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Objectives. To examine age and temporal trends in the proportion of COVID-19 deaths occurring out of hospital or in the emergency department and the proportion of all noninjury deaths assigned ill-defined causes in 2020. Methods. We analyzed newly released (March 2021) provisional COVID-19 death tabulations for the entire United States. Results. Children (younger than 18 years) were most likely (30.5%) and elders aged 64 to 74 years were least likely (10.4%) to die out of hospital or in the emergency department. In parallel, among all noninjury deaths, younger people had the highest proportions coded to symptoms, signs, and ill-defined conditions, and percentage symptoms, signs, and ill-defined conditions increased from 2019 to 2020 in all age–race/ethnicity groups. The majority of young COVID-19 decedents were racial/ethnic minorities. Conclusions. The high proportions of all noninjury deaths among children, adolescents, and young adults that were coded to ill-defined causes in 2020 suggest that some COVID-19 deaths were missed because of systemic failures in timely access to medical care for vulnerable young people. Public Health Implications. Increasing both availability of and access to the best hospital care for young people severely ill with COVID-19 will save lives and improve case fatality rates.

Substantial racial/ethnic and gender disparities in COVID-19 mortality have been previously documented. However, few studies have investigated the impact of individual socioeconomic position (SEP) on these disparities. Objectives: To determine the joint effects of SEP, race/ethnicity, and gender on the burden of COVID-19 mortality. A secondary objective was to determine whether differences in opportunities for remote work were correlated with COVID-19 death rates for sociodemographic groups. Design: Annual mortality study which used a special government tabulation of 2020 COVID-19-related deaths stratified by decedents’ SEP (measured by educational attainment), gender, and race/ethnicity. Setting: United States in 2020. Participants: COVID-19 decedents aged 25 to 64 years old (n = 69,001). Exposures: Socioeconomic position (low, intermediate, and high), race/ethnicity (Hispanic, Black, Asian, Indigenous, multiracial, and non-Hispanic white), and gender (women and men). Detailed census data on occupations held by adults in 2020 in each of the 36 sociodemographic groups studied were used to quantify the possibility of remote work for each group. Main Outcomes and Measures: Age-adjusted COVID-19 death rates for 36 sociodemographic groups. Disparities were quantified by relative risks and 95% confidence intervals. High-SEP adults were the (low-risk) referent group for all relative risk calculations. Results: A higher proportion of Hispanics, Blacks, and Indigenous people were in a low SEP in 2020, compared with whites. COVID-19 mortality was five times higher for low vs. high-SEP adults (72.2 vs. 14.6 deaths per 100,000, RR = 4.94, 95% CI 4.82–5.05). The joint detriments of low SEP, Hispanic ethnicity, and male gender resulted in a COVID-19 death rate which was over 27 times higher (178.0 vs. 6.5 deaths/100,000, RR = 27.4, 95% CI 25.9–28.9) for low-SEP Hispanic men vs. high-SEP white women. In regression modeling, percent of the labor force in never remote jobs explained 72% of the variance in COVID-19 death rates. Conclusions and Relevance: SARS-CoV-2 infection control efforts should prioritize low-SEP adults (i.e., the working class), particularly the majority with “never remote” jobs characterized by inflexible and unsafe working conditions (i.e., blue collar, service, and retail sales workers).

Compared to many other wealthy nations, the United States lacks a strong social safety net, has weak legal protections for workers, has suffered long-term declines in unionization, and has eroded the gains in prosperity achieved by the working class in the post-WWII era. Consequently, despite advancements in science and medicine, the U.S. working class has suffered great harms during the COVID-19 pandemic, from the direct effects of illness and mortality and from indirect familial, social, and economic impacts. The failure of the federal government to protect blue collar, service, and retail sales workers with strong mandatory worksite infection control regulations has further endangered working class communities. The dearth of federal leadership has been countered by solidarity and a diversified set of pandemic monitoring and mitigation efforts on the part of worker organizations (primarily labor unions), social service NGOs, Indigenous nations, and communities of color. Defeating the COVID-19 syndemic will require continued working class solidarity, an ethical framework for envisioning a future which prioritizes social and racial justice, and structural economic and sociopolitical transformations.

ImportanceSubstantial racial/ethnic disparities in COVID-19 mortality have been documented. Social class is a likely explanation of mortality disparities across and within racial/ethnic groups. This is the first U.S. study of social class and COVID-19 mortality in working age adults.ObjectivesTo determine the joint effects of social class, race/ethnicity, and gender on the burden of COVID-19 mortality. A secondary objective was to determine whether differences in opportunities for remote work were correlated with COVID-19 death rates for sociodemographic groups.DesignAnnual mortality study which used a special government tabulation of 2020 COVID-19 related deaths stratified by decedents’ social class (educational attainment) and race/ethnicity.SettingUnited States in 2020.ParticipantsCOVID-19 decedents aged 25 to 64 years old (n=69,001).ExposuresSocial class (working class, some college, college graduate), race/ethnicity (Hispanic, Black, Asian, Indigenous, multiracial, and non-Hispanic white), and gender (women, men). Detailed census data on occupations held by adults in 2020 in each of the 36 sociodemographic groups studied were used to quantify the possibility of remote work for each group.Main Outcomes and MeasuresAge-adjusted COVID-19 death rates for 36 sociodemographic groups defined by social class, race/ethnicity, and gender. Disparities were quantified by relative risks and 95% confidence intervals. College graduates were the (low risk) referent group for all relative risk calculations.ResultsA higher proportion of Hispanics, Blacks, and Indigenous people were working class in 2020. COVID-19 mortality was five times higher in the working class vs. college graduates (72.2 vs. 14.6 deaths per 100,000, RR=4.94, 95% CI 4.82-5.05). The joint detriments of lower socioeconomic position, Hispanic ethnicity, and male gender resulted in a COVID-19 death rate which was over 27 times higher (178.0 vs. 6.5 deaths/100,000, RR=27.4, 95%CI 25.9-28.9) for working class Hispanic men vs. college graduate white women. In regression modeling, percent employed in never remote jobs explained 72% of the variance in COVID-19 death rates.Conclusions and RelevanceSARS-CoV-2 infection control efforts should prioritize the working class (i.e. those with no college education), particularly those employed in “never remote” jobs with inflexible and unsafe working conditions (i.e. blue collar, service, and retail sales workers).KEY POINTSQuestionDid COVID-19 mortality rates among non-elderly adults vary significantly by social class, race/ethnicity, and gender in 2020?FindingsAmong 69,001 COVID-19 decedents, age-adjusted COVID-19 deaths rates were 5 times higher in working class vs. college graduate adults 25-64 years old. Working class Hispanic, Black, and Indigenous men suffered the highest burden of COVID-19 mortality, while college graduate white women experienced the lowest death rate.MeaningCOVID-19 mitigation efforts should prioritize the working class (i.e. those with no college education), particularly blue collar, service, and retail sales workers.

BackgroundWe examined the geographic and racial/ethnic distribution of the SARS-CoV-2 vaccine age-ineligible population (0-15 years old) in the U.S., and calculated the proportion of the age-eligible population that will need to be vaccinated in a given geo-demographic group in order to achieve either 60% or 75% vaccine coverage for that population as a whole.MethodsUS Census Bureau population estimates for 2019 were used to calculate the percent vaccine ineligible and related measures for counties, states, and the nation as a whole. Vaccination targets for the 30 largest counties by population were calculated. Study measures were calculated for racial/ethnic populations at the national (n=7) and state (n=6) levels.ResultsPercent of population ineligible for vaccine varied widely both geographically and by race/ethnicity. State values ranged from 15.8% in Vermont to 25.7% in Utah, while percent ineligible of the major racial/ethnic groups was 16.4% of non-Hispanic whites, 21.6% of non-Hispanic Blacks, and 27.5% of Hispanics. Achievement of total population vaccine coverage of at least 75% will require vaccinating more than 90% of the population aged 16 years and older in 29 out of 30 of the largest counties in the U.S.ConclusionsThe vaccine-ineligibility of most children for the next 1-2 years, coupled with reported pervasive vaccine hesitancy among adults, especially women and most minorities, means that achievement of adequate levels of vaccine coverage will be very difficult for many vulnerable geographic areas and for several racial/ethnic minority groups, particularly Hispanics, Blacks, and American Indians.

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Background For ICD-11, the WHO emphasized the clinical utility of communication and the need to involve service users and carers in the revision process. Aims The objective was to assess whether medical vocabulary was accessible, which kinds of feelings it activated, whether and how users and carers would like to rephrase terms, and whether they used diagnosis to talk about mental health experiences. Method An innovative protocol focused on two diagnoses (depressive episode and schizophrenia) was implemented in 15 different countries. The same issues were discussed with users and carers: understanding, feelings, rephrasing, and communication. Results Most participants reported understanding the diagnoses, but associated them with negative feelings. While the negativity of “depressive episode” mostly came from the concept itself, that of “schizophrenia” was largely based on its social impact and stigmatization associated with “mental illness”. When rephrasing “depressive episode”, a majority kept the root “depress*”, and suppressed the temporal dimension or renamed it. Almost no one suggested a reformulation based on “schizophrenia”. Finally, when communicating, no one used the phrase “depressive episode”. Some participants used words based on “depress”, but no one mentioned “episode”. Very few used “schizophrenia”. Conclusion Data revealed a gap between concepts and emotional and cognitive experiences. Both professional and experiential language and knowledge have to be considered as complementary. Consequently, the ICD should be co-constructed by professionals, service users, and carers. It should take the emotional component of language, and the diversity of linguistic and cultural contexts, into account.

Central nervous system tumors are the most common solid malignancy in childhood and the leading cause of cancer-related mortality in children. With an average of 13 new patients being diagnosed daily with a central nervous system tumor, many of these patients will present to the emergency department for evaluation and management. Furthermore, many children experience complications and/or adverse effects directly from the tumor itself, from multimodality treatment (ie, surgery, radiation therapy, and/or chemotherapy), and/or as long-term survivors. Oncologic emergencies include increased intracranial pressure, spinal cord compression, seizures/status epilepticus, central diabetes insipidus, and adrenal insufficiency. Evaluation and management by emergency medicine practitioners are critically important for these patients in all phases of their diagnosis and treatment and can contribute significantly to an improved prognosis.

tudy Objective To compare the rates and severity of hospital-acquired Clostridium difficile infection (CDI) among patients taking proton pump inhibitors (PPIs) versus those not taking PPIs. Design Retrospective, single-center, cohort study. Setting Tertiary community hospital with a teaching service. Patients A total of 41,663 patients with CDI who were hospitalized between January 2013 and May 2014; of those, 17,471 patients (41.9%) had received at least one dose of a PPI (PPI group), and 24,192 patients (58.1%) had no PPI exposure (control group). Measurements and Main Results A total of 348 patients had CDI during the study period, with 269 cases present on admission. Hospital-acquired CDI was defined as CDI diagnosis occurring on or after the third calendar day of admission. After excluding those patients with CDI on admission, 65 (0.38%) of 17,302 patients later developed CDI in the hospital in the PPI group compared with only 14 (0.058%) of 24,092 patients in the control group. Of these patients, 36 patients (0.21%) in the PPI group met the definition of severe CDI compared with 8 (0.03%) in the control group. This demonstrated an unadjusted relative risk (RR) of 6.46 (95% confidence interval [CI] 3.63–11.51, p

Dengue is a hemorrhagic virus contracted via the bite of a mosquito. Due to extreme changes in weather, increasing travel and immigration from tropical and subtropical climates, and increasing numbers of mosquito-borne illnesses, dengue virus infection presents a growing threat to the United States. The purpose of this article is to present etiology, pathology, management, and the latest treatment of dengue virus to prepare advanced practice nurses for early assessment and treatment of dengue virus.

Antibiotic-loaded bone cements, including poly(methyl methacrylate) (PMMA) and calcium sulfate (CaSO4), are often used for treatment of orthopaedic infections involvingStaphylococcusspp., although the effectiveness of this treatment modality may be limited due to the emergence of antimicrobial resistance and/or the development of biofilms within surgical sites. Gallium(III) is an iron analog capable of inhibiting essential iron-dependent pathways, exerting broad antimicrobial activity against multiple microorganisms, includingStaphylococcusspp. Herein, we evaluated PMMA and CaSO4as carriers for delivery of gallium(III) nitrate (Ga(NO3)3) to infected surgical sites by assessing the release kinetics subsequent to incorporation and antimicrobial activity againstS. aureusandS. epidermidis. PMMA and to a lesser extent CaSO4were observed to be compatible as carriers for Ga(NO3)3, eluting concentrations with antimicrobial activity against planktonic bacteria, inhibiting bacterial growth, and preventing bacterial colonization of beads, and effective against established bacterial biofilms ofS. aureusandS. epidermidis. Collectively, ourin vitroresults indicate that PMMA is a more suitable carrier compared to CaSO4for delivery of Ga(NO3)3; moreover they provide evidence for the potential use of Ga(NO3)3with PMMA as a strategy for the prevention and/or treatment for orthopaedic infections.

Biofilm formation is a major virulence factor for numerous pathogenic bacteria and is cited as a central event in the pathogenesis of chronic human infections, which is in large part due to excessive extracellular matrix secretion and metabolic changes that occur within the biofilm rendering them highly tolerant to antimicrobial treatments. Polyamines, including norspermidine, play central roles in bacterial biofilm development, but have also recently been shown to inhibit biofilm formation in select strains of various pathogenic bacteria. The aim of this study was to evaluate in vitro the biofilm dispersive and inhibitory activities of norspermidine against multidrug-resistant clinical isolates of Acinetobacter baumannii(n = 4), Klebsiella pneumoniae (n = 3), Pseudomonas aeruginosa (n = 5) and Staphylococcus aureus (n = 4) associated with chronic extremity wound infections using the semi-quantitative 96-well plate method and confocal laser microscopy. In addition to the antibiofilm activity, biocompatibility of norspermidine was also evaluated by measuring toxicity in vitro to human cell lines and whole porcine tissue explants using MTT viability assay and histological analysis. Norspermidine (5-20 mM) had variable dispersive and inhibitory activity on biofilms which was dependent on both the strain and species. Of the clinical bacterial species evaluated herein, A. baumannii isolates were the most sensitive to the effect of norspermidine, which was in part due to the inhibitory effects of norspermidine on bacterial motility and expression of genes involved in the production of homoserine lactones and quorum sensing molecules both essential for biofilm formation. Importantly, exposure of cell lines and whole tissues to norspermidine for prolonged periods of time (≥24 h) was observed to reduce viability and alter tissue histology in a time and concentration dependent manner, with 20 mM exposure having the greatest negative effects on both tissues and individual cell lines. Collectively our findings demonstrate that, similar to other polyamines, norspermidine displays both inhibitory and dispersive activities on biofilms of clinical multidrug-resistant bacterial isolates, in particular for strains of A. baumannii. Additionally our findings suggest that direct application may be considered on tissues, albeit for limited exposure times.

The prevalence of spontaneous mutations increases with age in the male germline; consequently, older men have an increased risk of siring children with genetic disease due to de novo mutations. The lacI transgenic mouse can be used to study paternal age effects, and in this system, the prevalence of de novo mutations increases in the male germline at old ages. Mutagenesis is linked with DNA repair capacity, and base excision repair (BER), which can ameliorate spontaneous DNA damage, decreases in nuclear extracts of spermatogenic cells from old mice. Mice heterozygous for a null allele of the Apex1 gene, which encodes apurinic/apyrimidinic endonuclease I (APEN), an essential BER enzyme, display an accelerated increase in spontaneous germline mutagenesis early in life. Here, the consequences of lifelong reduction of APEN on genetic instability in the male germline were examined, for the first time, at middle and old ages. Mutant frequency increased earlier in spermatogenic cells from Apex1+/− mice (by 6 months of age). Nuclear DNA damage increased with age in the spermatogenic lineage for both wild-type and Apex1+/− mice. By old age, mutant frequencies were similar for wild-type and APEN-deficient mice. Mitochondrial genome repair also depends on APEN, and novel analysis of mitochondrial DNA (mtDNA) damage revealed an increase in the Apex1+/− spermatogenic cells by middle age. Thus, Apex1 heterozygosity results in accelerated damage to mtDNA and spontaneous mutagenesis, consistent with an essential role for APEN in maintaining nuclear and mtDNA integrity in spermatogenic cells throughout life. Mol. Reprod. Dev. 78:906–919, 2011. Published 2011. This article is a U.S. Government work and is in the public domain in the USA.

Class V myosins are dimeric actin-associated motor proteins that deliver cellular cargoes to discrete cellular locations. Fission yeast possess two class V myosins, Myo51 and Myo52. Although Myo52 has been shown to have roles in vacuole distribution, cytokinesis and cell growth, Myo51 has no as yet discernible function in the vegetative life cycle. Here, we uncover distinct functions for this motor protein during mating and meiosis. Not only does Myo51 transiently localise to a foci at the site of cell fusion upon conjugation, but overexpression of the Myo51 globular tail also leads to disruption of cell fusion. Upon completion of meiotic prophase Myo51 localises to the outside of the spindle pole bodies (SPBs), where it remains until completion of meiosis II. Association of Myo51 with SPBs is not dependent upon actin or the septation initiation network (SIN); however, it is dependent on a stable microtubule cytoskeleton and the presence of the Cdc2-CyclinB complex. We observe a rapid and dynamic exchange of Myo51 at the SPB during meiosis I but not meiosis II. Finally, we show that Myo51 has an important role in regulating spore formation upon completion of meiosis.

This study assesses the relatively high incidence of the expression of paralogs of several pseudogenes within the cascade of expression of functional genes in the rat ovary in response to an ovulation-stimulating dose of gonadotropin. Immature Wistar rats were primed with 10 IU equine chorionic gonadotropin subcutaneously, and 48 h later the 12-h ovulatory process was initiated by 10 IU hCG subcutaneously. Ovarian RNA was extracted at 0, 2, 4, 8, 12, and 24 h after injecting the animals with hCG. The RNA extracts were used for RT-PCR differential display to detect gene expression in the ovarian tissue. Sequence analyses of differentially expressed cDNAs revealed that ∼27% (i.e. 22/82 clones) of the transcripts were fragments of paralogs of known pseudogenes. Out of the 22 clones reported here, 12 have high sequence similarity to the cytochrome P450 pseudogene Cyp21a1-ps, and 5 have high sequence similarity to both the Cyp21a1-ps and the aldo-keto reductase gene Akr1c6. The remaining five clones were paralogs of the endogenous retrovirus SC1 that has heavily infested the rat genome. Northern analyses reveal that peak expression of all the 22 paralogs occurs at 4–8 h into the ovulatory process. In situ hybridization shows that expression of these pseudogenes is primarily in the granulosa layer of ovulatory follicles. In summary, the results reveal that ovarian expression of Cyp21a1-ps- and SC1-like pseudogenes occurs concurrently with the ovulatory process.

Intracellular movement is a fundamental property of all cell types. Many organelles and molecules are actively transported throughout the cytoplasm by molecular motors, such as the dimeric type V myosins. These possess a long neck, which contains an IQ motif, that allow it to make 36-nm steps along the actin polymer. Live cell imaging of the fission yeast type V myosin Myo52 reveals that the protein moves rapidly throughout the cytoplasm. Here, we describe analysis of this movement and have established that Myo52 moves long distances on actin filaments in an ATP-dependent manner at ∼0.5 μm/second. Myo51 and the microtubule cytoskeleton have no discernable role in modulating Myo52 movements, whereas rigour mutations in Myo52 abrogated its movement. We go on to show that, although dimerisation is required for Myo52 movement, deleting its neck has no discernable affect on Myo52 function or velocity in vivo.

Spontaneous mutant frequency in the male germline increases with age, thereby increasing the risk of siring offspring with genetic disorders. In the present study we investigated the effect of age on ionizing radiation-induced male germline mutagenesis. lacI transgenic mice were treated with ionizing radiation at 4-, 15- and 26-month-old, and mutant frequencies were determined for pachytene spermatocytes and round spermatids at 15 days or 49 days after ionizing radiation treatment. Cells collected 15 days after treatment were derivatives of irradiated differentiating spermatogenic cells while cells collected 49 days later were derivatives of spermatogonial stem cells. The results showed that (1) spontaneous mutant frequency increased in spermatogenic cells recovered from nonirradiated old mice (26-months-old), particularly in the round spermatids; (2) mutant frequencies were significantly increased in round spermatids obtained from middle-aged mice (15-months-old) and old age mice (26-months-old) at 15 and 49 days after irradiation compared to the sham-treated old mice; and (3) pachytene spermatocytes obtained from 15- or 26-month-old mice displayed a significantly increased mutant frequency at 15 days post irradiation. This study indicates that age modulates the mutagenic response to ionizing radiation in the male germline.

The prevalence of spontaneous mutations increases with age in the male germline; consequently, older men have an increased risk of siring children with genetic disease due to de novo mutations. The lacI transgenic mouse can be used to study paternal age effects, and in this system, the prevalence of de novo mutations increases in the male germline at old ages. Mutagenesis is linked with DNA repair capacity, and base excision repair, which can ameliorate spontaneous DNA damage, decreases in nuclear extracts of spermatogenic cells from old mice. Mice heterozygous for a null allele of the Apex1 gene, which encodes apurinic/apyrimidinic endonuclease I (APEN), an essential base excision repair enzyme, display an accelerated increase in spontaneous germline mutagenesis early in life. Here, the consequences of lifelong reduction of APEN on genetic instability in the male germline were examined, for the first time, at middle and old ages. Mutation frequency increased earlier in spermatogenic cells from Apex1+/− mice (by 6 months of age). Nuclear DNA damage increased with age in the spermatogenic lineage for both wild-type and Apex1+/− mice. By old age, mutation frequencies were similar for wild-type and APEN-deficient mice. Mitochondrial genome repair also depends on APEN, and novel analysis of mitochondrial DNA damage revealed an increase in the Apex1+/− spermatogenic cells by middle age. Thus, Apex1 heterozygosity results in accelerated damage to mitochondrial DNA and spontaneous mutagenesis, consistent with an essential role for APEN in maintaining nuclear and mitochondrial DNA integrity in spermatogenic cells throughout life.

In 2009, a newly discovered human retrovirus, xenotropic murine leukemia virus (MuLV)-related virus (XMRV), was reported by Lombardi et al. in 67% of persons from the US with chronic fatigue syndrome (CFS) by PCR detection of gag sequences. Although six subsequent studies have been negative for XMRV, CFS was defined more broadly using only the CDC or Oxford criteria and samples from the US were limited in geographic diversity, both potentially reducing the chances of identifying XMRV positive CFS cases. A seventh study recently found polytropic MuLV sequences, but not XMRV, in a high proportion of persons with CFS. Here we tested blood specimens from 45 CFS cases and 42 persons without CFS from over 20 states in the United States for both XMRV and MuLV. The CFS patients all had a minimum of 6 months of post-exertional malaise and a high degree of disability, the same key symptoms described in the Lombardi et al. study. Using highly sensitive and generic DNA and RNA PCR tests, and a new Western blot assay employing purified whole XMRV as antigen, we found no evidence of XMRV or MuLV in all 45 CFS cases and in the 42 persons without CFS. Our findings, together with previous negative reports, do not suggest an association of XMRV or MuLV in the majority of CFS cases.

Xenotropic murine leukemia virus-related virus (XMRV) is a retrovirus implicated in prostate cancer and chronic fatigue syndrome (CFS). Press releases have suggested that it could contribute to autism spectrum disorder (ASD). In this study we used two PCR assays and one antibody assay to screen 25 blood samples from autistic children born to mothers with CFS and from 20 mixed controls including family members of the children assayed, people with fibromyalgia and people with chronic Lyme disease. Using a real-time PCR assay, we screened an additional 48 South Carolina autism disorder samples, 96 Italian ASD samples, 61 South Carolina ASD samples and 184 healthy controls. Despite having the ability to detect low copy number XMRV DNA in a large background of cellular DNA, none of the PCR assays found any evidence of XMRV infection in blood cells from patients or controls. Further, no anti-XMRV antibodies were detected, ruling out possible low level or abortive infections in blood or in other reservoirs. These results imply that XMRV is not associated with autism.

The Department of Veterans Affairs (VA) is committed to providing cost-effective, quality care to veterans. Given an aging veteran population and common, multiple co-morbid illnesses, the needs of the typical patient cared for within the VA system are complex. Thus, caregivers meeting these needs require additional nursing education. To ensure the staff will have the skills necessary to care for patients experiencing more complex illnesses, the Battle Creek VA Medical Center (VAMC) designed a program giving experienced nursing assistants the opportunity to enroll in a nursing program leading to practical nurse licensure. The Nursing Assistant to Licensed Practical Nurse Program has been established by developing a collaborative agreement with an affiliating educational institution, defining the selection criteria, helping to prepare funding requests, developing a mentoring program, coordinating with Human Resources and Fiscal Services, and outlining the service obligation. After the first year of this program, the VAMC and the academic institution consider it a successful collaborative effort.