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.

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.

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 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.

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.

A modified fast micro method in agarose for isotype, allotype, light chain and idiotype-specific analysis of antibody clonotypes to bacterial virulence antigens.

A modified fast micro method for spectrotypic/clonotypic analysis of human IgG1-4 antibodies against bacterial virulence antigens of polysaccharide or protein nature is described. Serum samples of as small volumes as 0.5 microliter were isoelectrically focused in micro agarose gels made in plexiglass matrices and blotted using immunoaffinity-mediated capillary blotting onto nitrocellulose membranes previously coated with antigen. The bands of the antigen-specific antibodies were identified with respect to isotypes, light chain types, allotypes or idiotypes by incubating the nitrocellulose membranes with mouse monoclonal anti-human IgG subclass antisera and then with alkaline phosphatase-conjugated rabbit anti-mouse immunoglobulins. The method was applied for characterization of human monoclonals against tetanus toxoid (TT) and for the analysis of variable patterns of clonotypes in IgG subclass-deficient patients. The usefulness of the technique was also demonstrated by comparing the variable specificity and reactivity of different commercial monoclonals against human IgG subclasses. This method is fast, specific, sensitive, uses little material, is simple and reproducible.

Transcriptional silencing by the mycobacteriophage L5 repressor.

The success of a temperate bacteriophage is dependent upon its ability to completely shut down expression of its lytic genes during lysogenic growth. Mycobacteriophage L5 accomplishes this by an atypical phage repressor, gp71, which binds to multiple asymmetric DNA sites. L5 gp71 regulates transcription initiation at an early lytic promoter, Pleft, but also affects downstream gene expression at 'stoperator' sites in the phage genome. The L5 genome is replete with stoperator sites located within short intergenic spaces in both the early and late lytic operons and oriented specifically with respect to transcription. Binding of gp71 to these sites results in a strong orientation-dependent polar effect on downstream gene expression and global silencing of prophage gene expression.

Nucleotide sequence analysis of a gene from Burkholderia (Pseudomonas) cepacia encoding an outer membrane lipoprotein involved in multiple antibiotic resistance.

Antibiotic-resistant Burkholderia (Pseudomonas) cepacia is an important etiologic agent of nosocomial and cystic fibrosis infections. The primary resistance mechanism which has been reported is decreased outer membrane permeability. We previously reported the cloning and characterization of a chloramphenicol resistance determinant from an isolate of B. cepacia from a patient with cystic fibrosis that resulted in decreased drug accumulation. In the present studies we subcloned and sequenced the resistance determinant and identified gene products related to decreased drug accumulation. Additional drug resistances encoded by the determinant include resistances to trimethoprim and ciprofloxacin. Sequence analysis of a 3.4-kb subcloned fragment identified one complete and one partial open reading frame which are homologous with two of three components of a potential antibiotic efflux operon from Pseudomonas aeruginosa (mexA-mexB-oprM). On the basis of sequence data, outer membrane protein analysis, protein expression systems, and a lipoprotein labelling assay, the complete open reading frame encodes an outer membrane lipoprotein which is homologous with OprM. The partial open reading frame shows homology at the protein level with the C terminus of the protein product of mexB. DNA hybridization studies demonstrated homology of an internal mexA probe with a larger subcloned fragment from B. cepacia. The finding of multiple antibiotic resistance in B. cepacia as a result of an antibiotic efflux pump is surprising because it has long been believed that resistance in this organism is caused by impermeability to antibiotics.

Suicide risk among people living with AIDS.

Using data from Louisiana vital statistics records, the authors found an increased suicide risk for people with AIDS. Between 1987 and 1991 the suicide rate of people with AIDS (175 per 10,000) was 134.6 times that of the general population (1.3 per 10,000). The suicide rate for people with AIDS in the metropolitan New Orleans area (126 per 10,000) was half that of the state's nonmetropolitan areas (249 per 10,000). This article explores the implications of this astounding suicide rate for social work practice.

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.

Further evaluation of a live hepatitis A vaccine in marmosets.

Live, attenuated F' hepatitis A vaccine virus was studied in vivo in Saguinus labiatus marmosets for possible reversion to virulence, for possible establishment of persistent infection and for its capacity as a parenterally administered vaccine to induce immunity to oral infection. Serial transmission of the virus in S. labiatus, using infectious stool extracts for the second and third passages, produced no evidence of reversion of the F' vaccine virus to virulence. Monitoring for live HAV in stools over a 135-day period post-inoculation of marmosets with the F' vaccine revealed no evidence of persistent infection. Vaccinated animals were also shown to be resistant to infection on challenge by the oral route as well as by the previously demonstrated parenteral route.

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.

Some characteristics of aggregates of IgG and plasma proteins in heat-treated factor VIII concentrates.

Eight batches of commercial heat-treated and one untreated factor VIII concentrate from 6 producers were analyzed for their content of IgG, IgG subclasses, IgG aggregates and the presence of other plasma proteins combined with the IgG as well as for anticomplement activity. Methods used were thin-layer gel filtration, immuno-gel filtration, spot immuno-precipitate assay in a double antibody version and an agarose plate haemolysis inhibition assay of complement fixation. The IgG content varied from 0.1-6.90 g/l. In all preparations IgG existed as monomers and aggregates. Associated with the IgG were also found, at significantly increased amounts compared to normal serum and intravenous immunoglobulin, one to four of the following plasma proteins; fibronectin, fibrinogen, von Willebrand factor antigen, Clq, albumin and IgA. Three batches from two producers had high anticomplementary activity, presumably caused by the IgG aggregates. Two of these deviated strikingly from normal human serum pools in percent distribution of IgG subclasses. It is hypothesized that these aggregates can induce side effects or cause immunological aberrations.

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.

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.

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.