The clinical, imaging, pathological and genetic landscape of bottom-of-sulcus dysplasia.

Bottom-of-sulcus dysplasia (BOSD) is increasingly recognized as a cause of drug-resistant, surgically-remediable, focal epilepsy, often in seemingly MRI-negative patients. We describe the clinical manifestations, morphological features, localization patterns and genetics of BOSD, with the aims of improving management and understanding pathogenesis. We studied 85 patients with BOSD diagnosed between 2005-2022. Presenting seizure and EEG characteristics, clinical course, genetic findings and treatment response were obtained from medical records. MRI (3 T) and 18F-FDG-PET scans were reviewed systematically for BOSD morphology and metabolism. Histopathological analysis and tissue genetic testing were performed in 64 operated patients. BOSD locations were transposed to common imaging space to study anatomical location, functional network localization and relationship to normal MTOR gene expression. All patients presented with stereotyped focal seizures with rapidly escalating frequency, prompting hospitalization in 48%. Despite 42% patients having seizure remissions, usually with sodium channel blocking medications, most eventually became drug-resistant and underwent surgery (86% seizure-free). Prior developmental delay was uncommon but intellectual, language and executive dysfunction were present in 24%, 48% and 29% when assessed preoperatively, low intellect being associated with greater epilepsy duration. BOSDs were missed on initial MRI in 68%, being ultimately recognized following repeat MRI, 18F-FDG-PET or image postprocessing. MRI features were grey-white junction blurring (100%), cortical thickening (91%), transmantle band (62%), increased cortical T1 signal (46%) and increased subcortical FLAIR signal (26%). BOSD hypometabolism was present on 18F-FDG-PET in 99%. Additional areas of cortical malformation or grey matter heterotopia were present in eight patients. BOSDs predominated in frontal and pericentral cortex and related functional networks, mostly sparing temporal and occipital cortex, and limbic and visual networks. Genetic testing yielded pathogenic mTOR pathway variants in 63% patients, including somatic MTOR variants in 47% operated patients and germline DEPDC5 or NPRL3 variants in 73% patients with familial focal epilepsy. BOSDs tended to occur in regions where the healthy brain normally shows lower MTOR expression, suggesting these regions may be more vulnerable to upregulation of MTOR activity. Consistent with the existing literature, these results highlight (i) clinical features raising suspicion of BOSD; (ii) the role of somatic and germline mTOR pathway variants in patients with sporadic and familial focal epilepsy associated with BOSD; and (iii) the role of 18F-FDG-PET alongside high-field MRI in detecting subtle BOSD. The anatomical and functional distribution of BOSDs likely explain their seizure, EEG and cognitive manifestations and may relate to relative MTOR expression.

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial.

BACKGROUND: Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. METHODS: In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0-2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. FINDINGS: Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6-13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7-46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. INTERPRETATION: Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations. FUNDING: Janssen Research & Development.

Age-related differences of vastus lateralis muscle morphology, contractile properties, upper body grip strength and lower extremity functional capability in healthy adults aged 18 to 70 years.

BACKGROUND: There is a lack of of cross-sectional research that has investigated muscle morphology, function, and functional capability in all age-bands of healthy adults. The primary aim of this study was to evaluate age-related differences in indices of vastus lateralis (VL) muscle morphology, function and functional capability in a sample of healthy males and females aged 18-70yrs. Secondary aims were to evaluate relationships between age and VL muscle morphology and function and functional capability. METHODS: B mode Ultrasonography and Tensiomyography were used to measure VL muscle thickness, pennation angle, fascicle length, and contractile properties in 274 healthy adults aged 18-70yrs. Measurements of grip strength and functional capability (1-min chair rise test) were also taken. Data analysis included descriptive statistics, correlations, one-way ANOVAs, and multiple regressions. RESULTS: Negative correlations were found between age and muscle thickness (rs = -.56), pennation angle (rs = -.50), fascicle length (rs = -.30), maximal displacement (rs = -.24), grip strength (rs = -.27) and the 1-min chair rise test (rs = -.32). Positive correlations were observed between age and the echo intensity of the muscle (rs = .40) and total contraction time (rs = .20). Differences in the indices of muscle health were noticeable between the 18-29 age band and the 50-59 and 60-70 age bands (p < 0.05). The interaction of age and level of physical activity predicted changes in the variables (r2 = .04-.32). CONCLUSION: Age-related differences in muscle health are noticeable at 50 years of age, and age-related differences are larger in females compared to males. It was suggested that the thickness of the VL changed the most with age across the adult lifespan and that physical activity likely acts to abate detrimental change.

Lean Mass, Muscle Strength, and Muscle Quality in Retired Rugby Players: The UK Rugby Health Project.

Although athletes from sports such as rugby have greater lean mass and strength during their playing careers, little is known about these characteristics post-retirement. Therefore, this study investigated lean mass, strength, and muscle quality in retired elite and amateur rugby players and non-contact athletes. Retired elite male rugby players (n=42, 43.9±10.3 y; 101.1±13.4 kg; 1.82±0.09 m), amateur rugby players (n=46, 48.0±10.5 y; 98.9±16.6 kg; 1.79±0.07 m) and non-contact athletes (n=30, 51.3±12.5 y; 91.3±13.4 kg; 1.79±0.07 m) received one total body dual-energy X-ray absorptiometry assessment of appendicular lean mass (ALM) and ALM index (ALMI). Grip strength was measured, and muscle quality (grip strength/unit of arm lean mass) was calculated. Sarcopenia was identified as ALMI<7.23 kg/m2 and handgrip strength<37.2 kg. Total lean mass, ALM and grip strength were greater in the elite rugby compared to amateur rugby and non-contact groups (p<0.01). There were no significant differences in muscle quality or sarcopenia prevalence. Retired elite rugby players had greater lean mass and grip strength than amateur rugby and non-contact athletes, although muscle quality was similar. The greater lean mass and strength might reflect genetic influences or previous participation in a highly physical sport.

Management of Patients with Metastatic Castration-Sensitive Prostate Cancer in the Real-World Setting in the United States.

PURPOSE: This study provides a contemporary assessment of the treatment patterns, health care resource utilization (HRU) and costs among metastatic castration-sensitive prostate cancer (mCSPC) patients in the U.S. MATERIALS AND METHODS: Adults with mCSPC were selected from Optum's de-identified Clinformatics® Data Mart Database (Commercial insurance/Medicare Advantage [COM/MA]; January 1, 2014-July 31, 2019) or Medicare Fee-for-Service (FFS; January 1, 2014-December 31, 2017). The index date was the first metastatic disease diagnosis date on/after the first prostate cancer diagnosis (without prior evidence of castration resistance). Patients were observed for 12 months pre-index (baseline) through their mCSPC period (from index until castration resistance or followup end). First-line (1L) mCSPC therapy was assessed during the mCSPC period; all-cause HRU and health plan-paid costs per-patient-per-year (PPPY) were measured during baseline and mCSPC periods. RESULTS: Among 6,517 COM/MA and 13,324 Medicare-FFS mCSPC patients over ∼10 months (median mCSPC period), 38% and 48% remained untreated/deferred treatment, and 45% and 46% received 1L androgen deprivation therapy (ADT) monotherapy, respectively. 1L abiraterone acetate and docetaxel were used among 7% and 6% of COM/MA and 1% and 2% of Medicare-FFS patients, respectively. HRU increased from baseline to mCSPC period, resulting in increased health plan-paid costs from $21,201 to $108,767 in COM/MA and from $16,819 to $69,639 PPPY in Medicare-FFS. CONCLUSIONS: This study highlights the limited use of newer therapies that improve survival in men with mCSPC in the U.S. HRU and costs increased substantially after onset of metastasis. Given the emergence of newer effective mCSPC therapies, further evaluation of future real-world mCSPC treatment patterns and outcomes is warranted.

Vertebral Anomalies in Retired Rugby Players and the Impact on Bone Density Calculation of the Lumbar Spine.

Dual energy X-ray absorptiometry (DXA) lumbar spine bone mineral density (BMD) measurements are subject to artificial elevation in the presence of structural abnormalities that are more common with age and injury, including osteoarthritis, fracture and osteophytes. The aims of this study were to investigate the presence of vertebral abnormalities on DXA scans in retired rugby players and a nonrugby control group, and to explore the effect of vertebral exclusion on the BMD diagnostic outcome. Eigty-seven male retired rugby players and 51 non-rugby controls from the UK Rugby Health Project participated in the study. Lumbar spine, total hip and femoral neck BMD were measured by DXA and scans were analyzed pre and post exclusion of anomalous vertebrae. Data were analyzed by age group to enable application of T-scores (≥50 y) and Z-scores (<50 y). From 138 lumbar spine scans, 66 required adjustment. One hundred twenty-two vertebral exclusions were made, and 12 lumbar spine scans (10 in retired rugby athletes) were un-reportable (<2 evaluable vertebrae). Vertebral exclusion significantly lowered lumbar spine BMD across all groups (p<0.01) and lowered the overall lowest T/Z-score. This effect was more pronounced in rugby groups (age <50 y, p < 0.001; age ≥50 y, p = 0.031) than in the control groups (age <50y, p = 0.125; age ≥50 y, p = 0.250). Vertebral abnormalities detected on lumbar spine scans, were highly prevalent and impacted final the T/Z-score in this cohort of retired rugby players. Current guidelines recommend exclusion of abnormalities from lumbar spine scans in adults aged ≥50 years. Our findings suggest that vertebral exclusions should also be applied to lumbar spine scans performed in those aged <50 years, particularly in former contact sports athletes, given their high risk for vertebral deformity.

Pain and Function in the Runner a Ten (din) uous Link.

A male runner (30 years old; 10-km time: 33 min, 46 sec) had been running with suspected insertional Achilles tendinopathy (AT) for ~2 years when the pain reached a threshold that prevented running. Diagnostic ultrasound (US), prior to a high-volume stripping injection, confirmed right-sided medial insertional AT. The athlete failed to respond to injection therapy and ceased running for a period of 5 weeks. At the beginning of this period, the runner completed the Victoria institute of sports assessment-Achilles questionnaire (VISA-A), the foot and ankle disability index (FADI), and FADI sport prior to undergoing an assessment of bi-lateral gastrocnemius medialis (GM) muscle architecture (muscle thickness (MT) and pennation angle (PA); US), muscle contractile properties (maximal muscle displacement (Dm) and contraction time (Tc); Tensiomyography (TMG)) and calf endurance (40 raises/min). VISA-A and FADI scores were 59%/100% and 102/136 respectively. Compared to the left leg, the right GM had a lower MT (1.60 cm vs. 1.74 cm), a similar PA (22.0° vs. 21.0°), a lower Dm (1.2 mm vs. 2.0 mm) and Tc (16.5 ms vs. 17.7 ms). Calf endurance was higher in the right leg compared to the left (48 vs. 43 raises). The athlete began a metronome-guided (15 BPM), 12-week progressive eccentric training protocol using a weighted vest (1.5 kg increments per week), while receiving six sessions of shockwave therapy concurrently (within 5 weeks). On returning to running, the athlete kept daily pain (Numeric Rating Scale; NRS) and running scores (miles*rate of perceived exertion (RPE)). Foot and ankle function improved according to scores recorded on the VISA-A (59% vs. 97%) and FADI (102 vs. 127/136). Improvements in MT (1.60 cm vs. 1.76 cm) and PA (22.0° vs. 24.8°) were recorded via US. Improvements in Dm (1.15 mm vs. 1.69 mm) and Tc (16.5 ms vs. 15.4 ms) were recorded via TMG. Calf endurance was lower in both legs and the asymmetry between legs remained (L: 31, R: 34). Pain intensity (mean weekly NRS scores) decreased between week 1 and week 12 (6.6 vs. 2.9), while running scores increased (20 vs. 38) during the same period. The program was maintained up to week 16 at which point mean weekly NRS was 2.2 and running score was 47.

Are changes in running economy associated with changes in performance in runners? A systematic review and meta-analysis.

Improvements in running economy (RE) are thought to lead to improvements in running performance (P). Multiple interventions have been designed with the aim of improving RE in middle and long-distance runners. The aim of this study was to assess the effect of interventions of at least 2-weeks' duration on RE and P and to determine whether there is a relationship between changes in RE (ΔRE) and changes in running performance (ΔP). A database search was carried out in Web of Science, Scopus and SPORTDiscus. In accordance with a PRISMA checklist 10 studies reporting 12 comparisons between interventions and controls were included in the review. There was no correlation between percentage ΔRE and percentage ΔP (r = 0.46, P = 0.936, 12 comparisons). There was a low risk of reporting bias but an unclear risk of bias for other items. Meta-analyses found no statistically significant differences between interventions and controls for RE (SMD (95% CI) = -0.37 (-1.43, 0.69), 204 participants, p = 0.49) or for P (SMD (95% CI) = -0.65 (-26.02, 24.72, 204 participants, p = 0.99). There is a need for studies of greater statistical power, methodological quality, duration and homogeneity of intervention and population. Standardised measures of performance and greater control over non-intervention training are also required.

The Proportion of Lower Limb Running Injuries by Gender, Anatomical Location and Specific Pathology: A Systematic Review.

Running is associated with a higher risk of overuse injury than other forms of aerobic exercise such as walking, swimming and cycling. An accurate description of the proportion of running injuries per anatomical location and where possible, per specific pathology, for both genders is required. The aim of this review was to determine the proportion of lower limb running injuries by anatomical location and by specific pathology in male and female runners (≥800m - ≤ marathon). The preferred reporting items for systematic reviews and meta-analyses guidelines were followed for this review. A literature search was performed with no restriction on publication year in Web of Science, Scopus, Sport-Discus, PubMed, and CINAHL up to July 2017. Retrospective, cross-sectional, prospective and randomised-controlled studies which surveyed injury data in runners were included. 36 studies were included to report the overall proportion of injury per anatomical location. The overall proportion of injury by specific pathology was reported from 11 studies. The knee (28%), ankle-foot (26%) and shank (16%) accounted for the highest proportion of injury in male and female runners, although the proportion of knee injury was greater in women (40% vs. 31%). Relative to women, men had a greater proportion of ankle-foot (26% vs. 19%) and shank (21% vs. 16%) injuries. Patellofemoral pain syndrome (PFPS; 17%), Achilles tendinopathy (AT; 10%) and medial tibial stress syndrome (MTS; 8%) accounted for the highest proportion of specific pathologies recorded overall. There was insufficient data to sub-divide specific pathology between genders. The predominate injury in female runners is to the knee. Male runners have a more even distribution of injury between the knee, shank and ankle-foot complex. There are several methodological issues, which limit the interpretation of epidemiological data in running injury.

The IMAAGEN Study: Effect of Abiraterone Acetate and Prednisone on Prostate Specific Antigen and Radiographic Disease Progression in Patients with Nonmetastatic Castration Resistant Prostate Cancer.

PURPOSE: We evaluated the use of abiraterone acetate (1,000 mg) plus prednisone (5 mg) in patients with high risk, nonmetastatic, castration resistant prostate cancer. MATERIALS AND METHODS: Patients considered at high risk for progression to metastatic disease (prostate specific antigen 10 ng/ml or greater, or prostate specific antigen doubling time 10 months or less) received abiraterone acetate plus prednisone daily in 28-day cycles. The primary study end point was the proportion of patients in whom a 50% or greater prostate specific antigen reduction was achieved during cycles 1 to 6. Secondary end points included time to prostate specific antigen progression, time to radiographic evidence of disease progression and safety. RESULTS: Of the 131 enrolled patients 44 (34%) remained on treatment with a median followup of 40.0 months. Median age was 72 years (range 48 to 90). Of the patients 82.4% were white and 14.5% were black. Median screening prostate specific antigen was 11.9 ng/dl and median prostate specific antigen doubling time was 3.4 months. Prostate specific antigen was significantly reduced (p <0.0001) with a 50% or greater prostate specific antigen reduction in 86.9% of cases and a 90% or greater reduction in 59.8%. Median time to prostate specific antigen progression was 28.7 months (95% CI 21.2-38.2). Median time to radiographic evidence of disease progression was not reached but on sensitivity analysis in 15 patients it was estimated to be 41.4 months (95% CI 27.6-not estimable). Baseline testosterone 12.5 ng/dl or greater and a 90% or greater prostate specific antigen reduction at cycle 3 were associated with longer time to prostate specific antigen progression and radiographic evidence of disease progression. Outcomes in black patients were similar to those in other patients. Adverse events, grade 3 or greater adverse events and serious adverse events were reported in 96.2%, 61.1% and 43.5% of patients, respectively. CONCLUSIONS: In patients with high risk, nonmetastatic, castration resistant prostate cancer treatment with abiraterone acetate plus prednisone demonstrated a significant 50% or greater prostate specific antigen reduction with encouraging results for the secondary end points, including the safety of 5 mg prednisone.

Measurement of muscle health in aging.

Muscle health is a critical component in the struggle against physical frailty and the efforts to maintain metabolic health until the limit of chronological age. Consensus opinion is to evaluate muscle health in terms of muscle mass, strength and functional capability. There has been considerable variability in the components of muscle health which have been investigated in addition to variability in the tools of assessment and protocol for measurement. This is in stark contrast to the validated measurement of bone health across the adult life span. The purpose of this review was to identify indices of muscle mass, strength and functional capability most responsive to change with ageing and where possible to provide an estimate of the rate of change. We suggest lean tissue mass (LTM) or skeletal muscle (SM) is best evaluated from the thigh region due to its greater responsiveness to ageing compared to the whole body. The anterior compartment of the thigh region undergoes a preferential age-related decline in SM and force generating capacity. Therefore, we suggest that knee extensor torque is measured to represent the force generating capacity of the thigh and subsequently, to express muscle quality (strength per unit tissue). Finally, we suggest measures of functional capability which allow participants perform to a greater maximum are most appropriate to track age-related difference in functional capacity across the adult lifespan. This is due to their ability encompass a broad spectrum of abilities. This review suggests indices of muscular health for which reference ranges can be generated across the lifespan.

Twelve weeks' progressive resistance training combined with protein supplementation beyond habitual intakes increases upper leg lean tissue mass, muscle strength and extended gait speed in healthy older women.

The age-related decline in functional capability is preceded by a reduction in muscle quality. The purpose of this study was to assess the combined effects of progressive resistance training (PRT) and protein supplementation beyond habitual intakes on upper leg lean tissue mass (LTM), muscle quality and functional capability in healthy 50-70 years women. In a single-blinded, randomized, controlled design, 57 healthy older women (age 61.1 ± 5.1 years, 1.61 ± 0.65 m, 65.3 ± 15.3 kg) consumed 0.33 g/kg body mass of a milk-based protein matrix (PRO) for 12 weeks. Of the 57 women, 29 also engaged in a PRT intervention (PRO + PRT). In comparison to the PRO group (n = 28), those in the PRO + PRT group had an increase in upper leg LTM [0.04 (95% CI -0.07 to 0.01) kg vs. 0.13 (95% CI 0.08-0.18) kg, P = 0.027], as measured by Dual-energy X-ray absorptiometry; an increase in knee extensor (KE) torque [-1.6 (95% CI -7.3 to 4.4 N m) vs. 10.2 (95% CI 4.3-15.8 N m), P = 0.007], as measured from a maximal voluntary isometric contraction (Con-Trex MJ; CMV AG); and an increase in extended gait speed [-0.01 (95% CI -0.52-0.04) m s-1 vs. 0.10 (95% CI 0.05-0.22) m s-1, P = 0.001] as measured from a maximal 900 m effort. There was no difference between groups in the time taken to complete 5 chair rises or the number of chair rises performed in 30 s (P > 0.05). PRT in healthy older women ingesting a dietary protein supplement is an effective strategy to improve upper leg LTM, KE torque and extended gait speed in healthy older women.

Protein Supplementation at Breakfast and Lunch for 24 Weeks beyond Habitual Intakes Increases Whole-Body Lean Tissue Mass in Healthy Older Adults.

BACKGROUND: Key areas of research on the preservation of lean tissue mass (LTM) during aging are determinations of the protein requirement and optimal protein intake at meals. OBJECTIVE: The aim of this study was to determine the effect of protein supplementation at breakfast and lunch for 24 wk beyond habitual intakes on whole-body LTM in healthy adults aged 50-70 y. METHODS: In a single-blinded, randomized, controlled design, 60 healthy older men and women (aged 61 ± 5 y) with a body mass index (in kg/m(2)) of 25.8 ± 3.6 consumed either 0.165 g/kg body mass of a milk-based protein matrix (PRO) or an isoenergetic, nonnitrogenous maltodextrin control (CON) at breakfast and midday meals, the lower protein-containing meals of the day, for 24 wk. Dual-energy X-ray absorptiometry was used to measure the change in LTM. RESULTS: After the intervention, protein intake in the PRO group increased from 0.23 ± 0.1 to 0.40 ± 0.1 g/kg for breakfast and from 0.31 ± 0.2 to 0.47 ± 2 g/kg for the midday meal. In response, LTM increased by 0.45 (95% CI: 0.06, 0.83) kg in the PRO group compared with a decrease of 0.16 (95% CI: -0.49, 0.17) kg in the CON group (P = 0.006). Appendicular LTM accounted for the majority of the difference in LTM, increasing by 0.27 (95% CI: 0.05, 0.48) kg in the PRO group compared with no change in the CON group (P = 0.002). CONCLUSIONS: Protein supplementation at breakfast and lunch for 24 wk in healthy older adults resulted in a positive (+0.6 kg) difference in LTM compared with an isoenergetic, nonnitrogenous maltodextrin control. These observations suggest that an optimized and balanced distribution of meal protein intakes could be beneficial in the preservation of lean tissue mass in the elderly. This trial was registered at clinicaltrials.gov as NCT02529124.

What's your lab's strategy?

Important strategic choices cascade throughout a laboratory. Senior management should create a document that answers each of the five key questions explained on page 60. Once this has been detailed in writing, it remains important to disseminate the basics to all employees so they are singing the same tune. A useful way to accomplish this is through a coherent strategy statement that specifies three components: 1) objectives; 2) scope; and 3) advantages. Commercial and hospital outreach labs should be in business to win. It all starts with a definition of what winning looks like. To "participate" in your market contributes to mediocrity-and it's self-defeating. With no clear strategic direction of where-to-play and how-to-win choices that associate with the aspiration, a mission or vision statement can be frustrating rather than inspiring for employees. Articulate it plainly and concisely for everybody. With a care-fully prepared and designed strategy, you will be on your way to winning in the zero-sum game!

A Comparison of Stride Length and Lower Extremity Kinematics during Barefoot and Shod Running in Well Trained Distance Runners.

Stride length, hip, knee and ankle angles were compared during barefoot and shod running on a treadmill at two speeds. Nine well-trained (1500m time: 3min:59.80s ± 14.7 s) male (22 ±3 years; 73 ±9 kg; 1.79 ±0.4 m) middle distance (800 m - 5,000 m) runners performed 2 minutes of running at 3.05 m·s-1 and 4.72 m·s-1 on an treadmill. This approach allowed continuous measurement of lower extremity kinematic data and calculation of stride length. Statistical analysis using a 2X2 factorial ANOVA revealed speed to have a main effect on stride length and hip angle and footwear to have a main effect on hip angle. There was a significant speed*footwear interaction for knee and ankle angles. Compared to shod running at the lower speed (3.05 m·s-1), well trained runners have greater hip, knee and ankle angles when running barefoot. Runners undertake a high volume (~75%) of training at lower intensities and therefore knowledge of how barefoot running alters running kinematics at low and high speeds may be useful to the runner.

Contribution of growth differentiation factor 6-dependent cell survival to early-onset retinal dystrophies.

Retinal dystrophies are predominantly caused by mutations affecting the visual phototransduction system and cilia, with few genes identified that function to maintain photoreceptor survival. We reasoned that growth factors involved with early embryonic retinal development would represent excellent candidates for such diseases. Here we show that mutations in the transforming growth factor-ß (TGF-ß) ligand Growth Differentiation Factor 6, which specifies the dorso-ventral retinal axis, contribute to Leber congenital amaurosis. Furthermore, deficiency of gdf6 results in photoreceptor degeneration, so demonstrating a connection between Gdf6 signaling and photoreceptor survival. In addition, in both murine and zebrafish mutant models, we observe retinal apoptosis, a characteristic feature of human retinal dystrophies. Treatment of gdf6-deficient zebrafish embryos with a novel aminopropyl carbazole, P7C3, rescued the retinal apoptosis without evidence of toxicity. These findings implicate for the first time perturbed TGF-ß signaling in the genesis of retinal dystrophies, support the study of related morphogenetic genes for comparable roles in retinal disease and may offer additional therapeutic opportunities for genetically heterogeneous disorders presently only treatable with gene therapy.

Obtaining medication histories via telepharmacy: an observational study.

BACKGROUND: Medication reconciliation is an effective strategy to reduce medication errors upon hospital admission. The process involves obtaining a best possible medication history (BPMH), which can be both time-consuming and resource-intensive. During the COVID-19 pandemic, telepharmacy was used to reduce the risk of viral transmission. Telepharmacy is the remote provision of pharmacy-led clinical services, such as obtaining BPMHs, using telecommunications. However, the accuracy of telephone-obtained BPMHs has not yet been evaluated. Therefore, the primary aim of this study was to evaluate the proportion of patients who have an accurate BPMH from the telephone-obtained BPMH compared to an in-person obtained BPMH. METHODS: This prospective, observational study took place in a large tertiary hospital. Recruited patients or carers had their BPMH obtained by a pharmacist over the telephone. The same patients or carers then had their BPMH conducted in-person to identify any deviations between the telephone-obtained and in-person obtained BPMH. All telephone-obtained BPMHs were timed with a stopwatch. Any deviations were categorised according to their potential consequence. An accurate BPMH was defined as having no deviations. Descriptive statistics were used to report all quantitative variables. A multivariable logistic regression was conducted to identify risk factors for patients and medications for having medication deviations. RESULTS: In total, 116 patients were recruited to receive both a telephone-obtained and in-person obtained BPMH. Of these, 91 patients (78%) had an accurate BPMH with no deviations. Of the 1104 medications documented across all the BPMHs, 1064 (96%) had no deviation. Of the 40 (4%) medication deviations, 38 were deemed low-risk (3%) and 2 high-risk (1%). A patient was more likely to have a deviation if they are taking more medications (aOR: 1.11; 95% CI: 1.01-1.22; p < 0.05). A medication was more likely to have a deviation if it was regular non-prescription medication (aOR: 4.82; 95% CI: 2.14-10.82; p < 0.001) or 'when required' non-prescription medication (aOR: 3.12; 95% CI: 1.20-8.11; p = 0.02) or a topical medication (aOR: 12.53; 95% CI: 4.34-42.17; p < 0.001). CONCLUSIONS: Telepharmacy represents a reliable and time-efficient alternative to in-person BPMHs.

Optimized Whole-Body PET MRI Sequence Workflow in Pediatric Hodgkin Lymphoma Patients.

18F-FDG PET/MRI might be the diagnostic method of choice for Hodgkin lymphoma patients, as it combines significant metabolic information from PET with excellent soft-tissue contrast from MRI and avoids radiation exposure from CT. However, a major issue is longer examination times than for PET/CT, especially for younger children needing anesthesia. Thus, a targeted selection of suitable whole-body MRI sequences is important to optimize the PET/MRI workflow. Methods: The initial PET/MRI scans of 84 EuroNet-PHL-C2 study patients from 13 international PET centers were evaluated. In each available MRI sequence, 5 PET-positive lymph nodes were assessed. If extranodal involvement occurred, 2 splenic lesions, 2 skeletal lesions, and 2 lung lesions were also assessed. A detection rate was calculated dividing the number of visible, anatomically assignable, and measurable lesions in the respective MRI sequence by the total number of lesions. Results: Relaxation time-weighted (T2w) transverse sequences with fat saturation (fs) yielded the best result, with detection rates of 95% for nodal lesions, 62% for splenic lesions, 94% for skeletal lesions, and 83% for lung lesions, followed by T2w transverse sequences without fs (86%, 49%, 16%, and 59%, respectively) and longitudinal relaxation time-weighted contrast-enhanced transverse sequences with fs (74%, 35%, 57%, and 55%, respectively). Conclusion: T2w transverse sequences with fs yielded the highest detection rates and are well suited for accurate whole-body PET/MRI in lymphoma patients. There is no evidence to recommend the use of contrast agents.

Health-related quality of life in GALAHAD: A multicenter, open-label, phase 2 study of niraparib for patients with metastatic castration-resistant prostate cancer and DNA-repair gene defects.

BACKGROUND: Niraparib is a highly selective poly (adenosine diphosphateribose) polymerase-1 and poly (adenosine diphosphate-ribose) polymerase-2 inhibitor indicated for select patients with ovarian, fallopian tube, and primary peritoneal cancer. The phase 2 GALAHAD trial (NCT02854436) demonstrated that niraparib monotherapy is tolerable and efficacious in patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations, particularly those with breast cancer gene (BRCA) alterations who had progressed on prior androgen signaling inhibitor therapy and taxane-based chemotherapy. OBJECTIVE: To report the prespecified patient-reported outcomes analysis from GALAHAD. METHODS: Eligible patients with alterations to BRCA1 and/or BRCA2 (BRCA cohort) and with pathogenic alterations in other HRR genes (other HRR cohort) were enrolled and received niraparib 300 mg once daily. Patient-reported outcome instruments included the Functional Assessment of Cancer Therapy-Prostate and the Brief Pain Inventory-Short Form. Changes from baseline were compared using a mixed-effect model for repeated measures. RESULTS: On average, health-related quality of life (HRQoL) improved in the BRCA cohort by cycle 3 (mean change = 6.03; 95% CI = 2.76-9.29) and was maintained above baseline until cycle 10 (mean change = 2.84; 95% CI = -1.95 to 7.63), whereas the other HRR cohort showed no early change in HRQoL from baseline (mean change = -0.07; 95% CI = -4.69 to 4.55) and declined by cycle 10 (mean change = -5.10; 95% CI = -15.3 to 5.06). Median time to deterioration in pain intensity and pain interference could not be estimated in either cohort. CONCLUSIONS: Patients with advanced mCRPC and BRCA alterations treated with niraparib experienced more meaningful improvement in overall HRQoL, pain intensity, and pain interference compared with those with other HRR alterations. In this population of castrate, heavily pretreated patients with mCRPC and HRR alterations, stabilization, and improvement in HRQoL may be relevant to consider when making treatment decisions. DISCLOSURES: This work was supported by Janssen Research & Development, LLC (no grant number). Dr Smith has received grants and personal fees from Bayer, Amgen, Janssen, and Lilly; and has received personal fees from Astellas Pharma, Novartis, and Pfizer. Dr Sandhu has received grants from Amgen, Endocyte, and Genentech; has received grants and personal fees from AstraZeneca and Merck; and has received personal fees from Bristol Myers Squibb and Merck Serono. Dr George has received personal fees from the American Association for Cancer Research, Axess Oncology, Capio Biosciences, Constellation Pharma, EMD Serono, Flatiron, Ipsen, Merck Sharp & Dohme, Michael J. Hennessey Association, Millennium Medical Publishing, Modra Pharma, Myovant Sciences, Inc., NCI Genitourinary, Nektar Therapeutics, Physician Education Resource, Propella TX, RevHealth, LLC, and UroGPO; has received grants and personal fees from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, and Pfizer; has received personal fees and nonfinancial support from Bayer and UroToday; has received grants from Calithera and Novartis; and has received grants, personal fees, and nonfinancial support from Exelixis, Inc., Sanofi, and Janssen Pharma. Dr Chi has received grants from Janssen during the conduct of the study; has received grants and personal fees from AstraZeneca, Bayer, Astellas Pharma, Novartis, Pfizer, POINT Biopharma, Roche, and Sanofi; and has received personal fees from Daiichi Sankyo, Merck, and Bristol Myers Squibb. Dr Saad has received grants, personal fees, and nonfinancial support from Janssen during the conduct of the study; and has received grants, personal fees, and nonfinancial support from AstraZeneca, Astellas Pharma, Pfizer, Bayer, Myovant, Sanofi, and Novartis. Dr Thiery-Vuillemin has received grants, personal fees, and nonfinancial support from Pfizer; has received personal fees and nonfinancial support from AstraZeneca, Janssen, Ipsen, Roche/Genentech, Merck Sharp & Dohme, and Astellas Pharma; and has received personal fees from Sanofi, Novartis, and Bristol Myers Squibb. Dr Olmos has received grants, personal fees, and nonfinancial support from AstraZeneca, Bayer, Janssen, and Pfizer; has received personal fees from Clovis, Daiichi Sankyo, and Merck Sharp & Dohme; and has received nonfinancial support from Astellas Pharma, F. Hoffman-LaRoche, Genentech, and Ipsen. Dr Danila has received research support from the US Department of Defense, the American Society of Clinical Oncology, the Prostate Cancer Foundation, Stand Up to Cancer, Janssen Research & Development, Astellas Pharma, Medivation, Agensys, Genentech, and CreaTV. Dr Gafanov has received grants from Janssen during the conduct of the study. Dr Castro has received grants from Janssen during the conduct of the study; has received grants and personal fees from Janssen, Bayer, AstraZeneca, and Pfizer; and has received personal fees from Astellas Pharma, Merck Sharp & Dohme, Roche, and Clovis. Dr Moon has received research funding from SeaGen, HuyaBio, Janssen, BMS, Aveo, Xencor, and has received personal fees from Axess Oncology, MJH, EMD Serono, and Pfizer. Dr Joshua has received nonfinancial support from Janssen; consulted or served in an advisory role for Neoleukin, Janssen Oncology, Ipsen, AstraZeneca, Sanofi, Noxopharm, IQvia, Pfizer, Novartis, Bristol Myers Squibb, Merck Serono, and Eisai; and received research funding from Bristol Myers Squibb, Janssen Oncology, Merck Sharp & Dohme, Mayne Pharma, Roche/Genentech, Bayer, MacroGenics, Lilly, Pfizer, AstraZeneca, and Corvus Pharmaceuticals. Drs Mason, Liu, Bevans, Lopez-Gitlitz, and Francis and Mr Espina are employees of Janssen Research & Development. Dr Mason owns stocks with Janssen. Dr Fizazi has participated in advisory boards and talks for Amgen, Astellas, AstraZeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis/AAA, Pfizer, and Sanofi, with honoraria to his institution (Institut Gustave Roussy); has participated in advisory boards for, with personal honoraria from, Arvinas, CureVac, MacroGenics, and Orion. Study registration number: NCT02854436.