Understanding quality of life issues in patients with advanced melanoma: Phase 1 and 2 in the development of the EORTC advanced melanoma module.

AIMS: We aimed to develop a European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) module tailored for patients with advanced (resectable or unresectable stage III/IV) melanoma receiving immune checkpoint inhibitors or targeted therapy. METHODS: Following the EORTC QoL Group module development guidelines, we conducted phases 1 and 2 of the development process. In phase 1, we generated a list of health-related (HR)QoL issues through a systematic literature review and semi-structured interviews with healthcare professionals (HCPs) and patients with advanced melanoma. In phase 2, these issues were converted into questionnaire items to create the preliminary module. RESULTS: Phase 1: we retrieved 8006 articles for the literature review, of which 35 were deemed relevant, resulting in 84 HRQoL issues being extracted to create the initial issue list. Semi-structured interviews with 18 HCPs and 28 patients with advanced melanoma resulted in 28 issues being added to the initial issue list. Following EORTC module development criteria, 26 issues were removed, and two issues were added after review by patient advocates. Phase 2: To ensure uniformity and avoid duplication, 16 issues were consolidated into eight items. Additionally, an independent expert contributed one new item, resulting in a preliminary module comprising 80 HRQoL items. CONCLUSION: We identified a range of HRQoL issues (dry skin, xerostomia, and arthralgia) relevant to patients with stage III/IV melanoma. Future module development phases will refine the questionnaire. Once completed, this module will enable standardized assessment of HRQoL in patients with (locally) advanced melanoma.

Development of Allison scanner to measure transverse emittance at low energy beam transport of rare-isotope accelerator complex for ON-line experiments.

The Rare-isotope Accelerator complex for ON-line experiments is a heavy-ion accelerator facility that accelerates a stable or rare isotope beam up to 400 kW with an energy of 200 MeV/u. Various heavy-ion beams are generated from the Electron Cyclotron Resonance Ion Source, with an energy of 10 keV/u and separated according to A/Q at the first dipole magnet (DM). To measure beam transverse emittance at the Low Energy Beam Transport section, two Allison scanners are installed behind the DM for the X and Y directions. It consist of a servo motor for driving, a Faraday cup for current measurement, deflection plates, and electronic device. The measurable range of beam angle in of the Allison scanner is determined by the structure of the deflection plate and designed based on mathematical calculations. Experimental Physics and Industrial Control System (EPICS) is adopted to integrate and control a variety of devices. To control the complex measurement sequence of the Allison scanner, an EPICS sequencer module was used. Normalized emittance is calculated by python code with Pyepics module using phase space distribution data. In this paper, we present the detailed design of the Allison scanner, the configuration of the control system, and the experimental results using an Ar9+ 30 µA beam.

CRITICAL CURRENT DENSITIES AND N-VALUES OF MGB2 CONDUCTORS FOR SMES, MRI, AND LOW AC LOSS APPLICATIONS.

Multifilamentary MgB2 strands (filament numbers 36 to 114) prepared by the in-situ power-in-tube (PIT) route with carbon doping contents of 0, 2, and 3.2% were wound on barrels for transport Jc and n-value measurement at 4.2 K in fields of up to 12 T. The strand and gauge lengths were 1 m and 0.5 m. Heat treatments at 675 °C and 650 °C centered around the melting point of Mg (650 °C) and both utilized the liquid-solid reaction. A pair of strands, with and without 2% C doping exhibited the Jc (B) crossover effect. Studied were the dependencies of Jc on field strength, dopant concentration, and cabling and the dependence of n-value on field strength.

Health-related quality of life in survivors of advanced melanoma treated with anti-PD1-based immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved survival in advanced melanoma but are associated with immune-related adverse events (irAEs). This single center, cross-sectional survey aimed to describe the long-term symptom burden and impact on health-related quality of life (HRQL) of advanced melanoma patients with sustained disease control following treatment with ICIs. METHODS: Advanced melanoma patients (stage IIB, III or IV, AJCCv8), treated with anti-PD1-based ICIs, who were off-treatment and had at least 6 months follow-up from their last infusion with an ongoing response in the metastatic setting or no evidence of disease recurrence in the adjuvant setting. A paper-based questionnaire, consisting of the EORTC QLQ-C30, EORTC QLQ-FA12, and the PRO-CTCAE was administered. RESULTS: Of 90 participants, 61 (68%) completed the questionnaire; 40 received single-agent anti-PD1, and 21 anti-PD1/anti-CTLA4. Thirty-three (54%) were treated in the adjuvant setting. At the time of enrolment, 31 (51%) participants had active treatment for a previous irAE. Overall, 18/61 (30%) participants reported long-term symptoms and trouble in physical and emotional functioning. Physical fatigue was common and interfered with daily activities (n = 12, 20%). In the PRO-CTCAE questionnaire, muscle ache (n = 12, 20%) and joint ache (n = 9, 15%) were commonly reported. Despite this, participants reported overall good health (6.00, range 2.00-7.00) and reasonable level of HRQL (6.00, range 3.00-7.00). DISCUSSION: Melanoma survivors experience long-term symptoms in physical and psychosocial HRQL domains after ICI treatment. These results underline the importance to address existing gaps in survivorship care, implement these findings in clinical practice and increase awareness for long-term symptoms in these patients.

Effects of genomic estimated breeding value and dietary energy to protein ratio on growth performance, carcass trait, and lipogenic gene expression in Hanwoo steer.

"Genome-based precision feeding" is a concept that involves the application of customised diets to different genetic groups of cattle. We investigated the effects of the genomic estimated breeding value (gEBV) and dietary energy to protein ratio (DEP) on growth performance, carcass traits, and lipogenic gene expression in Hanwoo (Korean cattle) steers. Forty-four Hanwoo steers (BW = 636 kg, age = 26.9 months) were genotyped using the Illumina Bovine 50 K BeadChip. The gEBV was calculated using genomic best linear unbiased prediction. Animals were separated into high gEBV of marbling score or low-gMS groups based on the upper and lower 50% groupings of the reference population, respectively. Animals were assigned to one of four groups in a 2 × 2 factorial arrangement: high gMS/high DEP (0.084 MJ/g), high gMS/low DEP (0.079 MJ/g), low gMS/high DEP, and low gMS/low DEP. Steers were fed concentrate with a high or low DEP for 31 weeks. The BW tended to be higher (0.05 < P < 0.1) in the high-gMS groups compared to the low-gMS groups at 0, 4, 8, 12, and 20 weeks. The average daily gain (ADG) tended to be lower (P = 0.08) in the high-gMS group than in the low-gMS group. Final BW and measured carcass weight (CW) were positively correlated with the gEBV of carcass weight (gCW). The DEP did not affect ADG. Neither the gMS nor the DEP affected the MS and beef quality grade. The intramuscular fat (IMF) content in the longissimus thoracis (LT) tended to be higher (P = 0.08) in the high-gMS groups than in the low-gMS groups. The mRNA levels of lipogenic acetyl-CoA carboxylase and fatty acid binding protein 4 genes in the LT were higher (P < 0.05) in the high-gMS group than in the low-gMS group. Overall, the IMF content tended to be affected by the gMS, and the genetic potential (i.e., gMS) was associated with the functional activity of lipogenic gene expression. The gCW was associated with the measured BW and CW. The results demonstrated that the gMS and the gCW may be used as early prediction indexes for meat quality and growth potential of beef cattle.

The "new" oligometastatic disease state and associated therapies in non-small cell lung cancer: A narrative review.

Patients with non-small cell lung cancer (NSCLC) at stage IV have typically been considered incurable. Nonetheless, there is growing evidence that certain patient groups with fewer metastases, or so-called oligometastatic disease, which may have a more indolent biological nature than widespread metastatic diseases, may survive longer if definitive local treatment is administered to all metastatic sites. According to several retrospective investigations, this subgroup had a better prognosis than other stage IV patients, and the eighth edition of TNM staging was revised to reflect these findings. As a result of rapidly emerging systemic therapies, such as immune checkpoint inhibitors and a growing number of targeted therapies, more patients with this uncommon clinical opportunity have been identified and have received greater clinical attention. Currently, there is no established protocol for the management of oligometastatic disease, and the majority of therapeutic decisions are made through multidisciplinary discussion. In addition to systemic treatment, the two primary local therapeutic options for oligometastatic diseases are surgery and radiotherapy. A few phase 2 trials suggest that aggressive local ablative therapy may significantly improve the prognosis of patients with oligometastatic NSCLC. This review summarizes the most recent data on the management of oligometastatic NSCLC, with a focus on the prognostic significance of local ablative therapy in these patients.

Risk factors for hospital-acquired infection during the SARS-CoV-2 pandemic.

OBJECTIVE: To evaluate risk factors for hospital-acquired infection (HAI) in patients during the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, including historical and concurrent cohorts. DESIGN: Retrospective cohort. SETTING: Three Missouri hospitals, data from 1st January 2017 to 30th September 2020. PARTICIPANTS: Patients aged ≥18 years and admitted for ≥48 h. METHODS: Univariate and multi-variate Cox proportional hazards models incorporating the competing risk of death were used to determine risk factors for HAI. A-priori sensitivity analyses were performed to assess the robustness of the urine-, blood- and respiratory-culture-based HAI definition. RESULTS: The cohort included 254,792 admissions, with 7147 (2.8%) HAIs (1661 blood, 3407 urine, 2626 respiratory). Patients with SARS-CoV-2 had increased risk of HAI (adjusted hazards ratio 1.65, 95% confidence interval 1.38-1.96), and SARS-CoV-2 infection was one of the strongest risk factors for development of HAI. Other risk factors for HAI included certain admitting services, chronic comorbidities, intensive care unit stay during index admission, extremes of body mass index, hospital, and selected medications. Factors associated with lower risk of HAI included year of admission (declined over the course of the study), admitting service and medications. Risk factors for HAI were similar in sensitivity analyses restricted to patients with diagnostic codes for pneumonia/upper respiratory infection and urinary tract infection. CONCLUSIONS: SARS-CoV-2 was associated with significantly increased risk of HAI.

Comparison of the Respiratory Resistomes and Microbiota in Children Receiving Short versus Standard Course Treatment for Community-Acquired Pneumonia.

Pediatric community-acquired pneumonia (CAP) is often treated with 10 days of antibiotics. Shorter treatment strategies may be effective and lead to less resistance. The impact of duration of treatment on the respiratory microbiome is unknown. Data are from children (n = 171), ages 6 to 71 months, enrolled in the SCOUT-CAP trial (NCT02891915). Children with CAP were randomized to a short (5 days) versus standard (10 days) beta-lactam treatment strategy. Throat swabs were collected at enrollment and the end of the study and used for shotgun metagenomic sequencing. The number of beta-lactam and multidrug efflux resistance genes per prokaryotic cell (RGPC) was significantly lower in children receiving the short compared to standard treatment strategy at the end of the study (Wilcoxon rank sum test, P < 0.05 for each). Wilcoxon effect sizes were small for beta-lactam (r: 0.15; 95% confidence interval [CI], 0.01 to 0.29) and medium for multidrug efflux RGPC (r: 0.23; 95% CI, 0.09 to 0.37). Analyses comparing the resistome at the beginning and end of the trial indicated that in contrast to the standard strategy group, the resistome significantly differed in children receiving the short course strategy. Relative abundances of commensals such as Neisseria subflava were higher in children receiving the standard strategy, and Prevotella species and Veillonella parvula were higher in children receiving the short course strategy. We conclude that children receiving 5 days of beta-lactam therapy for CAP had a significantly lower abundance of antibiotic resistance determinants than those receiving standard 10-day treatment. These data provide an additional rationale for reductions in antibiotic use when feasible. IMPORTANCE Antibiotic resistance is a major threat to public health. Treatment strategies involving shorter antibiotic courses have been proposed as a strategy to lower the potential for antibiotic resistance. We examined relationships between the duration of antibiotic treatment and its impact on resistance genes and bacteria in the respiratory microbiome using data from a randomized controlled trial of beta-lactam therapy for pediatric pneumonia. The randomized design provides reliable evidence of the effectiveness of interventions and minimizes the potential for confounding. Children receiving 5 days of therapy for pneumonia had a lower prevalence of two different types of resistance genes than did those receiving the 10-day treatment. Our data also suggest that children receiving longer durations of therapy have a greater abundance of antibiotic resistance genes for a longer period of time than do children receiving shorter durations of therapy. These data provide an additional rationale for reductions in antibiotic use.

Decreased fasting serum glucogenic amino acids with a higher compared to normal protein diet during energy restriction in women: a randomized controlled trial.

Dietary protein alters circulating amino acid (AAs) levels and higher protein intake (HP) is one means of losing weight. We examined 34 overweight and obese women (57 ± 4 years) during 6 months of energy restriction (7.3 ± 3.8% weight loss) divided into groups consuming either normal protein (NP; 18.6 energy% protein) or HP (24.3 energy% protein). There was a reduction in fasting serum glucogenic AAs (p = 0.015) that also associated with greater weight loss (p < 0.05) in the HP group, but not in the NP group. These findings have implications for nutrient prioritization during energy restriction.

The tumor microenvironment and immune responses in prostate cancer patients.

The landscape of cancer treatment has been transformed over the past decade by the success of immune-targeting therapies. However, despite sipuleucel-T being the first-ever approved vaccine for cancer and the first immunotherapy licensed for prostate cancer in 2010, immunotherapy has since seen limited success in the treatment of prostate cancer. The tumour microenvironment of prostate cancer presents particular barriers for immunotherapy. Moreover, prostate cancer is distinguished by being one of only two solid tumours where increased T cell-infiltration correlates with a poorer, rather than improved, outlook. Here, we discuss the specific aspects of the prostate cancer microenvironment that converge to create a challenging microenvironment, including myeloid-derived immune cells and cancer-associated fibroblasts. By exploring the immune microenvironment of defined molecular subgroups of prostate cancer, we propose an immunogenomic subtyping approach to single-agent and combination immune-targeting strategies that could lead to improved outcomes in prostate cancer treatment.

The levonorgestrel intrauterine system for prevention of endometrial cancer in women with obesity: A cost-effectiveness study.

OBJECTIVE: To estimate the cost-effectiveness of the levonorgestrel intrauterine system (LNG-IUS) as an endometrial cancer prevention strategy in women with obesity. METHODS: A Markov decision-analytic model was used to compare 5 strategies in women with a body mass index of 30 or greater: 1) Usual care 2) LNG-IUS for 5 years 3) LNG-IUS for 7 years 4) LNG-IUS for 5 years, replaced once for a total of 10 years 5) LNG-IUS for 7 years, replaced once for a total of 14 years. Obesity was presumed to be associated with a 3-fold relative risk of endometrial cancer incidence and a 2.65-fold disease-specific mortality. The LNG-IUS was assumed to confer a 50% reduction in cancer incidence over the period of the LNG-IUS insertion. Outcomes were incremental cost-effectiveness ratios, calculated in 2019 Canadian dollars (CAD) per year of life saved. One-way and two-way sensitivity analyses were performed. RESULTS: The LNG-IUS strategy was considered cost-effective if the cost of the intervention is less than $66,400 CAD ($50,000 US dollars) per year of life saved. The strategy becomes cost-effective if the LNG-IUS is inserted at age 57 (strategy #2), at age 52 for strategy #3, at age 51 for strategy #4 and at age 45 for strategy #5, when compared to usual care. The results are stable to variations in cost but sensitive to the estimated risk reduction of the LNG-IUS and the impact of obesity on endometrial cancer incidence and disease-specific mortality. CONCLUSION: The LNG-IUS is a cost-effective method of endometrial cancer prevention in women with obesity.

Humeral shaft fracture and radial nerve palsy in Korean soldiers: focus on arm wrestling related injury.

INTRODUCTION: Humeral shaft fractures can lead to radial nerve injury and may require surgery and rehabilitation. We determined the causative events of humeral fracture, including arm wrestling, in young Korean soldiers and examined whether humeral fracture is related to demographic characteristics and the presence of radial nerve palsy. METHODS: We reviewed 7.5 years (July 2012 to June 2019) of medical records covering patients who had experienced a humeral shaft fracture after entering military service and had received surgery for open reduction and internal fixation. Data were obtained on basic demographics, initial event provoking the fracture, presence of radial nerve palsy, initial and follow-up severity of the weakness, and any discharge from military service because of prolonged radial nerve palsy. RESULTS: Of 123 cases, arm wrestling was the leading cause (52.8%). A high energy injury, such as falling from a height (11.4%), and sports related slips (10.6%) were other causes. All humeral shaft fractures caused by forceful contraction were spiral, while 40% of the fractures caused by external force related events were of a transverse type. The percentage of left-sided fractures was significantly higher for fractures arising from an external force than in those caused by forceful contraction related events. Radial nerve palsy was found in 34 patients (27.6%), and 16 were discharged from the military because of prolonged radial nerve palsy 6 months after the fracture. The causative events and other factors did not affect the presence of radial nerve palsy. CONCLUSION: Arm wrestling was the leading cause of humeral fracture in young Korean soldiers but the chance of developing comorbid radial nerve palsy did not differ from that of other causes. These epidemiologic findings in this young active group may help in understanding the causes of humeral shaft fracture in soldiers and in the wider young population.

Association between mortality risk and the number, location, and sequence of subsequent fractures in the elderly.

The mortality risk showed a positive correlation as the number of subsequent fractures increased. Hip fracture showed the greatest association with mortality risk, followed by vertebral fracture. For the combination of hip and vertebral fracture, a hip fracture after a vertebral fracture showed the highest mortality risk. INTRODUCTION: It is unclear whether subsequent fractures or a certain location and sequence of subsequent fractures are associated with mortality risk in the elderly. We aimed to investigate the relationship between subsequent fractures and mortality risk. METHODS: Using the Korean National Health Insurance Research Database, we analyzed the cohort data of 24,756 patients aged > 60 years who sustained fractures between 2002 and 2013. Cox regression was used to assess the mortality risk associated with the number, locations, and sequences of subsequent fractures. RESULTS: Mortality hazard ratios (HRs) for women and men were shown to be associated with the number of subsequent fractures (one, 1.63 (95% confidence interval [CI], 1.48-1.80) and 1.42 (95% CI, 1.28-1.58); two, 1.75 (95% CI, 1.47-2.08) and 2.03 (95% CI, 1.69-2.43); three or more, 2.46(95% CI, 1.92-3.15) and 1.92 (95% CI, 1.34-2.74), respectively). For women, the mortality risk was high when hip (HR, 2.49; 95% CI, 1.80-3.44) or vertebral (HR, 1.40; 95% CI, 1.03-1.90) fracture occurred as a second fracture. Compared with a single hip fracture, there was a high mortality risk in the group with hip fracture after the first vertebral fracture (HR, 2.90; 95% CI, 1.86-4.54), followed by vertebral fracture after the first hip fracture (HR, 1.90; 95% CI, 1.12-3.22). CONCLUSION: The mortality risk showed a positive correlation as the number of subsequent fractures increased. Hip fracture showed the greatest association with mortality risk, followed by vertebral fracture. For the combination of hip and vertebral fracture, a hip fracture after a vertebral fracture showed the highest mortality risk.

Thermal neutron transmutation doping of GaN semiconductors.

High quality Ge doping of GaN is demonstrated using primarily thermal neutrons for the first time. In this study, GaN was doped with Ge to concentrations from 1016 Ge atoms/cm3 to 1018 Ge atoms/cm3. The doping concentrations were measured using gamma-ray spectroscopy and confirmed using SIMS analysis. The data from SIMS analysis also show consistent Ge doping concentration throughout the depth of the GaN wafers. After irradiation, the GaN was annealed in a nitrogen environment at 950 °C for 30 min. The neutron doping process turns out to produce spatially uniform doping throughout the whole volume of the GaN substrate.

Vaginal compared with intramuscular progestogen for preventing preterm birth in high-risk pregnant women (VICTORIA study): a multicentre, open-label randomised trial and meta-analysis.

OBJECTIVE: To compare the efficacy of two types of progestogen therapy for preventing preterm birth (PTB) and to review the relevant literature. DESIGN: A multicentre, randomised, open-label, equivalence trial and a meta-analysis. SETTING: Tertiary referral hospitals in South Korea. POPULATION: Pregnant women with a history of spontaneous PTB or short cervical length (<25 mm). METHODS: Eligible women were screened and randomised at 16-22 weeks of gestation to receive either 200 mg of vaginal micronised progesterone daily (vaginal group) or an intramuscular injection of 250 mg 17α-hydroxyprogesterone caproate weekly (IM group). Stratified randomisation was carried out according to participating centres and indications for progestogen therapy. This trial was registered at ClinicalTrials.gov (NCT02304237). MAIN OUTCOME MEASURE: Preterm birth (PTB) before 37 weeks of gestation. RESULTS: A total of 266 women were randomly assigned and a total of 247 women (119 and 128 women in the vaginal and IM groups, respectively) were available for the intention-to-treat analysis. Risks of PTB before 37 weeks of gestation did not significantly differ between the two groups (22.7 versus 25.8%, P = 0.571). The difference in PTB risk between the two groups was 3.1% (95% CI -7.6 to 13.8%), which was within the equivalence margin of 15%. The meta-analysis results showed no significant differences in the risk of PTB between the vaginal and IM progestogen treatments. CONCLUSION: Compared with vaginal progesterone, treatment with intramuscular progestin might increase the risk of PTB before 37 weeks of gestation by as much as 13.8%, or reduce the risk by as much as 7.6%, in women with a history of spontaneous PTB or with short cervical length. TWEETABLE ABSTRACT: Vaginal and intramuscular progestogen showed equivalent efficacy for preventing preterm birth before 37 weeks of gestation.

Multi-level anomalous Hall resistance in a single Hall cross for the applications of neuromorphic device.

We demonstrate the process of obtaining memristive multi-states Hall resistance (RH) change in a single Hall cross (SHC) structure. Otherwise, the working mechanism successfully mimics the behavior of biological neural systems. The motion of domain wall (DW) in the SHC was used to control the ascend (or descend) of the RH amplitude. The primary synaptic functions such as long-term potentiation (LTP), long-term depression (LTD), and spike-time-dependent plasticity (STDP) could then be emulated by regulating RH. Applied programmable magnetic field pulses are in varying conditions such as intensity and duration to adjust RH. These results show that analog readings of DW movement can be closely resembled with the change of synaptic weight and have great potentials for bioinspired neuromorphic computing.

Association between time to treatment and functional outcomes according to the Diffusion-Weighted Imaging Alberta Stroke Program Early Computed Tomography Score in endovascular stroke therapy.

BACKGROUND AND PURPOSE: The rate at which the chance of a good outcome of endovascular stroke therapy (EVT) decays with time when eligible patients are selected by baseline diffusion-weighted magnetic resonance imaging (DWI-MRI) and whether ischaemic core size affects this rate remain to be investigated. METHODS: This study analyses a prospective multicentre registry of stroke patients treated with EVT based on pretreatment DWI-MRI that was categorized into three groups: small [Diffusion-Weighted Imaging Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS)] (8-10), moderate (5-7) and large (<5) cores. The main outcome was a good outcome at 90 days (modified Rankin Scale 0-2). The interaction between onset-to-groin puncture time (OTP) and DWI-ASPECTS categories regarding functional outcomes was investigated. RESULTS: Ultimately, 985 patients (age 69 ± 11 years; male 55%) were analysed. Potential interaction effects between the DWI-ASPECTS categories and OTP on a good outcome at 90 days were observed (Pinteraction  = 0.06). Every 60-min delay in OTP was associated with a 16% reduced likelihood of a good outcome at 90 days amongst patients with large cores, although no associations were observed amongst patients with small to moderate cores. Interestingly, the adjusted rates of a good outcome at 90 days steeply declined between 65 and 213 min of OTP and then remained smooth throughout 24 h of OTP (Pnonlinearity  = 0.15). CONCLUSIONS: Our study showed that the probability of a good outcome after EVT nonlinearly decreased, with a steeper decline at earlier OTP than at later OTP. Discrepant effects of OTP on functional outcomes by baseline DWI-ASPECTS categories were observed. Thus, different strategies for EVT based on time and ischaemic core size are warranted.