Identification and characterization of domain-specific inhibitors of DENV NS3 and NS5 proteins by in silico screening methods.

The dengue virus (DENV) infects approximately 400 million people annually worldwide causing significant morbidity and mortality. Despite advances in understanding the virus life cycle and infectivity, no specific treatment for this disease exists due to the lack of therapeutic drugs. In addition, vaccines available currently are ineffective with severe side effects. Therefore, there is an urgent need for developing therapeutics suitable for effective management of DENV infection. In this study, we adopted a drug repurposing strategy to identify new therapeutic use of existing FDA approved drug molecules to target DENV2 non-structural proteins NS3 and NS5 using computational approaches. We used Drugbank database molecules for virtual screening and multiple docking analysis against a total of four domains, the NS3 protease and helicase domains and NS5 MTase and RdRp domains. Subsequently, MD simulations and MM-PBSA analysis were performed to validate the intrinsic atomic interactions and the binding affinities. Furthermore, the internal dynamics in all four protein domains, in presence of drug molecule binding were assessed using essential dynamics and free energy landscape analyses, which were further coupled with conformational dynamics-based clustering studies and cross-correlation analysis to map the regions that exhibit these structural variations. Our comprehensive analysis identified tolcapone, cefprozil, delavirdine and indinavir as potential inhibitors of NS5 MTase, NS5 RdRp, NS3 protease and NS3 helicase functions, respectively. These high-confidence candidate molecules will be useful for developing effective anti-DENV therapy to combat dengue infection.Communicated by Ramaswamy H. Sarma.

Comparable performance of antigen-detecting rapid test by healthcare worker-collected and self-collected swabs for SARS-CoV-2 diagnostic: A systematic review and meta-analysis.

Usage of self-screening tests has become increasingly relevant in public health perspective for early detection of SARS-CoV-2 infection in the transitioning era of the COVID-19 pandemic into an endemic. This study was designed to compare the diagnostic accuracy of self-conducted and health professional-conducted SARS-CoV-2 rapid antigen tests (Ag-RDTs) and whether the sample was taken from anterior nasal or nasal mid-turbinate. Eligible comparative Ag-RDTs accuracy studies were retrieved from electronic databases systematically, in accordance with PRISMA. Selected studies were assessed for risk of bias using QUADAS-2 and QUADAS-C. In total, we selected five out of 1952 studies retrieved using the keywords. The overall sensitivity for the self-collected nasal swab method and healthcare worker-collected nasopharyngeal swab method was 79% (95% CI 68-87; I2  = 62%) and 83% (95% CI 75-89; I2  = 32%), respectively, which was not statistically different (p = 0.499). Nasal mid-turbinate swabs have a significantly higher sensitivity compared to anterior nasal swabs (p < 0.01). Both sampling methods represent high and comparable specificity values of 98% (95% CI 97-99; I2  = 0%) and 99% (95% CI 98-99; I2  = 0%). Positive predictive value (range 90%-99%) and negative predictive value (range 87%-98%) were equivalent for both methods. Our findings indicated the accuracy of self-collected Ag-RDT on nasal swabs was comparable to those performed by healthcare worker-collected on nasopharyngeal swabs. Self-collected Ag-RDT could be considered as a transmission prevention method in the transition of COVID-19 pandemic.

The Construction of Biologically Relevant Fiber-Reinforced Hydrogel Geometries Using Air-Assisted Dual-Polarity Electrospinning.

Fiber-reinforced hydrogels are a class of soft composite materials that have seen increased use across a wide variety of biomedical applications. However, existing fabrication techniques for these hydrogels are unable to realize biologically relevant macro/mesoscale geometries. To address this limitation, this paper presents a novel air-assisted, dual-polarity electrospinning printhead that converges high-strength electric fields, with low velocity air flow to remove the collector dependency seen with traditional far-field electrospinning setups. The use of this printhead in conjunction with different configurations of deformable collection templates has resulted in the production of three classes of fiber-reinforced hydrogel prototype geometries, viz., (i) tubular geometries with bifurcations and mesoscale texturing; (ii) hollow, nontubular geometries with single and dual-entrances; and (iii) three-dimensional (3D) printed flat geometries with varying fiber density. All three classes of prototype geometries were mechanically characterized to have properties that were in line with those observed in living soft tissues. With the realization of this printhead, biologically relevant macro/mesoscale geometries can be realized using fiber-reinforced hydrogels to aid a wide array of biomedical applications.

COVID-19 Vaccines Portray the Bright Side of Human Creativity, But It Means Nothing until They Prove Their Worth: A Study on Seroconversion after the first Dose of Covishield Vaccine in Central Kerala.

Background: COVID-19 vaccines, we believe, have come to rescue us from the clutches of the dreaded severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With rapid ongoing mutations, it is difficult to predict the effectiveness of seroconversion following vaccination. This study aims to find out the proportion of people with seroconversion following first dose of Covishield vaccine. Methods: Randomly selected health-care workers were followed up for SARS-CoV-2 immunoglobulin G (IgG) antibodies between 28 and 42 days after receiving their first vaccine dose. The VITROS SARS-CoV-2 IgG test (Ortho-Clinical Diagnostics, USA) with 100% specificity and > 90% sensitivity was used to assess seroconversion. Results: The first dose of vaccine induced seroconversion in 91.7% of beneficiaries. Nearly one-third (30.2%) of them had high antibody titers, and it showed a significant association with female gender (9.6 ± 5.5 vs. 7.6 ± 5.6) and younger age (P = 0.008). In addition, those with previous COVID infection showed a more robust immune response when compared to others (P = 0.001). Conclusion: Seroconversion rate of more than 90% offers a promising hope toward successful pandemic control. In the current scenario, the inability to attain the targeted coverage due to an upsurge in vaccine hesitancy, compounded with only lower proportion of seroconversion in elderly, faster rollout of the vaccines without any age limit, will help achieve the herd threshold more rapidly.

Bacterial Cellulose Cultivations Containing Gelatin Form Tunable, Highly Ordered, Laminae Structures with Fourfold Enhanced Productivity.

Manipulation of bacterial cellulose (BC) morphology is important to tune BC properties to meet specific application requirements. In this study, gelatin was added to cultivation media at 0.1-7.5 wt %. After cultivations, gelatin was removed from the BC matrix, and its effects on BC matrix characteristics and fermentation production efficiency were determined. Higher contents of gelatin in cultivation media (up to 5%) resulted in BC that, from scanning electron microscopy observations, had larger pore sizes and formation of a lamina morphology that was highly unidirectional. Crystallinity remained unchanged between 0.1 and 5 wt % gelatin concentrations (92-95%); however, it decreased to 86% at a gelatin concentration of 7.5 wt %. Mechanical properties showed a positive trend as both the specific modulus and specific strength values increased as the gelatin concentration increased to 5 wt %. A breakdown in the ordered structure of the BC matrix occurs at 7.5 wt % gelatin, with corresponding decreases in the specific modulus and specific strength of the BC. The productivity increased by almost 4-fold relative to the control, reaching 1.64 g·L-1h-1 at the 2.5 wt % gelatin content. Also, the water holding capacity increased by 3-fold relative to the control, reaching 306.6 g of water per g BC at the 5.0 wt % gelatin content. The changes observed in these BC metrics can be explained based on literature findings associated with the formation of gelatin aggregates in the cultivation media and an increase in gel stiffness seen at higher media gelatin concentrations. Overall, this work provides a roadmap for manipulating BC properties while creating highly organized lamina morphologies.

Assessment of Squalor in Migrant Colonies of Thiruvalla Province of Kerala, India using Rapid Survey Technique.

BACKGROUND: Domestic squalor refers to households that are extremely cluttered, in a filthy condition, and where the accumulation of items such as personal possessions, rubbish, excrement and decomposing food creates an environment that jeopardizes the health and wellbeing of the occupant(s). In India, an estimated 258 million are migrants. They are more likely to live in squalor due to inferior socio-economic status and no permanent residence. This poses a threat to the health of the migrants and the neighbors. OBJECTIVE: To assess the squalor and morbidity pattern among the migrants of Migrant colonies in Thiruvalla using Rapid survey technique. METHODOLOGY: The state of squalor in migrant colonies was assessed by Lot Quality Assurance Sampling Methodology using the Environment Cleanliness and Clutter Scale (ECCS). The sample size for each lot/colony was '14' dwellings according to LQAS table. The details were collected from 14 inhabitants of different dwellings of the same colony. The inhabitants were selected randomly and were excluded if he belonged to the same dwelling. Fifteen colonies were randomly selected to achieve the sample size of 210 (15*14). The study was done in Tiruvalla municipality. RESULTS AND CONCLUSION: Only two colonies (n = 15) were squalor free. Majority of the dwellings (n = 210) were having an ECCS score between 13 and 15. Common ailments affecting migrants include Common cold, Skin disorders, and dental caries and gastritis. Squalor was found in most of the migrant colonies as they are living in inhuman conditions.

Together let us confront it: An outbreak investigation of hepatitis B in Pathanamthitta district, Kerala.

INTRODUCTION: Hepatitis B is a potentially life-threatening liver infection caused by the Hepatitis B virus (HBV). The established routes of transmission are from mother to infant, sexual contact, and exposure to blood or body fluids. Though HBV is preventable by vaccine and robust infection control practices, outbreaks of HBV infection do occur in India. However, the state of Kerala with its health parameters, one among the best in the country, cannot afford to have continuing outbreaks. An unusual increase in the reported cases of Hepatitis B in a rural area of Pathanamthitta district of Kerala, called for an outbreak investigation. AIMS: To describe the epidemiological features, to determine the risk factors associated with HBV transmission, and to suggest measures to prevent future transmission. METHODS: A community-based case-control study (1:2) was undertaken. A total of 162 participants (54 cases and 108 age, gender, and neighborhood matched controls) took part in the study. Focus group discussions were conducted with subject experts to develop an interview schedule assessing 40 risk factors. It was further reviewed by the University of Sydney. Data was collected by trained Junior Health Inspectors and Junior Public Health Nurses of the Primary Health Centers. Data was analyzed using SPSS v. 20. Proportions were compared by Univariate analysis, sub-group analysis, and logistic regression. Population Attributable Risk (PAR) was also calculated. RESULTS AND CONCLUSION: More than 90% of the infections were IgM anti-HBc positive, suggesting a recent infection. Interventions during hospitalization [OR: 7.98 (95% CI - 2.17--29.4)], family history of Hepatitis B [OR. 4.14 (95%CI - 1.73--9.9)], and laboratory investigations [OR: 3.99 (1.72--9.31)] were found to be significant risk factors. PAR was highest for laboratory interventions (32%). Vaccinating household contacts and strict enforcement of infection control practices could substantially reduce the burden of this fatal disease.

Assessing the combination of magnetic field stimulation, iron oxide nanoparticles, and aligned electrospun fibers for promoting neurite outgrowth from dorsal root ganglia in vitro.

Magnetic fiber composites combining superparamagnetic iron oxide nanoparticles (SPIONs) and electrospun fibers have shown promise in tissue engineering fields. Controlled grafting of SPIONs to the fibers post-electrospinning generates biocompatible magnetic composites without altering desired fiber morphology. Here, for the first time, we assess the potential of SPION-grafted scaffolds combined with magnetic fields to promote neurite outgrowth by providing contact guidance from the aligned fibers and mechanical stimulation from the SPIONs in the magnetic field. Neurite outgrowth from primary rat dorsal root ganglia (DRG) was assessed from explants cultured on aligned control and SPION-grafted electrospun fibers as well as on non-grafted fibers with SPIONs dispersed in the culture media. To determine the optimal magnetic field stimulation to promote neurite outgrowth, we generated a static, alternating, and linearly moving magnet and simulated the magnetic flux density at different areas of the scaffold over time. The alternating magnetic field increased neurite length by 40% on control fibers compared to a static magnetic field. Additionally, stimulation with an alternating magnetic field resulted in a 30% increase in neurite length and 62% increase in neurite area on SPION-grafted fibers compared to DRG cultured on PLLA fibers with untethered SPIONs added to the culture media. These findings demonstrate that SPION-grafted fiber composites in combination with magnetic fields are more beneficial for stimulating neurite outgrowth on electrospun fibers than dispersed SPIONs. STATEMENT OF SIGNIFICANCE: Aligned electrospun fibers improve axonal regeneration by acting as a passive guidance cue but do not actively interact with cells, while magnetic nanoparticles can be remotely manipulated to interact with neurons and elicit neurite outgrowth. Here, for the first time, we examine the combination of magnetic fields, magnetic nanoparticles, and aligned electrospun fibers to enhance neurite outgrowth. We show an alternating magnetic field alone increases neurite outgrowth on aligned electrospun fibers. However, combining the alternating field with magnetic nanoparticle-grafted fibers does not affect neurite outgrowth compared to control fibers but improves outgrowth compared to freely dispersed magnetic nanoparticles. This study provides the groundwork for utilizing magnetic electrospun fibers and magnetic fields as a method for promoting axonal growth.

Evaluation of Glucocorticoids Utilization in Central Kerala using Pharmacy Sales Overview.

Background: Misuse of prescription drugs is a major public health problem in India and developing countries. Emerging evidence indicates that glucocorticoids are a class of drugs that are silently misused. These drugs are inexpensive and easily available as over-the-counter drugs in India are widely used by local practitioners and self-prescribed by patients for swift symptomatic relief of febrile illnesses, joint pain, asthma, other respiratory illnesses, and skin diseases. Many people have become dependent on glucocorticoids unintentionally and remain completely unaware of the metabolic changes occurring in their bodies. Methodology: A descriptive cross-sectional study involving 38 pharmacies in Thiruvalla municipality of South India was conducted to indirectly assess the utilization of glucocorticoids in the region using a pharmacy sales overview. Results: Most people approach pharmacies with prescriptions than without. A high majority of pharmacists do not have any knowledge about the uses (37%) or adverse effects (66%) of glucocorticoids. More than 50% of the community pharmacies have more than 1% of their sales attributed to glucocorticoids when compared with the total sales volume of drugs.

Effect of Atomized Delivery of Nutrients on the Growth Characteristics and Microstructure Morphology of Bacterial Cellulose.

This work demonstrates a general strategy for introducing remarkable changes in matrix organization and, consequently, functional properties of bacterial cellulose (BC). BC-producing cells were induced, using a well-defined atomized droplet nutrient delivery (ADND) system, to form pellicles with a regular layered morphology that persists throughout the mat depth. In contrast, the morphology of mats formed by conventional static medium nutrient delivery (SMND) is irregular with no distinguishable pattern. ADND also resulted in larger meso-scale average pore sizes but did not alter the fibril diameter (∼70 nm) and crystallinity index (92-95%). The specific modulus and specific tensile strength of ADND mats are higher than those of SMND mats. This is due to the regularity of dense layers that are present in ADND mats that are able to sustain tensile loads, when applied parallel to these layers. The density of BC films prepared by ADND is 1.63-fold lower than that of the SMND BC film. Consequently, the water contents (g/g) of ADND- and SMND-prepared BC mats are 263 ± 8.85 and 99.6 ± 2.04, respectively. A model that rationalizes differences in mat morphology resulting from these nutrient delivery methods based on nutrient and oxygen concentration gradients is proposed. This work raises questions as to the extent that ADND can be used to fine-tune the matrix morphology and how the resulting lower density mats will alter the diffusion of actives from the films to wound sites and increase the ability of cells to infiltrate the matrix during tissue engineering.

Quantifying machining outputs of pristine human teeth relevant to dental preparation procedures.

Minimally-assisted tooth repair (MaTR) systems are envisioned to be capable of substituting for the skill of a dentist. If successfully developed, MaTR systems could enable lower-skilled dental technicians to provide dental care at a fraction of the overall medical cost. This paper explores a key initial step towards the development of such systems by quantifying the machining responses of pristine human teeth relevant to dental preparation procedures. The working hypothesis of the study is that such findings will enable the benchmarking of key process planning and control metrics relevant for the future development of MaTR systems. To this end, pristine human cadaver teeth were cut using a computer-controlled motion platform and dental hand-piece. Relevant cutting responses, such as cutting forces, in-process rotational speed of the dental bur, teeth morphology, and bur wear were captured. The trends in cutting forces show the potential for implementing region-specific process parameters for cutting the enamel and dentin regions of the tooth. A feed-per-tooth value of 0.1 µm at rotational speeds of 8 krpm and 50 krpm is seen to cut both the enamel and dentin regions at cutting forces lower than patient discomfort thresholds identified in literature. Cutting force signals were also successfully mapped against the CT-scan data of the tooth. This mapping indicates a clear identification of the enamel/dentin regions, and a transition region that is dependent on cutting parameters, tooth/tool geometry and tool pose. The trends in the in-process rotational speed of the dental bur indicate that stalling of the dental bur occurs at feed per tooth values greater than 0.25 µm. The evidence of stalling can be detected by both a drop in the cutting force signal and by surface morphology changes on the cut surface of the tooth. MaTR systems should be designed to avoid bur stalling regions by either operating at feed per tooth values ≤ 0.25 µm or by the use of dental spindles with higher torque capacity. Lastly, the type of fit present on the shank of the bur is seen to result in differences in the cutting force signals and wear of the cutting edges (flutes) of the dental bur. In general, a right-angle (RA) fit on the shank of the dental bur results in a larger tool runout leading to uneven loads on the flutes and increased tool wear. The friction grip (FG) fit avoids these problems and may be more suited for MaTR systems.

Stochasticity in materials structure, properties, and processing-A review.

We review the concept of stochasticity-i.e., unpredictable or uncontrolled fluctuations in structure, chemistry, or kinetic processes-in materials. We first define six broad classes of stochasticity: equilibrium (thermodynamic) fluctuations; structural/compositional fluctuations; kinetic fluctuations; frustration and degeneracy; imprecision in measurements; and stochasticity in modeling and simulation. In this review, we focus on the first four classes that are inherent to materials phenomena. We next develop a mathematical framework for describing materials stochasticity and then show how it can be broadly applied to these four materials-related stochastic classes. In subsequent sections, we describe structural and compositional fluctuations at small length scales that modify material properties and behavior at larger length scales; systems with engineered fluctuations, concentrating primarily on composite materials; systems in which stochasticity is developed through nucleation and kinetic phenomena; and configurations in which constraints in a given system prevent it from attaining its ground state and cause it to attain several, equally likely (degenerate) states. We next describe how stochasticity in these processes results in variations in physical properties and how these variations are then accentuated by-or amplify-stochasticity in processing and manufacturing procedures. In summary, the origins of materials stochasticity, the degree to which it can be predicted and/or controlled, and the possibility of using stochastic descriptions of materials structure, properties, and processing as a new degree of freedom in materials design are described.

Toward Morphologically Relevant Extracellular Matrix in Vitro Models: 3D Fiber Reinforced Hydrogels.

The extracellular matrix (ECM) is known to play an important role in the health of cells and tissues. Not only are chemical signals transmitted via bonds and tightly controlled diffusion, but the structure of the ECM also provides important physical signaling for the cells attached to it. The structure is composed of a mesh of fibrous proteins, such as collagen, embedded in a hydrated gel matrix of glycosaminoglycans. To study cell behavior with respect to the combined morphology and mechanics of such matrices is not currently possible with the types of 3D cell culture matrices available. Most of the cell culture matrices are single-phase bio- or polymeric hydrogels. Therefore, here we developed a continuous hybrid manufacturing process to make fiber-reinforced composite hydrogels. A far field electrospinning process was used to deposit the fibrous component with the aid of guiding electrodes; and a gravity-assisted, droplet-based system controlled the rate of addition of the cell-laden hydrogel component. The addition of the fibrous component slightly increased the elastic modulus of the pure hydrogel. The cells that were embedded into the fiber-reinforced hydrogels were viable for 8 days. The cells were randomly placed in the matrix such that some had no contact to the fibers and others were initially in proximity to fibers. The cells with no contact to fibers grew into spheroidal clusters within the hydrogel, and those in proximity to the fibers spread out and grew along the fibers showing that the fiber-reinforced hydrogels are able to control cell behavior with morphological cues.

Screening for obstructive sleep apnoea using the STOPBANG questionnaire and the Epworth sleepiness score in patients admitted on the unselected acute medical take in a UK hospital.

Obstructive sleep apnoea (OSA), which is often overlooked in patients presenting to primary and secondary care, is an increasingly common comorbidity. The prevalence of OSA has not been studied in the unselected acute medical take. The aim of this study was to screen for the prevalence of undiagnosed OSA using the STOPBANG Questionnaire and the Epworth sleepiness scale (ESS) score in an unselected acute medical take. This was a cross-sectional study in a busy UK general hospital. Patient demographics, comorbidities, ESS and STOPBANG scores on unselected acute medical takes were reviewed and analysed to assess the prevalence of OSA. Of 93 patients screened, more than 50% were obese. The STOPBANG score was ≥3 in 73%. The ESS was significantly increased (≥11) in 20%. On multivariate analysis, ESS continued to remain independently associated with the STOPBANG score with a p-value of 0.04. The routine use of the STOPBANG questionnaire followed by an ESS score in those with a score of ≥3 may focus evaluation for undetected OSA in the acute medical care setting.

Loculated pneumothorax due to a rare combination resulting in an interesting chest radiograph.

A 35 years old man presented with acute onset left sided pleuritic chest pain and shortness of breath. On evaluation, he was found to have an interesting chest radiograph which showed a loculated pneumothorax with collapse of the left upper lobe and lingula but fully expanded left lower lobe. He is a known asthmatic who had allergic broncho pulmonary aspergillosis (ABPA) previously with left upper lobe and lingular collapse secondary to mucous plugging. This resolved on treatment with steroids and itraconazole. An interesting combination of events is proposed to explain the current presentation. CT scan chest and blood tests confirmed this sequence of events. He was appropriately treated resulting in complete clinical and radiological recovery. The events leading to the presentation and the likely physiological background for this interesting chest radiograph are discussed.

Conundrum in an asthma exacerbation.

A 66-year-old man, an asthmatic, presented with symptoms suggestive of an acute exacerbation of asthma. His arterial blood gas revealed type 1 respiratory failure (PaO2 <8 kPa or 60 mm Hg with normal or low PaCO2) with a compensated lactic acidosis. He was treated for an asthma exacerbation and sepsis. Despite treatment, his respiratory rate remained elevated although his hypoxaemia improved. There was progressive worsening of the lactic acidosis. Treatment for sepsis was augmented. Peak flow measurements were not used to assess the severity of his exacerbation nor his response to treatment. An alternate diagnosis of acute coronary syndrome with acute pulmonary oedema was made and his asthma treatment was stopped. This coincided with a decline in his serum lactate. A diagnosis of salbutamol-induced lactic acidosis (SILA) was made. SILA is a relatively common complication of salbutamol therapy in moderate/severe asthma exacerbations. It is caused by a mechanism different from the lactataemia that is associated with septic shock and life-threatening asthma.

Machining characteristics of the haversian and plexiform components of bovine cortical bone.

This paper investigates the characteristic differences observed while machining the haversian and plexiform components of a bovine cortical femoral bone. To this end micro-milling slotting experiments are performed on both the components by varying both the cutting velocity and the feed-per-tooth values. The scale of machining is chosen specifically to ensure sensitivity to the microstructural variations in the bone. The material properties of the microstructural components and their size-scale relative to the feed-per-tooth values are seen to dictate the failure mechanisms encountered during machining. The cutting force, surface roughness, and tool wear are all uniquely affected by the plexiform and haversian components of the cortical bone. In general, plexiform bone requires a higher cutting force than the haversian bone. While a higher cutting velocity can lower the surface roughness of haversian bone, it typically results in the most surface damage. The cutting force and surface roughness values for both the components show strain rate sensitivity. The tool wear is seen to be the highest while cutting parallel to the lamellar structures seen in the plexiform bone.

Lack of Utility of Thoracoscore in Evaluating Fitness for Surgery in Lung Cancer.

BACKGROUND: The thoracic surgery scoring system (Thoracoscore) is a multivariate scoring system with nine parameters used for predicting inpatient mortality after thoracic surgery. In clinical practice, the value of the thoracoscore in evaluating the fitness of individual patients for surgery is not clear. OBJECTIVE: The study objective was to evaluate the performance of thoracoscore in evaluating fitness for surgery for lung cancer and compare it with cardiopulmonary exercise test (CPEX). METHODS: We retrospectively analysed data over a 2-year period from the CPEX database of patients referred for preoperative assessment prior to surgery for lung cancer. RESULTS: Twenty-two patients who had borderline lung function impairment had CPEX to assess fitness for surgery. Fifteen (68%) were deemed fit and went on to have thoracic surgery while 7 (32%) were considered high risk and were turned down. The predicted death rate based on thoracoscore for patients who had surgery was 3.5 ± 2.8 as compared to 3.4 ± 2.0 for patients who did not have surgery (p > 0.05). The mean peak VO2 (peak oxygen uptake during CPEX) among those who had surgery was significantly higher than those who did not have surgery (14.2 mL/kg/min versus 10.1 mL/kg/min). There was no correlation of thoracoscore with lung function parameters, duration of hospital stay and peak VO2. CONCLUSIONS: Our study showed that CPEX remains a standard and useful tool for functional assessment prior to lung cancer resection. There is no correlation between thoracoscore and either CPEX or pulmonary function parameters. Thoracoscore should not be used to assess fitness for surgery.

Effect of Opioids vs NSAIDs and Larger vs Smaller Chest Tube Size on Pain Control and Pleurodesis Efficacy Among Patients With Malignant Pleural Effusion: The TIME1 Randomized Clinical Trial.

IMPORTANCE: For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because they may reduce pleurodesis efficacy. Smaller chest tubes may be less painful than larger tubes, but efficacy in pleurodesis has not been proven. OBJECTIVE: To assess the effect of chest tube size and analgesia (NSAIDs vs opiates) on pain and clinical efficacy related to pleurodesis in patients with malignant pleural effusion. DESIGN, SETTING, AND PARTICIPANTS: A 2×2 factorial phase 3 randomized clinical trial among 320 patients requiring pleurodesis in 16 UK hospitals from 2007 to 2013. INTERVENTIONS: Patients undergoing thoracoscopy (n = 206; clinical decision if biopsy was required) received a 24F chest tube and were randomized to receive opiates (n = 103) vs NSAIDs (n = 103), and those not undergoing thoracoscopy (n = 114) were randomized to 1 of 4 groups (24F chest tube and opioids [n = 28]; 24F chest tube and NSAIDs [n = 29]; 12F chest tube and opioids [n = 29]; or 12F chest tube and NSAIDs [n = 28]). MAIN OUTCOMES AND MEASURES: Pain while chest tube was in place (0- to 100-mm visual analog scale [VAS] 4 times/d; superiority comparison) and pleurodesis efficacy at 3 months (failure defined as need for further pleural intervention; noninferiority comparison; margin, 15%). RESULTS: Pain scores in the opiate group (n = 150) vs the NSAID group (n = 144) were not significantly different (mean VAS score, 23.8 mm vs 22.1 mm; adjusted difference, -1.5 mm; 95% CI, -5.0 to 2.0 mm; P = .40), but the NSAID group required more rescue analgesia (26.3% vs 38.1%; rate ratio, 2.1; 95% CI, 1.3-3.4; P = .003). Pleurodesis failure occurred in 30 patients (20%) in the opiate group and 33 (23%) in the NSAID group, meeting criteria for noninferiority (difference, -3%; 1-sided 95% CI, -10% to ∞; P = .004 for noninferiority). Pain scores were lower among patients in the 12F chest tube group (n = 54) vs the 24F group (n = 56) (mean VAS score, 22.0 mm vs 26.8 mm; adjusted difference, -6.0 mm; 95% CI, -11.7 to -0.2 mm; P = .04) and 12F chest tubes vs 24F chest tubes were associated with higher pleurodesis failure (30% vs 24%), failing to meet noninferiority criteria (difference, -6%; 1-sided 95% CI, -20% to ∞; P = .14 for noninferiority). Complications during chest tube insertion occurred more commonly with 12F tubes (14% vs 24%; odds ratio, 1.91; P = .20). CONCLUSIONS AND RELEVANCE: Use of NSAIDs vs opiates resulted in no significant difference in pain scores but was associated with more rescue medication. NSAID use resulted in noninferior rates of pleurodesis efficacy at 3 months. Placement of 12F chest tubes vs 24F chest tubes was associated with a statistically significant but clinically modest reduction in pain but failed to meet noninferiority criteria for pleurodesis efficacy. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN33288337.