Cross-sectional study to assess the psychological morbidity of women facing possible miscarriage.

INTRODUCTION: Threatened miscarriage is a common complication of pregnancy. This study aimed to assess psychological morbidity in women with threatened miscarriage, with the goal of identifying early interventions for women at risk of anxiety or depression. METHODS: Women in their first trimester attending an Early Pregnancy Assessment Clinic were recruited between July 2013 and June 2015. They were asked to complete the 12-item General Health Questionnaire (GHQ-12), the Beck Depression Inventory (BDI), Spielberger's State Anxiety Inventory State form (STAI-S), the Fatigue Scale-14 (FS-14), and the Profile of Mood States (POMS) before consultation. They were also asked to rate anxiety levels before and after consultation using a visual analogue scale (VAS). RESULTS: In total, 1390 women completed the study. The mean ± standard deviation of GHQ-12 (bi-modal) and GHQ-12 (Likert) scores were 4.04 ± 3.17 and 15.19 ± 5.30, respectively. Among these women, 48.4% had a GHQ-12 (bi-modal) score ≥4 and 76.7% had a GHQ-12 (Likert) score >12, indicating distress. The mean ± standard deviation of BDI, STAI-S, and FS-14 scores were 9.35 ± 7.19, 53.81 ± 10.95, and 2.40 ± 0.51, respectively. The VAS score significantly decreased after consultation (P<0.001). Compared with women without a history of miscarriage, women with a previous miscarriage had higher GHQ-12, BDI, and POMS scores (except for fatigue-inertia and vigour-activity subscales). A higher bleeding score was strongly positively correlated with GHQ-12 (Likert) score. There were weak correlations between pain score and the GHQ-12 (bi-modal) ≥4, BDI >12, and POMS scores (except for confusion-bewilderment subscale which showed a strong positive correlation). CONCLUSION: Women with threatened miscarriage experience a considerable psychological burden, emphasising the importance of early recognition for timely management.

External validation of a simple scoring system to predict pregnancy viability in women presenting to an early pregnancy assessment clinic.

INTRODUCTION: A scoring system combining clinical history and simple ultrasound parameters was developed to predict early pregnancy viability beyond the first trimester. The scoring system has not yet been externally validated. This study aimed to externally validate this scoring system to predict ongoing pregnancy viability beyond the first trimester. METHODS: This prospective observational cohort study enrolled women with singleton intrauterine pregnancies before 12 weeks of gestation. Women underwent examination and ultrasound scan to assess gestational sac size, yolk sac size, and fetal pulsation status. A pregnancy-specific viability score was derived in accordance with the Bottomley score. Pregnancy outcomes at 13 to 16 weeks were documented. Receiver-operating characteristic curve analysis was used to assess the discriminatory performance of the scoring system. RESULTS: In total, 1508 women were enrolled; 1271 were eligible for analysis. After adjustment for covariates, miscarriage (13%) was significantly associated with age ≥35 years (odds ratio [OR]=1.99, 95% confidence interval [CI]: 1.19-3.34), higher bleeding score (OR=2.34, 95% CI: 1.25-4.38), gestational age (OR=1.17, 95% CI: 1.13-1.22), absence of yolk sac (OR=4.73, 95% CI: 2.11-10.62), absence of fetal heart pulsation (OR=3.57, 95% CI: 1.87-6.84), mean yolk sac size (OR=1.25, 95% CI: 1.06-1.47), and fetal size (OR=0.82, 95% CI: 0.77-0.88). The area under the receiver operating characteristic curve was 0.91 (95% CI: 0.89-0.93). Viability score of ≥1 corresponded to a >90% probability of viable pregnancy. CONCLUSIONS: The scoring system was easy to use. A score of ≥1 could be used to counsel women who have a high likelihood of viable pregnancy beyond the first trimester.

Elevated plasma ferritin in elderly individuals with high neocortical amyloid-ß load.

Ferritin, an iron storage and regulation protein, has been associated with Alzheimer's disease (AD); however, it has not been investigated in preclinical AD, detected by neocortical amyloid-ß load (NAL), before cognitive impairment. Cross-sectional analyses were carried out for plasma and serum ferritin in participants in the Kerr Anglican Retirement Village Initiative in Aging Health cohort. Subjects were aged 65-90 years and were categorized into high and low NAL groups via positron emission tomography using a standard uptake value ratio cutoff=1.35. Ferritin was significantly elevated in participants with high NAL compared with those with low NAL, adjusted for covariates age, sex, apolipoprotein E ɛ4 carriage and levels of C-reactive protein (an inflammation marker). Ferritin was also observed to correlate positively with NAL. A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve (AUC)=0.766), but was outperformed when plasma ferritin was added to the base model (AUC=0.810), such that at 75% sensitivity, the specificity increased from 62 to 71% on adding ferritin to the base model, indicating that ferritin is a statistically significant additional predictor of NAL over and above the base model. However, ferritin's contribution alone is relatively minor compared with the base model. The current findings suggest that impaired iron mobilization is an early event in AD pathogenesis. Observations from the present study highlight ferritin's potential to contribute to a blood biomarker panel for preclinical AD.

Uterine Fibroid Symptom and Health-related Quality of Life Questionnaire: a Chinese translation and validation study.

INTRODUCTION: The Uterine Fibroid Symptom and Health-related Quality of Life (UFS-QOL) questionnaire is a validated tool in English language to assess treatment outcomes for women with fibroids. We performed a Chinese (traditional) translation and cultural adaptation of it and evaluated its reliability, validity, and responsiveness. METHODS: Overall, 223 Chinese women aged ≥18 years with uterine fibroids self-administered the UFS-QOL, Short-Form Health Survey-12, pictorial blood loss assessment chart (PBAC), and a visual analogue scale (VAS) on fibroid-related symptom severity. Demographics and haemoglobin levels were recorded; physical examination and ultrasound for size of fibroids were performed. Half of the women were followed up 6 months later for responsiveness. RESULTS: Cronbach's alpha coefficients ranged from 0.706 to 0.937, demonstrating high internal reliability. The intra-class correlation coefficients to measure test-retest reliability implied excellent stability of symptom scores (0.819, P<0.001), health-related quality of life scores (0.897, P<0.001), and all subscales (range 0.721-0.870, P<0.001). Convergent validity was demonstrated by positive correlations between the findings of various symptom severity assessment tools (PBAC, VAS on fibroid-related symptoms severity) and the symptom severity domain of Chinese UFS-QOL. In addition, there were positive correlations between health-related quality of life scores of Chinese UFS-QOL and the corresponding subscales of the Short-Form Health Survey-12. Responsiveness was shown by reduction of symptom severity scores and improvement of health-related quality of life scores after treatment. CONCLUSIONS: The Chinese version of the UFS-QOL is valid, reliable, and responsive to changes after treatment.

A study of human neutrophil antigen genotype frequencies in Hong Kong.

BACKGROUND: Alloantibodies against human neutrophil antigens (HNA) are associated with a variety of clinical conditions. Over the past decade, the allelic and genotypic frequencies of the five HNA systems have been evaluated. Although the HNA system is less polymorphic than human leukocyte antigens (HLA), significant differences in the genotypic and allele frequencies still exist in different populations, even those living in close proximity. OBJECTIVES: To delineate HNA genotypic and allele frequencies to provide vital information on estimating the risk of HNA-associated diseases for our local population. METHODS: Using a validated, in-house-developed assay, genotyping for HNA-1, HNA-3, HLA-4 and HNA-5 was performed on 300 samples from Chinese blood donors from Hong Kong. In addition, the frequency of the HNA-2 c.843A > T allele was also determined. RESULTS: The allele frequencies of HNA-1a, -1b and -1c alleles were 67·8, 31·5 and 0%, respectively, whereas the frequencies of HNA-3a and HNA-3b were 71·0 and 29·0%, respectively. The frequencies of HNA-4a and -4b alleles were 99·5 and 0·5%, respectively, and for HNA-5a and -5b, alleles were 85·2 and 14·8%, respectively. Homozygotes for the HNA-2 c.843 TT variant were absent in our population, whereas only <4% of the population were c.843AT heterozygote carriers. CONCLUSIONS: This is the first study to define HNA genotype and allele frequencies using a validated modified in-house PCR-SSP method in the Hong Kong Chinese blood donor population. Our approach provides a cost-effective assay for conducting routine HNA typing and facilitates the incorporation of these assays into routine clinical service. Our results are comparable with those reported in the Guangzhou Chinese population, but the allele frequencies in our Hong Kong Chinese population are significantly different from the reported European frequencies, confirming that a geographical difference exists for HNA allele frequencies.

Clinical and genetic predictors of paclitaxel neurotoxicity based on patient- versus clinician-reported incidence and severity of neurotoxicity in the ICON7 trial.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of paclitaxel, with no reliable method to identify at-risk patients. We investigated the incidence and risk factors including genetic polymorphisms associated with the development of CIPN based on clinician and patient reporting of neuropathic symptoms. PATIENTS AND METHODS: Risk factors for the development of CIPN were examined in 454 patients treated with paclitaxel/carboplatin from the International Collaboration on Ovarian Neoplasms 7 (ICON7) trial. Neuropathy was graded by clinicians by standard adverse event reporting and by patients utilising OV28 questionnaire. Genetic risk factors were examined by selecting six single nucleotide polymorphisms in genes associated with microtubule function. Risk factors were assessed via dose-to-event cox regression models. RESULTS: Grade >2 neuropathy was reported by clinicians in 28% of patients, while 67% of patients reported 'quite a bit' or 'very much' tingling or numbness. Agreement between clinicians and patients was poor (κ = 0.236, 95% confidence interval, 0.177-0.296, P < 0.001). Older age, bevacizumab treatment and bowel resection were associated with clinician reported CIPN, while older age and volume of residual disease were associated with patient-reported neuropathy. There were no significant associations between clinician-reported neuropathy or patient-reported neuropathy and TUBB2, CEP72 or individual MAPT or GSK3B SNPs, however MAPT additive polymorphisms were associated with patient-reported neuropathy and GSK3B additive polymorphisms were associated with clinician reported CIPN. CONCLUSIONS: There was significant discordance between patient- and clinician-reported neurotoxicity. The lack of consensus regarding optimal outcome measures and whose opinion with regard to CIPN takes precedence is a limitation in the investigation of risk factors for CIPN. Care must be taken to select and include patient-reported outcome measures in CIPN assessment to enable accurate identification of genetic and other risk factors for neuropathy.

Histopathological analyses of murine menisci: implications for joint aging and osteoarthritis.

OBJECTIVE: To establish a standardized protocol for histopathological assessment of murine menisci that can be applied to evaluate transgenic, knock-out/in, and surgically induced OA models. METHODS: Knee joints from C57BL/6J mice (6-36 months) as well as from mice with surgically-induced OA were processed and cut into sagittal sections. All sections included the anterior and posterior horns of the menisci and were graded for (1) surface integrity, (2) cellularity, (3) Safranin-O staining distribution and intensity. Articular cartilage in the knee joints was also scored. RESULTS: The new histopathological grading system showed good inter- and intra-class correlation coefficients. The major age-related changes in murine menisci in the absence of OA included decreased Safranin O staining intensity, abnormal cell distribution and the appearance of acellular areas. Menisci from mice with surgically-induced OA showed severe fibrillations, partial/total loss of tissue, and calcifications. Abnormal cell arrangements included both regional hypercellularity and hypocellularity along with hypertrophy and cell clusters. In general, the posterior horns were less affected by age and OA. CONCLUSION: A new standardized protocol and histopathological grading system has been developed and validated to allow for a comprehensive, systematic evaluation of changes in aging and OA-affected murine menisci. This system was developed to serve as a standardized technique and tool for further studies in murine meniscal pathophysiology models.

The Chemorepulsive Protein Semaphorin 3A and Perineuronal Net-Mediated Plasticity.

During postnatal development, closure of critical periods coincides with the appearance of extracellular matrix structures, called perineuronal nets (PNN), around various neuronal populations throughout the brain. The absence or presence of PNN strongly correlates with neuronal plasticity. It is not clear how PNN regulate plasticity. The repulsive axon guidance proteins Semaphorin (Sema) 3A and Sema3B are also prominently expressed in the postnatal and adult brain. In the neocortex, Sema3A accumulates in the PNN that form around parvalbumin positive inhibitory interneurons during the closure of critical periods. Sema3A interacts with high-affinity with chondroitin sulfate E, a component of PNN. The localization of Sema3A in PNN and its inhibitory effects on developing neurites are intriguing features and may clarify how PNN mediate structural neural plasticity. In the cerebellum, enhanced neuronal plasticity as a result of an enriched environment correlates with reduced Sema3A expression in PNN. Here, we first review the distribution of Sema3A and Sema3B expression in the rat brain and the biochemical interaction of Sema3A with PNN. Subsequently, we review what is known so far about functional correlates of changes in Sema3A expression in PNN. Finally, we propose a model of how Semaphorins in the PNN may influence local connectivity.

Identification of a novel HLA-A*02:06:01:02 allele in a Chinese individual by sequence-based typing.

The new HLA-A*02:06:01:02 allele differs from HLA-A*02:06:01 by a C→G substitution in Intron 1.

Clinical heterogeneity of the C9orf72 genetic mutation in frontotemporal dementia.

The C9orf72 genetic mutation represents the most common cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Studies over the last 2 years have revealed a number of key features of this mutation in the fields of clinical neurology, imaging, pathology, and genetics. Despite these efforts, the clinical phenotype appears to extend beyond FTD and ALS into the realm of psychiatric disease, and while highly variable survival rates have been reported, the clinical course of carriers remains relatively unexplored. This report describes two contrasting C9orf72 cases, one with a protracted indolent course dominated by neuropsychiatric features and the other with a rapidly progressive dementia. In both cases, initial structural brain imaging was relatively normal.

Pharyngeal Constrictor Dose-Volume Histogram Metrics and Patient-Reported Dysphagia in Head and Neck Radiotherapy.

AIMS: Head and neck radiotherapy long-term survival continues to improve and the management of long-term side-effects is moving to the forefront of patient care. Dysphagia is associated with dose to the pharyngeal constrictors and can be measured using patient-reported outcomes to evaluate its effect on quality of life. The aim of the present study was to relate pharyngeal constrictor dose-volume parameters with patient-reported outcomes to identify prognostic dose constraints. MATERIALS AND METHODS: A 64-patient training cohort and a 24-patient testing cohort of oropharynx and nasopharynx cancer patients treated with curative-intent chemoradiotherapy were retrospectively examined. These patients completed the MD Anderson Dysphagia Inventory outcome survey at 12 months post-radiotherapy to evaluate late dysphagia: a composite score lower than 60 indicated dysphagia. The pharyngeal constrictor muscles were subdivided into four substructures: superior, middle, inferior and cricopharyngeal. Dose-volume histogram (DVH) metrics for each of the structure combinations were extracted. A decision tree classifier was run for each DVH metric to identify dose constraints optimising the accuracy and sensitivity of the cohort. A 60% accuracy threshold and feature selection method were used to ensure statistically significant DVH metrics were identified. These dose constraints were then validated on the 24-patient testing cohort. RESULTS: Existing literature dose constraints only had two dose constraints performing above 60% accuracy and sensitivity when evaluated on our training cohort. We identified two well-performing dose constraints: the pharyngeal constrictor muscle D63% < 55 Gy and the superior-middle pharyngeal constrictor combination structure V31Gy < 100%. Both dose constraints resulted in ≥73% mean accuracy and ≥80% mean sensitivity on the training and testing patient cohorts. In addition, a pharyngeal constrictor muscle mean dose <57 Gy resulted in a mean accuracy ≥74% and mean sensitivity ≥60%. CONCLUSION: Mid-dose pharyngeal constrictor muscle and substructure combination dose constraints should be used in the treatment planning process to reduce late patient-reported dysphagia.

Loop-mediated isothermal amplification for detection of HLA-B*58:01 allele.

Strong association of human leukocyte antigen (HLA)-B*58:01 allele with allopurinol-induced hypersensitivity was found worldwide, especially in the Han Chinese populations. This study aims to develop and evaluate a loop-mediated isothermal amplification (LAMP) assay for rapid detection of HLA-B*58:01. Two sets of LAMP primers targeting exons 2 and 3 of HLA-B*58:01 allele were designed and their annealing temperatures were optimized accordingly. The heating devices for LAMP assay were tested. The analytical sensitivities of the two sets of LAMP primers were determined by 1:10 serial dilution of a positive control with homozygous HLA-B*58:01 allele from 100 ng down to 1 fg. The analytical specificities of the LAMP primers were evaluated by 30 selected University of California, Los Angeles (UCLA) DNA Exchange Program samples with known HLA-B loci typings previously typed by sequencing. Both sets of LAMP primers targeting exons 2 and 3 amplified optimally at 67°C. Thermal cycler is essential in achieving a more precise and specific LAMP result. The sensitivity of the exon 2 LAMP primer set was found to be 1 pg, whereas it was 10 ng for the exon 3 primer set in a 60-min amplification. The LAMP primers were highly specific because LAMP results were perfectly concordant to the sequencing results. The HLA-B*58:01 LAMP assay has compatible sensitivity and specificity to routine genotyping assays, and it is potentially an alternative screening test for the detection of HLA-B*58:01 and ultimately allopurinol-induced hypersensitivity.

Identification of a novel HLA-DRB1*11:129 allele in a Chinese individual by sequence-based typing.

The new DRB1*11:129 allele differs from the closest matching allele HLA-DRB1*11:06:01 by one nucleotide substitution in exon 3 at position 623 (G→A).