Updates in the pathogenesis and management of immune-related enterocolitis, hepatitis and cardiovascular toxicities.

Immune checkpoint inhibitors (ICIs) have become a cornerstone of treatment for many solid organ malignancies. Alongside increasing use, the occurrence of immune-related adverse events (irAEs) has also increased and remains a significant challenge when treating patients with ICI. The underlying pathophysiology of irAE development for many organ systems is yet to be elucidated, but may involve unmasking of latent autoimmunity, increased T-cell recognition of shared antigens on cancer and normal tissue and ICI-triggered immune dysregulation with overactivation of proinflammatory pathways and suppression of immune control pathways. Management strategies for irAEs have historically been borrowed from paradigms for conventional autoimmune conditions such as inflammatory bowel disease and autoimmune hepatitis; however, recent translational efforts have clearly demonstrated key differences in underlying immune signalling pathways. As we begin to understand these differences, we must adapt a more targeted approach to immunosuppression and exercise a more nuanced approach with the multiple biologic agents available to mitigate ICI-related toxicity without reversing the antitumour effect of ICI. In this review, we focus on three key immune-related toxicities where recent clinical and translational work has provided nuanced insights into pathogenesis and treatment strategies: enterocolitis, hepatitis and cardiovascular toxicity including myocarditis.

Strategies for developing retinoic acid receptor alpha-selective antagonists as novel agents for male contraception.

Reported here are the synthesis and in vitro evaluation of a series of 26 retinoic acid analogs based on dihydronaphthalene and chromene scaffolds using a transactivation assay. Chromene amide analog 21 was the most potent and selective retinoic acid receptor α antagonist identified from this series. In vitro evaluation indicated that 21 has favorable physicochemical properties and a favorable pharmacokinetic PK profile in vivo with significant oral bioavailability, metabolic stability, and testes exposure. Compound 21 was evaluated for its effects on spermatogenesis and disruption of fertility in a mouse model. Oral administration of compound 21 at low doses showed reproducibly characteristic albeit modest effects on spermatogenesis, but no effects on fertility were observed in mating studies. The inhibition of spermatogenesis could not be enhanced by raising the dose and lengthening the duration of dosing. Thus, 21 may not be a good candidate to pursue further for effects on male fertility.

Evaluating Documentation of Prescribing Training Experiences in Pharmacy Residency Programs.

BACKGROUND: Clinical pharmacist specialists are ideal candidates to reduce healthcare costs and manage chronic disease states. However, it is unknown whether residency programs document prescribing training. PURPOSE: The aim of the study was to evaluate whether programs document prescriptive authority training in pharmacy residency programs. METHODS: To evaluate whether California residency programs document prescribing training, we conducted a systematic review utilizing the key search terms to examine residency information resources: American Society of Health-System Pharmacists (ASHP) residency program information and PubMed query. Primary outcome for documentation of prescriptive authority training was based on a defined search criterion. RESULTS: Out of 128 residency programs, 110 met criteria for evaluation. A total of 47 residency programs (13 institutions) met criteria for prescribing training. Most programs did not define which specialty clinics offered prescribing training. DISCUSSION: Based on search criterion, less than 50% met criteria for documentation of prescribing training in residency programs. With that said, there are limitations given a strict search criterion, so additional research is needed to further investigate whether prescribing trainings are offered. Given the limited amount of residency programs documenting prescribing training, it is essential to define standards and expand documentation of prescribing training.

Distinct Forms of Spinal Cysticercosis: A Vietnamese Case Series.

INTRODUCTION: Neurocysticercosis (NCC), a major contributor to the burden of seizure disorders and epilepsy in the world, is one of the most common parasitic infections of the central nervous system, which is usually located in the brain. Medical therapy for NCC should initially cover appropriate symptom control and then the use of antiparasitic agents should be considered. Antiparasitic treatment is of benefit in most cases of viable and degenerating NCC. Nevertheless, cysticercosis of the spinal cord is very uncommon. CASE SERIES: In this article, we recorded 5 cases of extramedullary-intradural lumbar spinal cysticercosis, in which one case displayed cystic lesions in both brain and spine, one case showed an independent cystic lesion in the spine, and three remaining cases showed diffuse lesions in the spinal canal. CONCLUSION: Thus, in any case of single or numerous cystic lesions or dispersed lesions entering the spinal canal, spinal cysticercosis should be considered.

Diversity-Oriented Library Synthesis from Steviol and Isosteviol-Derived Scaffolds.

The readily available natural product stevioside provides a unique diterpene core structure that can be explored for small molecule library development by diversity-oriented synthesis and functional group transformations. Validation arrays were prepared from steviol, isosteviol, and related analogues, derived from stevioside, to produce over 90 compounds. These compounds were submitted to the NIH Molecular Libraries Small Molecule Repository for screening in the Molecular Libraries Screening Center Network. Micromolar hits were identified in multiple high-throughput assays for several library members. A cheminformatics analysis of the compounds was performed that verified the expected diversity and complexity of this set of compounds. The screening results indicate that scaffolds-derived natural products can provide screening hits against multiple target proteins.

Online Learning of Gait Models From Older Adult Data.

This paper proposes a novel approach for online, individualized gait analysis, based on an adaptive periodic model of any gait signal. The proposed method learns a model of the gait cycle during online measurement, using a continuous representation that can adapt to inter- and intra-personal variability by creating an individualized model. Once the algorithm has converged to the input signal, key gait events can be identified based on the estimated gait phase and amplitude. The approach is implemented and tested on retirement home resident 6 min walk (6MW) data using wearable accelerometers at the ankle. The proposed approach converges within approximately four gait cycles and achieves 3% error in detecting initial swing events.11 An early version of this work was presented in [1]. A more extensive description of related work and an extended method, including optimization of learning rates, were added to this paper. Further, this paper applies and evaluates the method to a new and much larger gait dataset taken from older adults who each have a variety of medical conditions. Therefore, the experimental protocol was also updated and the results are entirely novel.

Cooling reverses pathological bifurcations to spontaneous firing caused by mild traumatic injury.

Mild traumatic injury can modify the key sodium (Na+) current underlying the excitability of neurons. It causes the activation and inactivation properties of this current to become shifted to more negative trans-membrane voltages. This so-called coupled left shift (CLS) leads to a chronic influx of Na+ into the cell that eventually causes spontaneous or "ectopic" firing along the axon, even in the absence of stimuli. The bifurcations underlying this enhanced excitability have been worked out in full ionic models of this effect. Here, we present computational evidence that increased temperature T can exacerbate this pathological state. Conversely, and perhaps of clinical relevance, mild cooling is shown to move the naturally quiescent cell further away from the threshold of ectopic behavior. The origin of this stabilization-by-cooling effect is analyzed by knocking in and knocking out, one at a time, various processes thought to be T-dependent. The T-dependence of the Na+ current, quantified by its Q 10-Na factor, has the biggest impact on the threshold, followed by Q 10-pump of the sodium-potassium exchanger. Below the ectopic boundary, the steady state for the gating variables and the resting potential are not modified by temperature, since our model separately tallies the Na+ and K+ ions including their separate leaks through the pump. When only the gating kinetics are considered, cooling is detrimental, but in the full T-dependent model, it is beneficial because the other processes dominate. Cooling decreases the pump's activity, and since the pump hyperpolarizes, less hyperpolarization should lead to more excitability and ectopic behavior. But actually the opposite happens in the full model because decreased pump activity leads to smaller gradients of Na+ and K+, which in turn decreases the driving force of the Na+ current.

Trabecular bone score in adults with cerebral palsy.

CONTEXT: Bone fragility in cerebral palsy (CP) is secondary to a complex interplay of functional, hormonal, and nutritional factors that affect bone remodelling. A greater understanding of bone microarchitectural changes seen in CP should assist therapeutic decision making. OBJECTIVE: To examine the relationship between trabecular bone score (TBS), BMD and fractures in adults with CP; the influence of clinical factors and body composition on bone microarchitecture were explored. DESIGN: Retrospective cross-sectional study. SETTING AND PARTICIPANTS: 43 adults (25 male) with CP of median age 25 years (interquartile range 21.4-33.9) who had evaluable dual-energy X-ray absorptiometry imaging of the lumbar spine from a single tertiary hospital between 2005-March 2018. RESULTS: 24/43 (55.8%) of patients had TBS values indicating intermediate or high risk of fracture (<1.31). TBS correlated with areal BMD at the lumbar spine, femoral neck and total body. TBS was significantly associated with arm and leg lean mass, with adjustment for age, gender and height (adjusted R2 = 0.18, p = 0.042 for arm lean mass; adjusted R2 = 0.19, p = 0.036 for leg lean mass). There was no difference in TBS when patients were grouped by fracture status, anticonvulsant use, gonadal status or use of PEG feeding. TBS was lower in non-ambulatory patients compared with ambulatory patients (1.28 vs 1.37, p = 0.019). CONCLUSIONS: Abnormal bone microarchitecture, as measured by TBS, was seen in >50% of young adults with CP. TBS correlated with both areal BMD and appendicular lean mass. Maintaining muscle function is likely to be important for bone health in young adults with CP and needs to be confirmed in further studies.

Neoadjuvant chemotherapy affects molecular classification of colorectal tumors.

The recent discovery of 'molecular subtypes' in human primary colorectal cancer has revealed correlations between subtype, propensity to metastasize and response to therapy. It is currently not known whether the molecular tumor subtype is maintained after distant spread. If this is the case, molecular subtyping of the primary tumor could guide subtype-targeted therapy of metastatic disease. In this study, we classified paired samples of primary colorectal carcinomas and their corresponding liver metastases (n=129) as epithelial-like or mesenchymal-like, using a recently developed immunohistochemistry-based classification tool. We observed considerable discordance (45%) in the classification of primary tumors and their liver metastases. Discordant classification was significantly associated with the use of neoadjuvant chemotherapy. Furthermore, gene expression analysis of chemotherapy-exposed versus chemotherapy naive liver metastases revealed expression of a mesenchymal program in pre-treated tumors. To explore whether chemotherapy could cause gene expression changes influencing molecular subtyping, we exposed patient-derived colonospheres to six short cycles of 5-fluorouracil. Gene expression profiling and signature enrichment analysis subsequently revealed that the expression of signatures identifying mesenchymal-like tumors was strongly increased in chemotherapy-exposed tumor cultures. Unsupervised clustering of large cohorts of human colon tumors with the chemotherapy-induced gene expression program identified a poor prognosis mesenchymal-like subgroup. We conclude that neoadjuvant chemotherapy induces a mesenchymal phenotype in residual tumor cells and that this may influence the molecular classification of colorectal tumors.

Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide.

BACKGROUND: Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients. PATIENTS AND METHODS: Blood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (≥6 months' exposure) were evaluated at baseline and disease progression in trial ARN-509-001. Mutations were detected in circulating tumor DNA using a digital polymerase chain reaction-based method known as BEAMing (beads, emulsification, amplification and magnetics) (Sysmex Inostics' GmbH). RESULTS: Of the 97 total patients, 51 had nmCRPC, 25 had AAP-naïve mCRPC, and 21 had post-AAP mCRPC. Ninety-three were assessable for the mutation analysis at baseline and 82 of the 93 at progression. The overall frequency of detected AR mutations at baseline was 7/93 (7.5%) and at progression was 6/82 (7.3%). Three of the 82 (3.7%) mCRPC patients (2 AAP-naïve and 1 post-AAP) acquired AR F877L during apalutamide treatment. At baseline, 3 of the 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in 1 patient who continued apalutamide treatment for 12 months. CONCLUSIONS: The overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide. CLINICALTRIALS.GOV IDENTIFIER: NCT01171898.

Fractures in spina bifida from childhood to young adulthood.

This study assessed the prevalence and types of fractures in spina bifida and examined risk factors for fracture. Fracture prevalence was highest in childhood and reduced in adolescence and young adulthood. The importance of maintaining mobility is highlighted by the increased risk of fracture in those who are non-ambulatory. INTRODUCTION: The aims of this study are to study the prevalence and types of fractures according to age group in spina bifida and examine risk factors associated with fracture. METHODS: This is a retrospective cohort study of 146 individuals with spina bifida aged 2 years or older who attended the paediatric or adult spina bifida multidisciplinary clinic at a single tertiary hospital. RESULTS: Median age at which first fracture occurred was 7 years (interquartile range 4-13 years). Fracture rates in children (ages 2-10), adolescents (ages 11-18) and adults (age > 18) were 10.9/1000 (95 % confidence interval 5.9-18.3), 5.4/1000 (95 % CI 1.5-13.8) and 2.9/1000 (95 % CI 0.6-8.1) patient years respectively. Childhood fractures predominantly involved the distal femur and femoral shaft; these fractures were rarely seen in adulthood. Non-ambulatory status was associated with a 9.8 times higher risk of fracture compared with ambulatory patients (odds ratio 9.8, p = 0.016, 95 % CI 1.5-63.0). Relative risk of re-fracture was 3.1 (95 % CI 1.4-6.8). Urological intervention with intestinal segments was associated with renal calculi (p = 0.037) but neither was associated with fracture. CONCLUSIONS: The risk of fracture is lower in adults compared with children with spina bifida. The predominant childhood fracture affects the distal femur, and immobility is the most significant risk factor for fracture. Clinical factors contributing to fracture risk need to be elucidated to enable selection of patients who require investigation and treatment of osteoporosis.

Impact of providing patients with copies of their medical correspondence: a randomised controlled study.

BACKGROUND: In Australia, correspondence is routinely sent to general practitioners following a specialist consultation. Written communication is an important way to enhance patient experiences and understanding, yet most patients do not receive copies of their medical correspondence. AIMS: To determine whether providing clinic correspondence and endoscopy reports to patients leads to improved understanding, satisfaction or anxiety. METHODS: This is a prospective, randomised controlled study conducted at an Australian tertiary hospital from October 2013 to February 2015. New adult referrals to the general gastroenterology clinic requiring an urgent endoscopic procedure were eligible for the study. The intervention group received a copy of their clinic correspondence and endoscopy report, while the control group received neither. Participants completed questionnaires, including visual analogue scales and the Hospital Anxiety and Depression Scale, at three time points. Primary outcomes were patient understanding, anxiety and satisfaction. RESULTS: A total of 70 participants was included in the study. There was no reduction in anxiety levels (P = 0.52), no increase in understanding (P = 0.73) or any increase in satisfaction (P = 0.33) in participants receiving correspondence. However, 97% of participants indicated that they wished to receive correspondence in the future, and 94% of participants in the correspondence group reported that receiving correspondence had helped them to understand their medical condition. CONCLUSION: Patients wish to receive copies of their correspondence and feel it improves their understanding of their medical condition. Although we were unable to demonstrate a measurable reduction in anxiety, increase in understanding or satisfaction, we recommend that patients be offered the choice of receiving copies of their clinic correspondence and endoscopy reports.

PLANET TOPERS: Planets, Tracing the Transfer, Origin, Preservation, and Evolution of their ReservoirS.

The Interuniversity Attraction Pole (IAP) 'PLANET TOPERS' (Planets: Tracing the Transfer, Origin, Preservation, and Evolution of their Reservoirs) addresses the fundamental understanding of the thermal and compositional evolution of the different reservoirs of planetary bodies (core, mantle, crust, atmosphere, hydrosphere, cryosphere, and space) considering interactions and feedback mechanisms. Here we present the first results after 2 years of project work.

Musculoskeletal and Endocrine Health in Adults With Cerebral Palsy: New Opportunities for Intervention.

CONTEXT: Cerebral palsy (CP) increases fracture risk through diminished ambulation, nutritional deficiencies, and anticonvulsant medication use. Studies examining bone mineral density (BMD) in adults with CP are limited. OBJECTIVE: To examine the relationship between body composition, BMD, and fractures in adults with CP. The effect of functional, nutritional, and endocrine factors on BMD and body composition is also explored. DESIGN: Retrospective cross-sectional study. SETTING AND PARTICIPANTS: Forty-five adults with CP (mean age, 28.3 ± 11.0 years) who had dual-energy x-ray absorptiometry imaging at a single tertiary hospital between 2005 and 2015. RESULTS: Seventeen (38%) had a past history of fragility fracture; 43% had a Z-score of ≤ -2.0 at the lumbar spine (LS) and 41% at the femoral neck (FN). In nonambulatory patients, every one unit decrease in FN Z-score increased the risk of fracture 3.2-fold (95% confidence interval, 1.07-9.70; P = .044). Stepwise linear regression revealed that the Gross Motor Function Classification System was the best predictor of LS Z-score (R(2) = 0.550; ß = -0.582; P = .002) and FN Z-score (R(2) = 0.428; ß = -0.494; P = .004); 35.7% of the variance in BMD was accounted for by lean tissue mass. Hypogonadism, present in 20% of patients, was associated with reduced lean tissue mass and reduced LS BMD. Lean tissue mass positively correlated with BMD in eugonadal patients, but not in hypogonadal patients. CONCLUSIONS: Low BMD and fractures are common in adults with CP. This is the first study to document hypogonadism in adults with CP with detrimental changes in body composition and BMD.

Effect of abiraterone acetate plus prednisone on the QT interval in patients with metastatic castration-resistant prostate cancer.

PURPOSE: Abiraterone is the active metabolite of the pro-drug abiraterone acetate (AA) and a selective inhibitor of CYP17, a key enzyme in testosterone synthesis, and improves overall survival in postdocetaxel metastatic castration-resistant prostate cancer (mCRPC). This open-label, single-arm phase 1b study was conducted to assess the effect of AA and abiraterone on the QT interval. METHODS: The study was conducted in 33 patients with mCRPC. Patients received AA 1,000 mg orally once daily + prednisone 5 mg orally twice daily. Electrocardiograms (ECGs) were collected in triplicate using 12-lead Holter monitoring. Baseline ECGs were obtained on Cycle 1 Day-1. Serial ECG recordings and time-matched pharmacokinetic (PK) blood samples were collected over 24 h on Cycle 1 Day 1 and Cycle 2 Day 1. Serial PK blood samples were also collected over 24 h on Cycle 1 Day 8. RESULTS: After AA administration, the upper bound of the 2-sided 90 % confidence interval (CI) for the mean baseline-adjusted QTcF change was <10 ms; no patients discontinued due to QTc prolongation or adverse events. No apparent relationship between change in QTcF and abiraterone plasma concentrations was observed [estimated slope (90 % CI): 0.0031 (-0.0040, 0.0102)]. CONCLUSIONS: There is no significant effect of AA plus prednisone on the QT/QTc interval in patients with mCRPC.

[Usefulness of diastolic deceleration time assessed by transthoracic Doppler measurement in the detection of sustained microvascular obstruction in STEMI patients treated by primary PTCA]. / Intérêt de la mesure du temps de décélération diastolique par Doppler transthoracique dans l'évaluation du phénomène de no-reflow au cours de l'infarctus du myocarde antérieur traité par angioplastie primaire.

AIMS: To assess the value of coronary flow measurement by transthoracic Doppler technique in the detection of "no-reflow" phenomenon. METHODS: Fourteen patients with first anterior wall infarction treated by successful (TIMI3) primary percutaneous angioplasty and left descending coronary artery stenting were investigated. Myocardial perfusion following PCI was assessed by (i) ST-segment resolution, (ii) MRI-detected microvascular obstruction (early hypoenhancement), (iii) coronary flow pattern measurement by transthoracic Doppler technique. RESULTS: Sustained impairment of myocardial perfusion following PCI was observed in a large proportion of the cohort (36% by MRI, 43% by ST regression analysis). Patients with a diastolic deceleration time inferior to 482 ms had higher troponin and CK peak value, higher wall motion index score, lower ST resolution and lower LVEF assessed by MRI. The concordance of the three methods was 80%. CONCLUSION: The measurement of diastolic deceleration time by transthoracic Doppler technique is a reliable technique to identify microvascular obstruction following PCI in acute anterior STEMI. A DDT inferior to 482 ms is associated with sustained "no-reflow" phenomenon.

Recurrent form of neurogenic stunned myocardium: is myocardial adrenergic receptor distribution a dynamic process?

Neurogenic stunned myocardium mediated by stress-induced catecholamine acute release is considered as the central causative mechanism of transient left ventricular dysfunction syndrome (TVLDS). Interindividual differences in both LV ß-adrenergic receptor density and sympathetic innervation were proposed to explain the atypical forms of TVLDS. Whether this distribution is independent of age or may vary during ageing still remains unclear. We report a recurrent form of TLVDS characterized by two different patterns. Whilst myocardial receptor distribution or sympathetic innervation appears to follow a dynamic process, the precise determinants of these variations remain largely unknown.