Multidisciplinary meeting review in nonsmall cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Lung cancer diagnosis, staging and treatment may be enhanced by multidisciplinary participation and presentation in multidisciplinary meetings (MDM). We performed a systematic review and meta-analysis to explore literature evidence of clinical impacts of MDM exposure. METHODS: A study protocol was registered (PROSPERO identifier CRD42021258069). Randomised controlled trials and observational cohort studies including adults with nonsmall cell lung cancer and who underwent MDM review, compared to no MDM, were included. MEDLINE, CENTRAL, Embase and ClinicalTrials.gov were searched on 31 May 2021. Studies were screened and extracted by two reviewers. Outcomes included time to diagnosis and treatment, histological confirmation, receipt of treatments, clinical trial participation, survival and quality of life. Risk of bias was assessed using the ROBINS-I (Risk of Bias in Non-randomised Studies - of Interventions) tool. RESULTS: 2947 citations were identified, and 20 studies were included. MDM presentation significantly increased histological confirmation of diagnosis (OR 3.01, 95% CI 2.30-3.95; p<0.00001) and availability of clinical staging (OR 2.55, 95% CI 1.43-4.56; p=0.002). MDM presentation significantly increased likelihood of receipt of surgery (OR 2.01, 95% CI 1.29-3.12; p=0.002) and reduced the likelihood of receiving no active treatment (OR 0.32, 95% CI 0.21-0.50; p=0.01). MDM presentation was protective of both 1-year survival (OR 3.23, 95% CI 2.85-3.68; p<0.00001) and overall survival (hazard ratio 0.63, 95% CI 0.55-0.72; p<0.00001). DISCUSSION: MDM presentation was associated with increased likelihood of histological confirmation of diagnosis, documentation of clinical staging and receipt of surgery. Overall and 1-year survival was better in those presented to an MDM, although there was some clinical heterogeneity in participants and interventions delivered. Further research is required to determine the optimal method of MDM presentation, and address barriers to presentation.

Pulmonary Hypertension in Interstitial Lung Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Pulmonary hypertension (PH) is a key complication in interstitial lung disease (ILD), with recent therapeutic advances. RESEARCH QUESTION: What are the diagnostic evaluation, epidemiologic features, associated factors, prognostic significance, and outcome measures in interventional trials for PH in patients with ILD in the current literature? STUDY DESIGN AND METHODS: Ovid MEDLINE, Embase, and CENTRAL databases were searched for original research evaluating PH in participants with ILD of any cause. The definition of PH was based on the investigators' criteria. RESULTS: Three hundred two studies were included, with varying diagnostic evaluations used to define PH. Commonly used diagnostic tests were right heart catheterization (RHC; 56%) and transthoracic echocardiography (TTE; 50%). The pooled prevalence for PH in general populations with ILD was 36% (95% CI, 30%-42%) using RHC and 34% (95% CI, 29%-38%) using TTE. Lower diffusion capacity of the lungs for carbon monoxide, worse oxygenation status, reduced exercise capacity, increased pulmonary artery to aorta ratio and pulmonary artery diameter, and elevated serum brain natriuretic peptide consistently were associated with the presence of PH in at least 60% of reported studies. The presence of PH was associated with increased symptom burden and worse prognosis. Outcome measures in interventional trials of PH in ILD focused on changes in pulmonary vascular hemodynamics and 6-min walk distance. INTERPRETATION: PH is a common complication in ILD with significant health impacts. A standardized definition with prospective evaluation of risk-stratified assessments for PH using identified associated risk factors is warranted. Our findings provide an evidence base for validation as surrogate end points in future PH interventional trials in ILD. TRIAL REGISTRY: International Prospective Register of Systematic Reviews; No.: CRD42021255394; URL: https://www.crd.york.ac.uk/prospero/.

Ubiquitous, B12-dependent virioplankton utilizing ribonucleotide-triphosphate reductase demonstrate interseasonal dynamics and associate with a diverse range of bacterial hosts in the pelagic ocean.

Through infection and lysis of their coexisting bacterial hosts, viruses impact the biogeochemical cycles sustaining globally significant pelagic oceanic ecosystems. Currently, little is known of the ecological interactions between lytic viruses and their bacterial hosts underlying these biogeochemical impacts at ecosystem scales. This study focused on populations of lytic viruses carrying the B12-dependent Class II monomeric ribonucleotide reductase (RNR) gene, ribonucleotide-triphosphate reductase (Class II RTPR), documenting seasonal changes in pelagic virioplankton and bacterioplankton using amplicon sequences of Class II RTPR and the 16S rRNA gene, respectively. Amplicon sequence libraries were analyzed using compositional data analysis tools that account for the compositional nature of these data. Both virio- and bacterioplankton communities responded to environmental changes typically seen across seasonal cycles as well as shorter term upwelling-downwelling events. Defining Class II RTPR-carrying viral populations according to major phylogenetic clades proved a more robust means of exploring virioplankton ecology than operational taxonomic units defined by percent sequence homology. Virioplankton Class II RTPR populations showed positive associations with a broad phylogenetic diversity of bacterioplankton including dominant taxa within pelagic oceanic ecosystems such as Prochlorococcus and SAR11. Temporal changes in Class II RTPR virioplankton, occurring as both free viruses and within infected cells, indicated possible viral-host pairs undergoing sustained infection and lysis cycles throughout the seasonal study. Phylogenetic relationships inferred from Class II RTPR sequences mirrored ecological patterns in virio- and bacterioplankton populations demonstrating possible genome to phenome associations for an essential viral replication gene.

The cost of divided attention for detection of simple visual features primarily reflects limits in post-perceptual processing.

Covert spatial attention allows us to prioritize processing at relevant locations. Perception is generally poorer when attention is distributed across multiple locations than when attention is focused on a single location. However, while divided attention typically impairs performance, recent work suggests that divided attention does not seem to impair detection of simple visual features. Here, we re-examined this possibility. In two experiments, observers detected a simple target (a vertical Gabor), and we manipulated whether attention was focused at one location (focal-cue condition) or distributed across two locations (distributed-cue condition). In Experiment 1, targets could appear independently at each location, such that observers needed to judge target presence for each location separately in the distributed-cue condition. Under these conditions, we found a robust cost of dividing attention. Next, we further probed what stage of processing gave rise to this cost. In Experiment 1, the cost of dividing attention could reflect a limit in the ability to make concurrent judgments about target presence. In Experiment 2, we simplified the task to test whether this was the case: just one target could appear on each trial, such that observers made a single judgment ("was a target present?") in both the focal-cue and distributed-cue conditions. Here, we found a marginal cost of dividing attention that was weaker than the cost in Experiment 1. Together, our results suggest that divided attention does impair detection of simple visual features, but that this cost is primarily due to a limit in post-perceptual processes.

Novel Viral DNA Polymerases From Metagenomes Suggest Genomic Sources of Strand-Displacing Biochemical Phenotypes.

Viruses are the most abundant and diverse biological entities on the planet and constitute a significant proportion of Earth's genetic diversity. Most of this diversity is not represented by isolated viral-host systems and has only been observed through sequencing of viral metagenomes (viromes) from environmental samples. Viromes provide snapshots of viral genetic potential, and a wealth of information on viral community ecology. These data also provide opportunities for exploring the biochemistry of novel viral enzymes. The in vitro biochemical characteristics of novel viral DNA polymerases were explored, testing hypothesized differences in polymerase biochemistry according to protein sequence phylogeny. Forty-eight viral DNA Polymerase I (PolA) proteins from estuarine viromes, hot spring metagenomes, and reference viruses, encompassing a broad representation of currently known diversity, were synthesized, expressed, and purified. Novel functionality was shown in multiple PolAs. Intriguingly, some of the estuarine viral polymerases demonstrated moderate to strong innate DNA strand displacement activity at high enzyme concentration. Strand-displacing polymerases have important technological applications where isothermal reactions are desirable. Bioinformatic investigation of genes neighboring these strand displacing polymerases found associations with SNF2 helicase-associated proteins. The specific function of SNF2 family enzymes is unknown for prokaryotes and viruses. In eukaryotes, SNF2 enzymes have chromatin remodeling functions but do not separate nucleic acid strands. This suggests the strand separation function may be fulfilled by the DNA polymerase for viruses carrying SNF2 helicase-associated proteins. Biochemical data elucidated from this study expands understanding of the biology and ecological behavior of unknown viruses. Moreover, given the numerous biotechnological applications of viral DNA polymerases, novel viral polymerases discovered within viromes may be a rich source of biological material for further in vitro DNA amplification advancements.

Multidisciplinary Care and Prognosis in Patients With COPD and Interstitial Lung Disease Prescribed Long-Term Oxygen Therapy.

BACKGROUND: Home oxygen therapy is prescribed for patients with advanced lung disease based on the criteria established in landmark trials in subjects with COPD. In clinical practice, its use has been extrapolated to other diseases, including interstitial lung disease (ILD). Patients with COPD and ILD experience a high symptom burden and require access to specialized multidisciplinary care. We aimed to evaluate the health-related outcomes and supportive care needs of patients with COPD and ILD receiving home oxygen therapy. METHODS: This was a retrospective cohort study using the oxygen database of a quaternary metropolitan teaching hospital. Patients with a diagnosis of COPD or ILD who were prescribed home oxygen therapy between January 2012-December 2018 were identified. Demographic information, results of physiologic testing, comorbidities, hospitalizations, and mortality data were collected. RESULTS: Three hundred and eighty-four subjects were included for analysis, of whom 56% were male. The median age was 75 y. The majority (59%) had a diagnosis of COPD. Long-term oxygen therapy (LTOT) was prescribed for 187 (48.7%), with no significant demographic differences between those with COPD or ILD. Another 187 were prescribed ambulatory oxygen alone, with 55 transitioning to LTOT during the study period. Most subjects (65.4%) were referred for pulmonary rehabilitation; however, palliative care referrals were generally low (22.9%). Referrals to other medical specialties and allied health were common (82%). Transplant-free survival after commencement of LTOT was poor, with 38% of subjects surviving at 5 y. The 5-y survival of subjects with ILD after commencing on LTOT was 10% compared to 52% for those with COPD. Multivariable Cox regression analyses showed that the only predictor of survival after commencing LTOT was the principal respiratory diagnosis. CONCLUSIONS: This study found that subjects prescribed LTOT had poor transplant-free survival after initiation, which was significantly worse for those with ILD compared to those with COPD. Despite their poor overall survival, worse than many cancers, only a minority were referred for palliative care input. Referrals to pulmonary rehabilitation were also suboptimal. This patient population had complex care needs requiring multidisciplinary management. Appropriate and early referrals to palliative care and improved care coordination for this complex group of patients are key areas for improvement in clinical practice.

Towards an integrative view of virus phenotypes.

Understanding how phenotypes emerge from genotypes is a foundational goal in biology. As challenging as this task is when considering cellular life, it is further complicated in the case of viruses. During replication, a virus as a discrete entity (the virion) disappears and manifests itself as a metabolic amalgam between the virus and the host (the virocell). Identifying traits that unambiguously constitute a virus's phenotype is straightforward for the virion, less so for the virocell. Here, we present a framework for categorizing virus phenotypes that encompasses both virion and virocell stages and considers functional and performance traits of viruses in the context of fitness. Such an integrated view of virus phenotype is necessary for comprehensive interpretation of viral genome sequences and will advance our understanding of viral evolution and ecology.

Elevated body temperature contributes to the increased heart rate response during eccentric compared to concentric cycling when matched for oxygen consumption.

A cardiovascular requirement to facilitate thermal homeostasis may partly contribute to the elevated heart rate during eccentric cycling. This study compared the body temperature response to a bout of eccentric (ECC) and concentric (CON) cycling to account for the difference in heart rate. Eight (N = 8) aerobically trained males (age 35 y [SD 8], peak oxygen consumption 3.82 L.min-1 [SD 0.79]) completed an ECC cycling trial (60% PPO) followed by an oxygen consumption/duration matched CON trial (30   ∘ C , 35% RH) on a separate day. Trial termination was determined as an elevation in aural temperature, a surrogate of deep body temperature, by +0.5   ∘ C during ECC. Mean skin (8-sites) and body temperature (weighting of 80:20 for auditory canal and mean skin temperature) were calculated. Matching the oxygen consumption between the trials increased external work during ECC cycling (CON: 71 [SD 14] ECC: 194 [SD 38] W, p < 0.05) and elevated aural temperature (+0.5   ∘ C ) by 20 min 32 s [SD 9 min 19 s] in that trial. The peak rate of rise in aural temperature was significantly greater in ECC (CON: 0.012 [SD 0.007] ECC: 0.031 [SD 0.002] oC.s-1, p < 0.05). Aural, mean skin and body temperature were significantly higher during the ECC trial (p < 0.05) and this was accompanied by elevated mean heart rate (CON: 103 [SD 14] ECC: 118 [SD 12] b.min-1, p < 0.05) and thermal discomfort (p < 0.05). Moderate load eccentric cycling imposes an elevated thermal strain when compared to concentric cycling. This requirement for dissipating heat, in part, explains the elevated heart rate during eccentric cycling.

The Acute Physiological Responses of Eccentric Cycling During the Recovery Periods of a High Intensity Concentric Cycling Interval Session.

Eccentric and concentric exercise is associated with disparate acute and chronic responses. We uniquely interspersed workload equivalent eccentric cycling during each recovery period of a high intensity interval training (HIIT) cycling trial to determine acute cardiopulmonary, thermal and psycho-physiological responses. Twelve males [age 28 years (SD 6), peak oxygen consumption 48 mL ⋅ kg-1 ⋅ min-1 (SD 6)] completed two high intensity interval cycling trials [4 × 5 min, 60% peak power output (PPO)] separated by 7-10 days. The CONR trial required participants to cycle concentrically during each recovery period (5 min, 30% PPO). The ECC R trial modified the recovery to be eccentric cycling (5 min, 60% PPO). High intensity workload (CONR : 187 ± 17; ECC R: 187 ± 21 W), oxygen consumption (CONR : 2.55 ± 0.17; ECC R: 2.68 ± 0.20 L ⋅ min-1), heart rate (CONR : 165 ± 7; ECC R: 171 ± 10 beats ⋅ min-1) and RPE legs (CONR : 15 ± 3; ECC R: 15 ± 3) were equivalent between trials. Eccentric cycling recovery significantly increased external workload (CONR : 93 ± 18; ECC R: 196 ± 24 W, P < 0.01) yet lowered oxygen consumption (CONR : 1.51 ± 0.18; ECC R: 1.20 ± 0.20 L ⋅ min-1, P < 0.05) while heart rate (CONR : 132 ± 13; ECC R: 137 ± 12 beats ⋅ min-1) and RPE of the legs (CONR : 11 ± 7; ECC R: 12 ± 7) remained equivalent. There was no significant difference in the aural temperature between the trials (ECC R: 37.3 ± 0.1°C; CONR : 37.4 ± 0.1°C, P > 0.05), yet during recovery periods mean skin temperature was significantly elevated in the ECC R (ECC R: 33.9 ± 0.2°C; CONR : 33.3 ± 0.2°C, P < 0.05). Participants preferred ECC R (10/12) and rated the ECC R as more achievable (82.8 ± 11.4 mm) than CONR (79.4 ± 15.9 mm, P < 0.01). In conclusion, eccentric cycling during the recovery period of a HIIT training session, offers a novel approach to concurrent training methodology. The unique cardiopulmonary and skeletal muscle responses facilitate the achievement of both training stimuli within a single exercise bout.

Iroki: automatic customization and visualization of phylogenetic trees.

Phylogenetic trees are an important analytical tool for evaluating community diversity and evolutionary history. In the case of microorganisms, the decreasing cost of sequencing has enabled researchers to generate ever-larger sequence datasets, which in turn have begun to fill gaps in the evolutionary history of microbial groups. However, phylogenetic analyses of these types of datasets create complex trees that can be challenging to interpret. Scientific inferences made by visual inspection of phylogenetic trees can be simplified and enhanced by customizing various parts of the tree. Yet, manual customization is time-consuming and error prone, and programs designed to assist in batch tree customization often require programming experience or complicated file formats for annotation. Iroki, a user-friendly web interface for tree visualization, addresses these issues by providing automatic customization of large trees based on metadata contained in tab-separated text files. Iroki's utility for exploring biological and ecological trends in sequencing data was demonstrated through a variety of microbial ecology applications in which trees with hundreds to thousands of leaf nodes were customized according to extensive collections of metadata. The Iroki web application and documentation are available at https://www.iroki.net or through the VIROME portal http://virome.dbi.udel.edu. Iroki's source code is released under the MIT license and is available at https://github.com/mooreryan/iroki.

Reannotation of the Ribonucleotide Reductase in a Cyanophage Reveals Life History Strategies Within the Virioplankton.

Ribonucleotide reductases (RNRs) are ancient enzymes that catalyze the reduction of ribonucleotides to deoxyribonucleotides. They are required for virtually all cellular life and are prominent within viral genomes. RNRs share a common ancestor and must generate a protein radical for direct ribonucleotide reduction. The mechanisms by which RNRs produce radicals are diverse and divide RNRs into three major classes and several subclasses. The diversity of radical generation methods means that cellular organisms and viruses typically contain the RNR best-suited to the environmental conditions surrounding DNA replication. However, such diversity has also fostered high rates of RNR misannotation within subject sequence databases. These misannotations have resulted in incorrect translative presumptions of RNR biochemistry and have diminished the utility of this marker gene for ecological studies of viruses. We discovered a misannotation of the RNR gene within the Prochlorococcus phage P-SSP7 genome, which caused a chain of misannotations within commonly observed RNR genes from marine virioplankton communities. These RNRs are found in marine cyanopodo- and cyanosiphoviruses and are currently misannotated as Class II RNRs, which are O2-independent and require cofactor B12. In fact, these cyanoviral RNRs are Class I enzymes that are O2-dependent and may require a di-metal cofactor made of Fe, Mn, or a combination of the two metals. The discovery of an overlooked Class I ß subunit in the P-SSP7 genome, together with phylogenetic analysis of the α and ß subunits confirms that the RNR from P-SSP7 is a Class I RNR. Phylogenetic and conserved residue analyses also suggest that the P-SSP7 RNR may constitute a novel Class I subclass. The reannotation of the RNR clade represented by P-SSP7 means that most lytic cyanophage contain Class I RNRs, while their hosts, B12-producing Synechococcus and Prochlorococcus, contain Class II RNRs. By using a Class I RNR, cyanophage avoid a dependence on host-produced B12, a more effective strategy for a lytic virus. The discovery of a novel RNR ß subunit within cyanopodoviruses also implies that some unknown viral genes may be familiar cellular genes that are too divergent for homology-based annotation methods to identify.

Inappropriate inhaled corticosteroid prescribing in chronic obstructive pulmonary disease patients.

The Australian National Chronic Obstructive Pulmonary Disease (COPD) guidelines recommend that inhaled corticosteroids (ICS) be reserved for patients with a post-bronchodilator forced expiratory volume in 1 s (FEV1 ) less than 50% predicted and those who experience ≥2 exacerbations in 12 months. In total, 707 COPD patients were identified from the lung function test database at our tertiary hospital; 52.4% of patients with a post-bronchodilator FEV1 ≥50% were prescribed an ICS. Significant discordance exists between guideline recommendations and inhaler prescription.