Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Single-Dose Intravenous Tranexamic Acid Does Not Increase Venous Thromboembolic Rate or Complication Rate During Hip Arthroscopy.

PURPOSE: To determine whether tranexamic acid (TXA) is safe to administer preoperatively in patients undergoing hip arthroscopy by comparing the venous thromboembolic rate and complication rate between patients who did and did not receive TXA preoperatively. METHODS: This was a multicenter consecutive-cohort series of patients who underwent arthroscopic hip surgery between 2014 and 2021. The 2 cohorts comprised patients who did and did not receive TXA preoperatively (single dose of 1-2 g), after a practice change. Data were collected via chart review. Surgical outcomes included days until follow-up, visual analog scale pain score at first follow-up, total operating room (OR) time, number of arthroscopic fluid bags (3 L/bag), and complications and revision operations up to 1 year after surgery. The Mann-Whitney U test was performed for continuous variables, and the χ2 test, for categorical variables. RESULTS: A total of 862 patients were identified: 449 (52%) received TXA and 413 (48%) did not. Patient demographic characteristics including age, sex, height, weight, body mass index, smoking status, and procedures performed, as well as number of anchors used (3.5 anchors for no TXA vs 3.7 anchors for TXA) and traction time (38 minutes for no TXA vs 40 minutes for TXA), did not significantly differ between groups. Significantly more patients underwent prior hip arthroscopy in the TXA group (n = 45; primary, n = 404) than in the group that did not receive TXA (n = 25; primary, n = 388) (P = .03). Visual analog scale pain scores at the first follow-up visit (2.61 for no TXA vs 2.62 for TXA, P = .62) and the need for subsequent revision surgery (24 patients with no TXA vs 18 patients with TXA, P = .68) were not significantly different. TXA use was associated with less arthroscopic fluid utilization (5.9 bags of 3 L of fluid for no TXA vs 5.3 bags of 3 L of fluid for TXA, P < .01) and less total OR time (99.5 minutes for no TXA vs 90.0 minutes for TXA, P < .01). There was a higher overall complication rate in the group that did not receive TXA (n = 27) than in the group that did (n = 10) (P = .01). However, if lateral femoral cutaneous nerve neurapraxia was excluded, then no difference in complication rate was observed (P = .24). CONCLUSIONS: There was no difference in the incidence of venous thromboembolic complications between patients who did and did not receive TXA preoperatively. We observed a lower overall complication rate in patients who received TXA preoperatively; however, this normalized between the 2 groups when lateral femoral cutaneous nerve neuritis was excluded. No difference in early pain control or revision surgery rate was observed between groups. Although there was statistically less arthroscopic fluid utilization and less total OR time in the group that received TXA, further studies are needed to clarify whether this is clinically meaningful. Preoperatively administered TXA is a safe adjunct medication in patients undergoing arthroscopic hip surgery. LEVEL OF EVIDENCE: Level III, retrospective multicenter consecutive series.

Fluoroscopy and Radiographs for Detecting Retained Surgical Needles in the Hand.

When a surgical needle is lost, the protocol is to explore the surgical field and to obtain a plain radiograph if the needle cannot be located. The size of the needle that can be detected with imaging is debated. Plain-film radiographs, C-arm, and mini C-arm fluoroscopy imaging was obtained of a cadaveric hand with retained needle of varying lengths (suture sizes 4-0 - 10-0). The authors performed analyses to determine the sensitivity and specificity of the imaging modalities. There were no differences in diagnostic area under the receiver operating characteristic curve between the three modalities. For plain film, optimal cutoff for needle size was 5.2 mm (sensitivity 0.87, specificity 0.75), for C-arm 6.8 mm (sensitivity 0.84, specificity 0.87), and for mini C-arm 5.9 mm (sensitivity 0.82, specificity 0.86). In the hand, the use of C-arm fluoroscopy is as sensitive as plain-film radiography at detecting retained needles greater than 5.9 mm. (Journal of Surgical Orthopaedic Advances 33(1):026-028, 2024).

Osteoarthritis consumers as co-researchers: identifying consumer insights to improve osteoarthritis management by co-designing translational research solutions.

INTRODUCTION: Co-design is a consumer-driven approach that facilitates consumer participation in creating meaningful solutions to complex problems. Poor uptake of core management strategies for osteoarthritis suggests there is a missing link in translation between research and practice. We partnered with osteoarthritis consumers as 'co-researchers' to identify translational research solutions to improve uptake of core management strategies that are grounded in lived experiences. OBJECTIVE: To transparently describe a theory-driven, generative co-design approach using an integrated conceptual framework to collaborate with consumers at the equal partnership level. DESIGN: We used co-design workshops with a non-hierarchical participatory framework. Three workshops with six co-researchers [2 female, mean age 68.7 (9.8) years, 3-30 years symptom duration] were conducted using activities to encourage creative thinking, promote deep reflection on personal/societal beliefs and minimise sensitivities around sharing personal beliefs (e.g., establishing a safe space, prompting questions, perspective-taking, counter-stereotypical exemplars). RESULTS: All six co-researchers actively participated in the workshops. Achievement of an equal collaborative partnership was evidenced by co-researchers challenging a project proposed by the research team and making alternative recommendations that have been implemented in prospective decision-making - representing a complete change in research focus driven by consumer input. A key suggested solution was to develop a scalable knowledge translation intervention that targets misconceptions about osteoarthritis and its management at the societal-level. CONCLUSIONS: Through an innovative co-design approach in partnership with co-researchers, we identified meaningful areas on which to focus translational research for osteoarthritis. Discordance between existing research priorities and novel solutions proposed by co-researchers highlights the value of co-design.

ICTV Virus Taxonomy Profile: Adenoviridae 2022.

The family Adenoviridae includes non-enveloped viruses with linear dsDNA genomes of 25-48 kb and medium-sized icosahedral capsids. Adenoviruses have been discovered in vertebrates from fish to humans. The family is divided into six genera, each of which is more common in certain animal groups. The outcome of infection may vary from subclinical to lethal disease. This is a summary of the ICTV Report on the family Adenoviridae, which is available at ictv.global/report/adenoviridae.

Effectiveness of PD-(L)1 inhibitors alone or in combination with platinum-doublet chemotherapy in first-line (1L) non-squamous non-small-cell lung cancer (Nsq-NSCLC) with PD-L1-high expression using real-world data.

BACKGROUND: Anti-programmed cell death protein (death-ligand) 1 [PD-(L)1] therapy alone [cancer immunotherapy (CIT)-mono] or combined with platinum-based chemotherapy (CIT-chemo) is used as the first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC). Our study compared clinical outcomes with CIT-mono versus CIT-chemo in the specific clinical scenario of non-squamous (Nsq)-NSCLC with a high PD-L1 expression of ≥50% [tumor proportion score (TPS) or tumor cells (TC)]. METHODS: This was a retrospective cohort study using a real-world de-identified database. Patients with metastatic Nsq-NSCLC with high PD-L1 expression initiating first-line CIT-mono or CIT-chemo between 24 October 2016 and 28 February 2019 were followed up until 28 February 2020. We compared overall survival (OS) and real-world progression-free survival (rwPFS) using the Kaplan-Meier methodology. Hazard ratios (HRs) were adjusted (aHR) for differences in baseline key prognostic characteristics using the inverse probability of treatment weighting methodology. RESULTS: Patients with PD-L1-high Nsq-NSCLC treated with CIT-mono (n = 351) were older and less often presented with de novo stage IV disease than patients treated with CIT-chemo (n = 169). With a median follow-up of 19.9 months for CIT-chemo versus 23.5 months for CIT-mono, median OS and rwPFS did not differ between the two groups [median OS: CIT-chemo, 21.0 months versus CIT-mono, 22.1 months, aHR = 1.03, 95% confidence interval (CI) 0.77-1.39, P = 0.83; median rwPFS: CIT-chemo, 10.8 months versus CIT-mono, 11.5 months, aHR = 1.04, 95% CI 0.78-1.37, P = 0.81]. CIT-chemo showed significant and meaningful improvement in OS and rwPFS versus CIT-mono only in the never-smoker subgroup, albeit among a small sample of patients (n = 50; OS HR = 0.25, 95% CI 0.07-0.83, interaction P = 0.02; rwPFS HR = 0.40, 95% CI 0.17-0.95, interaction P = 0.04). CONCLUSION: Except in the subgroup of never-smoker patients, sparing the chemotherapy in first-line CIT treatment does not appear to impact survival outcomes in Nsq-NSCLC patients with high PD-L1 expression.

Associations with sub-optimal clinic attendance and reasons for missed appointments among heterosexual women and men living with HIV in London.

Poor engagement in HIV care is associated with poorer health outcomes and increased mortality. Our survey examined experiential and circumstantial factors associated with clinic attendance among women (n = 250) and men (n = 106) in London with heterosexually-acquired HIV. While no associations were found for women, among men, sub-optimal attendance was associated with insecure immigration status (25.6% vs. 1.8%), unstable housing (32.6% vs. 10.2%) and reported effect of HIV on daily activities (58.7% vs. 40.0%). Among women and men on ART, it was associated with missing doses of ART (OR = 2.96, 95% CI:1.74-5.02), less belief in the necessity of ART (OR = 0.56, 95% CI:0.35-0.90) and more concern about ART (OR = 3.63, 95% CI:1.45-9.09). Not wanting to think about being HIV positive was the top reason for ever missing clinic appointments. It is important to tackle stigma and the underlying social determinants of health to improve HIV prevention, and the health and well-being of people living with HIV.

Fetal growth of left-sided structures and postnatal surgical outcome in borderline left heart varies by cardiac phenotype.

OBJECTIVES: There are two borderline left-heart phenotypes in the fetus: (1) severe aortic stenosis (AS), which is associated with a 'short, fat', globular left ventricle (LV), LV systolic dysfunction and LV growth arrest; and (2) severe left-heart hypoplasia (LHH), which is associated with a 'long, skinny' LV, laminar flow across hypoplastic mitral and aortic valves and arch hypoplasia. Both phenotypes may be counseled for possible single-ventricle palliation. We aimed to compare the rates of left-sided cardiac structure growth and Z-score change over gestation and to describe the postnatal outcomes associated with these two phenotypes. We hypothesized that the left-sided structures would grow faster in fetuses with LHH compared to those with AS, and that those with LHH would be more likely to achieve biventricular circulation. METHODS: This was a retrospective cohort study using data collected in an institutional cardiology database between April 2001 and April 2018. We included fetuses with severe AS or severe LHH, and with at least two fetal echocardiograms. Inclusion criteria for the AS group included: aortic-annulus Z-score < -2.0, severe AS, depressed LV function, retrograde systolic flow in the aortic arch and endocardial fibroelastosis. Inclusion criteria for the LHH group included: aortic-annulus Z-score < -2.0, hypoplastic but apex-forming LV, normal LV function and retrograde systolic flow in the aortic arch. Exclusion criteria were: abnormal cardiac connections, other forms of structural congenital heart disease, cardiomyopathy, history of fetal aortic valvuloplasty and participation in a maternal hyperoxygenation study. Measurements and respective Z-scores for the aortic-valve annulus, mitral-valve annulus, LV long- and short-axis dimensions, along with aortic-arch measurements, were collected longitudinally for each fetus and plotted over time for both cohorts. Mean slopes of change in dimension and Z-scores over gestation were calculated and compared between the two groups using mixed generalized linear regression accounting for repeated measures. A subanalysis was performed, matching six fetuses from each group for initial aortic-annulus Z-score and gestational age, due to the significant differences in these two variables between the original cohorts. RESULTS: In total, 53 fetuses with 158 echocardiograms were included. In the AS cohort, there were 20 (38%) fetuses with 65 echocardiograms, and in the LHH cohort there were 33 (62%) fetuses with 93 echocardiograms. On the first echocardiogram, LHH fetuses had a later gestational age and a larger aortic-annulus diameter. The rate of aortic-annulus growth was greater in the LHH group compared with the AS group (mean ± SD, 0.15 ± 0.01 mm/week for LHH vs 0.07 ± 0.01 mm/week for AS (P < 0.001)). While the LHH group had a decrease in aortic-annulus Z-score over time, this was at a slower rate than the decrease in the AS group (mean ± SD, -0.04 ± 0.02/week for LHH vs -0.13 ± 0.02/week for AS (P < 0.001)). A similar pattern was seen for the mitral-valve and LV short-axis-dimension Z-scores. Subanalysis of six fetuses from each group matched for initial aortic-annulus Z-score and gestational age demonstrated similar findings, with the LHH group Z-scores decreasing at a slower rate than those in the AS group. Fifty-two of the 53 fetuses were liveborn, one LHH fetus dying in utero. Of the 20 liveborn in the AS cohort, 15 (75%) infants underwent single-ventricle palliation, two (10%) underwent biventricular repair and three (15%) died prior to intervention. Of the 32 liveborn in the LHH cohort, three (9.4%) underwent single-ventricle palliation, 28 (87.5%) achieved biventricular circulation, of which six required no surgery, and one (3.1%) died prior to intervention. CONCLUSIONS: The left-sided cardiac structures grow at a faster rate in fetuses with severe LHH than they do in fetuses with severe AS, and the Z-scores decrease at a slower rate in fetuses with severe LHH than they do in those with severe AS. The majority of infants in the LHH group did not undergo single-ventricle palliation. This information can be useful in counseling families on the expected growth potential of the fetus's aortic valve, mitral valve and LV, depending on the cardiac phenotype. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Enhanced inhibition of Pseudomonas aeruginosa virulence factor production and biofilm development by sublethal concentrations of eugenol and phenyllactic acid.

Biofilm development in Pseudomonas aeruginosa is regulated by its quorum sensing (QS) systems. It has three major QS systems: LasI/R, RhlI/R and PQS/MvfR. Previous studies showed that phenyllactic acid (PLA) binds to RhlR and PqsR and inhibits the Rhl and PQS QS; and eugenol at sublethal concentration inhibits Las and PQS QS systems. Here, we have demonstrated that a combination of sublethal doses of eugenol and PLA enhanced the inhibition of the QS mediated production of the virulence factors and biofilm development of this pathogen. A combination of 50 µmol l-1 eugenol and 0·3 mmol l-1 PLA significantly inhibited the pyocyanin production, protease activity, swarming motility and cytotoxic activities of P. aeruginosa strain PAO1, whereas eugenol and PLA when added individually to PAO1 cultures were less effective in inhibiting its virulence factor expression. Biofilm formation of PAO1 was reduced by 32, 19 and 87% on glass surfaces; and 54, 49 and 93% on catheter surfaces when treated using 50 µmol l-1 eugenol or 0·3 mmol l-1 PLA and their combinations, respectively. The in vitro finding in the reduction of biofilm development was further validated in vivo using a catheter associated medaka fish biofilm model. Our results indicate that a combination of QS inhibitors targeting different QS pathways should be selected while designing therapeutic molecules to achieve maximum QS mediated biofilm inhibition and clinical outcome against P. aeruginosa.

The association between use of chemsex drugs and HIV clinic attendance among gay and bisexual men living with HIV in London.

OBJECTIVES: To investigate the association between chemsex drug use and HIV clinic attendance among gay and bisexual men in London. METHODS: A cross-sectional survey of adults (> 18 years) diagnosed with HIV for > 4 months, attending seven London HIV clinics (May 2014 to August 2015). Participants self-completed an anonymous questionnaire linked to clinical data. Sub-optimal clinic attenders had missed one or more HIV clinic appointments in the past year, or had a history of non-attendance for > 1 year. RESULTS: Over half (56%) of the 570 men who identified as gay or bisexual reported taking recreational drugs in the past 5 years and 71.5% of these men had used chemsex drugs in the past year. Among men reporting chemsex drug use (past year), 32.1% had injected any drugs in the past year. Sub-optimal clinic attenders were more likely than regular attenders to report chemsex drug use (past year; 46.9% vs. 33.2%, P = 0.001), injecting any drugs (past year; 17.1% vs. 8.9%, P = 0.011) and recreational drug use (past 5 years; 65.5% vs. 48.8%, P < 0.001). One in five sub-optimal attenders had missed an HIV clinic appointment because of taking recreational drugs (17.4% vs. 1.8%, P < 0.001). In multivariable logistic regression, chemsex drug use was significantly associated with sub-optimal clinic attendance (adjusted odds ratio = 1.71, 95% confidence interval: 1.10-2.65, P = 0.02). CONCLUSIONS: Our findings highlight the importance of systematic assessment of drug use and development of tools to aid routine assessment. We suggest that chemsex drug use should be addressed when developing interventions to improve engagement in HIV care among gay and bisexual men.

Visual Estimation of Length by Orthopaedic Surgeons: How Accurate Are Lengths Estimated in Digital Images Compared to In-Person Estimations?

Orthopaedic surgeons are frequently required to make estimations, often without the use of measuring tools, including the lengths of wounds, incisions, bone fragments, and soft tissue defects. To evaluate the accuracy of these estimations, simulated wounds of randomized lengths were drawn on a healthy volunteer. Resident and attending physicians estimated the length of each wound via digital photograph and subsequently in person. Comparison of digital photograph versus in-person estimation was completed with paired t-test. The accuracy of estimation by experience level was assessed using Spearman rank. Accuracy was higher with in-person measurement compared with digital photographs, but overall low in both settings. There was no correlation between better accuracy and more experience in either setting. In order to properly guide treatment decisions and document physical exam findings, a ruler should be used rather than visual estimation alone. Likewise, clinical photographs used for patient care should always include a ruler. (Journal of Surgical Orthopaedic Advances 30(2):108-111, 2021).

[Towards better management for sexual offenders: Presentation and conclusions of a public hearing concerning prevention, assessment, and care]. / Audition publique auteurs de violences sexuelles : prévention, évaluation, prise en charge des 14 et 15 juin 2018 : perspectives et préconisations.

In France, since the law of June 17, 1998, sexual offenders may be convicted to ambulatory mandatory care, articulated with the justice. Twenty years after the implementation of this law, while social and technological developments have redefined certain aspects of delinquency, reference documents and practice guidelines remain to be updated. This is why the professionals of the main structures and associations dealing with perpetrators of sexual violence organized a public hearing under the sponsorship of the French Federation of Resource Centers for Sexual Violence Perpetrators (FFCRIAVS) according to the methodology and with the accompaniment of the High Authority of Health. This article presents the global methodology of the public hearing "Sexual Offenders: Prevention, Evaluation and Care" which was conducted on June 14 and 15, 2018. Thirty-three experts replied to27 questions and presented their conclusions to an Audition Committee and an audience of 200 persons representative of the civil and professional society. After a public debate, the hearing committee prepared a report in which they proposed propositions in order to better care for sexual offenders.

Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial.

BACKGROUND: The addition of atezolizumab to carboplatin and etoposide (CP/ET) significantly improved progression-free and overall survival for patients with extensive-stage small-cell lung cancer (ES-SCLC) in the IMpower133 study (NCT02763579). We have evaluated adverse events (AEs) and patient-reported outcomes in IMpower133 to assess the benefit-risk profile of this regimen. PATIENTS AND METHODS: Patients received four 21-day cycles of CP/ET plus intravenous atezolizumab 1200 mg or placebo (induction phase), followed by atezolizumab or placebo (maintenance phase) until progression or loss of benefit. AEs were assessed and patient-reported outcomes were evaluated every 3 weeks during treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (QLQ-C30) and QLQ-LC13. RESULTS: Overall, 394 patients were assessable for safety in the induction phase and 318 in the maintenance phase. The frequency of AEs, grade 3-4 AEs, and serious AEs was similar between arms in both phases. Immune-related AEs were more frequent in the atezolizumab arm during both induction (28% versus 17%; leading to atezolizumab/placebo interruption 9% versus 5%, leading to withdrawal 4% versus 0%) and maintenance (26% versus 15%; leading to atezolizumab/placebo interruption, 3% versus 2%, leading to withdrawal 1% versus 1%), most commonly rash (induction 11% versus 9%, maintenance 14% versus 4%), and hypothyroidism (induction 4.0% versus 0%, maintenance 10% versus 1%). Changes in patient-reported treatment-related symptoms commonly associated with quality of life impairment were generally similar during induction and most of the maintenance phase. Patient-reported function and health-related quality of life (HRQoL) improved in both arms after initiating treatment, with more pronounced and persistent HRQoL improvements in the atezolizumab arm. CONCLUSIONS: In patients with ES-SCLC, atezolizumab plus CP/ET has a comparable safety profile to placebo plus CP/ET, and the addition of atezolizumab did not adversely impact patient-reported HRQoL. These data demonstrate the positive benefit-risk profile of first-line atezolizumab plus CP/ET in ES-SCLC and further support this regimen as a new standard of care in this setting. CLINICAL TRIALS NUMBER: NCT02763579.

A Zoonotic Adenoviral Human Pathogen Emerged through Genomic Recombination among Human and Nonhuman Simian Hosts.

Genomics analysis of a historically intriguing and predicted emergent human adenovirus (HAdV) pathogen, which caused pneumonia and death, provides insight into a novel molecular evolution pathway involving "ping-pong" zoonosis and anthroponosis. The genome of this promiscuous pathogen is embedded with evidence of unprecedented multiple, multidirectional, stable, and reciprocal cross-species infections of hosts from three species (human, chimpanzee, and bonobo). This recombinant genome, typed as HAdV-B76, is identical to two recently reported simian AdV (SAdV) genomes isolated from chimpanzees and bonobos. Additionally, the presence of a critical adenoviral replication element found in HAdV genomes, in addition to genes that are highly similar to counterparts in other HAdVs, reinforces its potential as a human pathogen. Reservoirs in nonhuman hosts may explain periods of apparent absence and then reemergence of human adenoviral pathogens, as well as present pathways for the genesis of those thought to be newly emergent. The nature of the HAdV-D76 genome has implications for the use of SAdVs as gene delivery vectors in human gene therapy and vaccines, selected to avoid preexisting and potentially fatal host immune responses to HAdV.IMPORTANCE An emergent adenoviral human pathogen, HAdV-B76, associated with a fatality in 1965, shows a remarkable degree of genome identity with two recently isolated simian adenoviruses that contain cross-species genome recombination events from three hosts: human, chimpanzee, and bonobo. Zoonosis (nonhuman-to-human transmission) and anthroponosis (human to nonhuman transmission) may play significant roles in the emergence of human adenoviral pathogens.

Healthcare utilization and monetary costs associated with agitation in UK care home residents with advanced dementia: a prospective cohort study.

OBJECTIVE: Nearly half of care home residents with advanced dementia have clinically significant agitation. Little is known about costs associated with these symptoms toward the end of life. We calculated monetary costs associated with agitation from UK National Health Service, personal social services, and societal perspectives. DESIGN: Prospective cohort study. SETTING: Thirteen nursing homes in London and the southeast of England. PARTICIPANTS: Seventy-nine people with advanced dementia (Functional Assessment Staging Tool grade 6e and above) residing in nursing homes, and thirty-five of their informal carers. MEASUREMENTS: Data collected at study entry and monthly for up to 9 months, extrapolated for expression per annum. Agitation was assessed using the Cohen-Mansfield Agitation Inventory (CMAI). Health and social care costs of residing in care homes, and costs of contacts with health and social care services were calculated from national unit costs; for a societal perspective, costs of providing informal care were estimated using the resource utilization in dementia (RUD)-Lite scale. RESULTS: After adjustment, health and social care costs, and costs of providing informal care varied significantly by level of agitation as death approached, from £23,000 over a 1-year period with no agitation symptoms (CMAI agitation score 0-10) to £45,000 at the most severe level (CMAI agitation score >100). On average, agitation accounted for 30% of health and social care costs. Informal care costs were substantial, constituting 29% of total costs. CONCLUSIONS: With the increasing prevalence of dementia, costs of care will impact on healthcare and social services systems, as well as informal carers. Agitation is a key driver of these costs in people with advanced dementia presenting complex challenges for symptom management, service planners, and providers.

Student perceptions of two simulated learning environments in paediatric audiology.

Objective: To determine audiology student perceptions of two simulated learning environments (SLE) in paediatric audiology.Design: A one-shot case study design.Study sample: Fifteen audiology students who completed questionnaires after participating in two SLEs, one simulating auditory brainstem response (ABR) assessments of neonates in a hospital ward and one simulating visually reinforced orientation audiometry (VROA) assessments of young children in an audiology clinic.Results: The students responded positively to 11/11 areas of audiometric testing and client interaction in both SLEs, to 7/7 aspects of their interactions with the mannequins in both SLEs, and to 8/8 aspects of their interactions with fellow students playing the role of parent in the ABR SLE and 7/8 of these aspects in the VROA SLE. The students reported low levels of anxiety towards both SLEs but rated the ABR SLE more highly than the VROA SLE in areas of preparedness, effectiveness, realism, pre-SLE training, reinforcement of lecture content, and overall usefulness.Conclusions: The participating students responded positively to almost all aspects of both SLEs. Further research is warranted using research designs capable of determining if these SLEs directly improve student abilities as they transition from academic settings to clinical placements in paediatric audiology.

Auto-Decompression - Preserved Neurological Function in Bilateral Cervical Facet Dislocations

Introduction Bilateral cervical facet dislocation (BCFD) is an uncommon injury with a high incidence of severe neurological impairment. We describe 4 cases of BCFD with preserved neurological function. Cases Case 1: A 78-year-old female who suffered two ground level falls (GLFs). Pre-operative American Spinal Injury Association (ASIA) Score was C5D. Imaging revealed a BCFD at C6/C7 and a C6 laminar fracture. Case 2: A 63-year-old male suffered a fall down 14 steps. Pre-operative ASIA score was E. Imaging demonstrated a BCFD at C7/T1, and a C6 laminar fracture. Case 3: A 46-year-old male collided with a tree while descending a hill on a bicycle. Pre-operative ASIA score was C6D. Imaging revealed a BCFD at C7/T1 and a C7 laminar fracture. Case 4: A 67-year-old male suffered a GLF while exiting a stationary car. Pre-operative ASIA score on admission was E. Imaging revealed a BCFD at C6/C7 with bilateral laminar fractures at C5 and C6. Outcome All cases underwent 2-stage surgical fixation. All cases maintained or had an improved ASIA score post-operatively. Conclusion In all cases, the presence of concurrent laminar fractures resulted in an auto-decompression of the spinal canal, preserving neurological function.

Behaviour of twin- and triplet-born lambs and their dam 3 to 18 hours after birth is not a useful predictor of lamb survival to weaning.

OBJECTIVE: An experiment was designed to determine if behaviour traits expressed by twinand triplet-bearing lambs and their dams at 3 to 18 hours of age (after the immediate ewelamb bonding had occurred) were associated with lamb survival to weaning. METHODS: The behaviour of twin and triplet lambs and their dams was assessed in the paddock at 3 to 18 hours after birth. Observations were made of the number of high- and low-pitched bleats, time to stand, make contact with dam, suck from dam and follow dam were recorded for each lamb. The maternal behaviour score of each dam was assessed. A random sub-sample of lambs were assessed during a maternal-recognition test at 12 or 24 hours of age. Traits included time spent standing, sitting, walking, time taken to reach the ewes and time spent with the ewes as well as the number of high- and low-pitched bleats emitted by the lamb. RESULTS: In the paddock, for each additional second required for twin-born lambs to follow their dam, lambs were 1.004 (95% confidence interval [CI] 1.000 to 1.008) times more likely to survive to weaning (p<0.05). The opposite relationship, however, was seen in triplet lambs. For each additional second required for triplet-born lambs to follow their dam, lambs were 0.996 (95% CI 0.993 to 0.999) times as likely to survive to weaning (p<0.05). During the maternal recognition test, twin-born lambs were 0.989 (95% CI 0.979 to 1.000) times as likely to survive to weaning for every additional second they took to reach the contact zone (p<0.05). Similarly, triplet-born lambs were 0.994 (95% CI 0.989 to 0.999) as likely to survive for every additional second they took to reach their dam (p<0.05). CONCLUSION: All ewe behaviours and the majority of lamb paddock and test behaviours were not associated with the survival of twin- or triplet-born lambs and, therefore, are of little use as indicators of lamb survival to weaning.

Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.

BACKGROUND: Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity. PATIENTS AND METHODS: This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy. RESULTS: A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107). CONCLUSION: Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits. CLINICAL TRAIL NUMBER: NCT02499770.

Measurement of the Electrical Properties of a Thundercloud Through Muon Imaging by the GRAPES-3 Experiment.

The GRAPES-3 muon telescope located in Ooty, India records rapid (∼10 min) variations in the muon intensity during major thunderstorms. Out of a total of 184 thunderstorms recorded during the interval of April 2011-December 2014, the one on December 1, 2014 produced a massive potential of 1.3 GV. The electric field measured by four well-separated (up to 6 km) monitors on the ground was used to help estimate some of the properties of this thundercloud, including its altitude and area that were found to be 11.4 km above mean sea level and ≥380 km^{2}, respectively. A charging time of 6 min to reach 1.3 GV implied the delivery of a power of ≥2 GW by this thundercloud that was moving at a speed of ∼60 km h^{-1}. This work possibly provides the first direct evidence for the generation of gigavolt potentials in thunderclouds that could also possibly explain the production of highest-energy (100 MeV) gamma rays in the terrestrial gamma-ray flashes.