Intraoperative kidney replacement therapy in acute liver failure.

Paediatric acute liver failure (PALF) is often characterised by its rapidity of onset and potential for significant morbidity and even mortality. Patients often develop multiorgan dysfunction/failure, including severe acute kidney injury (AKI). Whilst the management of PALF focuses on complications of hepatic dysfunction, the associated kidney impairment can significantly affect patient outcomes. Severe AKI requiring continuous kidney replacement therapy (CKRT) is a common complication of both PALF and liver transplantation. In both scenarios, the need for CKRT is a poor prognostic indicator. In adults, AKI has been shown to complicate ALF in 25-50% of cases. In PALF, the incidence of AKI is often higher compared to other critically ill paediatric ICU populations, with reports of up to 40% in some observational studies. Furthermore, those presenting with AKI regularly have a more severe grade of PALF at presentation. Observational studies in the paediatric population corroborate this, though data are not as robust-mainly reflecting single-centre cohorts. Perioperative benefits of CKRT include helping to clear water-soluble toxins such as ammonia, balancing electrolytes, preventing fluid overload, and managing raised intracranial pressure. As liver transplantation often takes 6-10 h, it is proposed that these benefits could be extended to the intraoperative period, avoiding any hiatus. Intraoperative CKRT (IoCKRT) has been shown to be practicable, safe and may help sicker recipients tolerate the operation with outcomes analogous with less ill patients not requiring IoCKRT. Here, we provide a comprehensive guide describing the rationale, practicalities, and current evidence base surrounding IoCKRT during transplantation in the paediatric population.

Simultaneous Focal Boost With Stereotactic Radiation Therapy for Localized Intermediate- to High-Risk Prostate Cancer: Primary Outcomes of the SPARC Phase 2 Trial.

PURPOSE: Dose-escalated radiation therapy is associated with better biochemical control at the expense of toxicity. Stereotactic body radiation therapy (SBRT) with dose escalation to the dominant intraprostatic lesion (DIL) provides a logical approach to improve outcomes in high-risk disease while limiting toxicity. This study evaluated the toxicity and quality of life (QoL) with CyberKnife-based SBRT and simultaneous integrated boost in localized prostate cancer. METHODS AND MATERIALS: Eligible participants included newly diagnosed, biopsy-proven unfavorable intermediate- to high-risk localized prostate cancer (at least 1 of the following: Gleason ≥4+3, magnetic resonance imaging(MRI)-defined T3a N0, prostate-specific antigen ≥20) with up to 2 MRI-identified DILs. Participants received 36.25 Gy in 5 fractions on alternative days with a simultaneous boost to DIL up to 47.5 Gy as allowed by organ-at-risk constraints delivered by CyberKnife. All participants received androgen deprivation therapy. The primary outcome measure was acute grade 2+ genitourinary toxicity. Acute and late genitourinary and gastrointestinal toxicity using Radiation Therapy Oncology Group scoring, biochemical parameters, International Prostate Symptom Score, International Index of Erectile Function 5, and EQ-5D QoL outcomes were assessed. RESULTS: Between 2013 and 2023, 20 participants were enrolled with a median follow-up of 30 months. The median D95 dose to DIL was 47.43 Gy. Cumulative acute grade 2+ genitourinary and gastrointestinal toxicity were 25% and 30%, respectively. One patient developed acute grade 3 genitourinary toxicity (5%). There is no late grade 3 genitourinary or gastrointestinal toxicity to date. International Prostate Symptom Score and urinary QoL scores recovered to baseline by 6 months. Patient-reported outcomes showed no significant change in EQ-5D QoL scores at 12 weeks and 1 year. There are no cases of biochemical relapse reported to date. CONCLUSIONS: CyberKnife SBRT-delivered dose of 36.25 Gy to the prostate with a simultaneous integrated boost up to 47.5 Gy is well tolerated. Acute and late genitourinary and gastrointestinal toxicity rates are comparable to other contemporary SBRT trials and series with focal boost.

Paraquat ingestion in an adult with cystic fibrosis (CF): Diagnostic and management dilemmas.

N,N'-dimethyl-4,4'bipyridinium dichloride (Paraquat) is a potent herbicide used widely in agriculture. We report the effects of an ingestion of paraquat by a 28 year old male with cystic fibrosis and the diagnostic and management challenges this posed in both the acute and longer term setting. We describe the effects of direct paraquat toxicity on the lung tissue secondary to aspiration and review the long-term sequelae of paraquat, namely osteonecrosis. Our case is the first to describe osteonecrosis of the knee in the context of paraquat toxicity. Survival following ingestion remains poor with a high associated mortality. However, timely treatment with NAC and immunosuppression may impact on survival. In those patients who do survive the acute phase post ingestion, follow-up over years may be required to detect the long-term effects of paraquat on bone health.

TSC2 S1365A mutation potently regulates CD8+ T cell function and differentiation and improves adoptive cellular cancer therapy.

MTORC1 integrates signaling from the immune microenvironment to regulate T cell activation, differentiation, and function. TSC2 in the tuberous sclerosis complex tightly regulates mTORC1 activation. CD8+ T cells lacking TSC2 have constitutively enhanced mTORC1 activity and generate robust effector T cells; however, sustained mTORC1 activation prevents generation of long-lived memory CD8+ T cells. Here we show that manipulating TSC2 at Ser1365 potently regulated activated but not basal mTORC1 signaling in CD8+ T cells. Unlike nonstimulated TSC2-KO cells, CD8+ T cells expressing a phosphosilencing mutant TSC2-S1365A (TSC2-SA) retained normal basal mTORC1 activity. PKC and T cell receptor (TCR) stimulation induced TSC2 S1365 phosphorylation, and preventing this with the SA mutation markedly increased mTORC1 activation and T cell effector function. Consequently, SA CD8+ T cells displayed greater effector responses while retaining their capacity to become long-lived memory T cells. SA CD8+ T cells also displayed enhanced effector function under hypoxic and acidic conditions. In murine and human solid-tumor models, SA CD8+ T cells used as adoptive cell therapy displayed greater antitumor immunity than WT CD8+ T cells. These findings reveal an upstream mechanism to regulate mTORC1 activity in T cells. The TSC2-SA mutation enhanced both T cell effector function and long-term persistence/memory formation, supporting an approach to engineer better CAR-T cells for treating cancer.

Intradermal delivery of a quadrivalent cell-based seasonal influenza vaccine using an adjuvanted skin patch vaccination platform.

All seasonal influenza vaccines for 2021-2022 in the US were quadrivalent and the market continues to be dominated by intramuscular delivery of non-adjuvanted, virion-derived antigens grown in chicken eggs. Up to four new egg-adapted production influenza vaccine strains must be generated each year. The introduction in 2012 of Flucelvax®, which is grown in mammalian suspension cell culture and uses vaccine production strains without adaptive mutations for efficient growth in eggs, represented a major advance in vaccine production technology. Here we demonstrate that Flucelvax can be reformulated and combined with a liposomal adjuvant containing QS-21 (Verndari Adjuvant System 1.1, VAS1.1) or QS-21 and 3D-PHAD (VAS1.2) for intradermal administration using a painless skin patch, VaxiPatch™. VAS1.2 is similar to AS01B, the adjuvant system used in Shingrix® and Mosquirix™. We show that Flucelvax, when reformulated and concentrated using tangential flow filtration (TFF), maintains hemagglutination and single radial immunodiffusion (SRID) potency. Loading the reformulated Flucelvax material onto VaxiPatch arrays conferred high levels of resistance to heat stress and room temperature stability. TFF enriched vaccine antigens were combined with VAS1.1 or VAS1.2 and dispensed in 10nL drops into the pockets of 36 (total 360 nL) stainless steel microneedles arranged in a microarray 1.2 cm in diameter. Using VaxiPatch delivery of 2 µg of antigen, we demonstrated intramusuclar-comparable IgG and hemagglutination inhibition (HAI) immune responses in Sprague Dawley® rats. With addition of VAS1.2, antigen-specific IgG titers were increased as much as 68-fold (47-fold for VAS1.1) with improvements in seroconversion for three of four strains (all four were improved by VAS1.1). TFF-reformulated antigens combined with VAS1.1 or VAS1.2 and delivered by VaxiPatch showed only minor skin reactogenicity after 1 h and no skin reactogenicity after 24 h. These data indicate that VaxiPatch and the VAS system have the potential to be transformative for vaccine delivery.

Intensity-modulated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): 2-year toxicity results from an open-label, randomised, phase 3, non-inferiority trial.

BACKGROUND: Localised prostate cancer is commonly treated with external beam radiotherapy and moderate hypofractionation is non-inferior to longer schedules. Stereotactic body radiotherapy (SBRT) allows shorter treatment courses without impacting acute toxicity. We report 2-year toxicity findings from PACE-B, a randomised trial of conventionally fractionated or moderately hypofractionated radiotherapy versus SBRT. METHODS: PACE is an open-label, multicohort, randomised, controlled, phase 3 trial conducted at 35 hospitals in the UK, Ireland, and Canada. In PACE-B, men aged 18 years and older with a WHO performance status 0-2 and low-risk or intermediate-risk histologically-confirmed prostate adenocarcinoma (Gleason 4 + 3 excluded) were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group to control radiotherapy (CRT; 78 Gy in 39 fractions over 7·8 weeks or, following protocol amendment on March 24, 2016, 62 Gy in 20 fractions over 4 weeks) or SBRT (36·25 Gy in five fractions over 1-2 weeks). Androgen deprivation was not permitted. Co-primary outcomes for this toxicity analysis were Radiation Therapy Oncology Group (RTOG) grade 2 or worse gastrointestinal and genitourinary toxicity at 24 months after radiotherapy. Analysis was by treatment received and included all patients with at least one fraction of study treatment assessed for late toxicity. Recruitment is complete. Follow-up for oncological outcomes continues. The trial is registered with ClinicalTrials.gov, NCT01584258. FINDINGS: We enrolled and randomly assigned 874 men between Aug 7, 2012, and Jan 4, 2018 (441 to CRT and 433 to SBRT). In this analysis, 430 patients were analysed in the CRT group and 414 in the SBRT group; a total of 844 (97%) of 874 randomly assigned patients. At 24 months, RTOG grade 2 or worse genitourinary toxicity was seen in eight (2%) of 381 participants assigned to CRT and 13 (3%) of 384 participants assigned to SBRT (absolute difference 1·3% [95% CI -1·3 to 4·0]; p=0·39); RTOG grade 2 or worse gastrointestinal toxicity was seen in 11 (3%) of 382 participants in the CRT group versus six (2%) of 384 participants in the SBRT group (absolute difference -1·3% [95% CI -3·9 to 1·1]; p=0·32). No serious adverse events (defined as RTOG grade 4 or worse) or treatment-related deaths were reported within the analysis timeframe. INTERPRETATION: In the PACE-B trial, 2-year RTOG toxicity rates were similar for five fraction SBRT and conventional schedules of radiotherapy. Prostate SBRT was found to be safe and associated with low rates of side-effects. Biochemical outcomes are awaited. FUNDING: Accuray.

Cohort study of sleep quality in adult patients with acute pulmonary exacerbations of cystic fibrosis.

BACKGROUND: The impact of an acute pulmonary exacerbation of cystic fibrosis (CF) on sleep quality has not been established. Patients have greater burden of symptoms, higher intensity of therapy and are often admitted to hospital outside of their usual sleeping environment. AIMS: To evaluate the prevalence of, and factors associated with, poor sleep quality in adult patients admitted to hospital with an acute exacerbation of CF lung disease. METHODS: This prospective, observational study determined the prevalence of impaired sleep quality and associated factors in adult patients admitted to a single CF unit with an acute pulmonary exacerbation of CF. Sleep quality was defined by the Pittsburgh Sleep Quality Index (PSQI), with >5 indicating poor sleep quality. Data were obtained through patient questionnaires, chart review and examination. RESULTS: Sixty-six percent of patients had impaired sleep quality. Patients with poor sleep had more sleep disruption due to pain (median response 'mild sleep disruption' vs 'no sleep disruption'; P = 0.003) and insomnia (mean Insomnia Severity Index (ISI) 13 vs 5; P < 0.001). In patients with symptoms of restless legs, poor sleepers had worse symptoms (mean International Restless Legs Severity Score (IRLSS) 15 vs 5; P = 0.029). Univariate modelling showed relationships between PSQI and symptoms of depression and anxiety as well as with sleep disruption due to pain, general noise and nursing observations. In a multivariable model, ISI was the only variable that remained significantly associated with PSQI. Mean PSQI score increased 0.58 units for each 1 unit increase in ISI (95% CI 0.42-0.73; P < 0.001). CONCLUSIONS: Poor sleep quality is common among patients admitted with an acute exacerbation of CF and is strongly associated with insomnia symptoms in this cohort.

Taste responsiveness of chimpanzees (Pan troglodytes) and black-handed spider monkeys (Ateles geoffroyi) to eight substances tasting sweet to humans.

Using a two-bottle choice test of short duration, we determined taste preference thresholds for eight substances tasting sweet to humans in three chimpanzees (Pan troglodytes) and four black-handed spider monkeys (Ateles geoffroyi). We found that the chimpanzees significantly preferred concentrations as low as 100-500 mM galactose, 250 mM sorbitol, 0.5-2 mM acesulfame K, 0.5-2.5 mM alitame, 0.5 mM aspartame, 0.2-2 mM sodium saccharin, 0.001-0.2 mM thaumatin, and 0.0025-0.005 mM monellin over tap water. The spider monkeys displayed lower taste preference threshold values, and thus a higher sensitivity than the chimpanzees, with five of the eight substances (2-20 mM galactose, 20-50 mM sorbitol, 0.2-1 mM acesulfame K, 0.002-0.005 mM alitame, and 0.002-0.5 mM sodium saccharin), but were generally unable to perceive the sweetness of the remaining three substances (aspartame, thaumatin, and monellin). The ranking order of sweetening potency of the eight taste substances used here correlates significantly between chimpanzees and humans, but not between spider monkeys and humans. This is in line with genetic findings reporting a higher degree of sequence identity in the Tas1r2 and the Tas1r3 genes coding for the mammalian heterodimer sweet-taste receptor between chimpanzees and humans compared to spider monkeys and humans. Taken together, the findings of the present study support the notion that taste responsiveness for substances tasting sweet to humans may correlate positively with phylogenetic relatedness. At the same time, they are also consistent with the notion that co-evolution between fruit-bearing plants and the sense of taste in animals that serve as their seed dispersers may explain between-species differences in sweet-taste perception.

Atrophy patterns in isolated subscapularis lesions.

BACKGROUND: While supraspinatus atrophy can be described according to the system of Zanetti or Thomazeau there is still a lack of characterization of isolated subscapularis muscle atrophy. The aim of this study was to describe patterns of muscle atrophy following repair of isolated subscapularis (SSC) tendon. METHODS: Forty-nine control shoulder MRI scans, without rotator cuff pathology, atrophy or fatty infiltration, were prospectively evaluated and subscapularis diameters as well as cross sectional areas (complete and upper half) were assessed in a standardized oblique sagittal plane. Calculation of the ratio between the upper half of the cross sectional area (CSA) and the total CSA was performed. Eleven MRI scans of patients with subscapularis atrophy following isolated subscapularis tendon tears were analysed and cross sectional area ratio (upper half /total) determined. To guarantee reliable measurement of the CSA and its ratio, bony landmarks were also defined. All parameters were statistically compared for inter-rater reliability, reproducibility and capacity to quantify subscapularis atrophy. RESULTS: The mean age in the control group was 49.7 years (± 15.0). The mean cross sectional area (CSA) was 2367.0 mm2 (± 741.4) for the complete subscapularis muscle and 1048.2 mm2 (± 313.3) for the upper half, giving a mean ratio of 0.446 (± 0.046). In the subscapularis repair group the mean age was 56.7 years (± 9.3). With a mean cross sectional area of 1554.7 mm2 (± 419.9) for the complete and of 422.9 mm2 (± 173.6) for the upper half of the subscapularis muscle, giving a mean CSA ratio of 0.269 (± 0.065) which was seen to be significantly lower than that of the control group (p < 0.05). CONCLUSION: Analysis of typical atrophy patterns of the subscapularis muscle demonstrates that the CSA ratio represents a reliable and reproducible assessment tool in quantifying subscapularis atrophy. We propose the classification of subscapularis atrophy as Stage I (mild atrophy) in case of reduction of the cross sectional area ratio < 0.4, Stage II (moderate atrophy) in case of < 0.35 and Stage III (severe atrophy) if < 0.3.

The Citizen Psychologist Curriculum-Preparing psychologists for public service: The 2018 American Psychological Association Presidential Initiative.

This article describes a curriculum developed as part of the American Psychological Association President Jessica Henderson Daniel's, 2018 Presidential Initiative-The Citizen Psychologist. The curriculum is designed to prepare the next generation of Citizen Psychologists to provide the broadest sense of service as leaders in their communities and in public service psychology. The curriculum prepares the learner to bring psychological knowledge, science, and expertise to bear on existing challenges to improve community well-being locally, nationally, and globally. This includes addressing the services needs of various vulnerable populations such as veterans, prisoners, the seriously mentally ill, those with substance abuse problems, children, and older adults. Competency-based curricula are presented in a series of modules, each dedicated to a level of education and training from high school through lifelong learning. Each module presents learning outcomes, activities, and resources designed to develop level-specific competencies. Steps for implementation and recommendations at the local and national level are provided. Implications of incorporating the Citizen Psychologist curriculum in education and training programs are discussed including encouraging students to explore volunteer and career opportunities in public service psychology. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Comparative Stiffness Characteristics of Ilizarov- and Hexapod-type External Frame Constructs.

BACKGROUND: The Ilizarov method and fixator are clinically recognised for the treatment of fractures, limb salvage and deformity correction. There have been extensive studies determining the basic mechanism for fracture healing using this technique. It is generally accepted that circular frames optimise the mechanical environment by reducing shear strain across the fracture while maintaining axial micromotion so as to promote fracture healing. There have been several new hexapod-type frames introduced into the market over the past 20 years with little comparative research into their biomechanical properties and resultant effects on the fracture environment. QUESTIONS/PURPOSES: To investigate the biomechanical behaviours of the TrueLok-Hex (TL-HEX) and Taylor spatial frame (TSF) hexapod-type circular external fixators with comparison to traditional Ilizarov-type (TL-Ilizarov and TSF-Ilizarov) constructs and potential performance in vivo. METHODS: Testing was performed on standardised four-ring TSF and TL-HEX constructs matched by identical frames using Ilizarov threaded rod constructs for each set of components. All frames were tested under physiological levels of axial, bending and torsional loading. Load-deformation properties for each construct under each mode of loading were calculated and analysed statistically using ANOVA. RESULTS: Under axial loading, the Ilizarov construct utilising TL-HEX components demonstrated the greatest rigidity followed by the Ilizarov construct using TSF components. Under bending loads, the difference in rigidity between constructs was similar but less marked. Under torsional loading, both hexapod frames were seen to be significantly more rigid than the Ilizarov constructs. Overall deformation around neutral loading was much higher in the TSF frame due to an observed significant "toe-in" laxity in the strut universal joints. The remaining deformation of both hexapod frames was similar with a higher level of TL-HEX rigidity in axial loading and a higher level of TSF rigidity in bending and torsion. CONCLUSION: In conclusion, both hexapod frame constructs were less rigid under axial loading but more rigid under bending and torsional loads than their comparative Ilizarov constructs. As a result of their Cardan universal joints, the TSF demonstrated greater overall planar strain due to the observed "toe-in" laxity around neutral loading while the TL-HEX, with ball-and-socket universal joints, demonstrated a minimal level of laxity. Beyond the initial deformation due to the preloaded laxity, both hexapod frames responded to loading in a similar manner. There were significant differences in the frames' mechanical behaviour under different loading conditions but further research is required to determine whether these translate in vivo into clinical significance. HOW TO CITE THIS ARTICLE: Fenton C, Henderson D, Samchukov M, et al. Comparative Stiffness Characteristics of Ilizarov- and Hexapod-type External Frame Constructs. Strategies Trauma Limb Reconstr 2021;16(3):138-143.

The V-shaped subscapularis tenotomy for anatomic total shoulder arthroplasty.

PURPOSE: Management of the subscapularis tendon during anatomic total shoulder arthroplasty (TSA) remains controversial. In our unit, subscapularis tenotomy is the preferred technique; however, the potential for tendon gapping and failure is recognised. The purpose of this study is to describe and provide early clinical results of a novel, laterally based V-shaped tenotomy (VT) technique hypothesised to provide greater initial repair strength and resistance to gapping than a transverse tenotomy (TT), with both clinically and radiologically satisfactory post-operative tendon healing and function. METHODS: A retrospective study of patients who underwent primary TSA with VT over a three year period was performed using shoulder and subscapularis-specific outcome scores, radiographs, and ultrasound. A separate cohort of patients who underwent TSA using a subscapularis sparing approach was also reviewed to provide comparative clinical outcomes of a group with TSA and an un-violated subscapularis. RESULTS: Eighteen patients were reviewed at mean 30.4 months (± 11.7). Constant (78.2 ± 12.3), UCLA (8.4 ± 1.5), pain VAS (2.3 ± 2.8), and strength in internal rotation were no different from the comparison group. Likewise, neither were the clinical outcomes of range-of-motion, belly-press, lift-off, and shirt-tuck tests. One patient (5.5%) was found to have a failed subscapularis repair on ultrasound. CONCLUSION: VT during TSA appears to provide healing rates at least equal to those reported for TT, and not dissimilar from those of lesser tuberosity osteotomy. Clinical outcomes are comparable to reported results in the literature for alternative techniques, and not different from those observed here in a comparison cohort with TSA performed without violating the subscapularis tendon. VT therefore potentially offers a more effective and secure tendon repair than a traditional TT, with at least comparable clinical outcomes.

Remote Patient Monitoring Program for Hospital Discharged COVID-19 Patients.

OBJECTIVE: We deployed a Remote Patient Monitoring (RPM) program to monitor patients with coronavirus disease 2019 (COVID-19) upon hospital discharge. We describe the patient characteristics, program characteristics, and clinical outcomes of patients in our RPM program. METHODS: We enrolled COVID-19 patients being discharged home from the hospital. Enrolled patients had an app, and were provided with a pulse oximeter and thermometer. Patients self-reported symptoms, O2 saturation, and temperature daily. Abnormal symptoms or vital signs were flagged and assessed by a pool of nurses. Descriptive statistics were used to describe patient and program characteristics. A mixed-effects logistic regression model was used to determine the odds of a combined endpoint of emergency department (ED) or hospital readmission. RESULTS: A total of 295 patients were referred for RPM from five participating hospitals, and 225 patients were enrolled. A majority of enrolled patients (66%) completed the monitoring period without triggering an abnormal alert. Enrollment was associated with a decreased odds of ED or hospital readmission (adjusted odds ratio: 0.54; 95% confidence interval: 0.3-0.97; p = 0.039). Referral without enrollment was not associated with a reduced odds of ED or hospital readmission. CONCLUSION: RPM for COVID-19 provides a mechanism to monitor patients in their home environment and reduce hospital utilization. Our work suggests that RPM reduces readmissions for patients with COVID-19 and provides scalable remote monitoring capabilities upon hospital discharge. RPM for postdischarge patients with COVID-19 was associated with a decreased risk of readmission to the ED or hospital, and provided a scalable mechanism to monitor patients in their home environment.

Stereotactic radiotherapy with focal boost for intermediate and high-risk prostate cancer: Initial results of the SPARC trial.

INTRODUCTION: Dose escalation to dominant intraprostatic lesions (DILs) is a novel method to increase the therapeutic ratio in localised prostate cancer. The Stereotactic Prostate Augmented Radiotherapy with Cyberknife (SPARC) trial was designed to determine the feasibility of a focal boost defined with multiparametric magnetic resonance imaging (mpMRI) using stereotactic ablative body radiotherapy (SABR). MATERIALS AND METHODS: Patients were included with newly diagnosed intermediate to high risk prostate cancer with at least one of: Gleason score 4 + 3, stage T3a, or PSA > 20 ng/ml. Visible disease on mpMRI was mandatory and up to 2 separate nodules were allowed. All patients received androgen deprivation. Patients received 36.25 Gy in 5 fractions using CyberKnife® and the DIL received a simultaneous boost to a maximum of 47.5 Gy, as allowed by OAR constraints. Genitourinary (GU) and gastrointestinal (GI) toxicity was reported using the RTOG scoring criteria. International Index of Erectile Function (IIEF) and EQ-5D global health scores were regularly captured. RESULTS: An interim safety analysis was performed on the first 8 patients, recruited between July 2013 and December 2015. Median follow up was 56 months (range 50-74). Median D95 values for the prostate PTV and boost volume were 36.55 Gy (range 35.87-36.99) and 46.62 Gy (range 44.85-48.25) respectively. Of the dose constraints, 10/80 were not achieved but all were minor dose variations. Grade 2+ acute GU and GI toxicities were 37.5% respectively while grade 2+ late GU and GI toxicities were 12.5% and 0% respectively. IIEF and quality of life scores recovered over time and all patients remain in biochemical remission. CONCLUSION: The first patients have been successfully treated with prostate SABR and focal boost on the SPARC trial, with excellent adherence to the planning protocol. Toxicity and efficacy results are promising and further recruitment is underway.

VaxiPatch™, a novel vaccination system comprised of subunit antigens, adjuvants and microneedle skin delivery: An application to influenza B/Colorado/06/2017.

This work introduces VaxiPatch, a novel vaccination system comprised of subunit glycoprotein vaccine antigens, adjuvants and dermal delivery. For this study, rHA of influenza virus B/Colorado/06/2017 was incorporated into synthetic virosomes, and adjuvant liposomes were formed with QS-21 from Saponaria quillaja, with or without the synthetic TLR4 agonist 3D - (6-acyl) PHAD. These components were concentrated and co-formulated into trehalose with dye. Dermal delivery was achieved using an economical 37-point stainless steel microneedle array, designed for automated fill/finish by microfluidic dispensers used for mass production of immunodiagnostics. Vaccine and adjuvant are deposited to form a sugar glass in a pocket on the side of each of the tips, allowing skin penetration to be performed directly by the rigid steel structure. In this study, Sprague Dawley rats (n = 6 per group) were vaccinated by VaxiPatches containing 0.3 µg of rHA, 0.5 µg QS-21 and 0.2 µg 3D - (6-acyl) PHAD and dye, resulting in antigen-specific IgG titers 100-fold higher than 4.5 µg of FluBlok (p = 0.001) delivered intramuscularly. Similarly, hemagglutination inhibition titers in these animals were 14-fold higher than FluBlok controls (p = 0.01). Non-adjuvanted VaxiPatches were also compared with rHA virosomes injected intramuscularly. Accelerated shelf life studies further suggest that formulated virosomal antigens retain activity for at least two months at 60° C. Further, co-formulation of a dye could provide a visible verification of delivery based on the temporary pattern on the skin. A room-temperature-stable vaccination kit such as VaxiPatch has the potential to increase vaccine use and compliance globally.

Cardiorespiratory fitness, sleep, and physiological responses to stress in women.

Epidemiological studies suggest that cardiorespiratory fitness (CRfitness) is associated with reduced risk of depression and anxiety in women, however, the mechanisms by which CRfitness may be protective against the development of these disorders are less clear. Because sleep problems are associated with both a higher risk for mental illness and altered physiological responses to stress, this study investigated whether sleep quality might influence the relationship between CRfitness and physiological stress responses in women. Thirty healthy women (18-45 y) who were medication-free, with regular menstrual cycles completed: (1) enrolment visit [including the assessment of CRfitness via maximal oxygen consumption during exercise]; (2) one-week sleep monitoring period including subjective (daily sleep diaries) and objective (wrist actigraphy) sleep measures; and (3) psychosocial stressor protocol (the Trier Social Stress Test; TSST) for the collection of heart rate (HR), blood pressure (BP), and salivary cortisol stress responses. Higher CRfitness was associated with reduced wake after sleep onset (WASO) duration (r = -.38, p = 0.04), higher self-reported sleep quality (higher scores reflect poorer sleep quality; r = -.37, p = 0.05), and lower HR (r = -.43, p = 0.02) during the stressor. Higher sleep quality was associated with a lower HR during the stressor (r = .44, p = 0.01). Increased WASO duration and WASO number were associated with blunted cortisol output during the stressor (r = -.44, p = 0.02, and r = -.46, p = 0.02, respectively). Results suggest that, in women, CRfitness may be protective against the deleterious effects of stress via improved sleep quality.

CRISPR-Cas9 disruption of PD-1 enhances activity of universal EGFRvIII CAR T cells in a preclinical model of human glioblastoma.

Despite remarkable success in the treatment of hematological malignancies, CAR T-cell therapies for solid tumors have floundered, in large part due to local immune suppression and the effects of prolonged stimulation leading to T-cell dysfunction and exhaustion. One mechanism by which gliomas and other cancers can hamper CAR T cells is through surface expression of inhibitory ligands such as programmed cell death ligand 1 (PD-L1). Using the CRIPSR-Cas9 system, we created universal CAR T cells resistant to PD-1 inhibition through multiplexed gene disruption of endogenous T-cell receptor (TRAC), beta-2 microglobulin (B2M) and PD-1 (PDCD1). Triple gene-edited CAR T cells demonstrated enhanced activity in preclinical glioma models. Prolonged survival in mice bearing intracranial tumors was achieved after intracerebral, but not intravenous administration. CRISPR-Cas9 gene-editing not only provides a potential source of allogeneic, universal donor cells, but also enables simultaneous disruption of checkpoint signaling that otherwise impedes maximal antitumor functionality.

Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial.

BACKGROUND: Localised prostate cancer is commonly treated with external-beam radiotherapy. Moderate hypofractionation has been shown to be non-inferior to conventional fractionation. Ultra-hypofractionated stereotactic body radiotherapy would allow shorter treatment courses but could increase acute toxicity compared with conventionally fractionated or moderately hypofractionated radiotherapy. We report the acute toxicity findings from a randomised trial of standard-of-care conventionally fractionated or moderately hypofractionated radiotherapy versus five-fraction stereotactic body radiotherapy for low-risk to intermediate-risk localised prostate cancer. METHODS: PACE is an international, phase 3, open-label, randomised, non-inferiority trial. In PACE-B, eligible men aged 18 years and older, with WHO performance status 0-2, low-risk or intermediate-risk prostate adenocarcinoma (Gleason 4 + 3 excluded), and scheduled to receive radiotherapy were recruited from 37 centres in three countries (UK, Ireland, and Canada). Participants were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group, to conventionally fractionated or moderately hypofractionated radiotherapy (78 Gy in 39 fractions over 7·8 weeks or 62 Gy in 20 fractions over 4 weeks, respectively) or stereotactic body radiotherapy (36·25 Gy in five fractions over 1-2 weeks). Neither participants nor investigators were masked to allocation. Androgen deprivation was not permitted. The primary endpoint of PACE-B is freedom from biochemical or clinical failure. The coprimary outcomes for this acute toxicity substudy were worst grade 2 or more severe Radiation Therapy Oncology Group (RTOG) gastrointestinal or genitourinary toxic effects score up to 12 weeks after radiotherapy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT01584258. PACE-B recruitment is complete and follow-up is ongoing. FINDINGS: Between Aug 7, 2012, and Jan 4, 2018, we randomly assigned 874 men to conventionally fractionated or moderately hypofractionated radiotherapy (n=441) or stereotactic body radiotherapy (n=433). 432 (98%) of 441 patients allocated to conventionally fractionated or moderately hypofractionated radiotherapy and 415 (96%) of 433 patients allocated to stereotactic body radiotherapy received at least one fraction of allocated treatment. Worst acute RTOG gastrointestinal toxic effect proportions were as follows: grade 2 or more severe toxic events in 53 (12%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 43 (10%) of 415 patients in the stereotactic body radiotherapy group (difference -1·9 percentage points, 95% CI -6·2 to 2·4; p=0·38). Worst acute RTOG genitourinary toxicity proportions were as follows: grade 2 or worse toxicity in 118 (27%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 96 (23%) of 415 patients in the stereotactic body radiotherapy group (difference -4·2 percentage points, 95% CI -10·0 to 1·7; p=0·16). No treatment-related deaths occurred. INTERPRETATION: Previous evidence (from the HYPO-RT-PC trial) suggested higher patient-reported toxicity with ultrahypofractionation. By contrast, our results suggest that substantially shortening treatment courses with stereotactic body radiotherapy does not increase either gastrointestinal or genitourinary acute toxicity. FUNDING: Accuray and National Institute of Health Research.

Functional improvements in active elevation, external rotation, and internal rotation after reverse total shoulder arthroplasty with isolated latissimus dorsi transfer: surgical technique and midterm follow-up.

HYPOTHESIS: This study investigated the hypothesis that reverse total shoulder arthroplasty (RSA) in combination with an isolated latissimus dorsi tendon (LDT) transfer in patients with pseudoparalysis of abduction and external rotation (combined loss of active elevation and external rotation [CLEER] syndrome) would demonstrate improved postoperative functional results. METHODS: This study was a retrospective single-surgeon case series of 13 consecutive patients with CLEER who underwent RSA without subscapularis repair and combined with an isolated LDT transfer. We reviewed 10 patients (77%), at a minimum of 2 years, with 3 cases lost to follow-up. Shoulder function was assessed preoperatively and postoperatively using the Constant score and postoperatively using the Oxford Shoulder Score, University of California-Los Angeles score, American Shoulder and Elbow Surgeons score, ADLEIR (activities of daily living [ADLs] requiring active external and internal rotation) score, and ADLIR (ADLs requiring active internal rotation) score. Force in internal rotation (IR) at 0° of abduction, external rotation (ER) at 0° of abduction, and ER at 90° of abduction, as well as IR in the belly-press position, was measured. RESULTS: The mean postoperative follow-up period was 57 months (range, 31-85 months). We observed improvement in the Constant score (from 29.8 ± 6.64 preoperatively to 71.9 ± 10.45 postoperatively, P < .05), as well as abduction force, ER, and forward elevation (P < .05). Postoperatively, the mean American Shoulder and Elbow Surgeons score was 95.1 ± 3.38 and the mean Oxford Shoulder Score was 46.6 ± 1.57. Mean force in IR at 0° of abduction was 5.45 ± 2.42 kg, and mean force in ER at 90° of abduction was 4 ± 1.20 kg. Mean force in ER at 0° of abduction (3.65 ± 1.24 kg) and IR in the belly-press position (4.5 ± 2.84 kg) demonstrated a positive correlation with ADLs. CONCLUSIONS: The results of this study demonstrate that RSA without subscapularis repair, combined with an isolated LDT transfer, provides improved postoperative functional outcomes for patients with CLEER while maintaining sufficiently balanced force in IR and ER to effectively perform ADLs.