Combining PARP inhibition and immune checkpoint blockade in ovarian cancer patients: a new perspective on the horizon?

Immune checkpoint inhibitors (ICIs) have completely reshaped the treatment of many malignancies, with remarkable improvements in survival outcomes. In ovarian cancer (OC), however, this emerging class of drugs has not yet found a favorable use due to results from phase I and II studies, which have not suggested a substantial antitumoral activity of these agents when administered as monotherapy. Robust preclinical data seem to suggest that the combination ICIs with poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) may result in a synergistic activity; furthermore, data from phase II clinical studies, evaluating this combination, have shown encouraging outcomes especially for those OC patients not suitable for platinum retreatment. While waiting for ongoing phase III clinical trial results, which will clarify the role of ICIs in combination with PARPis in the newly diagnosed OC, this review aims to summarize the preclinical data and clinical evidence available to date.

Evidence for changing intimate partner violence safety planning needs as a result of COVID-19: results from phase I of a rapid intervention.

OBJECTIVES: The aim of the study was to examine the need for modified safety planning strategies in response to COVID-19-related increases in intimate partner violence (IPV) as the initial phase of adapting an IPV safety planning intervention in Toronto, Ontario. METHODS: A rapid, systematic review was conducted to elucidate existing safety planning strategies used during public health emergencies. These were supplemented with strategies from an expert panel. A survey of IPV survivors and service providers gauged the helpfulness of each strategy during COVID-19. RESULTS: Together, the systematic review and expert panel yielded 26 conceptually distinct strategies, which were evaluated by 111 IPV survivors and providers. Of these, 19 (69%) were 'highly recommended', 3 (12%) were 'somewhat recommended' and 6 (23%) were not recommended for use during the COVID-19 pandemic because they might make the violence worse. CONCLUSIONS: Safety planning needs have changed owing to the effect of COVID-19 on IPV incidence, service provision and risk factors, as well as policies restricting freedom of movement. These results will be used to modify an existing IPV safety planning mobile application for use during COVID-19 and future public health emergencies.

Observation of inverse Compton emission from a long γ-ray burst.

Long-duration γ-ray bursts (GRBs) originate from ultra-relativistic jets launched from the collapsing cores of dying massive stars. They are characterized by an initial phase of bright and highly variable radiation in the kiloelectronvolt-to-megaelectronvolt band, which is probably produced within the jet and lasts from milliseconds to minutes, known as the prompt emission1,2. Subsequently, the interaction of the jet with the surrounding medium generates shock waves that are responsible for the afterglow emission, which lasts from days to months and occurs over a broad energy range from the radio to the gigaelectronvolt bands1-6. The afterglow emission is generally well explained as synchrotron radiation emitted by electrons accelerated by the external shock7-9. Recently, intense long-lasting emission between 0.2 and 1 teraelectronvolts was observed from GRB 190114C10,11. Here we report multi-frequency observations of GRB 190114C, and study the evolution in time of the GRB emission across 17 orders of magnitude in energy, from 5 × 10-6 to 1012 electronvolts. We find that the broadband spectral energy distribution is double-peaked, with the teraelectronvolt emission constituting a distinct spectral component with power comparable to the synchrotron component. This component is associated with the afterglow and is satisfactorily explained by inverse Compton up-scattering of synchrotron photons by high-energy electrons. We find that the conditions required to account for the observed teraelectronvolt component are typical for GRBs, supporting the possibility that inverse Compton emission is commonly produced in GRBs.

Italian Association of Sleep Medicine (AIMS) position statement and guideline on the treatment of menopausal sleep disorders.

Insomnia, vasomotor symptoms (VMS) and depression often co-occur after the menopause, with consequent health problems and reductions in quality of life. The aim of this position statement is to provide evidence-based advice on the management of postmenopausal sleep disorders derived from a systematic review of the literature. The latter yielded results on VMS, insomnia, circadian rhythm disorders, obstructive sleep apnea (OSA) and restless leg syndrome (RLS). Overall, the studies show that menopausal hormone therapy (MHT) improves VMS, insomnia, and mood. Several antidepressants can improve insomnia, either on their own or in association with MHT; these include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and mirtazapine. Long-term benefits for postmenopausal insomnia may also be achieved with non-drug strategies such as cognitive behavioral therapy (CBT) and aerobic exercise. Continuous positive airway pressure (CPAP) and mandibular advancement devices (MADs) both reduce blood pressure and cortisol levels in postmenopausal women suffering from OSA. However, the data regarding MHT on postmenopausal restless legs syndrome are conflicting.

Home and neighbourhood built environment features in family-based treatment for childhood obesity.

BACKGROUND: Family-based behavioural weight loss treatment (FBT) for childhood obesity helps families develop strategies to facilitate healthy choices in their home and other environments (e.g. home neighbourhood). The current study examines how the home food environment, both pre-FBT and post-FBT, and the neighbourhoods in which families live are associated with child weight and weight-related outcomes in FBT. METHODS: Parent-child dyads (n = 181) completed a 16-session FBT programme and completed home environment, anthropometric and child dietary/activity assessments at pre-FBT and post-FBT. Parents reported on availability of food, electronics and physical activity equipment in the home. The neighbourhood food and recreation environments around each dyad's residence was characterized using existing data within a geographic information system. RESULTS: Families successfully made healthy home environment modifications during FBT. Regression models showed reducing RED (e.g. high-energy-dense and low-nutrient-dense) foods and electronics in the home during FBT had positive effects on child weight and weight-related outcomes. No neighbourhood food or recreation environment variables were significantly related to outcomes, although having a larger density of public recreation spaces was associated with increases in physical activity at the trend-level. CONCLUSIONS: Modifying the home environment, specifically reducing RED foods and electronics, may be particularly important for FBT success.

Swift and NuSTAR observations of GW170817: Detection of a blue kilonova.

With the first direct detection of merging black holes in 2015, the era of gravitational wave (GW) astrophysics began. A complete picture of compact object mergers, however, requires the detection of an electromagnetic (EM) counterpart. We report ultraviolet (UV) and x-ray observations by Swift and the Nuclear Spectroscopic Telescope Array of the EM counterpart of the binary neutron star merger GW170817. The bright, rapidly fading UV emission indicates a high mass (≈0.03 solar masses) wind-driven outflow with moderate electron fraction (Ye ≈ 0.27). Combined with the x-ray limits, we favor an observer viewing angle of ≈30° away from the orbital rotation axis, which avoids both obscuration from the heaviest elements in the orbital plane and a direct view of any ultrarelativistic, highly collimated ejecta (a γ-ray burst afterglow).

[Development of an objective structured clinical examination (OSCE) for evaluating clinical competence in vascular medicine]. / Développement d'un examen clinique objectif structuré (ECOS) pour évaluer les compétences des étudiants en médecine vasculaire.

OBJECTIVES: Vascular medicine is now a clinical specialty in France. During their studies, students will acquire clinical reasoning in addition to technical skills. An Objective Structured Clinical Examination (OSCE) is considered as the gold standard for evaluating clinical competence. Our main objective was to evaluate the feasibility and acceptability of OSCE for the evaluation of students, secondarily their performance. METHODS: Three representative clinical cases of the specialty were developed. The OSCE consisted of a sequence of clinical situations presented in three stations of 7minutes each. The role of the simulated patient was played by medical students. At the end of the OSCE, observers and students completed the evaluation form. We compared the performances between junior and senior vascular medicine students. Written questionnaires were used to measure OSCE satisfaction. RESULTS: We were able to develop and organize this examination without difficulties. Fifteen students were evaluated. All participants agreed that the clinical situations were representative of vascular medicine practice, the cases were realistic and standardized patients were convincing. The performance of senior students was statistically higher than junior students in one case. DISCUSSION: Our study demonstrates the feasibility and acceptability of the OSCE in students in vascular medicine. The small number of stations and candidates requires further studies on a larger scale to evaluate their performance.

Supernovae. 44Ti gamma-ray emission lines from SN1987A reveal an asymmetric explosion.

In core-collapse supernovae, titanium-44 ((44)Ti) is produced in the innermost ejecta, in the layer of material directly on top of the newly formed compact object. As such, it provides a direct probe of the supernova engine. Observations of supernova 1987A (SN1987A) have resolved the 67.87- and 78.32-kilo-electron volt emission lines from decay of (44)Ti produced in the supernova explosion. These lines are narrow and redshifted with a Doppler velocity of ~700 kilometers per second, direct evidence of large-scale asymmetry in the explosion.

Transmission of infection to liver transplant recipients from donors with infective endocarditis: lessons learned.

Donors not meeting standard criteria, such as those with bacteremia, are now being used in response to the increasing need for organs for transplantation. Recommended strategies to prevent the occurrence of donor-derived bacteremia include the use of directed antibiotic prophylaxis. However, this approach does not eliminate the risk of infection transmission. Similarly, the management of organ recipients from donors with infective endocarditis (IE) remains uncharacterized. We report 2 cases of donor-derived bacterial infections in liver transplant recipients despite pathogen-specific antibiotic prophylaxis. In both instances, the donors had documented IE treated with appropriate antimicrobial therapy and clearance of bacteremia. Recipients had very distinctive clinical outcomes likely related to pathogen virulence and the extent of donor infection. Persistent infection in the transplanted liver should be suspected in organ recipients of a liver from donors with IE, despite the absence of bacteremia at the time of death and organ procurement. For eradication, recipients may require prolonged pathogen-directed antimicrobial therapy, such as is used for endovascular infections. Prompt recognition of donors with IE, appropriate notification, and prolonged antibiotic prophylaxis are key to reducing the risk of such donor-derived infections.

Asymmetries in core-collapse supernovae from maps of radioactive 44Ti in Cassiopeia A.

Asymmetry is required by most numerical simulations of stellar core-collapse explosions, but the form it takes differs significantly among models. The spatial distribution of radioactive (44)Ti, synthesized in an exploding star near the boundary between material falling back onto the collapsing core and that ejected into the surrounding medium, directly probes the explosion asymmetries. Cassiopeia A is a young, nearby, core-collapse remnant from which (44)Ti emission has previously been detected but not imaged. Asymmetries in the explosion have been indirectly inferred from a high ratio of observed (44)Ti emission to estimated (56)Ni emission, from optical light echoes, and from jet-like features seen in the X-ray and optical ejecta. Here we report spatial maps and spectral properties of the (44)Ti in Cassiopeia A. This may explain the unexpected lack of correlation between the (44)Ti and iron X-ray emission, the latter being visible only in shock-heated material. The observed spatial distribution rules out symmetric explosions even with a high level of convective mixing, as well as highly asymmetric bipolar explosions resulting from a fast-rotating progenitor. Instead, these observations provide strong evidence for the development of low-mode convective instabilities in core-collapse supernovae.

Interpreting elevated fetal hemoglobin in pathology and health at the basic laboratory level: new and known γ- gene mutations associated with hereditary persistence of fetal hemoglobin.

Fetal hemoglobin may be slightly or significantly elevated in post-natal life due to a number of causes. We report two novel mutations found on the promoter of the Aγ gene and summarize all common and rare determinants associated with hereditary persistence of fetal hemoglobin (HPFH) described thus far. Hematological and molecular analysis of the Aγ globin gene in two cases of HPFH. Comparison of the novel cases with all those described in the literature. We have found two novel mutations in three Italian patients with HbF values between 5.9% and 6.5% without an elevated HbA(2) and with normal hemoglobin parameters. In two probands (mother and son), a -197 C>T transition was observed, while in a single individual, a -113 A>G transition was present on the distal CCAAT box of the Aγ gene. As no other abnormalities were present in both γ-gene promoters and the changes are located on regulatory sequences, we may conclude that these mutations are responsible for the HPFH phenotype shown by the carriers. The laboratory should be able to discriminate between elevated HbF due to artifacts or to serious causes including bone marrow malignancies, aplastic anemia, and ß-thalassemia major or recessive traits such as ß-thalassemia minor, δß-thalassemia, or nonpathological conditions induced by mutations or polymorphisms of the γ-gene promoters that may even be beneficial when present in patients with thalassemia major or sickle cell disease and, in particular, when these patients are treated with hydroxyurea.

MR assessment of lumbar disk herniation treated with oxygen-ozone diskolysis: the role of DWI and related ADC versus intervertebral disk volumetric analysis for detecting treatment response.

We prospectively assessed the diagnostic criteria of morphologic MRI study (MMS) and the accuracy of DWI and related ADC values (DWI-ADC) versus intervertebral disk volumetric analysis (IDVA) for predicting shrinkage of lumbar disk herniation treated with oxygen-ozone (O2-O3) diskolysis. Sixty-eight patients (36 men and 32 women; mean age 39) with lumbosciatica underwent O2-O3 diskolysis. The six-month MRI follow-up was performed with FSE-T2 and T2-fat, SE-T1 and DWI-weighted images. IDVA was determined using OsiriX(®). Diagnostic criteria and accuracy were evaluated with regards to DWI and related ADC in detecting response to ozone therapy. Fifty-eight of 68 patients had successful outcomes (responders), whereas ten patients showed unsatisfactory outcomes (non-responders). MMS showed that a centrally located herniated disk and grade 1 nerve root compression were more common in the responder group (p < 0.05). DWI-ADC and IDVA showed statistically significant shrinkage in the sixth month of follow-up (p < 0.05) with a mean ADC value reduction of 2.10 × 10(-3) mm(2)/s +/- 0.19 SD in the second month of follow-up (p < 0.05). DWI-ADC had an accuracy of 0.81 in detecting response to therapy around the second month of follow-up. DWI-ADC appear to be useful adjuncts to MMS in the follow-up of patients undergoing O2-O3 diskolysis.

The Stanford Leisure-Time Activity Categorical Item (L-Cat): a single categorical item sensitive to physical activity changes in overweight/obese women.

BACKGROUND: Physical activity is essential for chronic disease prevention, yet <40% of overweight/obese adults meet the national activity recommendations. For time-efficient counseling, clinicians need a brief, easy-to-use tool that reliably and validly assesses a full range of activity levels, and, most importantly, is sensitive to clinically meaningful changes in activity. The Stanford Leisure-Time Activity Categorical Item (L-Cat) is a single item comprising six descriptive categories ranging from inactive to very active. This novel methodological approach assesses national activity recommendations as well as multiple clinically relevant categories below and above the recommendations, and incorporates critical methodological principles that enhance psychometrics (reliability, validity and sensitivity to change). METHODS: We evaluated the L-Cat's psychometrics among 267 overweight/obese women who were asked to meet the national activity recommendations in a randomized behavioral weight-loss trial. RESULTS: The L-Cat had excellent test-retest reliability (κ=0.64, P<0.001) and adequate concurrent criterion validity; each L-Cat category at 6 months was associated with 1059 more daily pedometer steps (95% CI 712-1407, ß=0.38, P<0.001) and 1.9% greater initial weight loss at 6 months (95% CI -2.4 to -1.3, ß=-0.38, P<0.001). Of interest, L-Cat categories differentiated from each other in a dose-response gradient for steps and weight loss (Ps<0.05) with excellent face validity. The L-Cat was sensitive to change in response to the trial's activity component. Women increased one L-Cat category at 6 months (M=1.0±1.4, P<0.001); 55.8% met the recommendations at 6 months whereas 20.6% did at baseline (P<0.001). Even among women not meeting the recommendations at both baseline and 6 months (n=106), women who moved 1 L-Cat categories at 6 months lost more weight than those who did not (M=-4.6%, 95% CI -6.7 to -2.5, P<0.001). CONCLUSIONS: Given strong psychometrics, the L-Cat has timely potential for clinical use such as tracking activity changes via electronic medical records, especially among overweight/obese populations who are unable or unlikely to reach national recommendations.

Isolation and molecular characterization of vancomycin-resistant Enterococcus faecium from swine in Michigan, USA.

In 2008, we identified vancomycin-resistant enterococci (VRE) in Michigan swine, which was the first report of VRE in livestock from North America. Continued sampling in 2009 and 2010 was conducted to determine whether VRE persisted in Michigan. In 2009, swine faecal and feed samples (n=56), county fair pig barn manure samples (n=9) and pooled Michigan State Fair pig barn manure samples (n=18) were screened for VRE. In 2010, swine faecal samples were collected from 26 county fairs (n=73) and nine commercial swine farms in six states (n=28). Recovered VRE isolates were molecularly evaluated by polymerase chain reaction, restriction fragment length polymorphism, pulsed-field gel electrophoresis (PFGE), S1 nuclease digestion and multilocus sequence typing (MLST). Six VRE isolates were identified in 2009 from the State Fair, and another six (8.2%) were recovered from the five county fairs in 2010. All 12 isolates were highly related to the first-reported VRE from Michigan swine: all were confirmed to be vancomycin-resistant Enterococcus faecium (VREf) carrying vanA gene on Tn1546 (Type D), were negative for IS1251, hyl and esp gene, carried a 150-160 kb megaplasmid, and have closely similar PFGE patterns with >80% similarity. Classified as ST5, ST6 or ST185 by MLST, all belong to the clonal complex 5, a strain recognized to be circulating among European pigs. This study reveals that VREf are widespread in Michigan swine and persist in the historical absence of the use of agricultural glycopeptides.

The impact of extended care on the long-term maintenance of weight loss: a systematic review and meta-analysis.

Behavioural weight management interventions consistently produce 8-10% reductions in body weight, yet most participants regain weight after treatment ends. One strategy for extending the effects of behavioural interventions has been the provision of extended care. The current study is a systematic review and meta-analysis of the literature on the effect of extended care on maintenance of weight loss. Through database searches (using PubMED, PsychInfo and Cochrane Reviews) and manual searches through reference lists of related publications, 463 studies were identified. Of these, 11 were included in the meta-analysis and an additional two were retained for qualitative analysis. The average effect of extended care on weight loss maintenance was g=0.385 (95% confidence interval: 0.281, 0.489; P<0.0001). This effect would lead to the maintenance of an additional 3.2 kg weight loss over 17.6 months post-intervention in participants provided extended care compared with control. There was no significant heterogeneity between studies, Q=5.63, P=0.845, and there was minimal evidence for publication bias. These findings suggest that extended care is a viable and efficacious solution to addressing long-term maintenance of lost weight. Given the chronic disease nature of obesity, extended care may be necessary for long-term health benefits.

Detection of methicillin-resistant Staphylococcus aureus (MRSA) in backyard pigs and their owners, Michigan, USA.

Methicillin-resistant Staphylococcus aureus (MRSA) have been reported in commercially raised pigs and their human handlers, raising concerns of zoonotic transmission. To determine whether MRSA in backyard-raised pigs is commonly transmitted to their human owners, a matched study of this type of pigs and their owners was conducted in selected counties in Michigan. Nasal swabs from matched owner-pig pairs (n = 50 pairs) with a few unmatched pig (n = 3) and human (n = 4) samples were collected and processed using standard isolation and identification protocols. No matched owner-pig pair was found; however, MRSA was isolated from 1/54 (1.9%) human samples and 2/53(3.8%) of the pigs. The single human isolate was not strain type USA100-1100 by pulsed-field gel electrophoresis (PFGE), was sequence type (ST) 8 by multilocus sequence typing (MLST), possessed SCCmec type IVb and agr I and was negative for the Panton-Valentine leukocidin (PVL) toxin gene. The two pig isolates were indistinguishable by PFGE (not USA100-1100), and both isolates were ST5 by MLST, possessed SCCmec type III and agr II and were negative for the PVL gene. Persons raising backyard swine from the selected Michigan counties had MRSA carriage rates similar to that of the general US population, suggesting that their avocational pig exposure did not increase their risk of MRSA.

Microbial response to limited nutrients in shallow water immediately after the end-Permian mass extinction.

Previous work indicates that a variety of microbes bloomed in the oceans after the end-Permian faunal mass extinction, but evidence is sporadically documented. Thus, the nature and geographic distribution of such microbes and their associations are unclear, addressed in this study using a series of biomarker groups. On the basis of microbial biomarker records of the 2-methylhopane index, evidence is presented for cyanobacterial blooms in both the western and eastern Tethys Sea and in both shallow and deep waters, after the mass extinction. The enhanced relative abundance of C(28) (expressed by the C(28) /C(29) ratio of) regular steranes suggests a bloom of prasinophyte algae occurred immediately after the end-Permian faunal extinction, comparable with those observed in some other mass extinctions in Phanerozoic. Significantly, cyanobacteria and prasinophyte algae show a synchronized onset of bloom in the shallow water Bulla section, north Italy, inferring for the first time their coupled response to the biotic crisis and the associated environmental conditions. However, in Meishan of Zhejiang Province in south China, the bloom declined earlier than in Bulla. The association of increased 2-methylhopane index with a negative shift in the nitrogen isotope composition infers a scenario of enhanced nitrogen fixation by cyanobacteria immediately after the faunal mass extinction. N(2) fixation by cyanobacteria is here interpreted to have provided prasinophyte algae with ammonium in nutrient-limited shallow waters, and thus caused their associated blooms.

9°Yttrium-hydroxyapatite: a new therapeutic option for radioactive synovectomy in haemophilic synovitis.

Recurrent haemarthroses often lead to chronic synovitis in patients with haemophilia and von Willebrand disease. Radioactive synovectomy with yttrium-90 (9°Y) citrate is frequently used to treat this complication, usually with good results. Since 2006, the Nuclear Energy Research Institute (IPEN, Sao Paulo, Brazil) has produced hydroxyapatite particles labelled with 9°Y for radioactive synovectomy. The aim of this study was to compare the results achieved by both forms of 9°Y in the treatment of haemophilic synovitis. We included 221 joints from 136 patients (age range: 6-20 years), treated by one of the two radiopharmaceuticals, at the Hemocenter of Mato Grosso, Brazil. The outcomes analysed were the annual frequency of haemarthrosis, articular pain and joint range of motion before and 1 year after RS. Similar results were achieved regardless of whether 9°Y hydroxyapatite or 9°Y citrate was used, and results were independent of the joint type, age, gender, radiologic stage and presence of inhibitors. 9°Y hydroxyapatite appears to be equivalent to the reference product 9°Y citrate in the treatment of chronic synovitis associated with bleeding disorders.

Radioactive synovectomy with Yttrium9° citrate in haemophilic synovitis: Brazilian experience.

Recurrent haemarthroses leading to chronic synovitis and arthropathy remain a major cause of morbidity in patients with haemophilia. Radioactive synovectomy (RS) is considered the first choice of treatment for chronic haemophilic synovitis. The aim of this study was to evaluate the effect of RS with Yttrium(90) citrate (C-Y(90)) in the joints of patients with chronic haemophilic synovitis. From 2003 to 2007, 245 joints (118 knees, 76 elbows, 49 ankles and two shoulders) of 190 patients with haemophilia or von Willebrand disease were submitted to RS with C-Y(90) at Hemocentro de Mato Grosso, Brazil. Forty joints had radiographic Pettersson scores above 8. There were 36 joints of 22 patients with inhibitors to factor VIII. The procedure was safe with low occurrence of adverse events. The main effect was the overall reduction in joint bleeding frequency, from 19.8 to 2.6 per year post-RS. Similar results were obtained in cases with high radiographic scores and in inhibitor patients. Pain reduction was observed in most cases. Average range of motion was maintained or increased 1 year post-RS in most joints. Extension was stable or increased in 88.2% of the knees and 86.5% of the elbows. Ankle plantarflexion was stable or increased in 90.9%, whereas dorsiflexion was maintained or increased in 87.9%. Worsening of the range of motion, when present, ranged from 14 to 17 degrees. We concluded that RS with C-Y(90) represents an important resource for the treatment of chronic haemophilic synovitis, markedly reducing joint bleeding frequency and pain, irrespective of the radiographic stage and inhibitor status.

New tactile sensing system for minimally invasive surgical tumour localization.

BACKGROUND: Minimally invasive surgery (MIS) suffers from the inability to directly palpate organs for tumour localization. A tactile sensing system (TSS), consisting of a probe and a visualization interface, was developed to present an active pressure map of the contact surface to locate tumours during MIS. METHODS: The TSS performance was compared to MIS graspers to locate occult 10 mm phantom tumours in ex vivo bovine liver and ex vivo porcine lung. Performance assessment included applied pressure, localization distance and accuracy. RESULTS: The TSS realized a relative 71% reduction in maximum applied pressure and a 31% increase in detection accuracy in liver tissue (when compared to MIS graspers) and demonstrated no significant differences in performance when palpating lung tissue. CONCLUSIONS: The TSS may help surgeons to identify occult tumours during surgery by restoring some of the haptic information lost during MIS.