Gullies on Mars could have formed by melting of water ice during periods of high obliquity.

Gullies on Mars resemble water-carved channels on Earth, but they are mostly at elevations where liquid water is not expected under current climate conditions. It has been suggested that sublimation of carbon dioxide ice alone could have formed Martian gullies. We used a general circulation model to show that the highest-elevation Martian gullies coincide with the boundary of terrain that experienced pressures above the triple point of water when Mars' rotational axis tilt reached 35°. Those conditions have occurred repeatedly over the past several million years, most recently ~630,000 years ago. Surface water ice, if present at these locations, could have melted when temperatures rose >273 kelvin. We propose a dual gully formation scenario that is driven by melting of water ice followed by carbon dioxide ice sublimation.

A retrospective evaluation of the indications, complications, and outcomes associated with epicardial pacemakers in 20 cats from a single institution.

INTRODUCTION: The objective of this retrospective study was to describe the indications, complications, and long-term outcomes in a group of cats that received an epicardial pacing (EP) system. ANIMALS: Twenty client-owned cats. MATERIALS AND METHODS: Medical records were reviewed for signalment, presenting complaint, primary electrocardiogram (ECG) diagnosis, presence of structural heart disease, presence of congestive heart failure (CHF), presence of major or minor complications, and survival time. RESULTS: The majority of cats were presented for syncope (n = 11), and the most common ECG diagnosis was advanced second-degree atrioventricular block (n = 9). Fifteen cats (15/20, 75%) had one or more major or minor complications. One cat died in the perioperative period as a result of a major complication. None of the variables evaluated were associated with a statistically significant increase in the occurrence of major or minor complications. The most common major complication was loss of ventricular capture (seven instances in six cats), which was successfully treated in all cases by increasing pacemaker output or replacing both the lead and the pulse generator. The most common minor complications were arrhythmias (n = 7) and sensing issues (n = 8). The overall median survival time (MST) was 948 days. No statistical difference in survival time was identified between cats that experienced a major complication and those that did not. CONCLUSIONS: Although complications were common in this feline population after EP, major and minor complications were successfully treated.

Earth-like Habitable Environments in the Subsurface of Mars.

In Earth's deep continental subsurface, where groundwaters are often isolated for >106 to 109 years, energy released by radionuclides within rock produces oxidants and reductants that drive metabolisms of non-photosynthetic microorganisms. Similar processes could support past and present life in the martian subsurface. Sulfate-reducing microorganisms are common in Earth's deep subsurface, often using hydrogen derived directly from radiolysis of pore water and sulfate derived from oxidation of rock-matrix-hosted sulfides by radiolytically derived oxidants. Radiolysis thus produces redox energy to support a deep biosphere in groundwaters isolated from surface substrate input for millions to billions of years on Earth. Here, we demonstrate that radiolysis by itself could produce sufficient redox energy to sustain a habitable environment in the subsurface of present-day Mars, one in which Earth-like microorganisms could survive wherever groundwater exists. We show that the source localities for many martian meteorites are capable of producing sufficient redox nutrients to sustain up to millions of sulfate-reducing microbial cells per kilogram rock via radiolysis alone, comparable to cell densities observed in many regions of Earth's deep subsurface. Additionally, we calculate variability in supportable sulfate-reducing cell densities between the martian meteorite source regions. Our results demonstrate that martian subsurface groundwaters, where present, would largely be habitable for sulfate-reducing bacteria from a redox energy perspective via radiolysis alone. We present evidence for crustal regions that could support especially high cell densities, including zones with high sulfide concentrations, which could be targeted by future subsurface exploration missions.

Quantitative analysis of movements in facial nerve palsy with surface electromyography and kinematic analysis.

Facial nerve paralysis (FNP) has a significant effect on a person's quality of life. In individuals with FNP undergoing facial rehabilitation, methods to analyze the loss of function are useful in diagnosis, treatment and follow up. To propose a protocol with kinematic analysis coupled with sEMG to evaluate the outcomes of FNP, quantifying the excursion degrees of the facial muscles and symmetry of voluntary movements. 10 patients (Group A) were followed by diagnosis until the end of the rehabilitation program. Kinematic analysis of 20 healthy adults (group B) was performed as a starting point to have a normality range and to test intra-subject and inter- intra rater reliability. An optoelectronic system and sEMG wireless electrodes were used. In Group A, a significant improvement in the movement of frontalis muscle (P = 0.0118) after 4-week treatment from the beginning (T0) 9.8 ± 4.5 mm to the end of rehabilitation (T1) 16.3 ± 5.8 mm and orbicularis oris (P = 0.0143) from T0 14.8 ± 5.5 mm to T1 20.3 ± 3.3 mm and, a reduction of % of maximum voluntary contractions (MVC) at T1 for frontalis and orbicularis compared to T0. This protocol provides meaningful data in a simple, reliable and objective way for the functional assessment of patients with PNF.

Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19.

PURPOSE: Hypovitaminosis D is a highly spread condition correlated with increased risk of respiratory tract infections. Nowadays, the world is in the grip of the Coronavirus disease 19 (COVID 19) pandemic. In these patients, cytokine storm is associated with disease severity. In consideration of the role of vitamin D in the immune system, aim of this study was to analyse vitamin D levels in patients with acute respiratory failure due to COVID-19 and to assess any correlations with disease severity and prognosis. METHODS: In this retrospective, observational study, we analysed demographic, clinical and laboratory data of 42 patients with acute respiratory failure due to COVID-19, treated in Respiratory Intermediate Care Unit (RICU) of the Policlinic of Bari from March, 11 to April 30, 2020. RESULTS: Eighty one percent of patients had hypovitaminosis D. Based on vitamin D levels, the population was stratified into four groups: no hypovitaminosis D, insufficiency, moderate deficiency, and severe deficiency. No differences regarding demographic and clinical characteristics were found. A survival analysis highlighted that, after 10 days of hospitalization, severe vitamin D deficiency patients had a 50% mortality probability, while those with vitamin D ≥ 10 ng/mL had a 5% mortality risk (p = 0.019). CONCLUSIONS: High prevalence of hypovitaminosis D was found in COVID-19 patients with acute respiratory failure, treated in a RICU. Patients with severe vitamin D deficiency had a significantly higher mortality risk. Severe vitamin D deficiency may be a marker of poor prognosis in these patients, suggesting that adjunctive treatment might improve disease outcomes.

Relugolix for the treatment of uterine fibroids.

INTRODUCTION: Uterine fibroids (UF) are benign tumors common in premenopausal women, with strong impact on the health-care systems. For many years, surgery represented the only therapy for symptomatic fibroids. However, clinicians are observing a switch from surgery to noninvasive methods; in particular, medical treatment has been shown to be efficacious in obtaining a bleeding reduction and in ameliorating patient conditions. AREAS COVERED: The authors review the current options available for the treatment of women with UF, with a special focus on the newest one, relugolix. It is an orally active non-peptide Gonadotropin-releasing hormone (GnRH)-receptor antagonist recently licensed for women with symptomatic fibroids. Relugolix is a well-tolerated safe drug; it is effective in inducing a dose-dependent decrease in menstrual blood loss, with faster reduction of heavy menstrual bleeding (HMB) and a greater shrinkage in fibroid volume compared to the current standard of GnRH agonist treatment. EXPERT OPINION: Relugolix is a promising drug for the non-surgical treatment of women with UF. To date, the only published data come from a well-selected Japanese female population study while results from worldwide ongoing studies are ongoing in order to confirm the efficacy of this GnRH agonist receptor.

Effects of a Six-Month Multi-Ingredient Nutrition Supplement Intervention of Omega-3 Polyunsaturated Fatty Acids, vitamin D, Resveratrol, and Whey Protein on Cognitive Function in Older Adults: A Randomised, Double-Blind, Controlled Trial.

OBJECTIVES: To investigate the impact of a six-month multi-ingredient nutrition supplement intervention (Smartfish®), containing omega-3 polyunsaturated fatty acids (PUFAs), vitamin D, resveratrol, and whey protein, on cognitive function in Irish older adults. DESIGN: Double-blind, randomised controlled trial (ClinicalTrials.gov: NCT02001831). A quantitative, mixed-model design was employed in which the dependent variable (cognitive function) was analysed with a between-subjects factor of group (placebo, intervention) and within-subjects factor of testing occasion (baseline, three-months, six-months). SETTING: Community-based intervention including assessments conducted at University College Dublin, Ireland. PARTICIPANTS: Thirty-seven community-dwelling older adults (68-83 years; mean (x̄)= 75.14 years; standard deviation (SD)= 3.64; 18 males) with normal cognitive function (>24 on the Mini Mental State Examination) were assigned to the placebo (n= 17) or intervention (n= 20) via a block randomisation procedure. INTERVENTION: Daily consumption for six-months of a 200mL liquid juice intervention comprising 3000mg omega-3 PUFAs [1500mg docosahexaenoic acid (DHA) and 1500mg eicosapentaenoic acid (EPA)], 10µg vitamin D3, 150mg resveratrol and 8g whey protein isolate. The placebo contained 200mL juice only. MEASUREMENTS: A standardised cognitive assessment battery was conducted at baseline and follow-ups. Individual test scores were z-transformed to generate composite scores grouped into cognitive domains: executive function, memory, attention and sensorimotor speed. Motor imagery accuracy and subjective awareness of cognitive failures variables were computed from raw scores. RESULTS: A hierarchical statistical approach was used to analyse the data; first, by examining overall cognitive function, then by domain, and then by individual test scores. Using mixed between-within subjects, analyses of variance (ANOVAs), no significant differences in overall cognitive function or composite cognitive domains were observed between groups over time. The only significant interaction was for Stroop Color-Word Time (p< 0.05). The intervention group demonstrated reduced task completion time at three- and six-month follow-ups, indicating enhanced performance. CONCLUSION: The present nutrition intervention encompassed a multi-ingredient approach targeted towards improving cognitive function, but overall had only a limited beneficial impact in the older adult sample investigated. Future investigations should seek to establish any potential clinical applications of such targeted interventions with longer durations of supplementation, or in populations with defined cognitive deficits.

Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma.

This multicentre, open-label phase 1/2 trial determined safety and efficacy of weekly carfilzomib plus cyclophosphamide-dexamethasone (wKCyd) in newly diagnosed multiple myeloma (NDMM) patients aged ⩾65 years or transplant ineligible. Patients received wKCyd for up to nine 28-day cycles, followed by maintenance with carfilzomib until progression/intolerance. The phase 1 portion used a 3+3 dose-escalation scheme to determine the maximum tolerated dose of weekly carfilzomib: 12 patients received wKCyd with carfilzomib doses of 45, 56 and 70 mg/m2. The recommended phase 2 dose was established at 70 mg/m2 and 54 patients (phase 1 and 2) received weekly carfilzomib 70 mg/m2: 85% of them achieved ⩾partial response (PR), 66% ⩾very good PR, 30%⩾near-complete response (CR) and 15% CR. Responses improved in 40 patients who started maintenance: 98% achieved ⩾PR, including 29% CR and 10% stringent CR. After a median follow-up of 18 months, the 2-year progression-free survival and overall survival rates were 53.2% and 81%, respectively. The most frequent grade 3-5 toxicities were neutropenia (22%) and cardiopulmonary adverse events (9%). This is the first study of weekly carfilzomib plus an alkylating agent in elderly patients with NDMM. wKCyd was effective, with an acceptable risk/benefit ratio, and thus can be a valid option in this setting.

Prospective multicentre study on barbed reposition pharyngoplasty standing alone or as a part of multilevel surgery for sleep apnoea.

OBJECTIVES: The aim of this study was to demonstrate in a prospective multicentre study that Barbed Reposition Pharyngoplasty (BRP) procedure is safe and effective in management of obstructive sleep apnoea/hypopnea syndrome (OSAHS) patients. DESIGN: Prospective study. SETTING: Multicentre study. PARTICIPANTS: Patients suffering from obstructive sleep apnoea. MAIN OUTCOMES MEASURES: Values of postoperative apnoea-hypopnea index (AHI), oxygen desaturation index (ODI), epworth sleepiness scale (ESS). RESULTS: 111 Barbed Reposition Pharyngoplasty procedures standing alone or as a part of multilevel surgery for OSAHS, performed between January and September 2016, were analysed in 15 different centres. The average hospitalisation period was 2.5 ± 0.5 days. The mean patient age was 46.3 ± 10.5 years. The average body mass index at the time of the procedure was 27.9 ± 3.2, and the majority of the patients were men (83%). The mean preoperative and postoperative apnoea/hypopnea index was 33.4 ± 19.5 and 13.5 ± 10.3, respectively (P < .001). The mean preoperative and postoperative ESS score was 10.2 ± 4.5 and 6.1 ± 3.6, respectively (P < .001). The mean preoperative and postoperative ODI were 29.6 ± 20.7 and 12.7 ± 10.8, respectively (P < .001). CONCLUSIONS: Patients undergoing BRP standing alone or as part of a multilevel approach for the treatment of OSAHS have a reasonable expectation for success with minimal morbidity.

Carfilzomib-lenalidomide-dexamethasone vs lenalidomide-dexamethasone in relapsed multiple myeloma by previous treatment.

Carfilzomib, a proteasome inhibitor, is approved as monotherapy and in combination with dexamethasone or lenalidomide-dexamethasone (Rd) for relapsed or refractory multiple myeloma. The approval of carfilzomib-lenalidomide-dexamethasone (KRd) was based on results from the randomized, phase 3 study ASPIRE (NCT01080391), which showed KRd significantly improved progression-free survival (PFS) vs Rd (median 26.3 vs 17.6 months; hazard ratio (HR)=0.690; P=0.0001). This subgroup analysis of ASPIRE evaluated KRd vs Rd by number of previous lines of therapy and previous exposure to bortezomib, thalidomide or lenalidomide. Treatment with KRd led to a 12-month improvement in median PFS vs Rd after first relapse (HR 0.713) and a 9-month improvement after ⩾2 previous lines of therapy (HR 0.720). Treatment with KRd led to an approximate 8-month improvement vs Rd in median PFS in bortezomib-exposed patients (HR 0.699), a 15-month improvement in thalidomide-exposed patients (HR 0.587) and a 5-month improvement in lenalidomide-exposed patients (HR 0.796). Objective response and complete response or better rates were higher with KRd vs Rd, irrespective of previous treatment. KRd had a favorable benefit-risk profile and should be considered an appropriate treatment option for patients with 1 or ⩾2 previous lines of therapy and those previously exposed to bortezomib, thalidomide or lenalidomide.

Proteomic characterization of human multiple myeloma bone marrow extracellular matrix.

The extracellular matrix (ECM) is a major component of the tumor microenvironment, contributing to the regulation of cell survival, proliferation, differentiation and metastasis. In multiple myeloma (MM), interactions between MM cells and the bone marrow (BM) microenvironment, including the BM ECM, are critical to the pathogenesis of the disease and the development of drug resistance. Nevertheless, composition of the ECM in MM and its role in supporting MM pathogenesis has not been reported. We have applied a novel proteomic-based strategy and defined the BM ECM composition in patients with monoclonal gammopathy of undetermined significance (MGUS), newly diagnosed and relapsed MM compared with healthy donor-derived BM ECM. In this study, we show that the tumor ECM is remodeled at the mRNA and protein levels in MGUS and MM to allow development of a permissive microenvironment. We further demonstrate that two ECM-affiliated proteins, ANXA2 and LGALS1, are more abundant in MM and high expression is associated with a decreased overall survival. This study points to the importance of ECM remodeling in MM and provides a novel proteomic pipeline for interrogating the role of the ECM in cancers with BM tropism.

The culturally adapted Italian version of the Barthel Index (IcaBI): assessment of structural validity, inter-rater reliability and responsiveness to clinically relevant improvements in patients admitted to inpatient rehabilitation centers.

The Barthel Index (BI) is widely used to determine eligibility criteria for inpatient rehabilitation and to monitor patients' recovery, irrespective of the illnesses that affect them. The culturally adapted Italian version of the Barthel Index (IcaBI) was recently validated. This paper reports the structural validity and inter-rater reliability of the IcaBI and its responsiveness to the results of inpatient rehabilitation. The IcaBI was administered to a cohort of 264 patients hospitalized in two rehabilitation centers in Rome, Italy. Factor analysis using principal component analysis revealed a monofactorial structure for neurological patients and, after removal of item 1 "feeding", also for orthopedic patients. Substantial to optimal inter-rater reliability was found (0.74 > intraclass correlation coefficient < 0.96). The IcaBI was found to be accurate (area under the curve= 0.72) with a minimal clinically important change score of 35 points. This work confirms that IcaBI is a useful tool for measuring disability in health and social care settings along the continuum of care. Further studies are needed to assess its criterion validity, interpretability and responsiveness in other specific disease conditions.

Autologous transplant vs oral chemotherapy and lenalidomide in newly diagnosed young myeloma patients: a pooled analysis.

In newly diagnosed myeloma patients, upfront autologous transplant (ASCT) prolongs progression-free survival 1 (PFS1) compared with chemotherapy plus lenalidomide (CC+R). Salvage ASCT at first relapse may still effectively rescue patients who did not receive upfront ASCT. To evaluate the long-term benefit of upfront ASCT vs CC+R and the impact of salvage ASCT in patients who received upfront CC+R, we conducted a pooled analysis of 2 phase III trials (RV-MM-209 and EMN-441). Primary endpoints were PFS1, progression-free survival 2 (PFS2), overall survival (OS). A total of 268 patients were randomized to 2 courses of melphalan 200 mg/m2 and ASCT (MEL200-ASCT) and 261 to CC+R. Median follow-up was 46 months. MEL200-ASCT significantly improved PFS1 (median: 42 vs 24 months, HR 0.53; P<0.001), PFS2 (4 years: 71 vs 54%, HR 0.53, P<0.001) and OS (4 years: 84 vs 70%, HR 0.51, P<0.001) compared with CC+R. The advantage was noticed in good and bad prognosis patients. Only 53% of patients relapsing from CC+R received ASCT at first relapse. Upfront ASCT significantly reduced the risk of death (HR 0.51; P=0.007) in comparison with salvage ASCT. In conclusion, these data confirm the role of upfront ASCT as the standard approach for all young myeloma patients.

Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR.

The randomized phase 3 study ENDEAVOR demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (MM). We conducted a preplanned subgroup analysis of ENDEAVOR to evaluate Kd vs Vd by cytogenetic risk. Of 785 patients with known cytogenetics, 210 (27%) had high-risk cytogenetics (Kd, n=97 (25%); Vd, n=113 (28%)) and 575 (73%) had standard-risk cytogenetics (Kd, n=284 (75%); Vd, n=291 (72%)). Median PFS in the high-risk group was 8.8 months for Kd vs 6.0 months for Vd (hazard ratio (HR), 0.65; 95% confidence interval (CI), 0.45-0.92; P=0.0075). Median PFS in the standard-risk group was not estimable for Kd vs 10.2 months for Vd (HR, 0.44; 95% CI, 0.33-0.58; P<0.0001). Overall response rates were 72.2% (Kd) vs 58.4% (Vd) in the high-risk group and 79.2% (Kd) vs 66.0% (Vd) in the standard-risk group. In the high-risk group, 15.5% (Kd) vs 4.4% (Vd) achieved a complete response (CR) or better. In the standard-risk group, 13.0% (Kd) vs 7.9% (Vd) achieved ⩾CR. This preplanned subgroup analysis found that Kd was superior to Vd in relapsed or refractory MM, regardless of cytogenetic risk.

Second primary malignancies in multiple myeloma: an overview and IMWG consensus.

Background: Therapeutic advancements following the introduction of autologous stem cell transplantation and 'novel' agents have significantly improved clinical outcomes for patients with multiple myeloma (MM). Increased life expectancy, however, has led to renewed concerns about the long-term risk of second primary malignancies (SPMs). This review outlines the most up-to-date knowledge of possible host-, disease-, and treatment-related risk factors for the development of SPMs in patients with MM, and provides practical recommendations to assist physicians. Design: A Panel of International Myeloma Working Group members reviewed the most relevant data published in the literature as full papers, or presented at meetings of the American Society of Clinical Oncology, American Society of Hematology, European Hematology Association, or International Myeloma Workshops, up to June 2016. Here, we present the recommendations of the Panel, based on this literature review. Results: Overall, the risk of SPMs in MM is low, multifactorial, and partially related to the length of patients' survival and MM intrinsic susceptibility. Studies suggest a significantly increased incidence of SPMs when lenalidomide is administered either following, or concurrently with, oral melphalan. Increased SPM incidence has also been reported with lenalidomide maintenance following high-dose melphalan, albeit to a lesser degree. In both cases, the risk of death from MM was significantly higher than the risk of death from SPMs, with lenalidomide possibly providing a survival benefit. No increase in SPM incidence was reported with lenalidomide plus dexamethasone (without melphalan), or with bortezomib plus oral melphalan, dexamethasone, or thalidomide. Conclusion: In general, the risk of SPMs should not alter the current therapeutic decision-making process in MM. However, regimens such as lenalidomide plus dexamethasone should be preferred to prolonged exposure to lenalidomide plus oral melphalan. SPM risk should be carefully discussed with the patient in the context of benefits and risks of different treatment options.

Impact of prior treatment on patients with relapsed multiple myeloma treated with carfilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study.

The randomized phase 3 ENDEAVOR study (N=929) compared carfilzomib and dexamethasone (Kd) with bortezomib and dexamethasone (Vd) in relapsed multiple myeloma (RMM). We performed a subgroup analysis from ENDEAVOR in patients categorized by number of prior lines of therapy or by prior treatment. Median progression-free survival (PFS) for patients with one prior line was 22.2 months for Kd vs 10.1 months for Vd, and median PFS for patients with ⩾2 prior lines was 14.9 months for Kd vs 8.4 months for Vd. For patients with prior bortezomib exposure, the median PFS was 15.6 months for Kd vs 8.1 months for Vd, and for patients with prior lenalidomide exposure the median PFS was 12.9 months for Kd vs 7.3 months for Vd. Overall response rates (Kd vs Vd) were 81.9 vs 65.5% (one prior line), 72.0 vs 59.7% (⩾2 prior lines), 71.2 vs 60.3% (prior bortezomib) and 70.1 vs 59.3% (prior lenalidomide). The safety profile in the prior lines subgroups was qualitatively similar to that in the broader ENDEAVOR population. In RMM, outcomes are improved when receiving treatment with carfilzomib compared with bortezomib, regardless of the number of prior therapy lines or prior exposure to bortezomib or lenalidomide.

A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS).

This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4-14.4) vs 10.0 months (95% CI 7.7-12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760-1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ⩾3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients.