Estimating state-specific population-based hospitalization rates from in-state hospital discharge data.

OBJECTIVE: To develop weights to estimate state population-based hospitalization rates for all residents of a state using only data from in-state hospitals which exclude residents treated in other states. DATA SOURCES AND STUDY SETTING: Agency for Healthcare Research and Quality, Healthcare Cost and Utilization Project (HCUP), State Inpatient Databases (SID), 2018-2019, 47 states+DC. STUDY DESIGN: We identified characteristics for patients hospitalized in each state differentiating movers (discharges for patients hospitalized outside state of residence) from stayers (discharges for patients hospitalized in state of residence) and created weights based on 2018 data informed by these characteristics. We calculated standard errors using a sampling framework and compared weight-based estimates against complete observed values for 2019. DATA COLLECTION/EXTRACTION METHODS: SID are based on administrative billing records collected by hospitals, shared with statewide data organizations, and provided to HCUP. PRINCIPAL FINDINGS: Of 34,186,766 discharged patients in 2018, 4.2% were movers. A higher share of movers (vs. stayers) lived in state border and rural counties; a lower share had discharges billed to Medicaid or were hospitalized for maternal/neonatal services. The difference between 2019 observed and estimated total discharges for all included states and DC was 9402 (mean absolute percentage error = 0.2%). We overestimated discharges with an expected payer of Medicaid, from the lowest income communities, and for maternal/neonatal care. We underestimated discharges with an expected payer of private insurance, from the highest income communities, and with injury diagnoses and surgical services. Estimates for most subsets were not within a 95% confidence interval, likely due to factors impossible to account for (e.g., hospital closures/openings, shifting consumer preferences). CONCLUSIONS: The weights offer a practical solution for researchers with access to only a single state's data to account for movers when calculating population-based hospitalization rates.

Adverse events among adult Medicaid enrollees with opioid use disorder and co-occurring substance use disorders.

BACKGROUND: It is common for adults with opioid use disorder (OUD) to misuse additional substances, and these individuals may be particularly at risk for adverse events, including mortality. Less is known about how continued receipt of prescription opioids or risk of adverse events (e.g., suicidality, overdose, poisoning) differs for people with co-occurring OUD and additional substance use disorders (SUDs). METHODS: We conducted a retrospective study using IBM® MarketScan® Multi-State Medicaid Database enrollment/claims data. We used logistic regression to measure the association between sample characteristics and our dependent variables. The sample consisted of non-Medicare-eligible adults aged 18-64 years who were continuously enrolled in Medicaid in 2016-2017 with an OUD diagnosis on at least one claim in 2016. RESULTS: Adults with OUD and a co-occurring SUD were more likely than adults with OUD only to have an opioid-related poisoning event (odds ratio [OR] = 1.488, p = .0052), all-cause poisoning (OR = 1.756, p < .0001), or suicidal ideation (OR = 1.796, p < .0001) but not to receive ongoing opioid prescriptions (OR = 0.973, p = .1626). Adverse events varied by OUD-SUD combination. For example, adults with OUD and cocaine use disorder had the highest odds of all-cause (OR = 2.393, p < .0001) or opioid-related (OR = 1.890, p = .0027) poisoning among those with a drug-specific diagnosis and were most likely to be diagnosed with suicidal ideation (OR = 2.465, p < .0001). CONCLUSIONS: This study provides evidence that adults with OUD and a co-occurring additional SUD have increased risk for several adverse events. Multisubstance use should be screened for and identified to determine the most appropriate course of treatment.

Utilization of treatment by Medicaid enrollees with opioid use disorder and co-occurring substance use disorders.

BACKGROUND: Multiple substance use is common among adults who misuse opioids. Adverse consequences of drugs are more severe among multisubstance users than among single drug users. This study sought to determine whether adults with opioid use disorder (OUD) and at least one other substance use disorder (SUD) are less likely than adults with OUD only to receive certain services. METHODS: We conducted a retrospective longitudinal study using the IBM® MarketScan® Multi-State Medicaid Database. We used logistic regression to measure associations between clinical characteristics and service utilization. The sample included non-Medicare-eligible adults aged 18-64 years with at least one claim in 2016 with a primary diagnosis of OUD who were continuously enrolled in Medicaid in 2016 and 2017. RESULTS: Of the 58,745 Medicaid enrollees with an initial OUD diagnosis in 2016, 29,267 had one or more additional SUD diagnoses. In the year following diagnosis, these adults were less likely than adults with OUD only to receive OUD medication treatment (OR = 0.88, p < .0001). This was true for all specifically diagnosed co-occurring SUDS. Adults with OUD and a co-occurring SUD, however, were more likely than those with OUD only to use any type of high-intensity services. CONCLUSIONS: Adults with OUD and at least one co-occurring SUD received more intensive services, which may reflect severity and lack of OUD medication treatment before misuse escalation. Programs should account for barriers to connecting these individuals to appropriate OUD treatment.

Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study.

OBJECTIVE: For patients with locally advanced rectal cancer (LARC), adjuvant chemotherapy selection following surgery remains a major clinical dilemma. Here, we investigated the ability of circulating tumour DNA (ctDNA) to improve risk stratification in patients with LARC. DESIGN: We enrolled patients with LARC (T3/T4 and/or N+) planned for neoadjuvant chemoradiotherapy. Plasma samples were collected pretreatment, postchemoradiotherapy and 4-10 weeks after surgery. Somatic mutations in individual patient's tumour were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. We then designed personalised assays to quantify ctDNA in plasma samples. Patients received adjuvant therapy at clinician discretion, blinded to the ctDNA results. RESULTS: We analysed 462 serial plasma samples from 159 patients. ctDNA was detectable in 77%, 8.3% and 12% of pretreatment, postchemoradiotherapy and postsurgery plasma samples. Significantly worse recurrence-free survival was seen if ctDNA was detectable after chemoradiotherapy (HR 6.6; P<0.001) or after surgery (HR 13.0; P<0.001). The estimated 3-year recurrence-free survival was 33% for the postoperative ctDNA-positive patients and 87% for the postoperative ctDNA-negative patients. Postoperative ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy use (chemotherapy: HR 10.0; P<0.001; without chemotherapy: HR 22.0; P<0.001). Postoperative ctDNA status remained an independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors (HR 6.0; P<0.001). CONCLUSION: Postoperative ctDNA analysis stratifies patients with LARC into subsets that are either at very high or at low risk of recurrence, independent of conventional clinicopathological risk factors. ctDNA analysis could potentially be used to guide patient selection for adjuvant chemotherapy.

Human cytomegalovirus pUL10 interacts with leukocytes and impairs TCR-mediated T-cell activation.

Human cytomegalovirus (HCMV) is known to exert suppressive effects on the host immune system through expression of various viral genes, thus directly and indirectly affecting antiviral immunity of the infected individuals. We report here that HCMV UL10 encodes a protein (pUL10) with immunosuppressive properties. UL10 has been classified as a member of the HCMV RL11 gene family. Although pUL10 is known to be dispensable for viral replication in cultured cells, its amino-acid sequence is well conserved among different HCMV isolates, suggesting that the protein has a crucial role in viral survival in the host environment. We show that pUL10 is cleaved from the cell surface of fibroblasts as well as epithelial cells and interacts with a cellular receptor ubiquitously expressed on the surface of human leukocytes, demonstrated by ex vivo cell-based assays and flow cytometric analyses on both lymphoid cell lines and primary blood cells. Furthermore, preincubation of peripheral blood mononuclear cells with purified pUL10 ectodomain results in significantly impaired proliferation and substantially reduced pro-inflammatory cytokine production, in particular in CD4+ T cells upon in vitro T-cell stimulation. The inhibitory effect of pUL10 is also observed on antigen receptor-mediated intracellular tyrosine phosphorylation in a T-cell line. Based on these observations, we suggest that pUL10 is a newly identified immunomodulatory protein encoded by HCMV. Further elucidation of interactions between pUL10 and the host immune system during HCMV may contribute to finding ways towards new therapies for HCMV infection.

The development of self-emulsifying oil-in-water emulsion adjuvant and an evaluation of the impact of droplet size on performance.

Microfluidization is an established technique for preparing emulsion adjuvant formulations for use in vaccines. Although this technique reproducibly yields high-quality stable emulsions, it is complex, expensive, and requires proprietary equipment. For this study, we developed a novel and simple low shear process to prepare stable reproducible emulsions without the use of any proprietary equipment. We found this process can produce a wide range of differently sized emulsions based on the modification of ratios of oil and surfactants. Using this process, we prepared a novel 20-nm-sized emulsion that was stable, reproducible, and showed adjuvant effects. During evaluation of this emulsion, we studied a range of emulsions with the same composition all sized below 200; 20, 90, and 160 nm in vivo and established a correlation between adjuvant size and immune responses. Our studies indicate that 160-nm-sized emulsions generate the strongest immune responses.

A cationic nanoemulsion for the delivery of next-generation RNA vaccines.

Nucleic acid-based vaccines such as viral vectors, plasmid DNA, and mRNA are being developed as a means to address a number of unmet medical needs that current vaccine technologies have been unable to address. Here, we describe a cationic nanoemulsion (CNE) delivery system developed to deliver a self-amplifying mRNA vaccine. This nonviral delivery system is based on Novartis's proprietary adjuvant MF59, which has an established clinical safety profile and is well tolerated in children, adults, and the elderly. We show that nonviral delivery of a 9 kb self-amplifying mRNA elicits potent immune responses in mice, rats, rabbits, and nonhuman primates comparable to a viral delivery technology, and demonstrate that, relatively low doses (75 µg) induce antibody and T-cell responses in primates. We also show the CNE-delivered self-amplifying mRNA enhances the local immune environment through recruitment of immune cells similar to an MF59 adjuvanted subunit vaccine. Lastly, we show that the site of protein expression within the muscle and magnitude of protein expression is similar to a viral vector. Given the demonstration that self-amplifying mRNA delivered using a CNE is well tolerated and immunogenic in a variety of animal models, we are optimistic about the prospects for this technology.

Generation of a parvovirus B19 vaccine candidate.

Parvovirus B19 is the causative agent of fifth disease in children, aplastic crisis in those with blood dyscrasias, and hydrops fetalis. Previous parvovirus B19 virus-like-particle (VLP) vaccine candidates were produced by co-infection of insect cells with two baculoviruses, one expressing wild-type VP1 and the other expressing VP2. In humans, the VLPs were immunogenic but reactogenic. We have developed new VLP-based parvovirus B19 vaccine candidates, produced by co-expressing VP2 and either wild-type VP1 or phospholipase-negative VP1 in a regulated ratio from a single plasmid in Saccharomyces cerevisiae. These VLPs are expressed efficiently, are very homogeneous, and can be highly purified. Although VP2 alone can form VLPs, in mouse immunizations, VP1 and the adjuvant MF59 are required to elicit a neutralizing response. Wild-type VLPs and those with phospholipase-negative VP1 are equivalently potent. The purity, homogeneity, yeast origin, and lack of phospholipase activity of these VLPs address potential causes of previously observed reactogenicity.

Potent immunogenicity of an HIV-1 gag-pol fusion DNA vaccine delivered by in vivo electroporation.

A plasmid DNA vaccine containing a fusion gene consisting of an HIV-1 subtype C gag and a modified subtype C pol was compared to a mixture of gag plus pol or gag plus HIV env plasmids. Plasmid DNA was delivered by intramuscular injection followed by electroporation in vivo. Two vaccinations were sufficient to induce high levels of Gag- and Pol-specific CD4 and CD8 T cells in peripheral blood. The gag-pol fusion plasmid was as immunogenic as the plasmid mixtures. Thus, DNA vaccination by intramuscular electroporation was an effective means for inducing high levels of Gag- and Pol-specific T cells, and a single gag-pol fusion DNA vaccine was sufficient for eliciting immune responses against both antigens.

Enhanced potency of plasmid DNA microparticle human immunodeficiency virus vaccines in rhesus macaques by using a priming-boosting regimen with recombinant proteins.

DNA vaccines have been used widely in experimental primate models of human immunodeficiency virus (HIV), but their effectiveness has been limited. In this study, we evaluated three technologies for increasing the potency of DNA vaccines in rhesus macaques. These included DNA encoding Sindbis virus RNA replicons (pSINCP), cationic poly(lactide-co-glycolide) (PLG) microparticles for DNA delivery, and recombinant protein boosting. The DNA-based pSINCP replicon vaccines encoding HIV Gag and Env were approximately equal in potency to human cytomegalovirus (CMV) promoter-driven conventional DNA vaccines (pCMV). The PLG microparticle DNA delivery system was particularly effective at enhancing antibody responses induced by both pCMV and pSINCP vaccines and had less effect on T cells. Recombinant Gag and Env protein boosting elicited rapid and strong recall responses, in some cases to levels exceeding those seen after DNA or DNA/PLG priming. Of note, Env protein boosting induced serum-neutralizing antibodies and increased frequencies of gamma interferon-producing CD4 T cells severalfold. Thus, PLG microparticles are an effective means of delivering DNA vaccines in nonhuman primates, as demonstrated for two different types of DNA vaccines encoding two different antigens, and are compatible for use with DNA prime-protein boost regimens.

Prediction of missed myocardial infarction among symptomatic outpatients without coronary heart disease.

BACKGROUND: Missed diagnoses of acute myocardial infarction (AMI) in the ambulatory setting can cause patient suffering and malpractice litigation. Multiple algorithms have been developed to detect the presence of coronary heart disease (CHD) or acute coronary ischemia. METHODS: We performed a case-control study of patients with no prior history of CHD presenting to outpatient practices with potential cardiac ischemia. Malpractice claims files were used to identify 18 cases of patients with missed AMIs. For each case, we identified 3 control patients who had office visits for chest pain during the same month and assessed the association of 4 different prediction tools with missed AMI. RESULTS: The 18 cases of missed AMI had a 39% 1-month mortality rate. Cases were more likely than controls to be men (67% vs 26%, P = .001), to be smokers (88% vs 39%, P < .001), and to have low HDL cholesterol (39 mg/dL vs 59 mg/dL, P < .001) and elevated total cholesterol (236 mg/dL vs 213 mg/dL, P = .01). A Framingham risk score predicting a 10-year risk of CHD > or =10% and a positive score using the Goldman risk predictor were associated with an increased risk of missed AMI (odds ratio 5.7, 95% CI 1.8-18.4 for Framingham risk score; odds ratio 7.2, 95% CI 1.4-36.8 for Goldman risk predictor). CONCLUSIONS: Among ambulatory patients with possible cardiac ischemia and no prior CHD, multiple algorithms may be useful for improvement of risk stratification.

Enhancement of DNA vaccine potency in rhesus macaques by electroporation.

The potency of an HIV DNA vaccine was enhanced in rhesus macaques by in vivo electroporation, as judged by increased onset, magnitude and duration of antibody and cell-mediated immune responses against both components of a combination Gag and Env vaccine. These data demonstrate the utility of the electroporation technology for use in large animals.

Induction of broad and potent anti-human immunodeficiency virus immune responses in rhesus macaques by priming with a DNA vaccine and boosting with protein-adsorbed polylactide coglycolide microparticles.

Several vaccine technologies were evaluated for their abilities to induce anti-human immunodeficiency virus Gag immune responses in rhesus macaques. While no vaccine alone was able to induce broad and strong immune responses, these were achieved by priming with Gag DNA and boosting with Gag protein adsorbed to polylactide coglycolide microparticles. This regimen elicited strong antibodies, helper T cells, and cytotoxic T lymphocytes and thus holds promise as an effective vaccination scheme.

Perfil de riesgo cardiovascular en el área rural de Guatemala: Situación actual en relación a países desarrollados y subdesarrollados / Current risk of cadiovascular disease in rural area of Guatemala: actual situation compared with developed and undeveloped countries

Con el objeto de estimar la prevalencia de factores de riesgo cardiovascular se estudiaron 375 sujetos, 142 hombres y 233 mujeres entre 20 y 78 años de edad, del interior de la república de Guatemala. Las variables de estudio incluyeron: hábito de fumar; presión arterial; antropometría; rendimiento físico y determinación de lípidos plasmáticos. Se excluyeron sujetos con antecedentes de enfermedad cardiovascular, mujeres que estuvieron tomando anticonceptivos y sujetos con valores de triglicéridos mayores de 400 mg/dl. El hábito de fumar 1 ó más cigarrillos por día fue reportado en el 41de los hombres y 4 de las mujeres. La prevalencia de hipertensión en hombres fue de 3.5 y 10.7 en mujeres. Se clasificó como sobrepeso al 21.8 y 30.9 de los hombres y mujeres respectivamente. El porcentaje de obesos para hombres y mujeres fue 4.2 y 15. La razón cintura: cadera como índice de distribución de grasa fue igual o menor de 1.0 en hombres y 0.8 en mujeres.El 32 de las mujeres y 27 de los hombres tuvieron valores de colesterol = 200 mg/dL de los cuales 11 de las mujres y 7 de los hombres tuvieron valores superiores a 240 mg/dL. Alrededor del 20 de los sujetos estudiados tuvieron valores de colesterol -LDL mayores de 130 mg/dL y 44 valores de colesterol -HDL menores de 35 mg/dL. Las prevalencias encontradas en esta población son similares a las reportadas en otros países en vías de desarrollo, pero menores que las de países desarrollados