Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage III non-small-cell lung cancer in the PACIFIC trial.

BACKGROUND: In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression. PATIENTS AND METHODS: Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo ≤12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (Kaplan-Meier-estimated medians). RESULTS: In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n = 473) or placebo (n = 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC ≥25%, <25%, ≥1%, <1%, and 1%-24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups [HR, 95% confidence interval (CI); medians]: TC ≥25% (0.41, 0.26-0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43-0.82; 16.9 versus 6.9 months), ≥1% (0.46, 0.33-0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48-1.11; 10.7 versus 5.6 months), 1%-24% [0.49, 0.30-0.80; not reached (NR) versus 9.0 months], and unknown (0.59, 0.42-0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ≥ 25% (0.50, 0.30-0.83; NR versus 21.1 months), <25% (0.89, 0.63-1.25; 39.7 versus 37.4 months), ≥1% (0.59, 0.41-0.83; NR versus 29.6 months), 1%-24% (0.67, 0.41-1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43-0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71-1.84; 33.1 versus 45.6 months). Safety was similar across subgroups. CONCLUSIONS: PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions.

Explaining the sawtooth: latitudinal periodicity in a circadian gene correlates with shifts in generation number.

Many temperate insects take advantage of longer growing seasons at lower latitudes by increasing their generation number or voltinism. In some insects, development time abruptly decreases when additional generations are fit into the season. Consequently, latitudinal 'sawtooth' clines associated with shifts in voltinism are seen for phenotypes correlated with development time, like body size. However, latitudinal variation in voltinism has not been linked to genetic variation at specific loci. Here, we show a pattern in allele frequency among voltinism ecotypes of the European corn borer moth (Ostrinia nubilalis) that is reminiscent of a sawtooth cline. We characterized 145 autosomal and sex-linked SNPs and found that period, a circadian gene that is genetically linked to a major QTL determining variation in post-diapause development time, shows cyclical variation between voltinism ecotypes. Allele frequencies at an unlinked circadian clock gene cryptochrome1 were correlated with period. These results suggest that selection on development time to 'fit' complete life cycles into a latitudinally varying growing season produces oscillations in alleles associated with voltinism, primarily through changes at loci underlying the duration of transitions between diapause and other life history phases. Correlations among clock loci suggest possible coupling between the circadian clock and the circannual rhythms for synchronizing seasonal life history. We anticipate that latitudinal oscillations in allele frequency will represent signatures of adaptation to seasonal environments in other insects and may be critical to understanding the ecological and evolutionary consequences of variable environments, including response to global climate change.

A recombination suppressor contributes to ecological speciation in OSTRINIA moths.

Despite unparalleled access to species' genomes in our post-genomic age, we often lack adequate biological explanations for a major hallmark of the speciation process-genetic divergence. In the presence of gene flow, chromosomal rearrangements such as inversions are thought to promote divergence and facilitate speciation by suppressing recombination. Using a combination of genetic crosses, phenotyping of a trait underlying ecological isolation, and population genetic analysis of wild populations, we set out to determine whether evidence supports a role for recombination suppressors during speciation between the Z and E strains of European corn borer moth (Ostrinia nubilalis). Our results are consistent with the presence of an inversion that has contributed to accumulation of ecologically adaptive alleles and genetic differentiation across roughly 20% of the Ostrinia sex chromosome (~4 Mb). Patterns in Ostrinia suggest that chromosomal divergence may involve two separate phases-one driving its transient origin through local adaptation and one determining its stable persistence through differential introgression. As the evolutionary rate of rearrangements in lepidopteran genomes appears to be one of the fastest among eukaryotes, structural mutations may have had a disproportionate role during adaptive divergence and speciation in Ostrinia and in other moths and butterflies.

A novel protocol allowing oral delivery of a protein complement inhibitor that subsequently targets to inflamed colon mucosa and ameliorates murine colitis.

While there is evidence of a pathogenic role for complement in inflammatory bowel disease, there is also evidence for a protective role that relates to host defence and protection from endotoxaemia. There is thus concern regarding the use of systemic complement inhibition as a therapeutic strategy. Local delivery of a complement inhibitor to the colon by oral administration would ameliorate such concerns, but while formulations exist for oral delivery of low molecular weight drugs to the colon, they have not been used successfully for oral delivery of proteins. We describe a novel pellet formulation consisting of cross-linked dextran coated with an acrylic co-polymer that protects the complement inhibitor CR2-Crry from destruction in the gastrointestinal tract. CR2-Crry containing pellets administered by gavage, were characterized using a therapeutic protocol in a mouse model of dextran sulphate sodium (DSS)-induced colitis. Oral treatment of established colitis over a 5-day period significantly reduced mucosal inflammation and injury, with similar therapeutic benefit whether or not the proton pump inhibitor, omeprazole, was co-administered. Reduction in injury was associated with the targeting of CR2-Crry to the mucosal surface and reduced local complement activation. Treatment had no effect on systemic complement activity. This novel method for oral delivery of a targeted protein complement inhibitor will reduce systemic effects, thereby decreasing the risk of opportunistic infection, as well as lowering the required dose and treatment cost and improving patient compliance. Furthermore, the novel delivery system described here may provide similar benefits for administration of other protein-based drugs, such as anti-tumour necrosis factor-α antibodies.

One phase of the dormancy developmental pathway is critical for the evolution of insect seasonality.

Evolutionary change in the timing of dormancy enables animals and plants to adapt to changing seasonal environments and can result in ecological speciation. Despite its clear biological importance, the mechanisms underlying the evolution of dormancy timing in animals remain poorly understood because of a lack of anatomical landmarks to discern which phase of dormancy an individual is experiencing. Taking advantage of the nearly universal characteristic of metabolic suppression during insect dormancy (diapause), we use patterns of respiratory metabolism to document physiological landmarks of dormancy and test which of the distinct phases of the dormancy developmental pathway contribute to a month-long shift in diapause timing between a pair of incipient moth species. Here, we show that divergence in life cycle between the earlier-emerging E-strain and the later-emerging Z-strain of European corn borer (ECB) is clearly explained by a delay in the timing of the developmental transition from the diapause maintenance phase to the termination phase. Along with recent findings indicating that life-cycle differences between ECB strains stem from allelic variation at a single sex-linked locus, our results demonstrate how dramatic shifts in animal seasonality can result from simple developmental and genetic changes. Although characterizing the multiple phases of the diapause developmental programme in other locally adapted populations and species will undoubtedly yield surprises about the nature of animal dormancy, results in the ECB moth suggest that focusing on genetic variation in the timing of the dormancy termination phase may help explain how (or whether) organisms rapidly respond to global climate change, expand their ranges after accidental or managed introductions, undergo seasonal adaptation, or evolve into distinct species through allochronic isolation.

A critical analysis of commercially available latex particle reagents for C-reactive protein (CRP) slide agglutination tests.

C-reactive protein (CRP) was assessed in pediatric serum samples using different commercial latex reagents, which were analyzed for species origin of the coating antibodies, homogeneity and density of the latex particles, and prozone agglutinating capacity. All reagents correctly agglutinated the positive and negative control sera. The antibodies coating the particles differed with regard to species origin: one was coated with rabbit, one with horse and goat, one with horse, goat, rabbit and swine, while the reference reagent had horse, goat and rabbit antibodies. Only the monospecies specific antibody-coated latex showed obvious prozoning; this reagent also had the smallest and most homogenous latex particles and showed the most clear-cut reactions. False agglutination was observed at 7-26% according to quantitation with the spot immunoprecipitate assay, which compared favorably with radial immunodiffusion measurements. The lowest percentage of false readings was noted for the rabbit antibody-coated particles; the highest for the reagent with particles coated using antibodies from 4 different species. No reagent had satisfactory precision for the low positive sera between 10 and 40 mg CRP/l.

Spot immunoprecipitate assay in gel compared with immune reactions in solution and applied to antibody titration.

Precipitation profiles of spot immunoprecipitate assay (SIA) reactions in gel are shown to have characteristics analogous to classic precipitin curves representing such immune reactions in solution. Thus SIA profiles of precipitated human albumin (HSA) and anti-HSA as checkerboard analysis permit: (1) determination of optimal proportions of antibody and antigen, (2) titration of antiserum as to antigen-binding capacity and (3) estimation of the concentration of specific antibody in an antiserum. The validity of the method was confirmed by similar results already reported for precipitin analysis of anti-HSA in solution. The stained protein assay method for determination of total protein used for the calculations had a reliable (r = 0.9979) working range for quantification between 0.1 and 0.83 microgram protein in 3 microliters samples (greater than or equal to 0.03 g/l). Study of SIA profiles in the extreme antibody excess region confirmed the validity of SIA quantification. The high sensitivity of SIA as compared with radial immunodiffusion is related to high ratios (8-9) of antibody to antigen; the reliable detection limit for SIA is 10 mg/l in a 3 microliters sample. SIA is easy to perform with simple laboratory equipment, allows measurement of any precipitable antigen with very small amounts of reactants, and gives results within an hour.

Mucosal immunity.

Mucosal defense is provided by a number of host factors countering the specific virulence factors of the many microorganisms infecting the mucous membranes. Secretory IgA antibodies presumably play an important role. Increase of the sIgA antibodies may most advantageously be attained by parenteral immunization, following mucosal priming. This was demonstrated in a rat model, where it was also noted that antigen injection into PP induced high milk IgA antibody levels. In man, parenteral vaccination against polio increased the sIgA antibody levels in the milk of mothers previously exposed naturally to the poliovirus. The response was relatively short-lived. In the previously unexposed, there was little or no response. By contrast peroral immunization with live poliovirus vaccine did not increase, or even decrease, the milk sIgA poliovirus antibody levels. Although salivary sIgA antibodies against antigens of colonizing E. coli appear during the first days of life, they are slow to increase. This deficiency is richly compensated for by all the sIgA antibodies that are provided the baby through the milk. No transfer of dimeric IgA into the milk could be shown in lactating rats, in contrast to what has been reported in mice. There is no evidence for a contribution to milk sIgA from serum in man. Close to parturition, human milk often contains some 7S IgA and various sizes of free SC, in addition to the dominating 11S sIgA. A few days later there is almost exclusively monomeric SC and 11S sIgA. IgG antibodies also play a role at the mucosal level. IgG2 antibodies against the bacterial polysaccharide capsule are as slow to appear as sIgA in ontogeny, possibly explaining the prevalence of infections with encapsulated bacteria and the poor response to polysaccharide vaccines in early childhood. Other defense factors preventing infections by way of mucous membranes may be important. Thus, oligosaccharides present in human milk seem to specifically prevent pneumococcal attachment to retropharyngeal cells. This anti-attachment capacity, in addition to that provided by milk and salivary IgA antibodies, may explain why breast-fed babies have less otitis media than formula-fed ones.

Efficacy of latex agglutination and quantification methods for determination of C-reactive protein (CRP) in pediatric sera.

Described is a procedure for serum C-reactive protein (CRP) determination, consisting of a semiquantitative rapid CRP latex agglutination test, using dilutions of the serum, and the quantitating spot immunoprecipitate assay (SIA). These methods are performed with standard laboratory equipment using no more than 30 microliters of serum for both assays. With visual inspection, the SIA results are available one to two hours after blood sampling. CRP levels obtained by agglutination testing with five batches of latex reagents coated with rabbit anti-CRP agree well with the quantification, i.e. essentially 100% for the negative sera and about 80% for positive sera containing greater than 40 mg CRP/l. The remaining 20% of the samples are classified as low positive at 10 to 40 mg/l on agglutination. False positive or negative agglutination findings are below 2.3% with concordance at 88% between SIA and the CRP agglutination with rabbit antibodies. Two lots of CRP-latex reagents coated with sheep antibodies, however, gave 15.3% and 10.1% false positive findings and poor concordance with SIA ratings, particularly for low positive sera at only 20 and 29%. SIA is suggested for CRP quantification because it compares well with radial immunodiffusion in accuracy (less than 91%) and provides results in 2 h rather than 1-2 days. Rocket electroimmunoassay is less reliable with lower ratings than found in SIA, probably due to the electrophoretic heterogeneity of CRP. This is demonstrated for two of three purified CRP preparations, for which varying agglutination is seen. The combination of methods is especially recommended for diagnosis and monitoring of CRP in infectious processes in neonates and infants because of the required small sample volume--0.5 ml heel-prick blood--the rapidity of reliable (greater than 80%) reporting and the possibility of rating sera with moderate levels of CRP.

Frozen shoulder.

Widespread use of the label "frozen shoulder" as a diagnosis for any stiff and painful shoulder condition has led to its becoming a rather meaningless, catchall term. In addition to confounding both the lay public and health care professionals, this indiscriminate labeling may prevent a patient from receiving appropriate treatment. In this article, I define frozen shoulder and review its pathologic and etiologic factors, epidemiology, natural history, and diagnosis. I present this information in correlation with an examination process to assist physical therapists in identifying suspected cases of frozen shoulder. I also present the current options for treatment, including physical therapy management with physical agents and exercise.

Intrarater reliability of manual muscle testing and hand-held dynametric muscle testing.

Physical therapists require an accurate, reliable method for measuring muscle strength. They often use manual muscle testing or hand-held dynametric muscle testing (DMT), but few studies document the reliability of MMT or compare the reliability of the two types of testing. We designed this study to determine the intrarater reliability of MMT and DMT. A physical therapist performed manual and dynametric strength tests of the same five muscle groups on 11 patients and then repeated the tests two days later. The correlation coefficients were high and significantly different from zero for four muscle groups tested dynametrically and for two muscle groups tested manually. The test-retest reliability coefficients for two muscle groups tested manually could not be calculated because the values between subjects were identical. We concluded that both MMT and DMT are reliable testing methods, given the conditions described in this study. Both testing methods have specific applications and limitations, which we discuss.

Energy cost, exercise intensity, and gait efficiency of standard versus rocker-bottom axillary crutch walking.

The purpose of this study was to investigate differences in selected biomechanical and physiological measurements and subjective preferences for ambulation with the standard single-tip axillary crutch versus the rocker-bottom-type axillary crutch. Self-selected walking velocities (S-SWVs) and stride length for each crutch type were determined for a two-point, non-weight-bearing, swing-through gait in 24 healthy volunteers. Relative exercise intensity, oxygen uptake (VO2), and gait efficiency were assessed for each crutch type at both S-SWVs. Subjects negotiated two architectural barriers (stairs and ramp) and completed a subjective questionnaire concerning crutch preferences. Walking with either crutch type resulted in slower S-SWVs, greater VO2, higher relative exercise intensity, and reduced gait efficiency compared with values for normal unassisted ambulation. An analysis of variance for these variables revealed nonsignificant between-crutch differences. Based on the subjective data, a preference for the standard single-tip crutch was evident. Within the scope of the study, the results supported no apparent advantage relative to energy expenditure to using the rocker-bottom crutch.

Validity and reliability testing of the Scoliometer.

This study was designed to evaluate the Scoliometer, an instrument that measures axial trunk rotation in individuals with scoliosis. The objectives included determining 1) the Scoliometer's screening capability and validity and 2) the intrarater and interrater reliability of Scoliometer measurements. Scoliometer measurements made by two raters on 65 persons with idiopathic scoliosis were correlated with radiographic assessment of vertebral (pedicle) rotation and lateral curvature (Cobb method). Correlation ranged from .32 to .46 with pedicle rotation and from .46 to .54 with the Cobb angle. Frequency analysis revealed relatively good specificity, sensitivity, and predictive capability of the Scoliometer. Intrarater and interrater reliability coefficients were high (r = .86-.97). These results indicate good measurement reproducibility. The less-than-optimal between-method correlation coefficients suggest that the validity of Scoliometer measurements is not sufficient to use this method alone for determining patient diagnosis and management. Based on the positive-frequency analysis, however, the use of this tool as a screening device would be appropriate.

Wrist and hand examination and interpretation.

Hand rehabilitation is an area with the potential for providing orthopaedic physical therapists a challenging and rewarding practice. However, success in treating the patient with hand dysfunction is closely associated with the therapist's understanding of essential anatomic and pathokinesiologic principles and the related ability to adequately evaluate, plan, and perform treatment. The first article (Wadsworth CT: Clinical anatomy and mechanics of the wrist and hand. J. Orthop Sports Phys Ther 4:205-216) in this two-part series covered the background anatomic and pathokinesiologic concepts. This, the second article of the series, describes the format for examination of the patient with hand dysfunction and presents a practical but comprehensive evaluation form for clinical use. It also supplies information for interpretation of the examination which lays the foundation for goal setting and treatment planning.J Orthop Sports Phys Ther 1983;5(3):108-120.

Clinical anatomy and mechanics of the wrist and hand.

Hand rehabilitation is an area with the potential for providing orthopaedic physical therapists a challenging and rewarding practice. However, success in treating the patient with hand dysfunction is closely associated with the therapist's understanding of essential anatomic and pathokinesiologic principles and the related ability to adequately evaluate, plan, and perform treatment. This article, the first of a two-part series, is intended to provide a working knowledge of clinical anatomy, mechanics, and pathology of the wrist and hand. Emphasis is placed on the structure and function of parts which commonly limit motion, and sufficient information is provided to aid the clinician in performing a differential diagnosis and developing treatment rationale. The second part of the series will describe a practical method of evaluation and offer treatment suggestions for specific disorders.J Orthop Sports Phys Ther 1983;4(4):206-216.

Stanley Paris Award Lecture. Reflections on the history and future of orthopaedic physical therapy.

Carolyn Wadsworth, MS, PT, CHT, OCS, deliver the 1998 Paris Distinguished Service Award Lecture at the Combined Sections Meeting in Boston in February. Wadsworth is the fifth recipient of the Paris Award, which is the Orthopaedic Section's highest honor given to commemorate a member's exceptional and enduring service. The Paris Distinguished Service Award was established in 1990 and is named after Stanley V. Paris, PhD, PT, founder and first president of the Orthopaedic Section. Born in Dunedin, New Zealand, Paris immigrated to the U.S. in 1966. He developed physical therapy practices in Boston, Hamilton, Bermuda, and Atlanta; established the Institute of Graduate Health Sciences in Atlanta, GA; and is currently president of the University of St. Augustine, St. Augustine, FL. Paris is a strong advocate of assertive professional practice, clinical specialization, and strengthening leadership in physical therapy. He also champions wellness, exemplified by his personal achievements in sailing the Atlantic Ocean, swimming the English Channel, and completing the Ironman Triathlon. Carolyn Wadsworth, recipient of the 1998 Paris Award, has served as secretary and president of the Orthopaedic Section and is currently editor of the Orthopaedic Section's Home Study Course. She owns a private practice, teaches nationally, and has written two books, Examination and Mobilization of the Spine and Extremities (1988) and Orthopedic Review for Physical Therapists (1998). Major components of the speech she presented at the Orthopaedic Section Awards Ceremony are highlighted in this article.

Interrater reliability of hand-held dynamometry: effects of rater gender, body weight, and grip strength.

Clinicians and authors of previous publications have not reached agreement on the interrater reliability of dynametric strength testing. This study investigates the effects of gender, body weight, and grip strength on the reliability of hand-held dynametric strength measurements. Ten male and 10 female raters tested five muscle groups on the same two subjects (one male and one female) with a Chatillon Series D hand-held, spring-scale dynamometer. Both the raters and the test subjects were blinded to the dynametric output readings throughout the testing. Interrater reliability was good for all tests except for female raters when testing the male subjects' stronger muscle groups. Standard deviations were 61% and 50% greater for female vs. male raters for elbow flexors and knee extensors, respectively. Female raters' body weight had a significant correlation with torque when testing male subjects' wrist extensors, ankle dorsiflexors, and knee extensors (r > 0.64). Likewise, female raters' grip strength significantly correlated with torque when testing males' wrist extensors and elbow flexors (r >/= 0.71). The results indicate that gender, body weight, and grip strength affect a rater's ability to stabilize a hand-held dynamometer and could influence reliability when testing stronger muscle groups. J Orthop Sports Phys Ther 1992;16(2):74-81.

Effect of the counterforce armband on wrist extension and grip strength and pain in subjects with tennis elbow.

This study investigated the effect of the lateral counterforce armband on wrist extension and grip strength, and pain of 14 subjects with tennis elbow. Dynametric strength tests and pain analogue scale assessments were obtained on the affected and unaffected arms of subjects, while wearing the armband and without wearing the armband. Use of the armband produced parallel effects in both the affected and unaffected arms, i.e., increases in wrist extension and grip strength. The greatest effects were seen in the affected arm. There was a statistically significant increase in wrist extension strength with the armband on relative to without the armband. The increase in wrist extension strength approximately doubled the increase in grip strength for both arms, indicating the armband's greater influence on wrist extension. Although there was a low negative correlation between changes in pain and strength, it was not statistically significant. J Orthop Sports Phys Ther 1989;11(5):192-197.

Use of the interview in admissions.

A description of one method of dealing with nonacademic information from applicants seeking acceptance into a physical therapy curriculum is presented. The strengths of this admission process are interviewer training sessions, use of simulated interviews presented by videotape, subsequent discussion of ratings, specific criteria to support interview ratings, and an arbitration procedure. Attempts were made to increase the objectivity of the interview through frequent meetings of the admission committee to decide on the areas of the interview and specific criteria on which to rate each area. In the areas of weighting factors, training of interviewers, development of specific interview criteria, arbitration procedure, and the use of the computer printout, this admission process could be easily adapted to other allied health programs. Details of the interview are discussed.