Real-world performance of blood-based proteomic profiling in first-line immunotherapy treatment in advanced stage non-small cell lung cancer.

PURPOSE: Immune checkpoint inhibition (ICI) therapy has improved patient outcomes in advanced non-small cell lung cancer (NSCLC), but better biomarkers are needed. A clinically validated, blood-based proteomic test, or host immune classifier (HIC), was assessed for its ability to predict ICI therapy outcomes in this real-world, prospectively designed, observational study. MATERIALS AND METHODS: The prospectively designed, observational registry study INSIGHT (Clinical Effectiveness Assessment of VeriStrat® Testing and Validation of Immunotherapy Tests in NSCLC Subjects) (NCT03289780) includes 35 US sites having enrolled over 3570 NSCLC patients at any stage and line of therapy. After enrolment and prior to therapy initiation, all patients are tested and designated HIC-Hot (HIC-H) or HIC-Cold (HIC-C). A prespecified interim analysis was performed after 1-year follow-up with the first 2000 enrolled patients. We report the overall survival (OS) of patients with advanced stage (IIIB and IV) NSCLC treated in the first-line (ICI-containing therapies n=284; all first-line therapies n=877), by treatment type and in HIC-defined subgroups. RESULTS: OS for HIC-H patients was longer than OS for HIC-C patients across treatment regimens, including ICI. For patients treated with all ICI regimens, median OS was not reached (95% CI 15.4 to undefined months) for HIC-H (n=196) vs 5.0 months (95% CI 2.9 to 6.4) for HIC-C patients (n=88); HR=0.38 (95% CI 0.27 to 0.53), p<0.0001. For ICI monotherapy, OS was 16.8 vs 2.8 months (HR=0.36 (95% CI 0.22 to 0.58), p<0.0001) and for ICI with chemotherapy OS was unreached vs 6.4 months (HR=0.41 (95% CI 0.26 to 0.67), p=0.0003). HIC results were independent of programmed death ligand 1 (PD-L1). In a subgroup with PD-L1 ≥50% and performance status 0-1, HIC stratified survival significantly for ICI monotherapy but not ICI with chemotherapy. CONCLUSION: Blood-based HIC proteomic testing provides clinically meaningful information for immunotherapy treatment decision in NSCLC independent of PD-L1. The data suggest that HIC-C patients should not be treated with ICI alone regardless of their PD-L1 expression.

Accuracy of reporting of Aboriginality on administrative health data collections using linked data in NSW, Australia.

BACKGROUND: Aboriginal people are under-reported on administrative health data in Australia. Various approaches have been used or proposed to improve reporting of Aboriginal people using linked records. This cross-sectional study used self-reported Aboriginality from the NSW Patient Survey Program (PSP) as a reference standard to assess the accuracy of reporting of Aboriginal people on NSW Admitted Patient (APDC) and Emergency Department Data Collections (EDDC), and compare the accuracy of selected approaches to enhance reporting Aboriginality using linked data. METHODS: Ten PSP surveys were linked to five administrative health data collections, including APDC, EDDC, perinatal, and birth and death registration records. Accuracy of reporting of Aboriginality was assessed using sensitivity, specificity, and positive and negative predictive values (PPVs and NPVs) and F score for the EDDC and APDC as baseline and four enhancement approaches using linked records: "Most recent linked record", "Ever reported as Aboriginal", and two approaches using a weight of evidence, "Enhanced Reporting of Aboriginality (ERA) algorithm" and "Multi-stage median (MSM)". RESULTS: There was substantial under-reporting of Aboriginality on APDC and EDDC records (sensitivities 84 and 77% respectively) with PPVs of 95% on both data collections. Overall, specificities and NPVs were above 98%. Of people who were reported as Aboriginal on the PSP, 16% were not reported as Aboriginal on any of their linked records. Record linkage approaches generally increased sensitivity, accompanied by decrease in PPV with little change in overall F score for the APDC and an increase in F score for the EDDC. The "ERA algorithm" and "MSM" approaches provided the best overall accuracy. CONCLUSIONS: Weight of evidence approaches are preferred when record linkage is used to improve reporting of Aboriginality on administrative health data collections. However, as a substantial number of Aboriginal people are not reported as Aboriginal on any of their linked records, improvements in reporting are incomplete and should be taken into account when interpreting results of any analyses. Enhancement of reporting of Aboriginality using record linkage should not replace efforts to improve recording of Aboriginal people at the point of data collection and addressing barriers to self-identification for Aboriginal people.

Factors influencing operative time in arthroscopic rotator cuff repair: a comparison of knotless single-row vs. transosseous equivalent dual-row techniques.

BACKGROUND: Despite the widespread use of arthroscopic rotator cuff repair (aRCR), there remains considerable debate on the benefits of a dual-row vs. a single-row (SR) repair technique. This study compares operative time of a knotless SR technique with transosseous equivalent (TOE) dual-row technique for aRCR and defines patient-specific factors that affect operative time. METHODS: Data from 118 patients who underwent aRCR with a knotless SR technique was compared with data from 95 patients who underwent aRCR with a TOE technique by a single surgeon between 2014 and 2018. Baseline patient demographic information and operative time were recorded and compared between the 2 groups. Subgroup analysis was performed to determine if demographic information or tear size influenced operative time. RESULTS: The average operative time in the SR group was 75.68 minutes and the average operative time in the TOE group was 89.24 minutes (P < .001). When controlling for all concomitant procedures, the operative time in the TOE group was 8.1 minutes longer than the SR group (P = .029). Average tear size in an anterior-posterior direction was larger in the TOE group vs. the SR group, 26.09 mm vs. 15.18 mm (P < .001). CONCLUSION: When controlling for concomitant procedures, a knotless, TOE dual-row technique for aRCR adds an average of 8 minutes' operative time compared with a knotless SR technique. This was despite a significantly larger tear size in the TOE group.

Desmoplastic Fibroma in the Distal Humerus of a 14-Year-Old Boy: A Case Report.

CASE: We present the case of a 14-year-old male who presented with a pathologic elbow fracture. Imaging demonstrated a lytic distal humerus metaphyseal lesion with a soap bubble appearance. After fracture healing, frozen sections obtained at open biopsy suggested fibrous tissue; thus, curettage and bone grafting was performed. Pathology confirmed desmoplastic fibroma. The patient experienced a recurrence 18 months later and had repeat curettage and allograft strutting. He had no evidence of re-recurrence 2 years after the second surgery. CONCLUSIONS: Desmoplastic fibroma may mimic the presentation of many bone lesions. Recurrence is common despite curettage and bone grafting. This patient performed well without wide resection.

Simplified Technique for Superior Capsular Reconstruction Using an Acellular Dermal Allograft.

Superior capsular reconstruction is a powerful tool for the treatment of massive irreparable rotator cuff tears. Several authors have described this evolving technique. Issues of graft sizing, graft passage, graft tensioning, and suture management make this a challenging procedure even in the hands of experienced shoulder surgeons. We describe our arthroscopic technique for superior capsular reconstruction using nonirradiated human acellular dermis. We introduce several techniques for graft passage and tensioning that may help to simplify this challenging procedure and make it more reproducible.

Total Knee Arthroplasty After Knee Arthroscopy in Patients Older Than 50 Years.

Several orthopedic registries have described the incidence of total knee arthroplasty (TKA) in patients who have undergone knee arthroscopy. Patient risk factors may play a role in the conversion rate from knee arthroscopy to TKA. This study quantifies the incidence of conversion of knee arthroscopy to TKA from a US mixed-payer database and describes some common patient risk factors for conversion. The medical records of more than 50 million patients who were treated between 1998 and 2014 were mined with a commercially available software platform. During the study period, a total of 68,090 patients older than 50 years underwent knee arthroscopy for partial meniscectomy, chondroplasty, or debridement. Reported rates of TKA at 1, 2, and 3 years after arthroscopy were 10.1%, 13.7%, and 15.6%, respectively. Obesity, depressive disorder, rheumatoid arthritis, diabetes, and age 70 years and older were associated with increased relative risk of conversion to TKA at 2 years. When obesity was combined individually with the top 5 other risk factors, no combination produced a higher relative risk than that of obesity alone. Patients who were 50 to 54 years of age had the lowest incidence of conversion to TKA (8.3%, P<.001). Men had a lower incidence of conversion to TKA (11.3%) than women (15.8%, P<.001). This information can help surgeons to counsel patients on the incidence of TKA after knee arthroscopy and identify preoperative risk factors that increase risk. [Orthopedics. 2016; 39(6):e1041-e1044.].

Testing a health research instrument to develop a state-wide survey on maternity care.

Partnerships between researchers and end users are an important strategy for research uptake in policy and practice. This paper describes how collaboration between an academic research organisation (the Kolling Institute) and a government performance reporting agency (the New South Wales [NSW] Bureau of Health Information) contributed to the development of a new state-wide maternity care survey for NSW.

Rib Stress Fracture in a Collegiate Softball Pitcher: A Case Report.

CASE: We present the case of a twenty-one-year-old right-hand-throwing, right-hand-batting female softball pitcher who presented with a three-month history of right rib pain. A bone scan showed increased uptake in the lateral aspect of the right seventh rib, consistent with a stress fracture. The patient was managed nonoperatively and made a full recovery. CONCLUSION: The forces created by the attachment of the serratus anterior during underhand throwing are the likely etiology of the injury in our patient. Physicians should maintain a high clinical index of suspicion for stress fracture in underhand athletes with lateral rib pain.

Dose escalation pharmacokinetics of intranasal scopolamine gel formulation.

Astronauts experience Space Motion Sickness requiring treatment with an anti-motion sickness medication, scopolamine during space missions. Bioavailability after oral administration of scopolamine is low and variable, and absorption form transdermal patch is slow and prolonged. Intranasal administration achieves faster absorption and higher bioavailability of drugs that are subject to extrahepatic, first pass metabolism after oral dosing. We examined pharmacokinetics of 0.1, 0.2, and 0.4 mg doses of the Investigational New Drug formulation of intranasal scopolamine gel (INSCOP) in 12 healthy subjects using a randomized, double-blind cross-over study design. Subjects received one squirt of 0.1 g of gel containing either 0.1 mg or 0.2 mg/0.1 mL scopolamine or placebo in each nostril. Serial blood samples and total urine voids were collected after dosing and drug concentrations were determined using a modified LC-MS-MS method. Results indicate dose-linear pharmacokinetics of scopolamine with linear increases in Cmax and AUC within the dose range tested. Plasma drug concentrations were significantly lower in females than in males after administration of 0.4 dose. All three doses were well tolerated with no unexpected or serious adverse side effects reported. These results suggest that intranasal scopolamine gel formulation (INSCOP) offers a fast, reliable, and safe alternative for the treatment of motion sickness.

A stitch in time: an unusual cause of enterovesical fistula.

A 64-year-old woman with a history of a Stamey procedure for stress incontinence 20 years previously, underwent a diagnostic flexible cystoscopy to investigate recurrent urinary sepsis. Cystoscopic examination demonstrated a large vesicular calculus. When traction was applied to the calculus it was shown to be attached to a 10 cm length of non-absorbable suture material. The suture was attached to two further calculi, apparently originating from outside the bladder wall. All visible calculi and the suture were removed. In the following weeks the patient reported passage of air and faeculent material per-urethra. A repeat cystoscopy revealed an opening in the posterolateral bladder wall and CT confirmed the presence of an enterovesical fistula. Laparoscopy demonstrated a fistula between the terminal ileum and bladder wall. A further 10 cm length of non-absorbable suture material was removed from the terminal ileum and omentum. Laparoscopic repair of the fistula was performed successfully and the patient has remained symptom free following the procedure.

Effect of azathioprine intolerance on outcomes of inflammatory bowel disease: a cross-sectional study.

BACKGROUND: Azathioprine is well established for the maintenance of remission in patients with inflammatory bowel disease (IBD). However, a significant proportion of patients are intolerant to azathioprine. It is not clear if intolerance of azathioprine is a marker of poor prognosis for patients who will have a more aggressive disease or be more likely to require surgery. OBJECTIVE: To determine if intolerance to azathioprine is a marker of poor prognosis, indicating patients who have a more aggressive disease course, and to analyse the risk factors and causes of intolerance. METHODS: A cross-sectional study using the Milton Keynes Hospital IBD database was performed to compare azathioprine-intolerant and azathioprine-tolerant patients. RESULTS: Two hundred and thirty-nine patients met the inclusion criteria comprising 141 patients with Crohn's disease (CD) and 98 patients with ulcerative colitis (UC). Overall, 28.0% of patients were intolerant to azathioprine. Risk factors for intolerance were female sex and age 50-70 years. Common reasons for intolerance were nausea and vomiting (34.3%), deranged liver function tests (28.4%) and headaches (11.9%). In patients with UC, there was no statistical difference in the disease activity scores between those who were azathioprine intolerant versus tolerant. In patients with CD, azathioprine intolerance was associated with significantly worse disease activity; 25% fewer patients were in clinical remission and 20% more had moderate/severe disease. Rates of surgery were similar between the groups for both UC/CD. CONCLUSIONS: We conclude that azathioprine intolerance acts as a surrogate marker for patients with CD who in future have poorer symptom control. Azathioprine intolerance marks out a group of patients with CD in whom increased vigilance of symptom control and early escalation of treatment is required.

Evaluation of physical and chemical changes in pharmaceuticals flown on space missions.

Efficacy and safety of medications used for the treatment of astronauts in space may be compromised by altered stability in space. We compared physical and chemical changes with time in 35 formulations contained in identical pharmaceutical kits stowed on the International Space Station (ISS) and on Earth. Active pharmaceutical content (API) was determined by ultra- and high-performance liquid chromatography after returning to Earth. After stowage for 28 months in space, six medications aboard the ISS and two of matching ground controls exhibited changes in physical variables; nine medications from the ISS and 17 from the ground met the United States Pharmacopeia (USP) acceptance criteria for API content after 28 months of storage. A higher percentage of medications from each flight kit had lower API content than the respective ground controls. The number of medications failing API requirement increased as a function of time in space, independent of expiration date. The rate of degradation was faster in space than on the ground for many of the medications, and most solid dosage forms met USP standard for dissolution after storage in space. Cumulative radiation dose was higher and increased with time in space, whereas temperature and humidity remained similar to those on the ground. Exposure to the chronic low dose of ionizing radiation aboard the spacecraft as well as repackaging of solid dosage forms in flight-specific dispensers may adversely affect stability of pharmaceuticals. Characterization of degradation profiles of unstable formulations and identification of chemical attributes of stability in space analog environments on Earth will facilitate development of space-hardy medications.

Identification and characterization of interactions between abscisic acid and mitochondrial adenine nucleotide translocators.

ABA (abscisic acid) is a plant hormone involved in important processes including development and stress responses. Recent reports have identified a number of plant ABA receptors and transporters, highlighting novel mechanisms of ABA action. In the present paper we describe application of a chemical proteomics approach leading to the identification of mitochondrial ANTs (adenine nucleotide translocators) as ABA-interacting proteins. Initial in vitro studies confirmed inhibition of ANT-dependent ATP translocation by ABA. Further analysis demonstrated ANT-dependent uptake of ABA into both recombinant Arabidopsis thaliana ANT2-containing proteoliposomes and native isolated spinach mitochondria; the latter with a Km of 3.5 µM and a Vmax of 2.5 nmol/min per g of protein. ATP was found to inhibit ANT-dependent ABA translocation. Specificity profiles highlight the possibility of mechanistic differences in translocation of ABA and ATP. Finally, ABA was shown to stimulate ATPase activity in spinach mitochondrial extracts. ABA concentrations in plant cells are estimated to reach the low micromolar range during stress responses, supporting potential physiological relevance of these in vitro findings. Overall, the present in vitro work suggests the possibility of as yet uncharacterized mechanisms of ABA action in planta related to inhibition of mitochondrial ATP translocation and functional localization of ABA in the mitochondrial matrix.

Joint modeling of performance and subjective reporting to assess sensitivity to drug-induced sleepiness.

In an NASA ground study, two forms of cognitive tests were evaluated in terms of their sensitivity to sleepiness induced by the drug promethazine (PMZ). Performance for the two test modes (Y(1) and Y(2)), PMZ concentration, and a self-reported sleepiness using the Karolinska Sleepiness Scale (KSS) were monitored for 12 h post dose. A problem arises when using KSS to establish an association between true sleepiness and performance because KSS scores are discrete and also because they tend to concentrate on certain values. Therefore, we define a latent sleepiness measure X as an unobserved continuous random variable describing a subject's actual state of sleepiness. Under the assumption that drug concentration affects X, which then affects Y(1), Y(2), and KSS, we use Bayesian methods to estimate joint equations that permit unbiased comparison of the performance measures' sensitivity to X. The equations incorporate subject random effects and include a negativity constraint on subject-specific slopes of performance with respect to sleepiness.

The efficacy of low-dose intranasal scopolamine for motion sickness.

INTRODUCTION: Scopolamine is an effective motion sickness prophylactic, but oral and transdermal formulations are slowly absorbed. To enhance absorption and potentially efficacy, an intranasal formulation of scopolamine (INSCOP) was tested. METHOD: There were 16 motion sickness susceptible subjects with an average age of 23.5 +/- 3.0 yr and an average score of 11.3 +/- 4.7 on the Modified Motion Sickness Susceptibility Questionnaire-Short Form who volunteered to participate in the study. Each subject was given 0.4 mg of INSCOP and a placebo in a randomized, double-blind crossover design and, at 40 min post-dose, experienced Coriolis cross-coupling in a staircase progression until moderate nausea. Efficacy data and cognitive, physiological, and alertness assessments were collected during baseline control and throughout experimental testing. RESULTS: Intranasal scopolamine significantly increased the mean number of head movements tolerated [INSCOP 275.9 +/- 120.5, Placebo 230.7 +/- 76.4; t (15) = 2.21]. Estimation of medication absorption via plasma concentration indicated the drug was absorbed relatively rapidly to measurable levels by 15 min post-administration. Diastolic blood pressures and heart rate were significantly lower after administration of INSCOP compared to placebo. No significant cognitive or medication side effects were reported. Subjects reported no significant decrease in alertness as indicated by the Karolinska Sleepiness Scale. CONCLUSIONS: Results of the current study strongly suggest that intranasal scopolamine is efficacious for the treatment of motion sickness in susceptible individuals with no significant cognitive or sedative effects. Intranasal delivery offers a promising alternative for use in dynamic operational environments without cognitive detriment or increased side effects.

Nature versus nurture in two highly enantioselective esterases from Bacillus cereus and Thermoanaerobacter tengcongensis.

There is an increasing need for the use of biocatalysis to obtain enantiopure compounds as chiral building blocks for drug synthesis such as antibiotics. The principal findings of this study are: (i) the complete sequenced genomes of Bacillus cereus ATCC 14579 and Thermoanaerobacter tengcongensis MB4 contain a hitherto undescribed enantioselective and alkaliphilic esterase (BcEST and TtEST respectively) that is specific for the production of (R)-2-benzyloxy-propionic acid ethyl ester, a key intermediate in the synthesis of levofloxacin, a potent antibiotic; and (ii) directed evolution targeted for increased thermostability of BcEST produced two improved variants, but in either case the 3-5 °C increase in the apparent melting temperature (T(m)) of the mutants over the native BcEST that has a T(m) of 50 °C was outperformed by TtEST, a naturally occurring homologue with a T(m) of 65 °C. Protein modelling of BcEST mapped the S148C and K272R mutations at protein surface and the I88T and Q110L mutations at more buried locations. This work expands the repertoire of characterized members of the α/ß-fold hydrolase superfamily. Further, it shows that genome mining is an economical option for new biocatalyst discovery and we provide a rare example of a naturally occurring thermostable biocatalyst that outperforms experimentally evolved homologues that carry out the same hydrolysis.

Sesquiterpene-like inhibitors of a 9-cis-epoxycarotenoid dioxygenase regulating abscisic acid biosynthesis in higher plants.

Abscisic acid (ABA) is a carotenoid-derived plant hormone known to regulate critical functions in growth, development and responses to environmental stress. The key enzyme which carries out the first committed step in ABA biosynthesis is the carotenoid cleavage 9-cis-epoxycarotenoid dioxygenase (NCED). We have developed a series of sulfur and nitrogen-containing compounds as potential ABA biosynthesis inhibitors of the NCED, based on modification of the sesquiterpenoid segment of the 9-cis-xanthophyll substrates and product. In in vitro assays, three sesquiterpene-like carotenoid cleavage dioxygenase (SLCCD) inhibitor compounds 13, 17 and 18 were found to act as inhibitors of Arabidopsis thaliana NCED 3 (AtNCED3) with K(i)'s of 93, 57 and 87 microM, respectively. Computational docking to a model of AtNCED3 supports a mechanism of inhibition through coordination of the heteroatom with the non-heme iron in the enzyme active site. In pilot studies, pretreatment of osmotically stressed Arabidopsis plants with compound 13 resulted lower levels of ABA and catabolite accumulation compared to levels in mannitol-stressed plant controls. This same inhibitor moderated known ABA-induced gene regulation effects and was only weakly active in inhibition of seed germination. Interestingly, all three inhibitors led to moderation of the stress-induced transcription of AtNCED3 itself, which could further contribute to lowering ABA biosynthesis in planta. Overall, these sesquiterpenoid-like inhibitors present new tools for controlling and investigating ABA biosynthesis and regulation.