High unmet treatment needs in patients with chronic kidney disease and type 2 diabetes: real-world evidence from a US claims database.

BACKGROUND: Chronic kidney disease (CKD), a serious complication of type 2 diabetes (T2D) increases the comorbid risk of cardiovascular disease (CVD) and end-stage kidney disease(ESKD). Treatment guidelines recommend renin-angiotensin blockade and antihyperglycemic treatment with metformin and sodium-glucose cotransporter 2 inhibitors (SGLT2is) as first-line treatment. We evaluated treatment initiation and discontinuation overall and in subgroups of T2D patients with incident CKD (incident cohort) and rates of clinical and economic outcomes in patients with T2D and any CKD (prevalent cohort). METHODS: In this retrospective study of administrative claims in the USA between 1 January 2007 and 31 March 2019, we evaluated the proportion of patients with concomitant, newly initiated and discontinued use of antihypertensive [angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blockers (ARBs), steroidal mineralocorticoid receptor antagonists (sMRAs)] and antidiabetic [SGLT2is, dipeptidyl peptidase-4 inhibitors (DPP4is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), insulin and sulfonylureas] medications, rates of clinical outcomes per 1000 person-years and mean total healthcare costs. RESULTS: We identified 63 127 and 326 763 patients in the incident and prevalent CKD cohorts, respectively. Low initiation and high discontinuation rates were observed with 17.8% and 56.0% for ACEi/ARBs, 1.3% and 66.0% for sMRAs, 2.5% and 65.0% for SGLT2is, 3.7% and 66.8% for DPP4is, 2.31% and 69.0% for GLP-1 RAs, 4% and 75.7% for insulin and 5.5% and 56.9% for sulfonylureas. Similar results were seen by subgroups. Rates of clinical outcomes ranged from 35.07 per 1000 person-years for all-cause mortality to 104.19 for ESKD, with rates of hospitalization ranging from 36.61 for kidney hospitalizations to 283.14 for all-cause hospitalizations. Among patients with comorbidities, higher clinical and economic outcomes were found. CONCLUSION: Our results highlight high unmet needs of CKD and T2D, particularly subgroups of patients with multimorbid CVD, high-risk CKD (low estimated glomerular filtration rate or high urinary albumin:creatinine ratio) or rapidly progressing CKD. Low initiation and high discontinuation of recommended treatments suggest that adherence to guidelines for halting CKD progression is suboptimal. These high-risk patients may benefit from further treatment options to improve morbidity and mortality and reduce the economic burden.

Predictors of cardio-kidney complications and treatment failure in patients with chronic kidney disease and type 2 diabetes treated with SGLT2 inhibitors.

BACKGROUND: Clinical practice guidelines recommend sodium-glucose co-transporter 2 inhibitors (SGLT2is) to mitigate adverse kidney and cardiovascular outcomes in patients with type 2 diabetes (T2D), including patients with comorbid chronic kidney disease (CKD), also referred to as diabetic kidney disease (DKD), who are at even higher risk. In this study, we sought to identify predictors of cardio-kidney events, cardio-kidney complications, and treatment failure (i.e., addition/initiation of a new T2D class, insulin, or discontinuation of SGLT2is) after new initiation of SGLT2is in patients with CKD and T2D (DKD). METHODS: In this retrospective cohort study, we identified adult patients with DKD who initiated SGLT2is between April 1, 2012, and June 30, 2019, in Optum claims data. Outcome rates per 1000 person-years (PY) are reported with 95% confidence intervals (CIs). Cox proportional hazards regression identified patient characteristics associated with each outcome. RESULTS: The study population consisted of 6389 initiators of SGLT2is. The rate of CV hospitalization was 26.0 (95% CI 21.6, 30.4) per 1000 PY. Baseline characteristics associated with higher risk of CV hospitalization included age, atrial fibrillation, peripheral vascular disease (PVD), and cancer. The rate of kidney hospitalization was 12.0 (95% CI 9.0, 15.0) per 1000 PY. The risk increased significantly with baseline evidence of heart failure, hyperkalemia, respiratory failure, depression, and use of loop diuretics. In total, 55.0% of all SGLT2i initiators discontinued treatment during the follow-up period. The rate of treatment failure was 510.5 (95% CI 492.9, 528.1) per 1000 PY. Analysis of key time-dependent SGLT2i-associated adverse events showed that experiencing diabetic ketoacidosis and volume depletion were associated with risk of treatment failure. CONCLUSIONS: Our study demonstrated high rates of residual cardio-kidney outcomes and treatment failure in patients with DKD treated with SGLT2is. Patients with high baseline CV risk and the presence of certain conditions, such as atrial fibrillation, PVD, and heart failure, were at higher risk for cardio-kidney events. Further research is needed to assess the potential relationship between adverse events and SGLT2i treatment failure.

Is there a difference in the acromiohumeral distances measured on radiographic and magnetic resonance images of the same shoulder with a massive rotator cuff tear?

BACKGROUND: The purpose of our study was to compare the acromiohumeral distance (AHD) between radiographic and magnetic resonance images (MRIs) of the same shoulder with massive rotator cuff tears (MRCTs). METHODS: Thirty-four shoulders with MRCTs that had an MRI and radiograph of the same shoulder within an average of 40.3 days (range: 8-109 days) were identified. AHD was measured digitally on radiograph and MRI by 3 examiners. Shoulders were grouped into Hamada grades <3 (group 1) and Hamada grades ≥3 (group 2). RESULTS: The mean age was 66.4 years (range: 51-89). There were 19 men (59%). The Kappa for inter-rater reliability was 0.982 (95% confidence interval [CI] 0.975, 0.988) for radiographs and 0.88 (95% CI 0.75, 0.94) for MRI. There was a significant difference in the mean AHD of group 1 on radiograph vs. MRI (7.9 mm vs. 2.5 mm, respectively; P < .0001), but no difference in group 2 (1.8 mm vs. 2.2 mm, respectively; P = .45). There was no difference in AHD in group 1 between shoulders with Goutallier stage <3 (8.1 ± 1.9 mm) and those with Goutallier stage ≥3 (7.3 ± 2.1 mm) (P = .3479). There was no difference in AHD in group 2 between shoulders with Goutallier stage <3 (3.0 ± 0.1 mm) and those with Goutallier stage ≥3 (1.5 ± 1.0 mm) (P = .079). CONCLUSION: There is a significant difference in AHD measurements between radiograph and MRI of the same shoulder with MRCT in early Hamada grades. AHDs measured on radiograph and MRI should not be used interchangeably in early Hamada grades to assess outcomes of superior capsule reconstruction and similar procedures.

Influence of Ambulatory Triglyceride Levels on Risk of Recurrence in Patients with Hypertriglyceridemic Pancreatitis.

BACKGROUND AND AIMS: To evaluate impact of ambulatory triglyceride levels on risk of recurrent pancreatitis in patients with hypertriglyceridemic pancreatitis. METHODS: We conducted a longitudinal retrospective cohort study of patients with serum triglyceride level ≥ 500 mg/dL during index hospitalization for acute pancreatitis within a regional integrated healthcare system between 2006 and 2013 (follow-up through 2015). Cases were identified based on combination of diagnosis codes and serum amylase/lipase. We used multivariable robust Poisson regression to determine independent effect of baseline (first outpatient) triglyceride measurement on risk of recurrent pancreatitis. Ambulatory triglyceride levels were categorized as normal (0-200 mg/dL), moderately elevated (201-500 mg/dL), and highly elevated (> 500 mg/dL). We further assessed factors related to likelihood of normalization of serum triglycerides (< 200 mg/dL) in the outpatient setting. RESULTS: One hundred and fifty-one patients met study inclusion criteria with median follow-up of 3 years. Overall, 45 (29.8%) patients experienced at least 1 recurrent attack with 25 (16.6%) experiencing multiple episodes. In multivariable analysis, patients that continued to have moderately elevated ((adjusted rate ratio RR 5.47 (95% CL 1.80, 16.65)) as well as highly elevated (RR 8.45 (2.55, 27.96)) triglycerides were at increased risk of disease recurrence compared to patients that achieved normalization. Patients with triglyceride measurement performed within 30 days from discharge were more likely to achieve normalization, 40 versus 26%, p = 0.03. CONCLUSIONS: For patients with hypertriglyceridemic pancreatitis, even modest elevation in subsequent triglyceride levels was associated with increased risk of recurrence. Future efforts should focus on ensuring timely care in the outpatient setting with a goal of normalizing triglycerides.

Complications of biceps tenodesis based on location, fixation, and indication: a review of 1526 shoulders.

BACKGROUND: Long head of the biceps tendon (LHBT) tenodesis is predominantly performed for 2 reasons: anterior shoulder pain (ASP) or structural reasons (partial tear, dislocation). METHODS: Between 2006 and 2014, all cases of primary LHBT tenodesis performed at an integrated health care system were retrospectively reviewed. Complications were analyzed by tenodesis location (below or out of the groove [OOG] vs leaving tendon in the groove [ITG]), fixation method (soft tissue vs implant), and indication (preoperative ASP vs structural). RESULTS: Among 1526 shoulders, persistent ASP did not differ by fixation method (11.0% for implant vs 12.8% for soft tissue, P = .550) or location (10.8% for OOG vs 12.9% for ITG, P = .472). Soft-tissue tenodesis cases had more frequent new-onset ASP (11.9% vs 2.6%, P < .001) and subjective weakness (8.50% vs 3.92%, P < .001) but less frequent revisions (0% vs 1.19%, P = .03) than implant tenodesis cases. No difference was found between ITG and OOG for persistent ASP (12.9% vs 10.8%, P = .550), new-onset ASP (6.5% vs 2.8%, P = .339), cramping (1.70% vs 2.31%, P = .737), deformity (4.72% vs 4.62%, P = .532), or subjective weakness (6.23% vs 4.32%, P = .334), but ITG cases had more revisions (1.51% vs 0.60%, P = .001). Among implant tenodesis cases, 1 shoulder (0.085%) sustained a fracture. CONCLUSION: The overall complication rate of LHBT tenodesis was low. Of the shoulders, 10.8% to 12.9% continued to have ASP, regardless of whether the LHBT was left ITG. Soft-tissue tenodesis cases had higher rates of new-onset ASP and subjective weakness. No significant difference for tenodesis ITG or OOG was found in biceps-related complications.

Dynamic Measurement of Disease Activity in Acute Pancreatitis: The Pancreatitis Activity Scoring System.

OBJECTIVES: Acute pancreatitis has a highly variable course. Currently there is no widely accepted method to measure disease activity in patients hospitalized for acute pancreatitis. We aimed to develop a clinical activity index that incorporates routine clinical parameters to assist in the measurement, study, and management of acute pancreatitis. METHODS: We used the UCLA/RAND appropriateness method to identify items for inclusion in the disease activity instrument. We conducted a systematic literature review followed by two sets of iterative modified Delphi meetings including a panel of international experts between November 2014 and November 2015. The final instrument was then applied to patient data obtained from five separate study cohorts across Southern California to assess profiles of disease activity. RESULTS: From a list of 35 items comprising 6 domains, we identified 5 parameters for inclusion in the final weighted clinical activity scoring system: organ failure, systemic inflammatory response syndrome, abdominal pain, requirement for opiates and ability to tolerate oral intake. We applied the weighted scoring system across the 5 study cohorts comprising 3,123 patients. We identified several distinct patterns of disease activity: (i) overall there was an elevated score at baseline relative to discharge across all study cohorts, (ii) there were distinct patterns of disease activity related to duration of illness as well as (iii) early and persistent elevation of disease activity among patients with severe acute pancreatitis defined as persistent organ failure. CONCLUSIONS: We present the development and initial validation of a clinical activity score for real-time assessment of disease activity in patients with acute pancreatitis.

Anaphylaxis in a health maintenance organization: International Classification of Diseases coding and epinephrine auto-injector prescribing.

BACKGROUND: Accurate estimates of the incidence of anaphylaxis are limited. Current International Classification of Diseases, Ninth Revision (ICD-9) codes complicate accurate diagnosis of anaphylaxis and assessment of appropriate epinephrine prescribing. OBJECTIVE: To quantify the incidence and demographic character of patients with anaphylaxis-related ICD-9 codes in a large health maintenance organization and analyze epinephrine prescribing and dispensing rates. METHODS: All patients included had at least 12 months of continuous membership over a 4-year period from January 1, 2008 to December 31, 2012 and were selected based on anaphylaxis-related ICD-9 codes (N = 159,172). This algorithm was extrapolated from a previous study that used expanded ICD-9 codes to identify more cases of anaphylaxis. Individual chart reviews found that many expanded ICD-9 codes represented unconfirmed cases of anaphylaxis and therefore were excluded, resulting in analysis of 52,405 patients. RESULTS: Incidence of anaphylaxis over 4 years was 2.07%, with female predominance (56.5%) over male predominance (43.5%). Epinephrine was prescribed in 16.2% of total cases. Highest rates of epinephrine prescription were for traditional ICD-9 codes 995.0 (other anaphylactic shock) and 995.60 to 995.69 (anaphylactic shock caused by food) at 49.3% and 58.6%, respectively. Of the cases in which an epinephrine auto-injector was prescribed, it was dispensed 95.9% of the time, independent of copayment amount. CONCLUSION: Low epinephrine auto-injector prescribing rates in cases of anaphylaxis suggest the continued difficulty in the diagnosis of anaphylaxis and could result in suboptimal treatment of potential future episodes.

Examining HIV Viral Load in a Matched Cohort of HIV Positive Individuals With and Without Psoriasis.

BACKGROUND: HIV-associated psoriasis is well-documented. Genetic, cellular, and cytokine profiles have been used as evidence to suggest psoriasis activates antiviral pathways. There has been a lack of epidemiologic evidence investigating whether psoriasis patients have lower HIV viral counts compared to non-psoriasis patients.

OBJECTIVE: Compare the viral load set point of HIV positive patients with and without psoriasis.

METHODS: A retrospective matched cohort study of HIV positive patients with and without psoriasis using the Kaiser Permanente Southern California Health Plan database.

RESULTS: We identified 101 HIV-positive psoriasis cases; 19 met inclusion criteria and were matched with 3-5 control patients; 94 total patients were analyzed. The mean age was 41.4 (12.07) years and 83% were male. Overall, the median log of the viral load of cases was slightly higher than controls (4.3 vs 4.2; P less than 0.01).

CONCLUSIONS: The serum viral load set point of patients with HIV and psoriasis was slightly higher than the viral load set point of HIV patients without psoriasis.

J Drugs Dermatol. 2017;16(4):372-377.

In Vivo Analysis of Biceps Tendon Characteristics in Subpectoral Tenodesis.

PURPOSE: To report the in vivo characteristics of the long head of the biceps tendon (LHBT); to evaluate the relation of age, gender, height, weight, and body mass index to the length and sutured and tubularized diameter of the LHBT; and to determine the smallest possible tunnel diameter for a subpectoral biceps tenodesis (SPBT) that can accommodate most patients. METHODS: The study included 66 patients (33 men and 33 women) with an average age of 54 years (range, 29-73 years) undergoing SPBT. After tenotomy, the length from the biceps musculotendinous junction to the released end was measured. The tendon was transected 3 cm proximal to the musculotendinous junction and sutured, and the diameter was measured. The depth of the reamed tunnel was recorded. RESULTS: The average tendon length was 84.0 mm, measuring 91.9 mm in men and 76.2 mm in women (P < .001), and the average tendon diameter was 4.4 mm, varying slightly between men (4.5 mm) and women (4.3 mm) (P < .001). Mean bone tunnel depth was 17.5 mm, with 19 mm in men and 16.1 mm in women (P < .001). Patient height showed a significant relation to both tendon length and tendon diameter. Weight was not correlated with tendon diameter but did show a significant relation to tendon length. CONCLUSIONS: We have characterized the in vivo length and diameter of the LHBT at the time of an SPBT. Our findings have shown that there was a statistically significant gender difference in tendon length and diameter, but the diameter of the sutured tendon, which was placed into the tunnel, averaged 4.4 mm and ranged from 3.5 to 5 mm for all ages, both genders, all heights, and all weights. This finding is clinically relevant in that a small tunnel measuring 5.5 mm or less is sufficient to perform an SPBT. LEVEL OF EVIDENCE: Level IV, case series, anatomic study.

Midline Capillary Formation Nuchae and Age.

Midline capillary formation nuchae (MCFN) consists of blanchable pink macules located around the midline of the occiput and nape. It has been implicated in the literature as a risk factor for angiosarcoma and might be related to a decrease in innervation of the involved capillaries. Although there is ample literature on its prevalence from birth through adult life, the literature in late life is sparse. The objective of this study was to determine the prevalence in late life, whether it is truly a risk factor for angiosarcoma and whether it might be an indication of a systemic neuroendocrine effect or a local reaction. In routine skin screening examinations of 411 patients, the prevalence of MCFN increased with age (P<.0001), by quartiles of age overall (P=.0001), and among men only (P=.0013). No difference in prevalence was observed across quartiles of age among women only (P=.0688). No association was found with routine parameters that might be influenced by the systemic neuroendocrine system. Prevalence increases in old age, is not a risk factor for angiosarcoma, and might represent a response of local capillaries to normal changes in the neuroendocrine system that occur with age.

Distribution of Biopsy-Proven Presumed Primary Glomerulonephropathies in 2000-2011 Among a Racially and Ethnically Diverse US Population.

BACKGROUND: The incidence and distribution of primary glomerulonephropathies vary throughout the world and by race and ethnicity. We sought to evaluate the distribution of primary glomerulonephropathies among a large racially and ethnically diverse population of the United States. STUDY DESIGN: Case series from January 1, 2000, through December 31, 2011. SETTING & PARTICIPANTS: Adults (aged ≥ 18 years) of an integrated health system who underwent native kidney biopsy and had kidney biopsy findings demonstrating focal segmental glomerulosclerosis (FSGS), membranous glomerulonephritis (MGN), minimal change disease (MCD), immunoglobulin A nephropathy (IgAN), and other. OUTCOMES: Rates and characteristics of the most common primary glomerulonephropathies overall and by race and ethnicity. RESULTS: 2,501 patients with primary glomerulonephropathy were identified, with a mean age 50.6 years, 45.7% women, 36.1% Hispanics, 31.2% non-Hispanic whites, 17.4% blacks, and 12.4% Asians. FSGS was the most common glomerulonephropathy (38.9%) across all race and ethnic groups, followed by MGN (12.7%), MCD (11.0%), IgAN (10.2%), and other (27.3%). The FSGS category had the greatest proportion of blacks, and patients with FSGS had the highest rate of poverty. IgAN was the second most common glomerulonephropathy among Asians (28.6%), whereas it was 1.2% among blacks. Patients with MGN presented with the highest proteinuria (protein excretion, 8.3g) whereas patients with FSGS had the highest creatinine levels (2.6mg/dL). Overall glomerulonephropathy rates increased annually in our 12-year observation period, driven by FSGS (2.7 cases/100,000) and IgAN (0.7 cases/100,000). MGN and MCD rates remained flat. LIMITATIONS: Missing data for urine albumin and sediment, indication bias in performing kidney biopsies, and inexact classification of primary versus secondary disease. CONCLUSIONS: Among a racially and ethnically diverse cohort from a single geographical area and similar environment, FSGS was the most common glomerulonephropathy, but there was variability of other glomerulonephropathies based on race and ethnicity.

Serum phosphorus and association with anemia among a large diverse population with and without chronic kidney disease.

BACKGROUND: We hypothesized that phosphorus has an effect on anemia in both normal kidney function and early chronic kidney disease (CKD). We sought to determine whether higher phosphorus levels are associated with anemia in a large diverse population without CKD and early CKD. METHODS: This study is a historical population-based study within the Kaiser Permanente Southern California health system (1 January 1998 to 31 December 2013) among individuals aged 18 years and older with estimated glomerular filtration rate >30 mL/min/1.73 m(2) and measurements of serum phosphorus, creatinine and hemoglobin. Individuals were excluded if they had secondary causes of anemia. Odds ratio (OR) estimated for moderate anemia defined as hemoglobin <11 g/dL for both sexes. Mild anemia was defined as <12 g/dL (females) and <13 g/dL (males). RESULTS: Among 155 974 individuals, 4.1% had moderate anemia and 12.9% had mild anemia. Serum phosphorus levels ≥3.5 mg/dL were associated with both mild and moderate anemia. Moderate anemia OR (95% confidence interval) was 1.16 (1.04-1.29) for every 0.5 mg/dL phosphorus increase and 1.26 (1.07-1.48) in the highest versus middle phosphorus tertile. Additional independent anemia risk factors, including female sex, Asian race, diabetes, low albumin and low iron saturation, were observed, but did not alter the anemia-phosphorus association. CONCLUSIONS: Higher phosphorus levels were associated with a greater likelihood for anemia in a population with early CKD and normal kidney function. Phosphorus may be a biomarker for anemia and may affect aspects of hematopoiesis.

Reliability of meat, fish, dairy, and egg intake over a 33-year interval in Adventist Health Study 2.

We studied Adventist Health Study 2 (AHS-2) cohort members to determine the reliability of long-term recall of adult dietary intake that occurred 33 years ago. Establishing the reliability of these measures supports studies of how dietary exposure across the life course affects risk of cancer and other noncommunicable disease outcomes. Among 1816 AHS-2 cohort members, we conducted a statistical comparison of long-term recall of meat, fish, dairy, and eggs at AHS-2 baseline with their report of current diet 33 years before AHS-2 baseline at an age of 30-60 years. Major findings are as follows: 1) a high correlation for frequency of red meat (R = 0.71), poultry (R = 0.67), and fish (R = 0.60); lower correlations for dairy (R = 0.19) and eggs (R = 0.28); 2) good concordance for dichotomous measures of red meat [sensitivity: 0.70; specificity: 0.92; positive predictive value (PPV): 0.91], poultry (sensitivity: 0.76; specificity: 0.87; PPV: 0.83), fish (sensitivity: 0.61; specificity: 0.93; PPV: 0.89), dairy (sensitivity: 0.95; specificity: 0.57; PPV: 0.99), and eggs (sensitivity: 0.95; specificity: 0.41; PPV: 0.96); negative predictive value for dairy and eggs was poor. Among older AHS-2 cohort members, we found good reliability of recall of red meat, poultry, and fish intake that occurred 33 years earlier.

Estimating the impact of smoking cessation during pregnancy: the San Bernardino County experience.

We examined the relation between maternal smoking and adverse infant outcomes [low birth weight (LBW), and preterm birth (PTB)] during 2007-2008 in San Bernardino County, California-the largest county in the contiguous United States which has one of the highest rates of infant mortality in California. Using birth certificate data, we identified 1,430 mothers in 2007 and 1,355 in 2008 who smoked during pregnancy. We assessed the effect of never smoking and smoking cessation during pregnancy relative to smoking during pregnancy for the 1,843/1,798 LBW, and 3,480/3,238 PTB's recorded for 2007/2008, respectively. To describe the effect of quitting smoking during pregnancy, we calculated the exposure impact number for smoking during pregnancy. Major findings are: (1) relative to smoking during pregnancy, significantly lower risk of LBW among never smoking mothers [OR, year: 0.56, 2007; 0.54, 2008] and for smoking cessation during pregnancy [0.57, 2007; 0.72, 2008]; (2) relative to smoking during pregnancy, significantly lower risk of PTB was found for never smoking mothers [0.68, 2007; 0.68, 2008] and for smoking cessation during pregnancy [0.69, 2007; 0.69, 2008]; (3) an exposure impact assessment indicating each LBW or PTB outcome in the county could have been prevented either by at least 35 mothers quitting smoking during pregnancy or by 25 mothers being never smokers during pre-pregnancy. Our findings identify an important burden of adverse infant outcomes due to maternal smoking in San Bernardino County that can be effectively decreased by maternal smoking cessation.

A Case for Synthetic Data in Regulatory Decision-Making in Europe.

Regulators are faced with many challenges surrounding health data usage, including privacy, fragmentation, validity, and generalizability, especially in the European Union, for which synthetic data may provide innovative solutions. Synthetic data, defined as data artificially generated rather than captured in the real world, are increasingly being used for healthcare research purposes as a proxy to real-world data (RWD). Currently, there are barriers particularly challenging in Europe, where sharing patient's data is strictly regulated, costly, and time-consuming, causing delays in evidence generation and regulatory approvals. Recent initiatives are encouraging the use of synthetic data in regulatory decision making and health technology assessment to overcome these challenges, but synthetic data have still to overcome realistic obstacles before their adoption by researchers and regulators in Europe. Thus, the emerging use of RWD and synthetic data by pharmaceutical and medical device industries calls regulatory bodies to provide a framework for proper evidence generation and informed regulatory decision making. As the provision of data becomes more ubiquitous in scientific research, so will innovations in artificial intelligence, machine learning, and generation of synthetic data, making the exploration and intricacies of this topic all the more important and timely. In this review, we discuss the potential merits and challenges of synthetic data in the context of decision making in the European regulatory environment. We explore the current uses of synthetic data and ongoing initiatives, the value of synthetic data for regulatory purposes, and realistic barriers to the adoption of synthetic data in healthcare.

Implementation of early goal-directed therapy and the surviving sepsis campaign resuscitation bundle in Asia.

OBJECTIVE: To examine the impact of implementing sepsis bundle in multiple Asian countries, having 'team' vs. 'non-team' models of patient care. DESIGN: Prospective cohort study. SETTING: Eight urban hospitals, five countries in Asia. PARTICIPANTS: Adult patients with severe sepsis or septic shock. INTERVENTIONS: Implementation was divided into six quartiles: Baseline, Education and four Quality Improvement quartiles. MAIN OUTCOME MEASURES: Quarterly bundle compliance and in-hospital mortality with respect to bundle completion and implementation model. METHODS: In the team model, the implementation was championed by intensivists, where the bundle was completed in the intensive care unit. The non-team model led by emergency physicians completed the bundle in the emergency department as part of standard care. RESULTS: Five hundred and fifty-six patients were enrolled. The overall in-hospital mortality rate was 29.9%, and 67.1% of the patients had septic shock. Compliance to the bundle was 13.3, 26.9, 37.5, 45.9, 48.8 and 54.5% over the six quartiles of implementation (P < 0.01). With team model, compliance increased from 37.5% baseline to 88.2% in the sixth quartile (P < 0.01), whereas hospitals with a non-team model increased compliance from 5.2 to 39.5% (P < 0.01). Crude in-hospital mortality was better in the patients who received the entire bundle (24.5 vs. 32.7%, P = 0.04). Bundle completion was associated with crude in-hospital mortality reduction (odds ratio 0.67, 95% confidence interval 0.45-0.99), but this survival benefit disappeared after adjustment for confounding variables. CONCLUSIONS: Through education and quality improvement efforts, initially low sepsis bundle compliance was improved in Asia. A team model was more effective in achieving bundle compliance compared with a non-team model.

Durability of the Single-Dose Ad26.COV2.S Vaccine in the Prevention of COVID-19 Infections and Hospitalizations in the US Before and During the Delta Variant Surge.

Importance: Vaccination against the SARS-CoV-2 virus is critical to control the pandemic. Randomized clinical trials demonstrated efficacy of the single-dose Ad26.COV2.S COVID-19 vaccine, but data on longer-term protection in clinical practice and effectiveness against variants are needed. Objective: To assess the association between receiving the Ad26.COV2.S vaccine and COVID-19-related infections and hospitalizations before and during the Delta variant surge. Design, Setting, and Participants: This cohort study included adults aged 18 years and older who were newly Ad26.COV2.S-vaccinated matched to as many as 10 unvaccinated individuals by date, location, age, sex, and comorbidity index. This was followed by 1:4 propensity score matching on COVID-19 risk factors. Data were collected from US insurance claims data from March 1, 2020, through August 31, 2021. Exposures: Vaccination with Ad26.COV2.S vs no vaccination. Main Outcomes and Measures: Vaccine effectiveness (VE) was estimated for recorded COVID-19 infection and COVID-19-related hospitalization, nationwide and in subgroups by age, high-risk factors, calendar time, and states with high incidences of the Delta variant. VE estimates were corrected for underrecording of vaccinations in insurance data. Results: Among 422 034 vaccinated individuals (mean [SD] age, 54.7 [17.4] years; 236 437 [56.0%] women) and 1 645 397 matched unvaccinated individuals (mean [SD] age, 54.5 [17.5] years; 922 937 [56.1%] women), VE was 76% (95% CI, 75%-77%) for COVID-19 infections and 81% (95% CI, 78%-82%) for COVID-19-related hospitalizations. VE was stable for at least 180 days after vaccination and over calendar time. Among states with high Delta variant incidence, VE during June to August 2021 was 74% (95% CI, 71%-77%) for infections and 81% (95% CI, 75%-86%) for hospitalizations. VE for COVID-19 was higher in individuals younger than 65 years (78%; 95% CI, 77%-79%) and lower in immunocompromised patients (64%; 95% CI, 59%-68%). All estimates were corrected for vaccination underrecording; uncorrected VE, which served as a lower bound, was 66% (95% CI, 64%-67%) for any recorded COVID-19 infection and 72% (95% CI, 69%-74%) for COVID-19-related hospitalization. Conclusions and Relevance: This cohort study in US clinical practice showed stable VE of Ad26.COV2.S for at least 6 months before as well as during the time the Delta variant emerged and became dominant.

Outcome effectiveness of the severe sepsis resuscitation bundle with addition of lactate clearance as a bundle item: a multi-national evaluation.

INTRODUCTION: Implementation of the Surviving Sepsis Campaign (SSC) guidelines has been associated with improved outcome in patients with severe sepsis. Resolution of lactate elevations or lactate clearance has also been shown to be associated with outcome. The purpose of the present study was to examine the compliance and effectiveness of the SSC resuscitation bundle with the addition of lactate clearance. METHODS: This was a prospective cohort study over 18 months in eight tertiary-care medical centers in Asia, enrolling adult patients meeting criteria for the SSC resuscitation bundle in the emergency department. Compliance and outcome results of a multi-disciplinary program to implement the Primary SSC Bundle with the addition of lactate clearance (Modified SSC Bundle) were examined. The implementation period was divided into quartiles, including baseline, education and four quality improvement phases. RESULTS: A total of 556 patients were enrolled, with median (25th to 75th percentile) age 63 (50 to 74) years, lactate 4.1 (2.2 to 6.3) mmol/l, central venous pressure 10 (7 to 13) mmHg, mean arterial pressure (MAP) 70 (56 to 86) mmHg, and central venous oxygen saturation 77 (69 to 82)%. Completion of the Primary SSC Bundle over the six quartiles was 13.3, 26.9, 37.5, 45.9, 48.8, and 54.5%, respectively (P <0.01). The Modified SSC Bundle was completed in 10.2, 23.1, 31.7, 40.0, 42.5, and 43.6% patients, respectively (P <0.01). The ratio of the relative risk of death reduction for the Modified SSC Bundle compared with the Primary SSC Bundle was 1.94 (95% confidence interval = 1.45 to 39.1). Logistic regression modeling showed that the bundle items of fluid bolus given, achieve MAP >65 mmHg by 6 hours, and lactate clearance were independently associated with decreased mortality - having odds ratios (95% confidence intervals) 0.47 (0.23 to 0.96), 0.20 (0.07 to 0.55), and 0.32 (0.19 to 0.55), respectively. CONCLUSIONS: The addition of lactate clearance to the SSC resuscitation bundle is associated with improved mortality. In our study patient population with optimized baseline central venous pressure and central venous oxygen saturation, the bundle items of fluid bolus administration, achieving MAP >65 mmHg, and lactate clearance were independent predictors of outcome.

Real-world healthcare resource utilization and costs of weekly versus every-2-week cetuximab in metastatic colorectal cancer.

Aim: To compare healthcare resource utilization (HRU) and healthcare costs (HC) for every-2-week (Q2W) versus weekly (Q1W) cetuximab in metastatic colorectal cancer (mCRC). Patients & methods: Patients with mCRC receiving cetuximab plus chemotherapy in a line-agnostic setting. Cohort study of patients with mCRC treated with cetuximab and chemotherapy in IBM MarketScan. Analyses were weighted by inverse probability of treatment based on propensity score. Results: HRU was numerically lower with the Q2W versus Q1W regimen (weighted mean, 8.1 vs 9.5 encounters per-patient-per-month). The weighted average of HC was $17,653 and $16,469 per-patient-per-month for the Q2W and Q1W regimens, respectively; the difference between regimens decreased when restricting to CRC-related claims. Conclusion: HRU was lower and HC were similar between the Q2W and Q1W regimens.