Time-resolved assessment of single-cell protein secretion by sequencing.

Secreted proteins play critical roles in cellular communication. Methods enabling concurrent measurement of cellular protein secretion, phenotypes and transcriptomes are still unavailable. Here we describe time-resolved assessment of protein secretion from single cells by sequencing (TRAPS-seq). Released proteins are trapped onto the cell surface and probed by oligonucleotide-barcoded antibodies before being simultaneously sequenced with transcriptomes in single cells. We demonstrate that TRAPS-seq helps unravel the phenotypic and transcriptional determinants of the secretion of pleiotropic TH1 cytokines (IFNγ, IL-2 and TNF) in activated T cells. In addition, we show that TRAPS-seq can be used to track the secretion of multiple cytokines over time, uncovering unique molecular signatures that govern the dynamics of single-cell cytokine secretions. Our results revealed that early central memory T cells with CD45RA expression (TCMRA) are important in both the production and maintenance of polyfunctional cytokines. TRAPS-seq presents a unique tool for seamless integration of secretomics measurements with multi-omics profiling in single cells.

Preparing the occupational safety and health workforce for future disruptions.

BACKGROUND: Despite some emerging lessons learned from the COVID-19 pandemic, evidence suggests the world remains largely underprepared for-and vulnerable to-similar threats in the future. METHODS: In 2022, researchers at the US National Institute for Occupational Safety and Health (NIOSH) led a team of volunteers to explore how future disruptions, such as pandemics, might impact work and the practice of occupational safety and health (OSH). This qualitative inquiry was framed as a strategic foresight project and included a series of activities designed to help better understand, prepare for, and influence the future. RESULTS: Findings from a thorough search for indicators of change were synthesized into nine critical uncertainties and four plausible future scenarios. Analysis of these outputs elucidated three key challenges that may impact OSH research, policy, and practice during future disruptions: (1) data access, (2) direct-to-worker communications, and (3) mis- and dis-information management. CONCLUSIONS: A robust strategic response is offered to address these challenges, and next steps are proposed to enhance OSH preparedness and institutionalize strategic foresight across the OSH community.

An urgent call to address work-related psychosocial hazards and improve worker well-being.

Work-related psychosocial hazards are on the verge of surpassing many other occupational hazards in their contribution to ill-health, injury, disability, direct and indirect costs, and impact on business and national productivity. The risks associated with exposure to psychosocial hazards at work are compounded by the increasing background prevalence of mental health disorders in the working-age population. The extensive and cumulative impacts of these exposures represent an alarming public health problem that merits immediate, increased attention. In this paper, we review the linkage between work-related psychosocial hazards and adverse effects, their economic burden, and interventions to prevent and control these hazards. We identify six crucial societal actions: (1) increase awareness of this critical issue through a comprehensive public campaign; (2) increase etiologic, intervention, and implementation research; (3) initiate or augment surveillance efforts; (4) increase translation of research findings into guidance for employers and workers; (5) increase the number and diversity of professionals skilled in preventing and addressing psychosocial hazards; and (6) develop a national regulatory or consensus standard to prevent and control work-related psychosocial hazards.

Chemically modified dsRNA induces RNAi effects in insects in vitro and in vivo: A potential new tool for improving RNA-based plant protection.

Global agriculture loses over $100 billion of produce annually to crop pests such as insects. Many of these crop pests either are not currently controlled by artificial means or have developed resistance against chemical pesticides. Long dsRNAs are capable of inducing RNAi in insects and are emerging as novel, highly selective alternatives for sustainable insect management strategies. However, there are significant challenges associated with RNAi efficacy in insects. In this study, we synthesized a range of chemically modified long dsRNAs in an approach to improve nuclease resistance and RNAi efficacy in insects. Our results showed that dsRNAs containing phosphorothioate modifications demonstrated increased resistance to southern green stink bug saliva nucleases. Phosphorothioate-modified and 2'-fluoro-modified dsRNA also demonstrated increased resistance to degradation by soil nucleases and increased RNAi efficacy in Drosophila melanogaster cell cultures. In live insects, we found chemically modified long dsRNAs successfully resulted in mortality in both stink bug and corn rootworm. These results provide further mechanistic insight into the dependence of RNAi efficacy on nucleotide modifications in the sense or antisense strand of the dsRNA in insects and demonstrate for the first time that RNAi can successfully be triggered by chemically modified long dsRNAs in insect cells or live insects.

Four Cases of Acute Kidney Injury Requiring Dialysis in Ultramarathoners.

Transient acute kidney injury (AKI) following ultraendurance footraces is a common biochemical diagnosis. However, severe AKI requiring renal replacement therapy is uncommon in ultramarathoners. We report 4 runners (3 men; mean age, 44 ± 3 y) who required prolonged (10-42 d) dialysis following the Western States 100 Mile Endurance Run over a 3-y span (0.38% of starters). The maximum ambient temperatures on the race day ranged from 36.6° to 38.3°C. The runners presented to local hospitals 17 to 32 h after running, with laboratories confirming rhabdomyolysis, hyponatremia (mean serum sodium concentration, 127±2 mmol⋅L-1), and AKI (mean serum creatinine concentration, 8.5±2 mg⋅dL-1). The case-cluster report highlights the potential synergistic effects of high ambient temperatures, muscle damage, and electrolyte imbalance on protracted renal dysfunction in ultramarathoners competing in a warming world.

TAPPing into the potential of inducible tau/APP transgenic mice.

AIMS: Our understanding of the pathological interactions between amyloidosis and tauopathy in Alzheimer's disease is incomplete. We sought to determine if the relative timing of the amyloidosis and tauopathy is critical for amyloid-enhanced tauopathy. METHODS: We crossed an inducible tauopathy model with two ß-amyloid models utilising the doxycycline-repressible transgenic system to modulate timing and duration of human tau expression in the context of amyloidosis and then assessed tauopathy, amyloidosis and gliosis. RESULTS: We combined inducible rTg4510 tau with APPswe/PS1dE9 [Line 85 (L85)] mice to examine the interactions between Aß and tauopathy at different stages of amyloidosis. When we initially suppressed mutant human tau expression for 14-15 months and subsequently induced tau expression for 6 months, severe amyloidosis with robust tauopathy resulted in rTg4510/L85 but not rTg4510 mice. When we suppressed mutant tau for 7 months before inducing expression for a subsequent 6 months in another cohort of rTg4510/L85 and rTg4510 mice, only rTg4510/L85 mice displayed robust tauopathy. Lastly, we crossed rTg4510 mice to tet-regulated APPswe/ind [Line 107 (L107)] mice, using doxycycline to initially suppress both transgenes for 1 month before inducing expression for 5 months to model early amyloidosis. In contrast to rTg4510, rTg4510/L107 mice rapidly developed amyloidosis, accompanied by robust tauopathy. CONCLUSIONS: These data suggest that tau misfolding is exacerbated by both newly forming Aß deposits in younger brain and mature deposits in older brains. Refined use and repurposing of these models provide new tools to explore the intersection of ageing, amyloid and tauopathy and to test interventions to disrupt the amyloid cascade.

NIOSH Risk-Based Model to Resume Field Research and Public Health Service in 2020 During the COVID-19 Pandemic.

In the early months of the COVID-19 pandemic, field research and public health service work conducted by the National Institute for Occupational Safety and Health (NIOSH) was put on hold. During this time, NIOSH developed a risk-based model to resume fieldwork, balancing the public health benefit of such fieldwork with the risks of severe acute respiratory syndrome coronavirus 2 exposure and transmission. We describe our experiences with this model, along with the broader public health significance of the methods used to inform risk management decisions. (Am J Public Health. 2022;112(8):1138-1141. https://doi.org/10.2105/AJPH.2022.306882).

Algorithms and the future of work.

An algorithm refers to a series of stepwise instructions used by a machine to perform a mathematical operation. In 1955, the term artificial intelligence (AI) was coined to indicate that a machine could be programmed to duplicate human intelligence. Even though that goal has not yet been reached, the use of sophisticated machine learning algorithms has moved us closer to that goal. While algorithm-enabled systems and devices will bring many benefits to occupational safety and health, this Commentary focuses on new sources of worker risk that algorithms present in the use of worker management systems, advanced sensor technologies, and robotic devices. A new "digital Taylorism" may erode worker autonomy, and lead to work intensification and psychosocial stress. The presence of large amounts of information on workers within algorithmic-enabled systems presents security and privacy risks. Reliance on indiscriminate data mining may reproduce forms of discrimination and lead to inequalities in hiring, retention, and termination. Workers interfacing with robots may face work intensification and job displacement, while injury in the course of employment by a robotic device is also possible. Algorithm governance strategies are discussed such as risk management practices, national and international laws and regulations, and emerging legal accountability proposals. Determining if an algorithm is safe for workplace use is rapidly becoming a challenge for manufacturers, programmers, employers, workers, and occupational safety and health practitioners. To achieve the benefits that algorithm-enabled systems and devices promise in the future of work, now is the time to study how to effectively manage their risks.

Advanced sensor technologies and the future of work.

Exposure science is fundamental to the field of occupational safety and health. The measurement of worker exposures to hazardous agents informs effective workplace risk mitigation strategies. The modern era of occupational exposure measurement began with the invention of the personal sampling device, which is still widely used today in the practice of occupational hygiene. Newer direct-reading sensor devices are incorporating recent advances in transducers, nanomaterials, electronics miniaturization, portability, batteries with high-power density, wireless communication, energy-efficient microprocessing, and display technology to usher in a new era in exposure science. Commercial applications of new sensor technologies have led to a variety of health and lifestyle management devices for everyday life. These applications are also being investigated as tools to measure occupational and environmental exposures. As the next-generation placeable, wearable, and implantable sensor technologies move from the research laboratory to the workplace, their role in the future of work will be of increasing importance to employers, workers, and occupational safety and health researchers and practitioners. This commentary discusses some of the benefits and challenges of placeable, wearable, and implantable sensor technologies in the future of work.

Measuring the benefits of occupational safety and health research with economic metrics: Insights from the National Institute for Occupational Safety and Health.

Measuring the ultimate impact of research on health and economic well-being has presented challenges that have rarely been surmounted, and research on preventing occupational injuries and illnesses is no exception. Nevertheless, there is an increasing need to demonstrate the value of publicly funded research. The National Institute for Occupational Safety and Health (NIOSH) recently contracted with the RAND Corporation to conduct six in-depth case studies that aimed to quantify the benefits of key NIOSH research efforts using economic metrics. These case studies focused on silica exposure in asphalt pavement milling, firefighter cancer risks, a multi-industry matching-grant program for purchase of safety equipment, personal coal dust monitors for coal miners, re-design of ambulance patient compartments for safety, and workplace amputation surveillance. In this article, we summarize what we learned about how measurement of research benefits may be pursued. We summarize the benefit measurement methods that were used and the results of these research efforts in terms of costs saved, injuries and illnesses prevented, and the statistical value of reductions in risk of death or illness. We then distill some observations about the characteristics of research efforts that make measurement of research benefits feasible and suggest steps that could make it feasible to apply the same methods more widely. We also outline key NIOSH activities that appear not to be amenable to benefit measurement but suggest potentials for progress toward at least partial or qualitative benefit assessment. Finally, we discuss implications of the benefit measurement case studies for strategic research planning.

The World Trade Center Health Program: Twenty years of health effects research.

It has been 20 years since the devastating terrorist attacks on September 11, 2001. Thousands were injured or killed during the attacks and many more are at risk of adverse health stemming from physical, psychological, and emotional stressors born out of the attacks. Private, federal, state, and local resources were gathered soon after the attacks to address impacts to the community, including the health and well-being of both responders and survivors. Many of these efforts are now largely consolidated under the federally mandated World Trade Center (WTC) Health Program. This program provides medical monitoring and treatment of qualifying conditions among the 9/11-exposed population and supports related physical and mental health research. In this commentary, we describe the WTC Health Program, with emphasis on the health-effects research it has funded since inception in 2011. We describe sentinel research publications, and how science has impacted the program. We provide examples relating studies in this special issue to important roles in the WTC Health Program research agenda. Finally, we provide a perspective on future research needs.

Review of cannabis reimbursement by workers' compensation insurance in the U.S. and Canada.

Changing public attitudes about cannabis consumption have currently led 36 U.S. states and the District of Columbia to approve laws that make cannabis available to consumers with qualifying medical conditions. This article reviews the 36 states and the District of Columbia with medical cannabis access laws to determine if the state or the District also allows reimbursement of the costs of cannabis for a work-related health condition under that state's or District's workers' compensation insurance (WCI) laws and administrative regulations. The legal basis for a state allowing or not allowing WCI reimbursement is described. The review found that only six of the 36 states expressly allow cannabis WCI reimbursement, six expressly prohibit it, 14 states do not require reimbursement, and 10 states, and the District of Columbia, are silent on the issue. The article describes the role of the insurer, treating physician, and worker in obtaining WCI reimbursement in the six states that expressly allow cannabis WCI reimbursement. Comparisons are made to how selected Canadian provinces and territories administer cannabis reimbursement under Canada's new national cannabis legalization law. The article discusses the future role of cannabis legalization in the United States and the evolving role of cannabis from an international perspective.

The World Trade Center Health Program: Petitions for adding qualifying health conditions.

The federally mandated World Trade Center Health Program provides limited health benefits for qualifying health conditions related to the 9/11 terrorist attacks. A qualifying health condition is an illness or health condition for which the member's exposure to airborne toxins, any other hazard, or any other adverse condition resulting from the 9/11 terrorist attacks is considered substantially likely to be a significant factor in aggravating, contributing to, or causing the illness or health condition. These qualifying health conditions are listed in federal regulations. The regulations also provide a process for amending this list. This commentary describes the methods developed for adding health conditions to the list of qualifying health conditions and discusses changes to the list that have occurred during the Program's 2011-2020 period.

PLR and NLR Are Poor Predictors of Survival Outcomes in Sarcomas: A New Perspective From the USSC.

BACKGROUND: Elevations in inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR) or platelet-to-lymphocyte ratio (PLR), are reportedly associated with decreased overall survival (OS) or recurrence-free survival (RFS) in patients with numerous cancers. A large multicenter sarcoma data set was used to determine if elevated NLR or PLR was associated with worse survival and can guide treatment selection. MATERIALS AND METHODS: A total of 409 patients with a primary retroperitoneal sarcoma (n = 268) or truncal (n = 141) sarcoma from 2000 to 2015 were analyzed using the US Sarcoma Collaboration database. Binary NLR and PLR values were developed using receiver operating characteristic curves. Kaplan-Meier model and Cox proportional hazards model identified predictors of decreased OS and RFS. Point biserial analyses were used to correlate binary and continuous data. RESULTS: Neither elevated NLR nor PLR was predictive of decreased OS or RFS. These findings persisted despite exclusion of comorbid inflammatory conditions. Further, NLR and PLR were not correlated with tumor grade. In multivariate models, decreased RFS was associated with tumor factors (e.g., positive margins, tumor grade, tumor size, necrosis, positive nodes); decreased OS was associated with histologic subtype, male gender, and nodal involvement. CONCLUSIONS: Although several small studies have suggested that elevated NLR and PLR are associated with decreased survival in patients with abdominal or truncal sarcoma, this large multicenter study demonstrates no association with decreased OS, decreased RFS, or tumor grade. Rather, survival outcomes are best predicted using previously established tumoral factors.

Analysis of textbook outcomes among patients undergoing resection of retroperitoneal sarcoma: A multi-institutional analysis of the US Sarcoma Collaborative.

BACKGROUND: The novel composite metric textbook outcome (TO) has increasingly been used as a quality indicator but has not been reported among patients undergoing surgical resection for retroperitoneal sarcoma (RPS) using multi-institutional collaborative data. METHODS: All patients who underwent resection for RPS between 2000 to 2016 from eight academic institutions were included. TO was defined as a patient with R0/R1 resection that discharged to home and was without transfusion, reoperation, grade ≥2 complications, hospital-stay >50th percentile, or 90-day readmission or mortality. Univariate and multivariable analyses were performed. RESULTS: Among 627 patients, 56.1% were female and the median age was 59 years. A minority of patients achieved a TO (34.9%). Factors associated with achieving a TO were tumor size <20 cm and low tumor grade, while ASA class ≥3, history of a prior cardiac event, resection of left colon/rectum, distal pancreatic resection, major venous resection and drain placement were associated with not achieving a TO (all P < .05). Achievement of a TO was associated with improved survival (median:12.7 vs 5.9 years, P < .01). CONCLUSIONS: Among patients undergoing resection for RPS, failure to achieve TO is common and associated with significantly worse survival. The use of TO may inform patient expectations and serve as a measure for patient-level hospital performance.

Retroperitoneal sarcoma perioperative risk stratification: A United States Sarcoma Collaborative evaluation of the ACS-NSQIP risk calculator.

BACKGROUND: The ACS-NSQIP risk calculator predicts perioperative risk. This study tested the calculator's ability to predict risk for outcomes following retroperitoneal sarcoma (RPS) resection. METHODS: The United States Sarcoma Collaborative database was queried for adults who underwent RPS resection. Estimated risk for outcomes was calculated twice in the risk calculator, once using sarcoma-specific CPT codes and once using codes indicative of most comorbid organ resection (eg nephrectomy). ROC curves were generated, with area under the curve (AUC) and Brier scores reported to assess discrimination and calibration. An AUC < 0.6 was considered ineffective discrimination. A negative ▲ Brier indicated improved performance relative to baseline outcome rates. RESULTS: In total, 482 patients were identified with a 42.3% 90-day complication rate. Discrimination was poor for all outcomes except "all complications" and "renal failure." Baseline outcome rates were better predictors than calculator estimates except for "discharge to nursing or rehab facility" and "renal failure." Replacing sarcoma-specific CPT codes with resection-specific codes did not improve performance. CONCLUSION: The ACS-NSQIP risk calculator poorly predicted outcomes following RPS resection. Changing sarcoma-specific CPT to resection-specific codes did not improve performance. Comorbidities in the calculator may not effectively capture perioperative risk. Future work should evaluate a sarcoma-specific calculator.

Tonsillar Kaposi sarcoma in a renal transplant patient.

Kaposi sarcoma (KS) is a vascular neoplasm caused by human herpesvirus-8 (HHV-8) infection. KS is most often seen in individuals with acquired immunodeficiency syndrome but can occur in patients who are on immunosuppressive therapy. While the skin and oral mucosa are the typical sites for KS, lesions of the tonsil are quite rare with only a few reported cases. Here, we present a case of tonsillar KS occurring in a renal transplant patient. He presented with dysphagia, odynophagia, and weight loss. Oral examination revealed tonsillar hypertrophy with purple discoloration. Imaging revealed diffuse enlargement of Waldeyer's ring with enlarged right cervical lymph nodes, worrisome for post-transplant lymphoproliferative disorder. Microscopic examination of the tonsillectomy specimen showed a vascular proliferation positive for HHV-8, consistent with KS. The patient was subsequently treated with immunosuppression reduction and the addition of sirolimus, which resulted in complete resolution of oropharyngeal and cervical lesions.

Cannabis and work: Need for more research.

Cannabis sativa is one of the oldest and most widely used plants in the world with a variety of industrial, medical, and nonmedical applications. Despite its long history, cannabis-derived products remain a source of controversy across the fields of medicine, law, and occupational safety and health. More favorable public attitudes about cannabis in the US have resulted in greater access to cannabis through legalization by states, leading to more consumption by workers. As more states adopt cannabis access laws, and as more workers choose to consume cannabis products, the implications for existing workplace policies, programs, and practices become more salient. Past workplace practices were grounded in a time when cannabis consumption was always viewed as problematic, considered a moral failing, and was universally illegal. Shifting cultural views and the changing legal status of cannabis indicate a need for research into the implications and challenges relating to cannabis and work. This commentary suggests research needs in the following areas: (a) data about industries and occupations where cannabis consumption among workers is most prevalent; (b) adverse health consequences of cannabis consumption among workers; (c) workplace supported recovery programs; (d) hazards to workers in the emerging cannabis industry; (e) relationship between cannabis consumption and occupational injuries; (f) ways to assess performance deficits and impairment from cannabis consumption; (g) consumption of synthetic cannabinoids to evade detection by drug testing; (h) cannabis consumption and its effect on occupational driving; and (i) ways to craft workplace policies and practices that take into consideration conflicting state and federal laws pertaining to cannabis.

Industrial exoskeletons: Need for intervention effectiveness research.

Exoskeleton devices are being introduced across several industry sectors to augment, amplify, or reinforce the performance of a worker's existing body components-primarily the lower back and the upper extremity. Industrial exoskeletons may play a role in reducing work-related musculoskeletal disorders arising from lifting and handling heavy materials or from supporting heavy tools in overhead work. However, wearing an exoskeleton may pose a number of risks that are currently not well-studied. There are only a few studies about the safety and health implications of wearable exoskeletons and most of those studies involve only a small number of participants. Before the widespread implementation of industrial exoskeletons occurs, there is need for prospective interventional studies to evaluate the safety and health effectiveness of exoskeletons across various industry sectors. Developing a research strategy to fill current safety and health knowledge gaps, understanding the benefits, risks, and barriers to adoption of industrial exoskeletons, determining whether exoskeleton can be considered a type of personal protective equipment, and advancing consensus standards that address exoskeleton safety, should be major interests of both the occupational safety and health research and practice communities.

Envisioning the future of work to safeguard the safety, health, and well-being of the workforce: A perspective from the CDC's National Institute for Occupational Safety and Health.

The future of work embodies changes to the workplace, work, and workforce, which require additional occupational safety and health (OSH) stakeholder attention. Examples include workplace developments in organizational design, technological job displacement, and work arrangements; work advances in artificial intelligence, robotics, and technologies; and workforce changes in demographics, economic security, and skills. This paper presents the Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health's Future of Work Initiative; suggests an integrated approach to address worker safety, health, and well-being; introduces priority topics and subtopics that confer a framework for upcoming future of work research directions and resultant practical applications; and discusses preliminary next steps. All future of work issues impact one another. Future of work transformations are contingent upon each of the standalone factors discussed in this paper and their combined effects. Occupational safety and health stakeholders are becoming more aware of the significance and necessity of these factors for the workplace, work, and workforce to flourish, merely survive, or disappear altogether as the future evolves. The future of work offers numerous opportunities, while also presenting critical but not clearly understood difficulties, exposures, and hazards. It is the responsibility of OSH researchers and other partners to understand the implications of future of work scenarios to translate effective interventions into practice for employers safeguarding the safety, health, and well-being of their workers.