Factors associated with loss to follow-up in outpatient parenteral antimicrobial therapy: A retrospective cohort study.

We assessed factors associated with increased risk to loss of follow-up with infectious diseases staff in OPAT patients. Discharge to subacute healthcare facilities is strongly associated with loss to follow-up. We did not identify sociodemographic disparities. Poor communication between OPAT providers and subacute healthcare facilities remains a serious issue.

PharmVar Tutorial on CYP2D6 Structural Variation Testing and Recommendations on Reporting.

The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human CYP2D6 gene locus and a comprehensive summary of structural variation. CYP2D6 contributes to the metabolism of numerous drugs and, thus, genetic variation in its gene impacts drug efficacy and safety. To accurately predict a patient's CYP2D6 phenotype, testing must include structural variants including gene deletions, duplications, hybrid genes, and combinations thereof. This tutorial offers a comprehensive overview of CYP2D6 structural variation, terms, and definitions, a review of methods suitable for their detection and characterization, and practical examples to address the lack of standards to describe CYP2D6 structural variants or any other pharmacogene. This PharmVar tutorial offers practical guidance on how to detect the many, often complex, structural variants, as well as recommends terms and definitions for clinical and research reporting. Uniform reporting is not only essential for electronic health record-keeping but also for accurate translation of a patient's genotype into phenotype which is typically utilized to guide drug therapy.

The Effectiveness of Ultraviolet Smart D60 in Reducing Contamination of Flexible Fiberoptic Laryngoscopes.

OBJECTIVE: To compare the effectiveness of disinfection protocols utilizing a ultraviolet (UV) Smart D60 light system with Impelux™ technology with a standard Cidex ortho-phthalaldehyde (OPA) disinfection protocol for cleaning flexible fiberoptic laryngoscopes (FFLs). METHODS: Two hundred FFLs were tested for bacterial contamination after routine use, and another 200 FFLs were tested after disinfection with one of four methods: enzymatic detergent plus Cidex OPA (standard), enzymatic detergent plus UV Smart D60, microfiber cloth plus UV Smart D60, and nonsterile wipe plus UV Smart D60. Pre- and post-disinfection microbial burden levels and positive culture rates were compared using Kruskal-Wallis ANOVA and Fisher's two-sided exact, respectively. RESULTS: After routine use, approximately 56% (112/200) of FFLs were contaminated, with an average contamination level of 9,973.7 ± 70,136.3 CFU/mL. The standard reprocessing method showed no positive cultures. The enzymatic plus UV, microfiber plus UV, and nonsterile wipe plus UV methods yielded contamination rates of 4% (2/50), 6% (3/50), and 12% (6/50), respectively, with no significant differences among the treatment groups (p > 0.05). The pre-disinfection microbial burden levels decreased significantly after each disinfection technique (p < 0.001). The average microbial burden recovered after enzymatic plus UV, microfiber plus UV, and nonsterile wipe plus UV were 0.40 CFU/mL ± 2, 0.60 CFU/mL ± 2.4, and 12.2 CFU/mL ± 69.5, respectively, with no significant difference among the treatment groups (p > 0.05). Micrococcus species (53.8%) were most frequently isolated, and no high-concern organisms were recovered. CONCLUSION: Disinfection protocols utilizing UV Smart D60 were as effective as the standard chemical disinfection protocol using Cidex OPA. LEVEL OF EVIDENCE: NA Laryngoscope, 133:3512-3519, 2023.

The Newfoundland and Labrador mosaic founder population descends from an Irish and British diaspora from 300 years ago.

The founder population of Newfoundland and Labrador (NL) is a unique genetic resource, in part due to its geographic and cultural isolation, where historical records describe a migration of European settlers, primarily from Ireland and England, to NL in the 18th and 19th centuries. Whilst its historical isolation, and increased prevalence of certain monogenic disorders are well appreciated, details of the fine-scale genetic structure and ancestry of the population are lacking. Understanding the genetic origins and background of functional, disease causing, genetic variants would aid genetic mapping efforts in the Province. Here, we leverage dense genome-wide SNP data on 1,807 NL individuals to reveal fine-scale genetic structure in NL that is clustered around coastal communities and correlated with Christian denomination. We show that the majority of NL European ancestry can be traced back to the south-east and south-west of Ireland and England, respectively. We date a substantial population size bottleneck approximately 10-15 generations ago in NL, associated with increased haplotype sharing and autozygosity. Our results reveal insights into the population history of NL and demonstrate evidence of a population conducive to further genetic studies and biomarker discovery.

Planetary Mapping Using Deep Learning: A Method to Evaluate Feature Identification Confidence Applied to Habitats in Mars-Analog Terrain.

The goals of Mars exploration are evolving beyond describing environmental habitability at global and regional scales to targeting specific locations for biosignature detection, sample return, and eventual human exploration. An increase in the specificity of scientific goals-from follow the water to find the biosignatures-requires parallel developments in strategies that translate terrestrial Mars-analog research into confident identification of rover-explorable targets on Mars. Precisely how to integrate terrestrial, ground-based analyses with orbital data sets and transfer those lessons into rover-relevant search strategies for biosignatures on Mars remains an open challenge. Here, leveraging small Unmanned Aerial System (sUAS) technology and state-of-the-art fully convolutional neural networks for pixel-wise classification, we present an end-to-end methodology that applies Deep Learning to map geomorphologic units and quantify feature identification confidence. We used this method to assess the identification confidence of rover-explorable habitats in the Mars-analog Salar de Pajonales over a range of spatial resolutions and found that spatial resolutions two times better than are available from Mars would be necessary to identify habitats in this study at the 1-σ (85%) confidence level. The approach we present could be used to compare the identifiability of habitats across Mars-analog environments and focus Mars exploration from the scale of regional habitability to the scale of specific habitats. Our methods could also be adapted to map dome- and ridge-like features on the surface of Mars to further understand their origin and astrobiological potential.

Assessment of risk factors associated with outpatient parenteral antimicrobial therapy (OPAT) complications: A retrospective cohort study.

Objective: To characterize factors associated with increased risk of outpatient parenteral antimicrobial therapy (OPAT) complication. Design: Retrospective cohort study. Setting: Four hospitals within NYU Langone Health (NYULH). Patients: All patients aged ≥18 years with OPAT episodes who were admitted to an acute-care facility at NYULH between January 1, 2017, and December 31, 2020, who had an infectious diseases consultation during admission. Results: Overall, 8.45% of OPAT patients suffered a vascular complication and 6.04% suffered an antimicrobial complication. Among these patients, 19.95% had a 30-day readmission and 3.35% had OPAT-related readmission. Also, 1.58% of patients developed a catheter-related bloodstream infection (CRBSI). After adjusting for key confounders, we found that patients discharged to a subacute rehabilitation center (SARC) were more likely to develop a CRBSI (odds ratio [OR], 4.75; P = .005) and to be readmitted for OPAT complications (OR, 2.89; P = .002). Loss to follow-up with the infectious diseases service was associated with increased risks of CRBSI (OR, 3.78; P = .007) and 30-day readmission (OR, 2.59; P < .001). Conclusions: Discharge to an SARC is strongly associated with increased risks of readmission for OPAT-related complications and CRBSI. Loss to follow-up with the infectious diseases service is strongly associated with increased risk of readmission and CRBSI. CRBSI prevention during SARC admission is a critically needed public health intervention. Further work must be done for patients undergoing OPAT to improve their follow-up retention with the infectious diseases service.

Mitigation of nontuberculous mycobacteria in hospital water: challenges for infection prevention.

PURPOSE OF REVIEW: The purpose of this review is to summarize recent literature on nontuberculous mycobacteria in water of healthcare systems. Despite improvement in identification techniques and emergence of infection prevention and control programs, nontuberculous mycobacteria remain present in hospital water systems, causing outbreaks and pseudo-outbreaks in healthcare settings. RECENT FINDINGS: Waterborne outbreaks and pseudo-outbreaks of nontuberculous mycobacteria continue to affect hospitals. Improvements in methods of identification and investigation, including MALDI-TOF and whole genome sequencing with evaluation of single nucleotide polymorphisms, have been used successfully in outbreak and pseudo-outbreak investigations. Recent studies have shown control of outbreaks in immunocompromised patients through the use of sterile water for consumption, as well as control of pseudo-outbreaks by using sterile water for procedures. Construction activities have been implicated in outbreaks and pseudo-outbreaks of nontuberculous mycobacteria. Water management programs are now required by the Joint Commission, which will likely improve water risk mitigation. SUMMARY: Improvement in detection and identification of nontuberculous mycobacteria has led to increasing recognition of waterborne outbreaks and pseudo-outbreaks. Water management programs are of vital importance in infection prevention.

Rate and consequences of missed Clostridioides (Clostridium) difficile infection diagnosis from nonreporting of Clostridioides difficile results of the multiplex GI PCR panel: experience from two-hospitals.

INTRODUCTION: It is common among microbiology laboratories to blind the Clostridioides difficile (C. difficile) BioFire FilmArray GI Panel result in fear of overdiagnosis. METHODS: We examined the rate of missed community-onset C. difficile infection (CDI) diagnosis and associated outcomes. Adult patients with FilmArray GI Panel positive for C. difficile on hospital admission who lacked dedicated C. difficile testing were included. RESULTS: Among 144 adults with a FilmArray Panel positive for C. difficile, 18 did not have concurrent dedicated C. difficile testing. Eight patients were categorized as possible, 5 as probable and 4 as definite cases of missed CDI diagnosis. We observed associated delays in initiation of appropriate therapy, intensive care unit admissions, hospital readmissions, colorectal surgery and death/discharge to hospice. Five out of 17 lacked risk factors for CDI. CONCLUSION: The practice of concealing C. difficile FilmArray GI Panel results needs to be reconsidered in patients presenting with community-onset colitis.

A mathematical model and inference method for bacterial colonization in hospital units applied to active surveillance data for carbapenem-resistant enterobacteriaceae.

Widespread use of antibiotics has resulted in an increase in antimicrobial-resistant microorganisms. Although not all bacterial contact results in infection, patients can become asymptomatically colonized, increasing the risk of infection and pathogen transmission. Consequently, many institutions have begun active surveillance, but in non-research settings, the resulting data are often incomplete and may include non-random testing, making conventional epidemiological analysis problematic. We describe a mathematical model and inference method for in-hospital bacterial colonization and transmission of carbapenem-resistant Enterobacteriaceae that is tailored for analysis of active surveillance data with incomplete observations. The model and inference method make use of the full detailed state of the hospital unit, which takes into account the colonization status of each individual in the unit and not only the number of colonized patients at any given time. The inference method computes the exact likelihood of all possible histories consistent with partial observations (despite the exponential increase in possible states that can make likelihood calculation intractable for large hospital units), includes techniques to improve computational efficiency, is tested by computer simulation, and is applied to active surveillance data from a 13-bed rehabilitation unit in New York City. The inference method for exact likelihood calculation is applicable to other Markov models incorporating incomplete observations. The parameters that we identify are the patient-patient transmission rate, pre-existing colonization probability, and prior-to-new-patient transmission probability. Besides identifying the parameters, we predict the effects on the total prevalence (0.07 of the total colonized patient-days) of changing the parameters and estimate the increase in total prevalence attributable to patient-patient transmission (0.02) above the baseline pre-existing colonization (0.05). Simulations with a colonized versus uncolonized long-stay patient had 44% higher total prevalence, suggesting that the long-stay patient may have been a reservoir of transmission. High-priority interventions may include isolation of incoming colonized patients and repeated screening of long-stay patients.

Oral vancomycin prophylaxis against recurrent Clostridioides difficile infection: Efficacy and side effects in two hospitals.

OBJECTIVE: The data regarding the effectiveness of chemical prophylaxis against recurrent C. difficile infection (CDI) remain conflicting. DESIGN: Retrospective cohort study on the effectiveness of oral vancomycin for prevention of recurrent CDI. SETTING: Two academic centers in New York. METHODS: Two participating hospitals implemented an automated alert recommending oral vancomycin 125 mg twice daily in patients with CDI history scheduled to receive systemic antimicrobials. Measured outcomes included breakthrough and recurrent CDI rates, defined as CDI during and 1 month after initiation of prophylaxis, respectively. A self-controlled, before-and-after study design was employed to examine the effect of vancomycin prophylaxis on the prevalence of vancomycin-resistant Enterococcus spp (VRE) colonization and infection. RESULTS: We included 264 patients in the analysis. Breakthrough CDI was identified in 17 patients (6.4%; 95% confidence interval [CI], 3.8%-10.1%) and recurrent in 22 patients (8.3%; 95% CI, 5.3%-12.3%). Among the 102 patients with a history of CDI within the 3 months preceding prophylaxis, 4 patients (3.9%; 95% CIs, 1.1%-9.7%) had breakthrough CDI and 9 had recurrent disease (8.8%; 95% CIs, 4.1%-16.1%). In the 3-month period following vancomycin prophylaxis, we detected a statistically significant increase in both the absolute number of VRE (χ2, 0.003) and the ratio of VRE to VSE isolates (χ2, 0.003) compared to the combined period of 1.5 months preceding and the 3-4.5 months following prophylaxis. This effect persisted 6 months following prophylaxis. CONCLUSIONS: Prophylactic vancomycin is an effective strategy to prevent CDI recurrence, but it increases the risk of VRE colonization. Thus, a careful selection of patients with high benefit-to-risk ratio is needed for the implementation of this preventive policy.

PharmVar GeneFocus: CYP2D6.

The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human CYP2D6 gene locus. CYP2D6 genetic variation impacts the metabolism of numerous drugs and, thus, can impact drug efficacy and safety. This GeneFocus provides a comprehensive overview and summary of CYP2D6 genetic variation and describes how the information provided by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

A prospective study of the impact of AGTR1 A1166C on the effects of candesartan in patients with heart failure.

AIM: To evaluate the impact of AGTR1 A1166C (rs5186) on the response to candesartan in patients with heart failure. MATERIALS & METHODS: Prospective, multicentre, open-label study. We studied 299 symptomatic patients with heart failure presenting a left ventricular ejection fraction ≤40%. RESULTS: Reductions in the primary end points of natriuretic peptides were not significantly associated with AGTR1 A1166C. Nevertheless, carrying the 1166C allele was associated with a greater compensatory increase in renin activity (p = 0.037) after 16 weeks of treatment with candesartan and a more modest effect on aldosterone concentrations (p = 0.022). CONCLUSION: AGTR1 1166C carriers may experience a greater long-term compensatory renin-angiotensin-aldosterone system activation following treatment with candesartan. Whether these associations ultimately influence clinical outcomes requires investigation. Clinicaltrials.gov : NCT00400582.

Mycobacterium chimaera left ventricular assist device infections.

A global outbreak of invasive Mycobacterium chimaera infections after cardiac surgery has recently been linked to bioaerosols from contaminated heater-cooler units. The majority of cases have occurred after valvular surgery or aortic graft surgery and nearly half have resulted in death. To date, infections in patients with left ventricular assist devices (LVADs) have not been characterized in the literature. We report two cases of device-associated M. chimaera infection in patients with continuous-flow LVADs and describe challenges related to diagnosis and management in this population.

Expanded Gram-Negative Antimicrobial Prophylaxis Reduces Surgical Site Infections in Hip Arthroplasty.

BACKGROUND: A first-generation cephalosporin is the recommended antibiotic prophylaxis for implants. However, this standard does not address the increasing prevalence and virulence of gram-negative pathogens infecting patients. We found that gram-negative bacilli caused 30% of our surgical site infections (SSIs) following hip procedures, whereas only 10% of knee SSIs were caused by gram-negative bacilli. To address this, we instituted Expanded Gram-Negative Antimicrobial Prophylaxis (EGNAP) for our hip arthroplasty patients. The purpose of this study is to measure the effect of EGNAP on the SSI rates following primary total hip arthroplasty. METHODS: The study consisted of 10,084 total patients. Before July 2012, all patients were administered 1 g of cefazolin. After July 2012, our protocol was adjusted by adding the EGNAP with either gentamicin or aztreonam to hip patients (group 1) and not to the knee arthroplasty patients (group 2). RESULTS: Group 1 consisted of the 5389 primary hip arthroplasty patients. Of these patients, 4122 (before July 2012) did not receive weight-based high-dose gentamicin and 1267 (after July 2012) did. Before the introduction of EGNAP, group 1 SSI rate was 1.19% (49/4122). After July 2012 when EGNAP was added, the overall group 1 SSI rate decreased to 0.55% (7/1267) (P = .05). During the study period, there was not a significant difference in SSI rate of knee arthroplasty (group 2): 1.08% vs 1.02% (P = .999). CONCLUSIONS: The addition of EGNAP for hip arthroplasty is a safe and effective method to decrease SSIs. LEVEL OF EVIDENCE: III. Case-control study.

Risk Factors for Infection Following Total Knee Arthroplasty: A Series of 3836 Cases from One Institution.

Higher PJI rates may be related to identifiable risk factors, which may or may not be modifiable. Identifying risk factors preoperatively provides opportunities for modification and potentially decreasing the incidence of PJI. The purposes of this study were to: (1) retrospectively identify and quantify risk factors for PJI following primary TKA, and (2) to classify those significant risk factors as either non-modifiable or modifiable for intervention prior to surgery. Optimization of modifiable risk factors such as Staphylococcus aureus colonization, and tobacco use prior to primary TKA may decrease the incidence of periprosthetic joint infection after primary TKA, thereby reducing morbidity and the costs associated with treating those infections.

Is routine antibiotic prophylaxis cost effective for total joint replacement patients?

The routine use of amoxicillin antibiotic prophylaxis prior to dental procedures for patients with total joint prostheses in place remains controversial. This analysis shows that the practice may not be cost-effective for patients in whom the risk of infection with dental work is low. However, specific data quantifying the risk and the impact prophylactic antibiotics can have is needed. Patients and physicians will need to continue to consider their use on an individual basis and should consider the risk of infection as well as the risk of adverse drug reaction when making treatment decisions.

SNP arrays: comparing diagnostic yields for four platforms in children with developmental delay.

BACKGROUND: Molecular karyotyping is now the first-tier genetic test for patients affected with unexplained intellectual disability (ID) and/or multiple congenital anomalies (MCA), since it identifies a pathogenic copy number variation (CNV) in 10-14% of them. High-resolution microarrays combining molecular karyotyping and single nucleotide polymorphism (SNP) genotyping were recently introduced to the market. In addition to identifying CNVs, these platforms detect loss of heterozygosity (LOH), which can indicate the presence of a homozygous mutation or uniparental disomy. Since these abnormalities can be associated with ID and/or MCA, their detection is of particular interest for patients whose phenotype remains unexplained. However, the diagnostic yield obtained with these platforms is not confirmed, and the real clinical value of LOH detection has not been established. METHODS: We selected 21 children affected with ID, with or without congenital malformations, for whom standard genetic analyses failed to provide a diagnosis. We performed high-resolution SNP array analysis with four platforms (Affymetrix Genome-Wide Human SNP Array 6.0, Affymetrix Cytogenetics Whole-Genome 2.7 M array, Illumina HumanOmni1-Quad BeadChip, and Illumina HumanCytoSNP-12 DNA Analysis BeadChip) on whole-blood samples obtained from children and their parents to detect pathogenic CNVs and LOHs, and compared the results with those obtained on a moderate resolution array-based comparative genomic hybridization platform (NimbleGen CGX-12 Cytogenetics Array), already used in the clinical setting. RESULTS: We identified a total of four pathogenic CNVs in three patients, and all arrays successfully detected them. With the SNP arrays, we also identified a LOH containing a gene associated with a recessive disorder consistent with the patient's phenotype (i.e., an informative LOH) in four children (including two siblings). A homozygous mutation within the informative LOH was found in three of these patients. Therefore, we were able to increase the diagnostic yield from 14.3% to 28.6% as a result of the information provided by LOHs. CONCLUSIONS: This study shows the clinical usefulness of SNP arrays in children with ID, since they successfully detect pathogenic CNVs, identify informative LOHs that can lead to the diagnosis of a recessive disorder. It also highlights some challenges associated with the use of SNP arrays in a clinical laboratory.

CKM and LILRB5 are associated with serum levels of creatine kinase.

BACKGROUND: Statins (HMG-CoA reductase inhibitors) are the most prescribed class of lipid-lowering drugs for the treatment and prevention of cardiovascular disease. Creatine kinase (CK) is a commonly used biomarker to assist in the diagnosis of statin-induced myotoxicity but the normal range of CK concentrations is wide, which limits its use as a diagnostic biomarker. METHODS AND RESULTS: We conducted a genome-wide association study of serum CK levels in 3412 statin users. Patients were recruited in Quebec, Canada, and genotyped on Illumina Human610-Quad and an iSelect panel enriched for lipid homeostasis, hypertension, and drug metabolism genes. We found a strong association signal between serum levels of CK and the muscle CK (CKM) gene (rs11559024: P=3.69×10(-16); R(2)=0.02) and with the leukocyte immunoglobulin-like receptor subfamily B member 5 (LILRB5) gene (rs2361797: P=1.96×10(-10); R(2)=0.01). Genetic variants in those 2 genes were independently associated with CK levels in statin users. Results were successfully replicated in 5330 participants from the Montreal Heart Institute Biobank in statin users for CKM (rs11559024: P=4.32×10(-16); R(2)=0.02) and LILRB5 (rs12975366 P=4.45×10(-10); R(2)=0.01) and statin nonusers (P=4.08×10(-7), R(2)=0.01; P=3.17×10(-9), R(2)=0.02, respectively). CONCLUSIONS: This is the first genome-wide study to report on the underlying genetic determinants of CK variation in a population of statin users. We found statistically significant association for variants in the CKM and LILRB5 genes.

Development of a broad-based ADME panel for use in pharmacogenomic studies.

AIM: To optimally address the interindividual variability observed in pharmacokinetic drug response, we have created a custom genotyping panel that interrogates most of the key genetic variations present in a set of 181 prioritized genes responsible for the absorption, distribution, metabolism and excretion (ADME) of many therapeutic agents. This consensus list of genes and variants was based on the ADME core and extended gene lists compiled by a group of pharmaceutical companies as having relevance. Although these pharmacokinetic genes and pathways are well known, tools that can interrogate a large number of these genes simultaneously within a single experiment are not currently available. METHODS: Using novel design strategies, we have developed an optimized and validated ADME genotyping panel, encompassing approximately 3000 variants, that has broad applicability to any study or clinical trial that would benefit from the evaluation of an extensive list of ADME genes. RESULTS & CONCLUSION: Over the course of three design iterations, overall assay conversion rates were improved from 83 to 97% resulting in a panel that fills in many of the gaps in coverage present on currently available commercial genotyping assays. The utility of the assay has been demonstrated by the screening of more than 1000 samples resulting in the discovery of novel pharmacogenomic associations. The assay, and the underlying methods, will continue to be a valuable tool for use in future pharmacogenomic studies.