Functioning and well-being in older children and adolescents with achondroplasia: A qualitative study.

The study aimed to explore how having achondroplasia affects older children and adolescents' day-to-day functioning and well-being. Individual/focus group interviews were conducted with older children/adolescents between the ages of 9 to <18 years and diagnosed with achondroplasia to elicit key concepts. An adapted grounded theory approach informed the qualitative analysis of interview data. Thirty-two children and adolescents completed interviews. Study results revealed five impact domains, including physical health, functioning, school impacts, emotional well-being, and social well-being. Frequently reported impacts on physical health included low stamina/tiring easily (81%) and back pain (69%). Key impacts in the functioning domain were difficulty with reaching objects or high places (84%) and walking long distances (75%). Emotional impacts included feeling different (63%), worried/scared (47%), and embarrassed/self-conscious (47%). Impacts on social well-being included difficulty with sports or physical play (81%) and others treating child as younger than their actual age (75%). The most frequent school impact was trouble participating in physical education (81%). A preliminary theoretical model depicting the experiences of older children/adolescents with achondroplasia was constructed based on the analysis. The preliminary theoretical model of older children and adolescents' experiences of living with achondroplasia may be used to inform future research and clinical practice.

Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamics results of a long-acting C-type natriuretic peptide prodrug, TransCon CNP.

AIM: TransCon CNP is a novel prodrug designed to provide sustained release of C-type natriuretic peptide (CNP) for once-weekly therapy, addressing the pathology leading to aberrant skeletal development in achondroplasia. This phase 1 trial was initiated to assess the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of TransCon CNP. METHODS: This randomized, placebo-controlled, single-ascending dose phase 1 trial was performed at two sites in Australia and enrolled 45 healthy adult males. Subjects received placebo or TransCon CNP (single-ascending dose cohorts [3, 10, 25, 75 or 150 µg CNP/kg]). The primary endpoint was frequency of adverse events and other safety outcomes. Other endpoints included PK and PD measured by cyclic guanosine-monophosphate (cGMP) and amino-terminal propeptide of CNP (NTproCNP). RESULTS: TransCon CNP provided continuous systemic exposure to CNP over at least 7 days post-dose. Plasma and urine levels of cGMP were significantly increased in subjects administered TransCon CNP at 75-150 µg CNP/kg, indicating target engagement of active CNP at the natriuretic peptide receptor-B (NPR-B) for at least 1 week post-dose. TransCon CNP was well-tolerated, with no serious treatment-emergent adverse events or discontinuations. Extensive cardiac safety assessments did not reveal any clinically relevant effects on electrocardiogram parameters, including heart rate, PR, QRS and QTcF intervals. CONCLUSIONS: Safety and PD data from this phase 1 trial support that TransCon CNP is well tolerated, with a PK profile compatible with a once-weekly dosing regimen. Further studies are ongoing to evaluate the potential of TransCon CNP to positively impact abnormal endochondral ossification in children with achondroplasia.

Effectiveness of monoclonal antibody therapy for COVID-19 patients using a risk scoring system.

INTRODUCTION: Monoclonal antibody therapy has been reported to be highly effective for preventing hospitalisation and severe cases in patients with Coronavirus Disease 2019 (COVID-19). However, since the drug is not readily available, it is important to rapidly and appropriately identify high-risk patients who can benefit most from therapy. Therefore, we designed a risk scoring system to identify at-risk COVID-19 patients in our region during the largest surge of COVID-19, from July to September 2021. METHODS: According to the risk scores, confirmed COVID-19 patients were introduced to receive REGN-CoV-2 to our hospital by regional health centre from 18th August (Term 3). The primary outcome was the comparison of the number of hospitalisation and severe condition with other periods, the 4th wave (Term 1) and the early part of the 5th wave (Term 2) in Japan. RESULTS: During Term 3, 115 patients were stratified with the scoring system and administered REGN-COV-2. The number of hospitalisation vs severe cases were 60 (5.2%) vs 14 (1.2%), 8 (1.5%) vs 3 (0.6%) and 21 (1.2%) vs 2 (0.1%), in term 1, 2 and 3, respectively. Among those aged <60 years, compared with term 1, the relative risk of hospitalisation and severe condition were 0.25 (95% CI: 0.12-0.53) and 0.10 (95% CI: 0.01-0.80), respectively, in term 3. Drug adverse events were fever (3: 2.6%), headache (1: 0.9%) and neck rash (1: 0.9%), all events were resolved within 24 h wth no serious adverse event. CONCLUSIONS: The administration of monoclonal antibody therapy using a risk scoring system significantly reduced the number of hospitalisation and disease severity of COVID-19 without any serious adverse events and avoided regional medical collapse.

Assessing physical symptoms, daily functioning, and well-being in children with achondroplasia.

This study's purpose was to provide qualitative evidence to support the development of two observer-reported outcome measures assessing the physical symptoms/complications of achondroplasia in children and impacts on children's quality of life. Individual/focus group concept elicitation interviews were conducted with parents of children aged 2 to <12 years with achondroplasia and experts. Qualitative analysis of transcripts, based on an adapted grounded theory approach, informed item generation and measure development. Cognitive debriefing (CD) interviews were conducted with parents to confirm relevance and understanding. Thirty-six parents participated in concept elicitation interviews. The analysis identified major physical symptoms/complications and impacts of achondroplasia, which informed the development of the Achondroplasia Child Experience Measures (ACEMs): ACEM-Symptom and ACEM-Impact. ACEM-Symptom was comprised of eight major symptoms/complications including pain (58%), ear infections/fluid in ear (56%), and low stamina/tiring easily (56%). ACEM-Impact consisted of 31 major impacts in the domains of daily functioning, emotional well-being, social well-being, and need for assistance/adaptive devices. Impacts on functioning included difficulty reaching objects/high places (89%) and toileting (67%). Emotional impacts included feeling different (53%) and feeling frustrated/annoyed (47%). Social impacts included difficulty participating in sports/physical play (86%) and being treated as younger than age (83%). Following CD interviews with 16 additional parents, validation-ready ACEM measures were generated. The study improves our understanding of the experiences of children with achondroplasia and provides evidence supporting the content validity of the ACEMs. Validated ACEMs may be used to assess potential benefits of future treatments for comorbidities of achondroplasia.

Assessing the impacts of having a child with achondroplasia on parent well-being.

PURPOSE: This study's purpose was to develop a better understanding of the experiences of parents of children with achondroplasia and to provide qualitative evidence to support the development of a patient-reported outcome (PRO) measure of parent impacts. METHODS: Concept elicitation (CE) individual/focus group interviews were conducted with parents of children aged 2 to < 12 years with achondroplasia in the United States and Spain. The qualitative analysis informed the PRO measure development. Cognitive debriefing (CD) interviews were conducted to ensure parent understanding and item relevance. RESULTS: Thirty-six parents participated in individual/focus group CE interviews. The analysis identified parent impacts in four domains, including caretaking responsibilities, emotional well-being, family, and work, and results informed the development of the Achondroplasia Parent Experience Measure (APEM). Caretaking responsibilities included managing child's medical care (92%), helping child with self-care (67%), advocating for child (64%), assisting child (56%), and observing/monitoring child (e.g., to ensure safety; 47%). Impacts on parents' emotional well-being included worry about the future (75%), worry about child's physical health (67%), safety concerns (50%), feeling stressed/overwhelmed (44%), and worry about child's social relationships (42%). Impacts on family and work included family strain (56%), limiting/adapting family activities (42%), and missed work time (50%). CD interviews with an additional 16 parents of children with achondroplasia confirmed understanding and item relevance. CONCLUSION: The results improve our understanding of the experiences of parents of children with achondroplasia and provide qualitative evidence to support the content validity of the APEM. A psychometric study is needed to validate the measure.

Clinical outcomes by relative docetaxel dose and dose intensity as chemotherapy for Japanese patients with castration-resistant prostate cancer: a retrospective multi-institutional collaborative study.

BACKGROUND: The aim of this study was to retrospectively investigate clinical outcomes by relative dose and dose intensity of docetaxel (DOC) as chemotherapy for Japanese patients with castration-resistant prostate cancer (CRPC). METHODS: A total of 145 CRPC patients who received more than 4 courses of DOC chemotherapy at 14 hospitals between 2005 and 2011 were enrolled. Patients were divided into two groups--those receiving a higher or lower dose (mg/m(2)) or dose intensity (mg/m(2)/week). Differences between the groups regarding treatment outcomes and adverse events (AEs) were determined. Additionally, prognostic factors predictive of cancer-specific survival (CSS) in these patients were identified by both univariate and multivariate analysis. RESULTS: The total patient group underwent a mean of 11.2 ± 7.4 DOC cycles, and the mean CSS after therapy was 15.6 ± 10.1 months. The higher-dose group had a better prostate-specific antigen (PSA) response than the lower-dose group. However, there was no significant difference between the groups in prognosis after DOC chemotherapy. Leukopenia and neutropenia were observed more frequently in the higher-dose group. Serum biomarkers (including PSA, lactate dehydrogenase and alkaline phosphatase), hemoglobin levels and presence of pain at initiation of chemotherapy, as well as the PSA nadir level on first-line hormone therapy, all were significant predictors of CSS. CONCLUSIONS: In the Japanese population, relatively low-dose DOC chemotherapy had no deleterious effect on the CSS of CRPC patients, and a lower incidence of AEs occurred, in spite of a diminished PSA response compared with those receiving a higher dose.

Thyroid hormone negatively regulates CDX2 and SOAT2 mRNA expression via induction of miRNA-181d in hepatic cells.

Thyroid hormones (THs) regulate transcription of many metabolic genes in the liver through its nuclear receptors (TRs). Although the molecular mechanisms for positive regulation of hepatic genes by TH are well understood, much less is known about TH-mediated negative regulation. Recently, several nuclear hormone receptors were shown to downregulate gene expression via miRNAs. To further examine the potential role of miRNAs in TH-mediated negative regulation, we used a miRNA microarray to identify miRNAs that were directly regulated by TH in a human hepatic cell line. In our screen, we discovered that miRNA-181d is a novel hepatic miRNA that was regulated by TH in hepatic cell culture and in vivo. Furthermore, we identified and characterized two novel TH-regulated target genes that were downstream of miR-181d signaling: caudal type homeobox 2 (CDX2) and sterol O-acyltransferase 2 (SOAT2 or ACAT2). CDX2, a known positive regulator of hepatocyte differentiation, was regulated by miR-181d and directly activated SOAT2 gene expression. Since SOAT2 is an enzyme that generates cholesteryl esters that are packaged into lipoproteins, our results suggest miR-181d plays a significant role in the negative regulation of key metabolic genes by TH in the liver.

Real-World Experience of the Comparative Effectiveness and Safety of Molnupiravir and Nirmatrelvir/Ritonavir in High-Risk Patients with COVID-19 in a Community Setting.

Molnupiravir (MOV) and nirmatrelvir/ritonavir (NMV/r) are efficacious oral antiviral agents for patients with the 2019 coronavirus (COVID-19). However, little is known about their effectiveness in older adults and those at high risk of disease progression. This retrospective single-center observational study assessed and compared the outcomes of COVID-19 treated with MOV and NMV/r in a real-world community setting. We included patients with confirmed COVID-19 combined with one or more risk factors for disease progression from June to October 2022. Of 283 patients, 79.9% received MOV and 20.1% NMV/r. The mean patient age was 71.7 years, 56.5% were men, and 71.7% had received ≥3 doses of vaccine. COVID-19-related hospitalization (2.8% and 3.5%, respectively; p = 0.978) or death (0.4% and 3.5%, respectively; p = 0.104) did not differ significantly between the MOV and NMV/r groups. The incidence of adverse events was 2.7% and 5.3%, and the incidence of treatment discontinuation was 2.7% and 5.3% in the MOV and NMV/r groups, respectively. The real-world effectiveness of MOV and NMV/r was similar among older adults and those at high risk of disease progression. The incidence of hospitalization or death was low.

A qualitative study of the impacts of having an infant or young child with achondroplasia on parent well-being.

BACKGROUND: Currently, there is limited research on how having a child diagnosed with achondroplasia affects parents' lives. The purpose of the study was to investigate the experiences of parents of infants and young children less than two years of age with achondroplasia. METHODS: Concept elicitation interviews were conducted with parents of children less than 2 years of age with achondroplasia in the United States and Spain. Using grounded theory methods modified for health outcomes research, a qualitative analysis of interview transcripts was conducted. Based on the qualitative analysis, a preliminary theoretical model of the experiences of parents of infants and young children with achondroplasia was developed. RESULTS: Fifteen parents, including 14 mothers and 1 father from 15 unique families, participated in individual or focus group concept elicitation interviews in the US (n = 9) and Spain (n = 6). The qualitative analysis identified four key parent impact domains, which included caretaking responsibilities, impacts on emotional well-being, having worries and concerns about their child, and impacts on daily well-being. Frequently discussed caretaking responsibilities among parents were managing child's medical care/treatment (93%), obtaining adaptations/items for child (73%), and monitoring child to avoid complications of achondroplasia (67%). Emotional impacts included feeling stressed/overwhelmed (67%), depressed/sad (40%), and anxious/nervous (33%). Worries and concerns included worry/concern about the future (100%), concerns regarding child's physical health (87%), worry about child's social well-being (80%), concern for child's emotional well-being (73%), and worry about child being able to function independently (67%). Daily well-being impacts included family strain (60%), missed work time (47%), and missed/limited social activities (33%). Based on the qualitative findings, a preliminary theoretical model depicting the experiences of parents of infants and young children with achondroplasia was created. CONCLUSIONS: The study sheds light on the range of impacts that parents of infants and young children with achondroplasia may experience, including caretaking responsibilities, impacts on emotional well-being, worries/concerns regarding their child, and impacts on daily well-being. The theoretical model of parent experiences may provide a helpful framework for informing future research and clinical practice.

Clinical effect of naftopidil on the quality of life of patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a prospective study.

OBJECTIVES: To investigate the benefit of alpha1-adrenoceptor antagonist naftopidil on the quality of life (QOL) of patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH/LUTS). METHODS: A total of 99 men with BPH/LUTS were prospectively recruited. The Short Form-8 (SF-8) was used for generic QOL assessment and each parameter was compared with the norm in these patients. Longitudinal changes were evaluated using the SF-8 and the International Prostatic Symptoms Score (I-PSS) at baseline, 4 and 8 weeks after naftopidil administration. The relationship between SF-8 and I-PSS was analyzed. RESULTS: Five of eight components in the SF-8 were significantly lower than the Japanese national norm at baseline. SF-8 score was improved by naftopidil at 4 and 8 weeks in general health (GH) and physical component summary (PCS) in the patients in their 70s. Mental health (MH) and mental component summary (MCS) were improved at 8 weeks in patients in their 60s. When analyzing the whole cohort, SF-8 GH, role emotional (RE) and MH had improved at 8 weeks, which was similar to the norm, and bodily pain (BP) results were better. Compared with the baseline, total I-PSS, storage/voiding symptoms and QOL index scores improved significantly under naftopidil. Each component of I-PSS (except for hesitancy) correlated with SF-8 sub-scales (except for BP) to some extent. CONCLUSIONS: BPH/LUTS impairs generic QOL, which is improved by naftopidil treatment. SF-8 can be a useful instrument to assess the efficacy of BPH/LUTS treatment because its simplicity to complete and analyze, and its meaningful relationship to I-PSS.

Clinical effect of alpha 1D/A adrenoceptor inhibitor naftopidil on benign prostatic hyperplasia: an international prostate symptom score and King's Health Questionnaire assessment.

OBJECTIVES: To examine the effect of alpha 1D/A adrenoceptor inhibitor naftopidil on health-related quality of life (QOL) in men with benign prostatic hyperplasia (BPH). METHODS: A total of 56 newly diagnosed patients with symptomatic BPH were prospectively enrolled and treated with 50 mg naftopidil daily for more than 12 weeks. All underwent pre-treatment documentation of lower urinary tract symptoms, QOL assessment using the international prostate symptom score (IPSS) and King's Health Questionnaire (KHQ), and uroflowmetry. A post-treatment assessment was performed at 12 weeks. RESULTS: IPSS scores as well as QOL index showed a significant improvement after naftopidil administration. Similarly, all seven domains except general health perceptions and social limitations in the KHQ questionnaire were significantly improved. When dividing the patients into overactive bladder (OAB) and non-OAB groups, only the OAB group showed significant improvement in almost all the domains of KHQ. Change ratios of the IPSS were not associated with those of KHQ domain scores in the OAB group. On the other hand, in the non-OAB group more domains presented improvements, which were associated with those of IPSS scores. CONCLUSIONS: Twelve-week treatment with naftopidil for symptomatic BPH patients is associated with significant improvement in the IPSS, QOL index, maximum urinary flow rate, post-void residual urine volume (PVR) and almost all domains in KHQ. KHQ is useful for the evaluation of clinical response in BPH patients, particularly in those with associated OAB.

Suppression of metastasis of rat prostate cancer by introduction of human chromosome 13.

AIM: Chromosome 13 is one of the most frequently altered chromosomes in prostate cancer. The present study was undertaken to examine the role of human chromosome 13 in the progression of prostate cancer. METHODS: Human chromosome 13 was introduced into highly metastatic rat prostate cancer cells via microcell-mediated chromosome transfer. RESULTS: Microcell hybrid clones containing human chromosome 13 showed suppression of metastasis to the lung without any suppression of tumorigenicity, except for one clone, which contained the smallest sized human chromosome 13 and did not show any suppression on lung metastasis. Expression of two known tumor suppressor genes, BRCA2 and RB1, which map to chromosome 13, was examined by reverse transcription- polymerase chain reaction analysis. BRCA2 was expressed only in the metastasis-suppressed microcell-hybrid clones, whereas RB1 was expressed in all clones. CONCLUSION: Human chromosome 13 contains metastasis suppressor gene(s) for prostate cancer derived from rat. Furthermore, the RB1 gene is unlikely to be involved in the suppression of metastasis evident in this system.

Clinical impact of tamsulosin on generic and symptom-specific quality of life for benign prostatic hyperplasia patients: using international prostate symptom score and Rand Medical Outcomes Study 36-item Health Survey.

AIM: To examine the efficiency of alpha1-blocker treatment on disease-specific and generic quality of life (QOL) in men with clinically diagnosed benign prostatic hyperplasia (BPH), the improvement of QOL scores with International prostate symptom score (I-PSS) and Rand Medical Outcomes Study 36-item Health Survey (SF-36) was prospectively analyzed. METHODS: A total of 68 newly diagnosed patients with symptomatic BPH that satisfied all inclusion and none of the exclusion criteria were prospectively recruited. All patients received 0.2 mg/day of tamsulosin for 12 weeks. All patients underwent pretreatment documentation of lower urinary tract symptoms (LUTS) and assessment of symptom-specific QOL. Symptoms and general health-related QOL (HRQOL) were assessed using the I-PSS and SF-36, respectively. Also, other objective variables, such as prostate volume, maximal urinary flow and postvoid residual urine volume, were evaluated. RESULTS: After 12 weeks, decrease in I-PSS was 27% compared with baseline (from 16.4 +/- 7.18 to 11.9 +/- 7.56). All questionnaires in the I-PSS showed improvement after tamsulosin treatment and the I-PSS QOL score was improved from 4.51 +/- 1.14 to 3.17 +/- 1.38 (P < 0.0001) at 12 weeks after tamsulosin administration. In intragroup comparisons of HRQOL scores with age-gender adjusted SF-36 Japanese national norms, three SF-36 subscales (bodily pain, BP; social function, SF; and mental health, MH) were worse in the BPH group aged over 70 years, while younger BPH groups aged <70 had better mean SF-36 physical function (PF) scores compared with age-gender adjusted Japanese national norms. In the BPH group with a prostatic volume > or =20 mL, three mean SF-36 scales (BP, SF and MH) were significantly improved after tamsulosin treatment. It is noteworthy that these SF-36 subscales were identical to those observed to worsen in the older BPH group compared to Japanese national norms. CONCLUSIONS: Treatment with tamsulosin for symptomatic BPH patients is associated with significant improvement in the generic HRQOL, in addition to disease-specific QOL and symptoms, at 3 months after drug administration. In particularly, for generic HRQOL with SF-36, tamsulosin treatment can efficiently improve three mean SF-36 subscales (BP, SF and MH) that are decreased in older BPH patients.