Longitudinal characterisation of haematological and biochemical parameters in cancer patients prior to and during COVID-19 reveals features associated with outcome.

BACKGROUND: Cancer patients are at increased risk of death from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer and its treatment affect many haematological and biochemical parameters, therefore we analysed these prior to and during coronavirus disease 2019 (COVID-19) and correlated them with outcome. PATIENTS AND METHODS: Consecutive patients with cancer testing positive for SARS-CoV-2 in centres throughout the United Kingdom were identified and entered into a database following local governance approval. Clinical and longitudinal laboratory data were extracted from patient records. Data were analysed using Mann-Whitney U test, Fisher's exact test, Wilcoxon signed rank test, logistic regression, or linear regression for outcomes. Hierarchical clustering of heatmaps was performed using Ward's method. RESULTS: In total, 302 patients were included in three cohorts: Manchester (n = 67), Liverpool (n = 62), and UK (n = 173). In the entire cohort (N = 302), median age was 69 (range 19-93 years), including 163 males and 139 females; of these, 216 were diagnosed with a solid tumour and 86 with a haematological cancer. Preinfection lymphopaenia, neutropaenia and lactate dehydrogenase (LDH) were not associated with oxygen requirement (O2) or death. Lymphocyte count (P < 0.001), platelet count (P = 0.03), LDH (P < 0.0001) and albumin (P < 0.0001) significantly changed from preinfection to during infection. High rather than low neutrophils at day 0 (P = 0.007), higher maximal neutrophils during COVID-19 (P = 0.026) and higher neutrophil-to-lymphocyte ratio (NLR; P = 0.01) were associated with death. In multivariable analysis, age (P = 0.002), haematological cancer (P = 0.034), C-reactive protein (P = 0.004), NLR (P = 0.036) and albumin (P = 0.02) at day 0 were significant predictors of death. In the Manchester/Liverpool cohort 30 patients have restarted therapy following COVID-19, with no additional complications requiring readmission. CONCLUSION: Preinfection biochemical/haematological parameters were not associated with worse outcome in cancer patients. Restarting treatment following COVID-19 was not associated with additional complications. Neutropaenia due to cancer/treatment is not associated with COVID-19 mortality. Cancer therapy, particularly in patients with solid tumours, need not be delayed or omitted due to concerns that treatment itself increases COVID-19 severity.

State of knowledge on the occupational exposure to carbon nanotubes.

Carbon nanotubes (CNT) trigger fascination as well as anxiety, given their unique physical and chemical properties, and continuing concerns around their possible health effects. CNT exposure assessment is an integral component of occupational and environmental epidemiology, risk assessment, and management. We conducted a systematic review to analyze the quality of CNT occupational exposure assessments in field studies and to assess the relevance of available quantitative data from occupational hygiene and epidemiological perspectives. PubMed and Scopus databases were searched for the period 2000-2018. To grade the quality of each study, we used a standardized grid of seven criteria. The first criterion addressed 12 items deemed most relevant CNT physical-chemical properties with respect to their in vitro and in vivo toxicity. We included 27 studies from 11 countries in the review and graded them high (n = 2), moderate (n = 15) and low quality (n = 10). Half of the studies measured elemental carbon mass concentration (EC) using different methods and aerosol fractions. In 85% of studies, the observed values exceed the US National Institute for Occupational Safety and Health Recommended Exposure Limit. The quantification of CNT agglomerates and/or CNT contained fibers becomes increasingly common although lacking methodological standardization. Work activities with the greatest mean CNT mass concentrations were non-enclosed and included sieving, harvesting, packaging, reactor cleaning, extrusion and pelletizing. Some of the large studies defined standardized job titles according to exposure estimates at corresponding workstations and classified them by decreasing CNT exposure level: technicians > engineers > chemists. The already initiated harmonization of CNT exposure assessment and result reporting need to continue to favor not only studies in the field, but also to identify companies and workers using CNTs to characterize their exposures as well as monitor their health. This will enable an objective and realistic evaluation of risks associated with CNT applications and an appropriate risk management.

Comparison of digital mammography and digital breast tomosynthesis in the detection of architectural distortion.

OBJECTIVES: To compare interobserver variability (IOV), reader confidence, and sensitivity/specificity in detecting architectural distortion (AD) on digital mammography (DM) versus digital breast tomosynthesis (DBT). METHODS: This IRB-approved, HIPAA-compliant reader study used a counterbalanced experimental design. We searched radiology reports for AD on screening mammograms from 5 March 2012-27 November 2013. Cases were consensus-reviewed. Controls were selected from demographically matched non-AD examinations. Two radiologists and two fellows blinded to outcomes independently reviewed images from two patient groups in two sessions. Readers recorded presence/absence of AD and confidence level. Agreement and differences in confidence and sensitivity/specificity between DBT versus DM and attendings versus fellows were examined using weighted Kappa and generalised mixed modeling, respectively. RESULTS: There were 59 AD patients and 59 controls for 1,888 observations (59 × 2 (cases and controls) × 2 breasts × 2 imaging techniques × 4 readers). For all readers, agreement improved with DBT versus DM (0.61 vs. 0.37). Confidence was higher with DBT, p = .001. DBT achieved higher sensitivity (.59 vs. .32), p < .001; specificity remained high (>.90). DBT achieved higher positive likelihood ratio values, smaller negative likelihood ratio values, and larger ROC values. CONCLUSIONS: DBT decreases IOV, increases confidence, and improves sensitivity while maintaining high specificity in detecting AD. KEY POINTS: • Digital breast tomosynthesis decreases interobserver variability in the detection of architectural distortion. • Digital breast tomosynthesis increases reader confidence in the detection of architectural distortion. • Digital breast tomosynthesis improves sensitivity in the detection of architectural distortion.

Pityriasis lichenoides chronica associated with use of HMG-CoA reductase inhibitors.

Herein, we present three cases of Pityriasis lichenoides chronica (PLC) in patients who developed the rash after use of 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMG-CoA) reductase inhibitors. The patients had complete resolution after standard treatment by dermatologists and withdrawal of the offending agents. In one case, the patient had a previous episode of a similar rash that occurred with HMG-CoA reductase inhibitors use many years previously. Pityriasis lichenoides chronica is a condition of unknown aetiology. Several agents have been associated with its presentation. We postulate HMG-CoA reductase inhibition in skin presents a final common pathway for the presentation of PLC in select patients.

TARGETING THE NS5A PROTEIN OF HCV: AN EMERGING OPTION.

Hepatitis C virus (HCV) infects more than 3% of the world's population, leading to an increased risk of cirrhosis and hepatocellular carcinoma. The current standard of care, a combination of pegylated interferon alfa and ribavirin, is poorly tolerated and often ineffective against the most prevalent genotype of the virus, genotype 1. The very recent approval of boceprevir and telaprevir, two HCV protease inhibitors, promises to significantly improve treatment options and outcomes. In addition to the viral protease NS3 and the viral polymerase NS5B, direct-acting antivirals are now in development against NS5A. A multifunctional phosphoprotein, NS5A is essential to HCV genome replication, but has no known enzymatic function. Here we report how the design of small-molecule inhibitors against NS5A has evolved from promising monomers to highly potent dimeric compounds effective against many HCV genotypes. We also highlight recent clinical data and how the inhibitors may bind to NS5A, itself capable of forming dimers.

Inhalation vs. aspiration of single-walled carbon nanotubes in C57BL/6 mice: inflammation, fibrosis, oxidative stress, and mutagenesis.

Nanomaterials are frontier technological products used in different manufactured goods. Because of their unique physicochemical, electrical, mechanical, and thermal properties, single-walled carbon nanotubes (SWCNT) are finding numerous applications in electronics, aerospace devices, computers, and chemical, polymer, and pharmaceutical industries. SWCNT are relatively recently discovered members of the carbon allotropes that are similar in structure to fullerenes and graphite. Previously, we (47) have reported that pharyngeal aspiration of purified SWCNT by C57BL/6 mice caused dose-dependent granulomatous pneumonia, oxidative stress, acute inflammatory/cytokine responses, fibrosis, and decrease in pulmonary function. To avoid potential artifactual effects due to instillation/agglomeration associated with SWCNT, we conducted inhalation exposures using stable and uniform SWCNT dispersions obtained by a newly developed aerosolization technique (2). The inhalation of nonpurified SWCNT (iron content of 17.7% by weight) at 5 mg/m(3), 5 h/day for 4 days was compared with pharyngeal aspiration of varying doses (5-20 microg per mouse) of the same SWCNT. The chain of pathological events in both exposure routes was realized through synergized interactions of early inflammatory response and oxidative stress culminating in the development of multifocal granulomatous pneumonia and interstitial fibrosis. SWCNT inhalation was more effective than aspiration in causing inflammatory response, oxidative stress, collagen deposition, and fibrosis as well as mutations of K-ras gene locus in the lung of C57BL/6 mice.

Fine particle number and mass concentration measurements in urban Indian households.

Fine particle number concentration (D(p)>10 nm, cm(-3)), mass concentrations (approximation of PM(2.5), microg m(-3)) and indoor/outdoor number concentration ratio (I/O) measurements have been conducted for the first time in 11 urban households in India, 2002. The results indicate remarkable high indoor number and mass concentrations and I/O number concentration ratios caused by cooking. Besides cooking stoves that used liquefied petroleum gas (LPG) or kerosene as the main fuel, high indoor concentrations can be explained by poor ventilation systems. Particle number concentrations of more than 300,000 cm(-3) and mass concentrations of more than 1000 microg m(-3) were detected in some cases. When the number and mass concentrations during cooking times were statistically compared, a correlation coefficient r>0.50 was observed in 63% of the households. Some households used other fuels like wood and dung cakes along with the main fuel, but also other living activities influenced the concentrations. In some areas, outdoor combustion processes had a negative impact on indoor air quality. The maximum concentrations observed in most cases were due to indoor combustion sources. Reduction of exposure risk and health effects caused by poor indoor air in urban Indian households is possible by improving indoor ventilation and reducing penetration of outdoor particles.

Thoracic size-selective sampling of fibres: performance of four types of thoracic sampler in laboratory tests.

The counting of fibres on membrane filters could be facilitated by using size-selective samplers to exclude coarse particulate and fibres that impede fibre counting. Furthermore, the use of thoracic size selection would also remove the present requirement to discriminate fibres by diameter during counting. However, before thoracic samplers become acceptable for sampling fibres, their performance with fibres needs to be determined. This study examines the performance of four thoracic samplers: the GK2.69 cyclone, a Modified SIMPEDS cyclone, the CATHIA sampler (inertial separation) and the IOM thoracic sampler (porous foam pre-selector). The uniformity of sample deposit on the filter samples, which is important when counts are taken on random fields, was examined with two sizes of spherical particles (1 and 10 microm) and a glass fibre aerosol with fibres spanning the aerodynamic size range of the thoracic convention. Counts by optical microscopy examined fields on a set scanning pattern. Hotspots of deposition were detected for one of the thoracic samplers (Modified SIMPEDS with the 10 microm particles and the fibres). These hotspots were attributed to the inertial flow pattern near the port from the cyclone pre-separator. For the other three thoracic samplers, the distribution was similar to that on a cowled sampler, the current standard sampler for fibres. Aerodynamic selection was examined by comparing fibre concentration on thoracic samples with those measured on semi-isokinetic samples, using fibre size (and hence calculated aerodynamic diameter) and number data obtained by scanning electron microscope evaluation in four laboratories. The size-selection characteristics of three thoracic samplers (GK2.69, Modified SIMPEDS and CATHIA) appeared very similar to the thoracic convention; there was a slight oversampling (relative to the convention) for d(ae) < 7 microm, but that would not be disadvantageous for comparability with the cowled sampler. Only the IOM thoracic sampler tended to undersample the fibres relative to the thoracic convention. With the data divided into four classes based on fibre length, the size-selection characteristics appeared to be unaffected by fibre length for GK2.69, Modified SIMPEDS and CATHIA. Only the IOM thoracic sampler (with the foam selector) showed slightly lower selection for longer length classes of fibres. These results indicate that the tested samplers follow the thoracic sampling convention for fibres, and may be used to improve the quality and reliability of samples that are taken when there is likely to be significant background dust.

Predicting within-family variability in juvenile height growth of Salix based upon similarity among parental AFLP fingerprints.

Willow is being developed as a crop for biomass plantations in the Northeast and North-central United States, but has only recently been the subject of controlled breeding to generate improved genotypes. Maximizing variability among progeny within full-sib families produced by controlled pollination may increase the probability of producing willow clones exhibiting desirable extreme phenotypes. Yet, predicting combinations of parents yielding highly variable progeny is not currently possible. Controlled pollinations were completed among 15 Salix eriocephala clones and the resulting progeny were vegetatively propagated and planted in a greenhouse progeny test. Heights of rooted cuttings were measured after 4 months of growth. Genetic similarity among parents was estimated based on 77 polymorphic AFLP bands. Strong negative correlation ( r = -0.88) was detected between mean female-parent similarity indices and the standard deviation of height among half-sib progeny from those females. Parent combinations that had relatively low similarity indices tended to produce progeny that had greater variability in height. This negative relationship suggests that AFLP fingerprints of S. eriocephala parents may be useful for predicting parent combinations that will yield families with large variability.

Management of multiple burn casualties in a high volume ED without a verified burn unit.

The objective of the study was to evaluate the effectiveness of triage, treatment, and transfer interventions on multiple burn casualties managed in a high volume ED that does not have a verified in-hospital burn unit. The charts of 11 male patients injured in a 1999 foundry explosion and brought to Baystate Medical Center (BMC), a level I trauma center, were reviewed. All patients sustained deep partial and full thickness burns. The injury severity score (ISS) ranged from 9 to 75. Five patients had total body surface area (TBSA) burns of 10% to 50% and 6 patients had TBSA burns of 70% to 95%. Transfer times from the scene to BMC ranged from less than 5 minutes to 22 minutes. All 11 were initially triaged, resuscitated, and evaluated at BMC. Of the 9 patients transferred to verified burn units, 8 were intubated, 6 of 6 had negative abdominal ultrasounds, 4 had undergone escharatomies, and 1 had undergone bronchoscopy before transfer. Nine critically injured burn patients with ISS of 9 to 75 were transferred from BMC to verified burn units. For 8 of these patients, the average time from triage, evaluation, and treatment to transfer was 2 hours. The ninth patient was initially admitted overnight then promptly transferred after re-evaluation of his hand burns indicated a need for more specialized care. Two of 9 transferred patients, both with ISS of 75 died. Although 7 other patients had prolonged and complex courses, none of their subsequent complications were referable to missed injuries from this transferring facility. The resources and expertise of a high volume ED without an in-hospital burn unit can be effectively used in the initial resuscitation and treatment of multiple burn casualties. Coordinated responses among emergency medicine, trauma, anesthesia, and nursing personnel are instrumental to the rapid triage, resuscitation, and treatment of critically injured burn patients. Future disaster planning should incorporate a clearly demarcated, ED command center led by an easily identifiable "captain of the ship," as well as more accurate patient identification systems and improved communications with family members.

Reactivity of zinc finger cores: analysis of protein packing and electrostatic screening.

The chemical stability of 207 zinc fingers, derived from 92 experimental protein structures, is evaluated according to the protein packing and electrostatic screening of their zinc cores. These properties are used as measures of the protein protection of zinc cores, to predictively rank relative zinc finger reactivities and assess differences in function. On average, there is a substantial and concomitant increase in the screening of increasingly anionic core motifs, suggesting zinc fingers have evolved in a manner that promotes shielding of their potentially reactive core thiolates. In contrast, enzymatic zinc cores are functionally differentiated by negative electrostatic screening. Zinc finger cores are predominantly screened by networks of backbone:core NH-S hydrogen bonds that electronically stabilize core thiolates and enhance backbone packing. Stabilizing protein:core interactions can be mapped to conserved residues, including [Arg,Lys]:core salt-bridges in some protein families. Labile zinc fingers are identified by poorly screened cores, possibly indicating redox or metallothionein (MT) regulated function. Consistent with experiment, the cores of the C-terminal finger of the human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein p7 (NCp7) and Escherichia coli Ada protein (Ada) "finger" are identified as reactive. The C-terminal zinc fingers of nuclear receptors are predicted to be the most labile in this study, particularly the human estrogen receptor (hER), which contains a triad of reactive thiolates. We propose that hER DNA binding is redox and MT regulated through the C-terminal finger and that weak electrophilic agents may inhibit hER-mediated transcription, implicated in breast cancer progression.

Money or your life? The health-wealth trade-off in pharmaceutical regulation.

For decades the development of pharmaceuticals has been regulated by safety, efficacy and quality rules for product registration. In public health care systems, these three 'hurdles' are increasingly being supplemented by a fourth: the mandatory requirement to demonstrate economic efficiency in order to obtain reimbursement. This requirement challenges the wealth creation ethic of industry (money) with the population health ethic of public health and health economics (your life). Despite practical and methodological obstacles to the use of economic evidence in decisions, the logic of this development is evident: in order to maximise improvements in population health, scarce resources must be targeted towards developing and applying technologies that deliver the greatest health gains per unit cost. The impact of this policy change on industry practice and profits will be considerable, and companies that fail to demonstrate the economic efficiency of their products will stumble at the fourth hurdle.

Workforce productivity and incentive structures in the UK National Health Service.

The UK National Health Service (NHS) is a labour-intensive service, yet the productivity of one of the largest labour forces in the world has been relatively ignored over the last 50 years. The data available to measure productivity over time are limited and focus on inputs and activity, not outcome. However, what data there are indicate that, despite major increases in NHS funding and staffing, changes in technology and continuous reorganisation of structures, productivity tends to show little or no change over successive decades. The challenges to policy-makers are how to improve the measurement of productivity and how to alter the behaviour of hospital clinicians and general practitioners by reform of incentive structures in the UK NHS.