Rate and Risk Factors Associated With Prolonged Opioid Use After Surgery: A Systematic Review and Meta-analysis

Importance: Prolonged opioid use after surgery may be associated with opioid dependency and increased health care use. However, published studies have reported varying estimates of the magnitude of prolonged opioid use and risk factors associated with the transition of patients to long-term opioid use. Objectives: To evaluate the rate and characteristics of patient-level risk factors associated with increased risk of prolonged use of opioids after surgery. Data Sources: For this systematic review and meta-analysis, a search of MEDLINE, Embase, and Google Scholar from inception to August 30, 2017, was performed, with an updated search performed on June 30, 2019. Key words may include opioid analgesics, general surgery, surgical procedures, persistent opioid use, and postoperative pain. Study Selection: Of 7534 articles reviewed, 33 studies were included. Studies were included if they involved participants 18 years or older, evaluated opioid use 3 or more months after surgery, and reported the rate and adjusted risk factors associated with prolonged opioid use after surgery. Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed. Two reviewers independently assessed and extracted the relevant data. Main Outcomes and Measures: The weighted pooled rate and odds ratios (ORs) of risk factors were calculated using the random-effects model. Results: The 33 studies included 1 922 743 individuals, with 1 854 006 (96.4%) from the US. In studies with available sex and age information, participants were mostly female (1 031 399; 82.7%) and had a mean (SD) age of 59.3 (12.8) years. The pooled rate of prolonged opioid use after surgery was 6.7% (95% CI, 4.5%-9.8%) but decreased to 1.2% (95% CI, 0.4%-3.9%) in restricted analyses involving only opioid-naive participants at baseline. The risk factors with the strongest associations with prolonged opioid use included preoperative use of opioids (OR, 5.32; 95% CI, 2.94-9.64) or illicit cocaine (OR, 4.34; 95% CI, 1.50-12.58) and a preoperative diagnosis of back pain (OR, 2.05; 95% CI, 1.63-2.58). No significant differences were observed with various study-level factors, including a comparison of major vs minor surgical procedures (pooled rate: 7.0%; 95% CI, 4.9%-9.9% vs 11.1%; 95% CI, 6.0%-19.4%; P = .20). Across all of our analyses, there was substantial variability because of heterogeneity instead of sampling error. Conclusions and Relevance: The findings suggest that prolonged opioid use after surgery may be a substantial burden to public health. It appears that strategies, such as proactively screening for at-risk individuals, should be prioritized

Copy Number Variation at the APOL1 Locus

Two coding variants in the APOL1 gene (G1 and G2) explain most of the high rate of kidney disease in African Americans. APOL1-associated kidney disease risk inheritance follows an autosomal recessive pattern: The relative risk of kidney disease associated with inheritance of two high-risk variants is 7–30 fold, depending on the specific kidney phenotype. We wished to determine if the variability in phenotype might in part reflect structural differences in APOL1 gene. We analyzed sequence coverage from 1000 Genomes Project Phase 3 samples as well as exome sequencing data from African American kidney disease cases for copy number variation. 8 samples sequenced in the 1000 Genomes Project showed increased coverage over a ~100kb region that includes APOL2, APOL1 and part of MYH9, suggesting the presence of APOL1 copy number greater than 2. We reasoned that such duplications should be enriched in apparent G1 heterozygotes with kidney disease. Using a PCR-based assay, we observed the presence of this duplication in additional samples from apparent G0G1 or G0G2 individuals. The frequency of this APOL1 duplication was compared among cases (n = 123) and controls (n = 255) with apparent G0G1 heterozygosity. The presence of APOL1 duplication was observed in 4.06% of cases and 0.78% controls, preliminary evidence that this APOL1 duplication may alter susceptibility to kidney disease (p = 0.03). Taqman-based copy number assays confirmed the presence of 3 APOL1 copies in individuals positive for this specific duplication by PCR assay, but also identified a small number of individuals with additional APOL1 copies of presumably different structure. These observations motivate further studies to better assess the contribution of APOL1 copy number on kidney disease risk and on APOL1 function. Investigators and clinicians genotyping APOL1 should also consider whether the particular genotyping platform used is subject to technical errors when more than two copies of APOL1 are present

Hypokalemia: A potentially life-threatening complication of tenofovir therapy

Tenofovir is a nucleotide analog reverse transcriptase inhibitor approved for the treatment of HIV and hepatitis B infections. It is widely prescribed and an integral part of the recommended regimens for the treatment of HIV infection in antiretroviral-naive patients. Tenofovir is implicated in renal proximal tubular dysfunction, which can be associated with Fanconi syndrome and hypokalemia. When the hypokalemia is severe, it can lead to life-threatening complications. We describe the case of a 59-year-old woman who suffered a cardiac arrest secondary to severe hypokalemia from tenofovir use

Development of a personalized diagnostic model for kidney stone disease tailored to acute care by integrating large clinical, demographics and laboratory data: the diagnostic acute care algorithm - kidney stones (DACA-KS)

Abstract Background Kidney stone (KS) disease has high, increasing prevalence in the United States and poses a massive economic burden. Diagnostics algorithms of KS only use a few variables with a limited sensitivity and specificity. In this study, we tested a big data approach to infer and validate a ‘multi-domain’ personalized diagnostic acute care algorithm for KS (DACA-KS), merging demographic, vital signs, clinical, and laboratory information. Methods We utilized a large, single-center database of patients admitted to acute care units in a large tertiary care hospital. Patients diagnosed with KS were compared to groups of patients with acute abdominal/flank/groin pain, genitourinary diseases, and other conditions. We analyzed multiple information domains (several thousands of variables) using a collection of statistical and machine learning models with feature selectors. We compared sensitivity, specificity and area under the receiver operating characteristic (AUROC) of our approach with the STONE score, using cross-validation. Results Thirty eight thousand five hundred and ninety-seven distinct adult patients were admitted to critical care between 2001 and 2012, of which 217 were diagnosed with KS, and 7446 with acute pain (non-KS). The multi-domain approach using logistic regression yielded an AUROC of 0.86 and a sensitivity/specificity of 0.81/0.82 in cross-validation. Increase in performance was obtained by fitting a super-learner, at the price of lower interpretability. We discussed in detail comorbidity and lab marker variables independently associated with KS (e.g. blood chloride, candidiasis, sleep disorders). Conclusions Although external validation is warranted, DACA-KS could be integrated into electronic health systems; the algorithm has the potential used as an effective tool to help nurses and healthcare personnel during triage or clinicians making a diagnosis, streamlining patients’ management in acute care

Copy number variation at APOL1 locus.

<p>a. Sequence coverage analysis of samples from 1000 Genomes Project. Grey lines are used to depict coverage of each of 2,527 samples at genomic loci to which sequence reads map. Red lines indicate coverage for 8 samples with apparent duplication. The black line depicts median coverage for all samples showing elevated coverage over a region of this locus, including APOL1, suggesting duplication. Coordinates of the genome are plotted on the X-axis against normalized read depth on the Y-axis. Coordinates of APOL1 gene are chr22: 36,649,117–36,663,571 (hg19). b. Pictorial representation of the duplication event. An approximately 100kb region of chromosome 22, beginning from a region adjacent to APOL2, and involving all of APOL1 and part of MYH9 is duplicated (chr22:36,612,938–36,714,262, hg19). c. Gel electrophoresis (3% agarose) of the PCR product of the qualitative PCR assay used for detection of duplication. The PCR assay amplifies sequence across the junction between the duplicated segments, and results in a 291 bp size product, if present. Lane 1 corresponds to 100 bp ladder with size of each fragment indicated. Lanes 2 and 3 represent samples from individuals of European ancestry, who are negative for duplication. Lanes 4, 5 and 6 show a band of the expected size and indicate the presence of a duplication in these three unrelated African American individuals. Lanes 7, 8 and 9 show the absence of a PCR product in three other African American individuals. One of these three (lane 7) showed 3 copies using the Taqman copy number assay, indicating an insertional variant of different structure. Lane 10 is a non-template control reaction. d. Allelic discrimination digest assay: Gel electrophoresis of the PCR products obtained during allelic discrimination assay. Lane 1 shows a 100 bp ladder. Lane 2 (a, b and c) corresponds to sample NA 19701, Lane 3 (a, b and c) corresponds to sample NA 19372, Lane 4 (a, b and c) corresponds to sample NA 19700 and lane 5 corresponds to sample NA 19702. The band in the lanes 2a, 3a, 4a and 5a represent PCR products not subjected to any digestion (314 bp in size). Lanes 2b, 3b, 4b and 5b represent PCR products after digestion with HindIII. Lanes 2c, 3c, 4c and 5c represent PCR products after digestion with NspI. Since sample NA 19700 is homozygous for G0, there are only 2 bands in lane 4b and 1 band in lane 4c. Of note, with HindIII digestion, which cleaves the PCR product only if G0 allele is present, bands are expected to be 100 bp and 214 bp in size. With NspI, which cleaves the PCR product only in the presence of I384M G1 allele, the bands are expected to be 228 and 86 bp in size.</p

Two informative pedigrees.

<p>Pedigrees referred to in the text. CN2 or CN3 refers to 2 or 3 copies of APOL1 as determined by Taqman-based quantitative PCR assay. PCR+ or PCR- refers to presence or absence of the specific insertional event that appears to be the most common copy number variant at this locus, as detected by a PCR-based assay that amplifies the region across the insertional junction. Inferred genotype is indicated, with the two haplotypes separated by '/'.</p

Fraction of case and control samples in which an extra copy of APOL1 was detected by either a PCR assay designed to amplify across the insertional junction, or by a quantitative Taqman-based copy number assay.

<p>Fraction of case and control samples in which an extra copy of APOL1 was detected by either a PCR assay designed to amplify across the insertional junction, or by a quantitative Taqman-based copy number assay.</p

South Asian medical cohorts reveal strong founder effects and high rates of homozygosity.

Acknowledgements: We thank Abhijit Chowdhury, Anamitra Barik, Rajesh Kumar Rai, the Birbhum Health and Demographic Surveillance System, the Parkinson Research Alliance of India (PRAI), Syed Qasim Mehdi (deceased), and Partha Majumder for providing samples and sample metadata. J.D.W., J.R., and D.S. were supported in part by NIH grant R01 HG010689. A.V.K. was supported in part by NIH grants 1K08HG010155 and 1U01HG011719. Sequence data collection was supported by NIH grant 5UM1HG008895 to S.K. and by Genentech Research. We are grateful to all of our colleagues for their support and discussions throughout the course of this work and to all of the participants in this study.The benefits of large-scale genetic studies for healthcare of the populations studied are well documented, but these genetic studies have traditionally ignored people from some parts of the world, such as South Asia. Here we describe whole genome sequence (WGS) data from 4806 individuals recruited from the healthcare delivery systems of Pakistan, India and Bangladesh, combined with WGS from 927 individuals from isolated South Asian populations. We characterize population structure in South Asia and describe a genotyping array (SARGAM) and imputation reference panel that are optimized for South Asian genomes. We find evidence for high rates of reproductive isolation, endogamy and consanguinity that vary across the subcontinent and that lead to levels of rare homozygotes that reach 100 times that seen in outbred populations. Founder effects increase the power to associate functional variants with disease processes and make South Asia a uniquely powerful place for population-scale genetic studies

South Asian medical cohorts reveal strong founder effects and high rates of homozygosity.

The benefits of large-scale genetic studies for healthcare of the populations studied are well documented, but these genetic studies have traditionally ignored people from some parts of the world, such as South Asia. Here we describe whole genome sequence (WGS) data from 4806 individuals recruited from the healthcare delivery systems of Pakistan, India and Bangladesh, combined with WGS from 927 individuals from isolated South Asian populations. We characterize population structure in South Asia and describe a genotyping array (SARGAM) and imputation reference panel that are optimized for South Asian genomes. We find evidence for high rates of reproductive isolation, endogamy and consanguinity that vary across the subcontinent and that lead to levels of rare homozygotes that reach 100 times that seen in outbred populations. Founder effects increase the power to associate functional variants with disease processes and make South Asia a uniquely powerful place for population-scale genetic studies