has been shown to influence brain edema, synapse function, and cellular migration. AQP4 was recently found to have six isoforms, where AQP4a (also known as M1), AQP4c (also known as M23), and AQP4e are functional water transport channels. Furthermore, by two-dimensional blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis of the internal composition of square arrays, three distinct isoforms were visualized. Here we combine these advances in technique with mutational analysis to test a series of current hypotheses about AQP4 functional structure. We find that the square array destabilizing N-terminus of AQP4a is partly functional through the C13 and C17 amino acids, and not through R8 and R9. We find a discrepancy between our data and the proposed tetramer-tetramer binding site based on the in vitro AQP4 two-dimensional crystal structure. On the other hand, we find that isoforms AQP4a and AQP4e, while not being able to form square arrays alone, are able to interact with AQP4c and be incorporated into higher-order structures. Our results with the novel BN-PAGE analysis technique point toward a model in which the presence of accessory isoforms (AQP4a and AQP4e) regulates the square array assembly process of the main isoform, AQP4c.

The influence of Fen1 loss on trinucleotide-repeat expansion varies between species. In yeast, loss or haploinsufficiency of the Fen1 homolog Rad27 leads to triplet expansion. In mice, haploinsufficiency of Fen1 leads to expansion of a Huntingtin locus CAG repeat. However, no expansion was seen of a (CTG)(n).(CAG)(n) repeat in a Myotonic dystrophy type 1 (DM1) knock-in model. In contrast, in Drosophila, a SCA7 CAG90 repeat was completely stable in a series of strains with mutations of DNA repair genes, among them PCNA, MutS and Fen1. In light of the apparent species dependence of triplet expansion, we have investigated in human cells the effect of Fen1 loss on the Huntingtin CAG repeat. We constructed a cell line, Fen-Rex, which in a reversible manner allows regulation of endogenous Fen1 expression, by using RNA interference (RNAi). Keeping the Fen1 protein knocked down 10-fold over 27 successive cell passages (10(17)-fold expansion in total) and measuring the Huntingtin triplet expansion by both length profiling of PCR products on PAGE gels, and cloning and sequencing of the repeat region, we find the Huntingtin locus completely stable. Our results argue against a role for Fen1 in triggering Huntingtin triplet expansion in human cells.

Aquaporin-4 (AQP4) is a brain aquaporin implicated in the pathophysiology of numerous clinical conditions including brain edema. Here we show that rat AQP4 has six cDNA isoforms, formed by alternative splicing. These are named AQP4a-f, where AQP4a and AQP4c correspond to the two classical M1 and M23 isoforms, respectively. The various isoforms are differentially expressed in kidney and brain, and their prevalence does not correspond to the level of the respective mRNAs, pointing to posttranscriptional regulation. The three isoforms lacking exon 2, AQP4b, AQP4d, and AQP4f, have an intracellular localization when expressed in cell lines and do not transport water when expressed in Xenopus oocytes. In contrast, the largest of the new isoforms, AQP4e, which contains a novel N-terminal domain, is localized at the plasma membrane in cell lines and functions as a water transporter in Xenopus oocytes.

Square arrays are prominent structures in plasma membranes of brain, muscle, and kidneys with an unknown function. So far, the analysis of these arrays has been restricted to freeze fracture preparations, which have shown square arrays to contain the water channel Aquaporin-4 (AQP4). Using Blue-Native PAGE immunoblots, we provide evidence that higher-order AQP4 complexes correspond to square arrays, with the AQP4 isoform M23 playing a dominant role. Our data are consistent with the idea that square arrays consist of aggregates of AQP4 tetramers complexed with multiples of dimers. By comparison, Aquaporin-1 and Aquaporin-9 form tetramers, but not higher-order complexes. AQP4 square arrays are stable under several biochemical purification steps. Analyzing the internal composition of the higher-order complexes by 2D gels, we demonstrate that the square arrays in addition to M23 also invariably contain AQP4, M1, and a novel AQP4 isoform that we call Mz. The visualization AQP4 square arrays by a rapid, biochemical assay provides new insight in the molecular organization of square arrays and gives further proof of the heterogeneity of AQP4 square arrays in vivo.

Aquaporin-4 (AQP4) has been reported to be upregulated post-partum in pregnancy and in early lung development. Several technical challenges exist in measuring AQP4 protein levels, among them sensitivity to detergent solubilization, sample heating and gel composition. Here we have optimized quantification of AQP4 using immuno-blots. Using improved methodology we find no evidence for AQP4 upregulation post-partum or in the early lung development. However, in the nasal epithelium AQP4 is upregulated as early as in the brain. Furthermore, AQP4 is strongly expressed in the glomerulus, the synaptic unit of the olfactory bulb, suggesting a role for AQP4 in olfactory function.

RNA interference (RNAi) has become an invaluable tool for functional genomics. A critical use of this tool depends on an understanding of the factors that determine the specificity and activity of the active agent, small interfering RNA (siRNA). Several studies have concluded that tolerance of mutations can be considerable and hence lead to off-target effects. In this study, we have investigated in vivo the toleration of wobble (G:U) mutations in high activity siRNAs against Flap Endonuclease 1 (Fen1) and Aquaporin-4 (Aqp4). Mutations in the central part of the antisense strand caused a pronounced decrease in activity, while mutations in the 5' and 3'ends were tolerated very well. Furthermore, based on analysis of nine different mutated siRNAs with widely differing intrinsic activities, we conclude that siRNA activity can be significantly enhanced by wobble mutations (relative to mRNA), in the 5' terminal of the antisense strand. These findings should facilitate design of active siRNAs where the target mRNA offers limited choice of siRNA positions.