A Multisite Electronic Health Record Integrated Remote Monitoring Intervention for Hypertension Improvement: Protocol for a Randomized Pragmatic Comparative Effectiveness Trial.

BACKGROUND: Hypertension is a major contributor to various adverse health outcomes. Although previous studies have shown the benefits of home blood pressure (BP) monitoring over office-based measurements, there is limited evidence comparing the effectiveness of whether a BP monitor integrated into the electronic health record is superior to a nonintegrated BP monitor. OBJECTIVE: In this paper, we describe the protocol for a pragmatic multisite implementation of a quality improvement initiative directly comparing integrated to nonintegrated BP monitors for hypertension improvement. METHODS: We will conduct a randomized, comparative effectiveness trial at 3 large academic health centers across California. The 3 sites will enroll a total of 660 participants (approximately n=220 per site), with 330 in the integrated BP monitor arm and 330 in the nonintegrated BP control arm. The primary outcome of this study will be the absolute difference in systolic BP in mm Hg from enrollment to 6 months. Secondary outcome measures include binary measures of hypertension (controlled vs uncontrolled), hypertension-related health complications, hospitalizations, and death. The list of possible participants will be generated from a central data warehouse. Randomization will occur after enrollment in the study. Participants will use their assigned BP monitor and join site-specific hypertension interventions. Cross-site learning will occur at regular all-site meetings facilitated by the University of California, Los Angeles Value-Based Care Research Consortium. A pre- and poststudy questionnaire will be conducted to further evaluate participants' perspectives regarding their BP monitor. Linear mixed effects models will be used to compare the primary outcome measure between study arms. Mixed effects logistic regression models will be used to compare secondary outcome measures between study arms. RESULTS: The study will start enrolling participants in the second quarter of 2023 and will be completed by the first half of 2024. Results will be published by the end of 2024. CONCLUSIONS: This pragmatic trial will contribute to the growing field of chronic care management using remote monitoring by answering whether a hypertension intervention coupled with an electronic health record integrated home BP monitor improves patients' hypertension better than a hypertension intervention with a nonintegrated BP monitor. The outcomes of this study may help health system decision makers determine whether to invest in integrated BP monitors for vulnerable patient populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT05390502; clinicaltrials.gov/study/NCT05390502. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/45915.

KRAS mutation as a prognostic factor and predictive factor in advanced/metastatic non-small cell lung cancer: A systematic literature review and meta-analysis.

KRAS (Kirsten Rat Sarcoma) is the most common oncogenic mutation detected in patients with non-small cell lung cancer (NSCLC). However, the role of KRAS as either a prognostic factor or predictive factor (modifier of treatment effects) in NSCLC is not well established at this time. This systematic literature review (SLR) and meta-analysis synthesized the available evidence regarding the role of KRAS mutation as a predictive factor and/or prognostic factor of survival and response outcomes in patients with advanced/metastatic (stage IIIB-IV) NSCLC. Relevant clinical trials and observational studies were identified by searching MEDLINE, Embase and Cochrane Register of Controlled Trials. Meta-analyses were performed using data extracted from multivariable and univariable analyses from clinical studies to assess the empirical evidence of KRAS mutation status as a prognostic or/and predicitive factor. 43 selected studies were identified by the SLR and included in this meta-analysis. Pairwise meta-analyses of hazard ratios (HRs) reported in randomized controlled trials (RCTs) did not demonstrate a significant prognostic effect of mutant KRAS on overall survival (OS) (HR=1.10; 95% CI [0.88, 1.38]) or progression free survival (PFS) (HR=1.03; 95% CI [0.80, 1.33]). However, when conducting meta-analyses on HRs reported in observational studies, a statistically significant negative prognostic effect of mutant KRAS was observed (OS HR=1.71; 95% CI [1.07, 2.84]; PFS HR=1.18; 95% CI [1.02, 1.36]). Meta-analyses of objective response rate (ORR) in RCTs demonstrated a negative prognostic effect of mutant KRAS (RR=0.38; 95% CI [0.16, 0.63]). Limited data were available to evaluate the role of KRAS mutation as a predictive factor. In conclusion, this research offers evidence that KRAS mutation may be a negative prognostic factor for survival and response outcomes in patients with advanced/metastatic NSCLC, but further research is needed to address conflicting results on the importance of KRAS mutations as a predictive factor.

Host age and Plasmodium falciparum multiclonality are associated with gametocyte prevalence: a 1-year prospective cohort study.

BACKGROUND: Since Plasmodium falciparum transmission relies exclusively on sexual-stage parasites, several malaria control strategies aim to disrupt this step of the life cycle. Thus, a better understanding of which individuals constitute the primary gametocyte reservoir within an endemic population, and the temporal dynamics of gametocyte carriage, especially in seasonal transmission settings, will not only support the effective implementation of current transmission control programmes, but also inform the design of more targeted strategies. METHODS: A 1-year prospective cohort study was initiated in June 2013 with the goal of assessing the longitudinal dynamics of P. falciparum gametocyte carriage in a village in Mali with intense seasonal malaria transmission. A cohort of 500 individuals aged 1-65 years was recruited for this study. Gametocyte prevalence was measured monthly using Pfs25-specific RT-PCR, and analysed for the effects of host age and gender, seasonality, and multiclonality of P. falciparum infection over 1 year. RESULTS: Most P. falciparum infections (51-89%) in this population were accompanied by gametocytaemia throughout the 1-year period. Gametocyte prevalence among P. falciparum-positive individuals (proportion of gametocyte positive infections) was associated with age (p = 0.003) but not with seasonality (wet vs. dry) or gender. The proportion of gametocyte positive infections were similarly high in children aged 1-17 years (74-82% on median among 5 age groups), while older individuals had relatively lower proportion, and those aged > 35 years (median of 43%) had significantly lower than those aged 1-17 years (p < 0.05). Plasmodium falciparum-positive individuals with gametocytaemia were found to have significantly higher P. falciparum multiclonality than those without gametocytaemia (p < 0.033 in two different analyses). CONCLUSIONS: Taken together, these results suggest that a substantial proportion of Pf-positive individuals carries gametocytes throughout the year, and that age is a significant determinant of gametocyte prevalence among these P. falciparum-positive individuals. Furthermore, the presence of multiple P. falciparum genotypes in an infection, a common feature of P. falciparum infections in high transmission areas, is associated with gametocyte prevalence.

High Plasmodium falciparum longitudinal prevalence is associated with high multiclonality and reduced clinical malaria risk in a seasonal transmission area of Mali.

The effects of persistent Plasmodium falciparum (Pf) infection and multiclonality on subsequent risk of clinical malaria have been reported, but the relationship between these 2 parameters and their relative impacts on the clinical outcome of infection are not understood. A longitudinal cohort study was conducted in a seasonal and high-transmission area of Mali, in which 500 subjects aged 1-65 years were followed for 1 year. Blood samples were collected every 2 weeks, and incident malaria cases were diagnosed and treated. Pf infection in each individual at each time point was assessed by species-specific nested-PCR, and Pf longitudinal prevalence per person (PfLP, proportion of Pf-positive samples over 1 year) was calculated. Multiclonality of Pf infection was measured using a 24-SNP DNA barcoding assay at 4 time-points (two in wet season, and two in dry season) over one year. PfLP was positively correlated with multiclonality at each time point (all r≥0.36; all P≤0.011). When host factors (e.g., age, gender), PfLP, and multiclonality (at the beginning of the transmission season) were analyzed together, only increasing age and high PfLP were associated with reduced clinical malaria occurrence or reduced number of malaria episodes (for both outcomes, P<0.001 for age, and P = 0.005 for PfLP). When age, PfLP and baseline Pf positivity were analyzed together, the effect of high PfLP remained significant even after adjusting for the other two factors (P = 0.001 for malaria occurrence and P<0.001 for number of episodes). In addition to host age and baseline Pf positivity, both of which have been reported as important modifiers of clinical malaria risk, our results demonstrate that persistent parasite carriage, but not baseline multiclonality, is associated with reduced risk of clinical disease in this population. Our study emphasizes the importance of considering repeated parasite exposure in future studies that evaluate clinical malaria risk.

Variation in Private Payer Coverage of Rheumatoid Arthritis Drugs.

BACKGROUND: Payers in the United States issue coverage determinations to guide how their enrolled beneficiaries use prescription drugs. Because payers create their own coverage policies, how they cover drugs can vary, which in turn can affect access to care by beneficiaries. OBJECTIVE: To examine how the largest private payers based on membership cover drugs indicated for rheumatoid arthritis and to determine what evidence the payers reported reviewing when formulating their coverage policies. METHODS: Coverage policies issued by the 10 largest private payers that make their policies publicly available were identified for rheumatoid arthritis drugs. Each coverage determination was compared with the drug's corresponding FDA label and categorized according to the following: (a) consistent with the label, (b) more restrictive than the label, (c) less restrictive than the label, or (d) mixed (i.e., more restrictive than the label in one way but less restrictive in another). Each coverage determination was also compared with the American College of Rheumatology (ACR) 2012 treatment recommendations and categorized using the same relative restrictiveness criteria. The policies were then reviewed to identify the evidence that the payers reported reviewing. The identified evidence was divided into the following 6 categories: randomized controlled trials; other clinical studies (e.g., observational studies); health technology assessments; clinical reviews; cost-effectiveness analyses; and clinical guidelines. RESULTS: Sixty-nine percent of coverage determinations were more restrictive than the corresponding FDA label; 15% were consistent; 3% were less restrictive; and 13% were mixed. Thirty-four percent of coverage determinations were consistent with the ACR recommendations, 33% were more restrictive; 17% were less restrictive; and 17% were mixed. Payers most often reported reviewing randomized controlled trials for their coverage policies (an average of 2.3 per policy). The payers reported reviewing an average of 1.4 clinical guidelines, 1.1 clinical reviews, 0.8 other clinical studies, and 0.5 technology assessments per policy. Only 1 payer reported reviewing cost-effectiveness analyses. The evidence base that the payers reported reviewing varied in terms of volume and composition. CONCLUSIONS: Payers most often covered rheumatoid arthritis drugs more restrictively than the corresponding FDA label indication and the ACR treatment recommendations. Payers reported reviewing a varied evidence base in their coverage policies. DISCLOSURES: Funding for this study was provided by Genentech. Chambers has participated in a Sanofi advisory board, unrelated to this study. The authors report no other potential conflicts of interest. Study concept and design were contributed by Chambers. Anderson, Wilkinson, and Chenoweth collected the data, assisted by Chambers, and data interpretation was primarily performed by Chambers, along with Anderson and with assistance from Wilkinson and Chenoweth. The manuscript was written primarily by Chambers, along with Wilkinson and with assistance from Anderson and Chenoweth. Chambers, Chenoweth, Wilkinson, and Anderson revised the manuscript.

Mapping US commercial payers' coverage policies for medical interventions.

OBJECTIVES: To examine coverage policies for medical interventions issued by the largest US commercial payers. STUDY DESIGN: Review of publicly accessible coverage policies for medical interventions. METHODS: We categorized the 20 largest commercial payers' medical benefit coverage policies for medical technologies-current as of August 1, 2014-with respect to technology type (eg, medical devices, pharmaceuticals, surgeries). We identified the interventions most commonly subject to coverage policies and compared payer coverage determinations in terms of whether they covered the intervention and the evidence they reported reviewing. RESULTS: Eighteen payers made their coverage policies publicly available and 17 reported the evidence they reviewed in formulating policies. The types of technologies considered varied across payers, although most focused on devices and diagnostics. Of the 28 interventions most commonly subject to coverage policies, the coverage of 9 varied (ie, some payers covered the intervention and others did not). On average, payers reported reviewing clinical studies in 87% of coverage policies (range = 25%-100%). Two payers did not report reviewing systematic reviews or meta-analyses in any coverage policies, and 9 reported reviewing such evidence in at least half of their policies. Fourteen payers reported reviewing cost-effectiveness analyses at least some of the time, with frequency ranging from 8% to 43%. Commercial payers' coverage decisions did not appear to reflect direct input from patients or patient advocates, at least as stated in published coverage policies. CONCLUSIONS: Coverage of medical interventions varies across US private payers. Payers often report reviewing different evidence when formulating coverage policies, but do not report considering input directly from patients in evidence assessments.

Private payers disagree with Medicare over medical device coverage about half the time.

There are multiple payers in the US health care system, each making its own coverage determinations for medical technologies. For each of the forty-seven medical devices considered in national coverage determinations (NCDs) of the Centers for Medicare and Medicaid Services (CMS) issued between February 1999 and August 2013, we compared CMS's coverage policy with the policies issued by the largest sixteen private payers that made their decisions publicly available. Overall, we found that NCDs were equivalent to the corresponding private payer policies roughly half of the time, more restrictive approximately a quarter of the time, and less restrictive about a quarter of the time. Our findings indicate that patients may have variable access to medical technology across Medicare and private plans. They also suggest that private plans do not necessarily follow CMS's lead in making coverage decisions.

Medicare is scrutinizing evidence more tightly for national coverage determinations.

We examined Medicare national coverage determinations for medical interventions to determine whether or not they have become more restrictive over time. National coverage determinations address whether particular big-ticket medical items, services, treatment procedures, and technologies can be paid for under Medicare. We found that after we adjusted for the strength of evidence and other factors known to influence the determinations of the Centers for Medicare and Medicaid Services (CMS), the evidentiary bar for coverage has risen. More recent coverage determinations (from mid-March 2008 through August 2012) were twenty times less likely to be positive than earlier coverage determinations (from February 1999 through January 2002). Furthermore, coverage during the study period was increasingly and positively associated both with the degree of consistency of favorable findings in the CMS reviewed clinical evidence and with recommendations made in clinical guidelines. Coverage policy is an important payer tool for promoting the appropriate use of medical interventions, but CMS's rising evidence standards also raise questions about patients' access to new technologies and about hurdles for the pharmaceutical and device industries as they attempt to bring innovations to the market.

CHANGING FACE OF MEDICARE'S NATIONAL COVERAGE DETERMINATIONS FOR TECHNOLOGY.

OBJECTIVES: The Centers for Medicare and Medicaid Services (CMS) issues National Coverage Determinations (NCDs) for medical interventions expected to have a significant impact on Medicare, the health insurance program for US citizens aged 65 years and older and certain people with disabilities under the age of 65 years. The objective of this study was to evaluate NCDs issued from 1999 to 2013 to identify key trends, and to discuss implications for future CMS policy. METHODS: We used the Tufts Medical Center Medicare National Coverage Determination Database to examine characteristics of NCDs from 1999 through 2013. We examined various characteristics of NCDs, including: whether the intervention under review is used for prevention or treatment of disease, the type of intervention considered, evidence limitations cited by CMS, and coverage determination outcome. We evaluated longitudinal trends in categorical and continuous variables in the database, using Cochran-Armitage trend tests and linear regression, respectively. RESULTS: We found that NCDs increasingly focus on preventive care (p = 0.072), pertain to diagnostic imaging (p = 0.033), and evaluate health education/behavioral therapy interventions (p = 0.051). CMS increasingly cites the lack of relevant outcomes (p = 0.019) and the lack of applicability of study results to the Medicare population (p < 0.001) as evidence limitations. CMS less often restricts coverage to certain population subgroups in NCDs (p < 0.001), but increasingly applies coverage with evidence development policies (p < 0.001). CONCLUSIONS: Identified trends reflect broader changes in Medicare as CMS shifts its focus from treatment to prevention of disease, addresses potentially overutilized technologies, and attempts to issue flexible coverage policies.

Despite high costs, specialty drugs may offer value for money comparable to that of traditional drugs.

Specialty drugs are often many times more expensive than traditional drugs, which raises questions of affordability and value. We compared the value of specialty and traditional drugs approved by the Food and Drug Administration (FDA) in the period 1999-2011. To do this, we identified published estimates of additional health gains (measured in quality-adjusted life-years, or QALYs) and increased costs of drug and health care resource use that were associated with fifty-eight specialty drugs and forty-four traditional drugs, compared to preexisting care. We found that specialty drugs offered greater QALY gains (0.183 versus 0.002 QALYs) but were associated with greater additional costs ($12,238 versus $784), compared to traditional drugs. The two types of drugs had comparable cost-effectiveness. However, the distributions across the two types differed, with 26 percent of specialty drugs--but only 9 percent of traditional drugs--associated with incremental cost-effectiveness ratios of greater than $150,000 per QALY. Our study suggests that although specialty drugs often have higher costs than traditional drugs, they also tend to confer greater benefits and hence may still offer reasonable value for money.

Complex regulation of the DnaJ homolog CbpA by the global regulators sigmaS and Lrp, by the specific inhibitor CbpM, and by the proteolytic degradation of CbpM.

CbpA is a DnaJ homolog that functions as a DnaK cochaperone. Several cellular processes, including growth at low and high temperatures and septum formation during cell division, require either CbpA or DnaJ. CbpA is encoded in an operon with the gene for CbpM, which is a specific in vivo and in vitro inhibitor of CbpA. Here, we have cooverexpressed CbpA with CbpM in a DeltacbpAM DeltadnaJ strain and examined the resulting phenotypes. Under these conditions, sufficient free CbpA activity was present to support growth at low temperatures, but not at high temperatures. Defects in cell division and in lambda replication were also partially complemented by CbpA when cooverexpressed with CbpM. Utilizing reporter fusions, we demonstrated that the cbpAM operon was maximally transcribed at the transition from exponential growth to stationary phase. Transcription was controlled by the sigma(S) and Lrp global regulators, and both leucine availability and growth temperature influenced transcription. CbpA and CbpM accumulated to similar levels in stationary phase, approximately 2,300 monomers per cell. When not bound to CbpA, CbpM was unstable and was degraded by the Lon and ClpAP proteases. These data demonstrate that CbpA activity is controlled at multiple levels.

In vivo modulation of a DnaJ homolog, CbpA, by CbpM.

CbpA, an Escherichia coli DnaJ homolog, can function as a cochaperone for the DnaK/Hsp70 chaperone system, and its in vitro activity can be modulated by CbpM. We discovered that CbpM specifically inhibits the in vivo activity of CbpA, preventing it from functioning in cell growth and division. Furthermore, we have shown that CbpM interacts with CbpA in vivo during stationary phase, suggesting that the inhibition of activity is a result of the interaction. These results reveal that the activity of the E. coli DnaK system can be regulated in vivo by a specific inhibitor.

Predominant outer membrane antigens of Bartonella henselae.

A hallmark of Bartonella henselae is persistent bacteremia in cats despite the presence of a vigorous host immune response. To understand better the long-term survival of B. henselae in cats, we examined the feline humoral immune response to B. henselae outer membrane (OM) proteins in naturally and experimentally infected cats. Initially, a panel of sera (n = 42) collected throughout North America from naturally infected cats was used to probe B. henselae total membranes to detect commonly recognized antigens. Twelve antigens reacted with sera from at least 85% of cats, and five were recognized by sera from all cats. To localize these antigens further, OMs were purified on discontinuous sucrose density step gradients. Each membrane fraction (OM, hybrid or inner membrane [IM]) contained less than 1% of the total malate dehydrogenase activity (soluble marker), indicating very little contamination by cytoplasmic proteins. FtsI, an integral IM cell division protein, was used to identify the low-density fraction (rho = 1.13 g/cm3) as putative IM (<5% of the total FtsI localized to the high-density fraction) while lipopolysaccharide (LPS) and Pap31, a homolog of the Bartonella quintana heme-binding protein A (HbpA), defined the high-density fraction (rho = 1.20 g/cm3) as putative OM. Additionally, little evidence of cross-contamination between the IM and OM was evident by two-dimensional gel electrophoresis. When purified OMs were probed with feline sera, antigenic proteins profiles were very similar to those observed with total membranes, indicating that many, but not all, of the immunoreactive proteins detected in the initial immunoblots were OM components. Interestingly, two-dimensional immunoblots indicated that B. henselae LPS and members of the Hbp family of proteins did not appear to stimulate an humoral response in any infected cats. Seven proteins were recognized by at least 70% of sera tested, but only three were recognized by all sera. Nanospray-tandem mass spectrometry was used to identify OM components, including the immunodominant OM proteins. Recognition of the nonimmunogenic nature of the major OM components, such as LPS, and identification of the predominant immunogens should elucidate the mechanisms by which B. henselae establishes persistent bacteremic infections within cats. Additionally, the common antigens may serve as potential feline vaccine candidates to eliminate the pathogen from its animal reservoir.