Chemokine receptors are required for effector T cell trafficking to GVHD tissues but not to bone marrow.

In allogeneic hematopoietic stem cell transplantation (alloSCT), alloreactive donor T cells mediate the graft-versus-leukemia (GVL) effect but also attack nonhematopoietic tissues causing graft-versus-host disease (GVHD). Reducing alloreactive T cell trafficking to GVHD target tissues while allowing their access to bone marrow (BM) and spleen, major sites of malignant hematopoiesis, is a rational strategy for reducing the GVHD risk when using alloreactive T cells as a therapeutic. Here we show that effector T cell (Teff) entry into BM and spleen in unmanipulated mice and in mice transplanted without alloreactive T cells is augmented by pertussis toxin-sensitive (PTX) chemokine receptor signaling. However, unexpectedly, in the presence of a GVH response, chemokines no longer draw T cells into BM and spleen but remain critical for their recruitment to GVHD target tissues. Consistent with this, PTX-treated Teff cells were as efficacious as untreated T cells in killing leukemia cells in BM and spleen in mice with a concurrent GVHD response. These results suggest a strategy to improve the safety of alloreactive T cell therapeutics in treating leukemias in the context of an alloSCT.

The Prevalence and Rate of Undiagnosed Celiac Disease in an Adult General Population, the Trøndelag Health Study, Norway.

BACKGROUND & AIMS: This study aimed to determine the total prevalence of celiac disease (CeD), including undiagnosed cases, in a population-based study of adults screened for CeD. METHODS: The study used the fourth Trøndelag Health Study (HUNT4), conducted in 2017-2019, where 56,042 adult (aged >20 years) residents of Nord-Trøndelag County, Norway, participated. Serum samples from 54,505 participants were analyzed for anti-transglutaminase 2 IgA and IgG. Seropositive individuals were invited for a clinical assessment, including upper endoscopy with duodenal biopsies. Previously diagnosed and seronegative CeD cases were identified through linkage to hospital records and the Norwegian Patient Registry. RESULTS: The rate of CeD seropositivity was 2.0% (1107/54,505). Out of these, 724 individuals attended the clinical assessment. Additionally, the hospital records and registry identified individuals with a known CeD diagnosis, that were seronegative or without serology in HUNT4 or seropositive in HUNT4 but did not participate in the clinical assessment. In total, the study confirmed a new CeD diagnosis after participation in HUNT4 in 470 individuals and a known CeD diagnosis before participation in HUNT4 in 383 individuals. The total biopsy-confirmed prevalence of CeD was 1.5% (853/56,042), and the ratio of new, previously undiagnosed CeD cases (after HUNT4) to known, previously diagnosed CeD cases (before HUNT4) was 1.2:1 (470/383). CONCLUSIONS: The total prevalence of CeD in this population-based study of adults in Norway was high and many individuals were previously undiagnosed. Detection of CeD should be improved, because early diagnosis is crucial for effective management and prevention of complications.

A Multimodal Assistive-Robotic-Arm Control System to Increase Independence After Tetraplegia.

Following tetraplegia, independence for completing essential daily tasks, such as opening doors and eating, significantly declines. Assistive robotic manipulators (ARMs) could restore independence, but typically input devices for these manipulators require functional use of the hands. We created and validated a hands-free multimodal input system for controlling an ARM in virtual reality using combinations of a gyroscope, eye-tracking, and heterologous surface electromyography (sEMG). These input modalities are mapped to ARM functions based on the user's preferences and to maximize the utility of their residual volitional capabilities following tetraplegia. The two participants in this study with tetraplegia preferred to use the control mapping with sEMG button functions and disliked winking commands. Non-disabled participants were more varied in their preferences and performance, further suggesting that customizability is an advantageous component of the control system. Replacing buttons from a traditional handheld controller with sEMG did not substantively reduce performance. The system provided adequate control to all participants to complete functional tasks in virtual reality such as opening door handles, turning stove dials, eating, and drinking, all of which enable independence and improved quality of life for these individuals.

Relationship between chlorhexidine gluconate concentration and microbial colonization of patients' skin.

OBJECTIVE: To characterize the relationship between chlorhexidine gluconate (CHG) skin concentration and skin microbial colonization. DESIGN: Serial cross-sectional study. SETTING/PARTICIPANTS: Adult patients in medical intensive care units (ICUs) from 7 hospitals; from 1 hospital, additional patients colonized with carbapenemase-producing Enterobacterales (CPE) from both ICU and non-ICU settings. All hospitals performed routine CHG bathing in the ICU. METHODS: Skin swab samples were collected from adjacent areas of the neck, axilla, and inguinal region for microbial culture and CHG skin concentration measurement using a semiquantitative colorimetric assay. We used linear mixed effects multilevel models to analyze the relationship between CHG concentration and microbial detection. We explored threshold effects using additional models. RESULTS: We collected samples from 736 of 759 (97%) eligible ICU patients and 68 patients colonized with CPE. On skin, gram-positive bacteria were cultured most frequently (93% of patients), followed by Candida species (26%) and gram-negative bacteria (20%). The adjusted odds of microbial recovery for every twofold increase in CHG skin concentration were 0.84 (95% CI, 0.80-0.87; P < .001) for gram-positive bacteria, 0.93 (95% CI, 0.89-0.98; P = .008) for Candida species, 0.96 (95% CI, 0.91-1.02; P = .17) for gram-negative bacteria, and 0.94 (95% CI, 0.84-1.06; P = .33) for CPE. A threshold CHG skin concentration for reduced microbial detection was not observed. CONCLUSIONS: On a cross-sectional basis, higher CHG skin concentrations were associated with less detection of gram-positive bacteria and Candida species on the skin, but not gram-negative bacteria, including CPE. For infection prevention, targeting higher CHG skin concentrations may improve control of certain pathogens.

Effects of prednisolone tapering on effectiveness of infliximab in patients with ulcerative colitis: data from a retrospective cohort.

BACKGROUND AND OBJECTIVE: The influence of concomitant prednisolone on clinical outcomes and safety in infliximab-treated ulcerative colitis (UC) patients is unknown. DESIGN, SETTING, PARTICIPANTS AND OUTCOME MEASURES: A retrospective cohort study was performed, including 147 UC patients treated with infliximab at a tertiary inflammatory bowel disease (IBD) centre. Primary outcome was corticosteroid-free clinical remission (CFCR) at week 14 and week 52. Patients were grouped according to prednisolone tapering regimens: standard (≤5 mg/week), fast (>5 mg/week), direct discontinuation or no prednisolone. Patients intolerant to corticosteroids and patients stopping corticosteroids in preparation for surgery including colectomy during their initial admission were excluded. RESULTS: There was no overall association between prednisolone exposure or no exposure and CFCR at weeks 14 or 52 of infliximab. The proportion of patients with C reactive protein ≤5 mg/L was higher in the standard tapering at week 14 as compared with faster regimens or no prednisolone. In subgroup analyses, the standard tapering was associated with a higher rate of CFCR at week 14 compared with the fast-tapering regimen in patients receiving ≥40 mg prednisolone at initiation of infliximab (64.3% vs 26.3%, p=0.04) and among patients admitted with acute severe UC (66.6% vs 23.5%, p<0.05). Similar data were seen at week 52. Prednisolone did not affect infliximab trough levels but increased infection rates (10/77 vs 2/70, p=0.03), in particular C. difficile infection. CONCLUSION: In UC patients with limited disease burden, prednisolone did not affect effectiveness of infliximab. However, patients with increased disease burden seem to benefit from corticosteroid combination therapy.

Efficient CAR T cell targeting of the CA125 extracellular repeat domain of MUC16.

BACKGROUND: Ovarian cancer (OC) is the leading cause of death from gynecologic malignancies in the Western world. Contributing factors include a high frequency of late-stage diagnosis, the development of chemoresistance, and the evasion of host immune responses. Currently, debulking surgery and platinum-based chemotherapy are the treatment cornerstones, although recurrence is common. As the clinical efficacy of immune checkpoint blockade is low, new immunotherapeutic strategies are needed. Chimeric antigen receptor (CAR) T cell therapy empowers patients' own T cells to fight and eradicate cancer, and has been tested against various targets in OC. A promising candidate is the MUC16 ectodomain. This ectodomain remains on the cell surface after cleavage of cancer antigen 125 (CA125), the domain distal from the membrane, which is currently used as a serum biomarker for OC. CA125 itself has not been tested as a possible CAR target. In this study, we examined the suitability of the CA125 as a target for CAR T cell therapy. METHODS: We tested a series of antibodies raised against the CA125 extracellular repeat domain of MUC16 and adapted them to the CAR format. Comparisons between these candidates, and against an existing CAR targeting the MUC16 ectodomain, identified K101 as having high potency and specificity. The K101CAR was subjected to further biochemical and functional tests, including examination of the effect of soluble CA125 on its activity. Finally, we used cell lines and advanced orthotopic patient-derived xenograft (PDX) models to validate, in vivo, the efficiency of our K101CAR construct. RESULTS: We observed a high efficacy of K101CAR T cells against cell lines and patient-derived tumors, in vitro and in vivo. We also demonstrated that K101CAR functionality was not impaired by the soluble antigen. Finally, in direct comparisons, K101CAR, which targets the CA125 extracellular repeat domains, was shown to have similar efficacy to the previously validated 4H11CAR, which targets the MUC16 ectodomain. CONCLUSIONS: Our in vitro and in vivo results, including PDX studies, demonstrate that the CA125 domain of MUC16 represents an excellent target for treating MUC16-positive malignancies.

Subcutaneous Vedolizumab Treatment in a Real-World Inflammatory Bowel Disease Cohort Switched From Intravenous Vedolizumab: Eighteen-Month Prospective Follow-up Study.

Background: Vedolizumab has since 2021 been available as a subcutaneous formulation. We aimed to assess 18-month drug persistence and possible predictive factors associated with discontinuation, safety, serum drug profile, drug dosing, and disease activity in a real-world cohort of patients with inflammatory bowel disease switched from intravenous to subcutaneous vedolizumab maintenance treatment. Methods: Eligible patients were switched to subcutaneous vedolizumab and followed for 18 months or until discontinuation of subcutaneous treatment. Data on preferred route of administration, adverse events, drug dosing, serum-vedolizumab, disease activity, fecal calprotectin, and C-reactive protein were collected. Persistence was described using Kaplan-Meier analysis. The impact of clinical and biochemical variables on persistence was analyzed with Cox proportional hazard models. Results: We included 108 patients, and the estimated 18-month drug persistence was 73.6% (95% CI [64.2-80.1]). Patients in clinical remission at switch were less likely to discontinue SC treatment (HR = 0.34, 95% CI [0.16-0.73], P = .006), and patients favoring intravenous treatment at switch were almost 3 times more likely to discontinue (HR = 2.78, 95% CI [1.31-5.90], P = .008). Four patients discontinued subcutaneous vedolizumab due to injection site reactions. At 18 months, 88% of patients administered subcutaneous vedolizumab with an interval of ≥ 14 days, and serum-vedolizumab was 39.1 mg/L. Disease activity was stable during follow-up. Conclusions: Three of the four patients remained on subcutaneous vedolizumab after 18 months, a large proportion received treatment at standard dosing intervals, and disease activity remained stable. This indicates that switching from intravenous to subcutaneous vedolizumab treatment is convenient and safe.

Measurement of Functional Brain Network Connectivity in People with Orthostatic Tremor.

Orthostatic tremor is a rare movement disorder characterized by a sensation of unsteadiness and leg tremor while standing. It has been hypothesized that the disorder is attributable to dysregulation of a central oscillatory network in the brain. This putative network includes primary motor cortex, supplementary motor area, cerebellum, thalamus, and pontine tegmentum. We studied this brain network by recording resting-state functional MRI data from individuals with orthostatic tremor. For each participant, we measured resting-state functional connectivity using a seed-based approach. Regions of interest included were components of the putative central oscillatory network and a primary motor thumb region (identified via transcranial magnetic stimulation). A non-central oscillatory network region of interest-posterior cingulate cortex-was included for comparative analysis of a well-characterized intrinsic network, the default mode network. Demographic information, medical history, and tremor characteristics were collected to test associations with functional connectivity. For normative context, data from the 1000 Functional Connectomes Project were analyzed using an identical approach. We observed that tremor and demographic variables were correlated with functional connectivity of central oscillatory network components. Furthermore, relative to healthy comparison participants, patients with orthostatic tremor exhibited qualitatively different patterns of cerebellar resting state functional connectivity. Our study enhances the current understanding of brain network differences related to orthostatic tremor and is consistent with a hypothesized selective decoupling of cerebellum. Additionally, associations observed between functional connectivity and factors including medical history and tremor features may suggest targets for treatment of orthostatic tremor.

Development of a feline model for preclinical research of a new translabyrinthine auditory nerve implant.

Cochlear implants are among the most successful neural prosthetic devices to date but exhibit poor frequency selectivity and the inability to consistently activate apical (low frequency) spiral ganglion neurons. These issues can limit hearing performance in many cochlear implant patients, especially for understanding speech in noisy environments and in perceiving or appreciating more complex inputs such as music and multiple talkers. For cochlear implants, electrical current must pass through the bony wall of the cochlea, leading to widespread activation of auditory nerve fibers. Cochlear implants also cannot be implanted in some individuals with an obstruction or severe malformations of the cochlea. Alternatively, intraneural stimulation delivered via an auditory nerve implant could provide direct contact with neural fibers and thus reduce unwanted current spread. More confined current during stimulation can increase selectivity of frequency fiber activation. Furthermore, devices such as the Utah Slanted Electrode Array can provide access to the full cross section of the auditory nerve, including low frequency fibers that are difficult to reach using a cochlear implant. However, further scientific and preclinical research of these Utah Slanted Electrode Array devices is limited by the lack of a chronic large animal model for the auditory nerve implant, especially one that leverages an appropriate surgical approach relevant for human translation. This paper presents a newly developed transbullar translabyrinthine surgical approach for implanting the auditory nerve implant into the cat auditory nerve. In our first of a series of studies, we demonstrate a surgical approach in non-recovery experiments that enables implantation of the auditory nerve implant into the auditory nerve, without damaging the device and enabling effective activation of the auditory nerve fibers, as measured by electrode impedances and electrically evoked auditory brainstem responses. These positive results motivate performing future chronic cat studies to assess the long-term stability and function of these auditory nerve implant devices, as well as development of novel stimulation strategies that can be translated to human patients.

Clinical consequences of infliximab immunogenicity and the effect of proactive therapeutic drug monitoring: exploratory analyses of the randomised, controlled NOR-DRUM trials.

BACKGROUND: Antidrug antibodies to TNF inhibitors might affect clinical outcomes. Proactive therapeutic drug monitoring allows for early detection of antidrug antibodies and might reduce negative clinical consequences. We aimed to explore how antidrug antibodies to the TNF inhibitor infliximab influence treatment outcomes, and to assess the effect of proactive therapeutic drug monitoring. METHODS: This was a predefined exploratory analysis of data from the randomised, controlled NOR-DRUM trials. The trials were conducted in rheumatology, gastroenterology, and dermatology departments at 21 Norwegian hospitals. Adult patients (aged 18-75 years) with immune-mediated inflammatory diseases were randomly assigned to proactive therapeutic drug monitoring or standard infliximab dosing in the NOR-DRUM A trial (30-week follow-up) and the NOR-DRUM B trial (52-week follow-up). Antidrug antibodies were assessed with a drug-sensitive assay before each infusion. The outcomes of remission (at week 30), disease worsening (during 52 weeks), infusion reactions, and infliximab discontinuation were assessed according to the presence of antidrug antibodies and use of therapeutic drug monitoring. FINDINGS: Between March 1, 2017, and Dec 12, 2019, 616 patients were included in the NOR-DRUM trials, of whom 615 had at least one serum infliximab and antidrug antibody assessment and were included in the present analyses. Mean age was 45 years (IQR 32-56), 305 (50%) patients were women, and 310 (50%) patients were men. Antidrug antibodies were detected in 147 (24%) patients. Remission at week 30 occurred in 25 (35%) of 72 patients with antidrug antibodies and 180 (54%) of 335 without antidrug antibodies (risk ratio 0·62 [95% CI 0·45-0·86]; p=0·0037). In patients with antidrug antibodies compared with patients without antidrug antibodies, higher rates were found for: disease worsening over 52 weeks (0·76 per person-year vs 0· 35 per person-year, hazard ratio [HR] 2·02 [95% CI 1·33-3·07]; p=0·0009), infusion reactions (0·16 per person-year vs 0·03 per person-year, HR 17·02 [6·98-41·47]; p<0·0001), and infliximab discontinuation (1·00 per person-year vs 0·20 per person-year, HR 6·64 [4·84-9·11]; p<0·0001). These associations were more pronounced in patients with high concentrations of antidrug antibodies than in those with low concentrations of antidrug antibodies. Independent of antibody status, therapeutic drug monitoring was associated with a lower risk of disease worsening (HR 0·41 [0·29-0·59]; p=0·0001) or an infusion reaction (HR 0·30 [0·12-0·73]; p=0·0076), and was associated with an increase in the rate of infliximab discontinuation (HR 1·37 [1·02-1·83]; p=0·037). INTERPRETATION: In patients where antidrug antibodies were detected, remission was less likely to be reached and sustained, and infusion reaction or discontinuation of infliximab was more likely. Timely detection of antidrug antibodies by proactive therapeutic drug monitoring facilitated treatment decisions that reduced the negative consequences, both regarding infliximab effectiveness and safety. This highlights the role of proactive therapeutic drug monitoring in optimising infliximab therapy. FUNDING: Inter-regional KLINBEFORSK grants and South-Eastern Norway Regional Health Authority grants.

Machine learning enables non-Gaussian investigation of changes to peripheral nerves related to electrical stimulation.

Electrical stimulation of the peripheral nervous system (PNS) is becoming increasingly important for the therapeutic treatment of numerous disorders. Thus, as peripheral nerves are increasingly the target of electrical stimulation, it is critical to determine how, and when, electrical stimulation results in anatomical changes in neural tissue. We introduce here a convolutional neural network and support vector machines for cell segmentation and analysis of histological samples of the sciatic nerve of rats stimulated with varying current intensities. We describe the methodologies and present results that highlight the validity of the approach: machine learning enabled highly efficient nerve measurement collection, while multivariate analysis revealed notable changes to nerves' anatomy, even when subjected to levels of stimulation thought to be safe according to the Shannon current limits.

Coeliac disease in the Trøndelag Health Study (HUNT), Norway, a population-based cohort of coeliac disease patients.

PURPOSE: Coeliac disease (CD) is a common disorder and affects about 1% of the population worldwide. CD in the Trøndelag Health Study (HUNT) is a population-based cohort study which was established to provide new knowledge about CD that can improve the diagnostics and management, prevent the onset or progression and expand the knowledge about the role of genetics of the disease. PARTICIPANTS: The cohort is based on the fourth wave of the population-based HUNT study (HUNT4), Norway, performed during 2017-2019, also including linkage to hospital records and the Norwegian Patient Registry (NPR). A total of 54 541 HUNT4 participants with available sera were screened for CD by serology. All seropositive participants were invited to a clinical assessment, including endoscopy with duodenal biopsies, during 2019-2023. FINDINGS TO DATE: A total of 1107 HUNT4 participants (2%) were seropositive for CD and 1048 were eligible for clinical assessment, including biopsy. Of these, 724 participants attended the clinical assessment and 482 were identified with CD. In addition, 371 participants with CD were identified through the hospital records and NPR. In total, 853 participants in HUNT4 with biopsy-verified CD diagnosis were identified. FUTURE PLANS: All participants in the study will be invited to a follow-up assessment after at least 1 year, including repeated standard serological testing, endoscopy and tissue sampling. The collected data and material will be used to establish the true population-based prevalence of CD. The consequences of CD, including symptoms, deficiencies and comorbidity, will be investigated and possible triggers and predictors, will be studied. With access to serum samples from the previous HUNT surveys in HUNT Biobank, serological signs of CD in prediagnostic samples of seropositive individuals will be used. Genetic studies will identify new CD markers, assess genotype-phenotype links and explore gene-environment correlations. REGISTRATION: clinicaltrials.gov identifier: NCT04041622.

Impact of diagnostic stewardship interventions in the collection process of fungal blood cultures.

We implemented 2 interventions to improve utilization and contamination at our institution: kits to improve appropriate sample collection and an electronic order alert displaying appropriate indications of fungal blood cultures. An electronic order alert when ordering fungal blood cultures was associated with decreased utilization without decrease in positivity rate.

Epidemiology and preventability of hospital-onset bacteremia and fungemia in 2 hospitals in India.

OBJECTIVE: Studies evaluating the incidence, source, and preventability of hospital-onset bacteremia and fungemia (HOB), defined as any positive blood culture obtained after 3 calendar days of hospital admission, are lacking in low- and middle-income countries (LMICs). DESIGN, SETTING, AND PARTICIPANTS: All consecutive blood cultures performed for 6 months during 2020-2021 in 2 hospitals in India were reviewed to assess HOB and National Healthcare Safety Network (NHSN) reportable central-line-associated bloodstream infection (CLABSI) events. Medical records of a convenience sample of 300 consecutive HOB events were retrospectively reviewed to determine source and preventability. Univariate and multivariable logistic regression analyses were performed to identify factors associated with HOB preventability. RESULTS: Among 6,733 blood cultures obtained from 3,558 hospitalized patients, there were 409 and 59 unique HOB and NHSN-reportable CLABSI events, respectively. CLABSIs accounted for 59 (14%) of 409 HOB events. There was a moderate but non-significant correlation (r = 0.51; P = .070) between HOB and CLABSI rates. Among 300 reviewed HOB cases, CLABSIs were identified as source in only 38 (13%). Although 157 (52%) of all 300 HOB cases were potentially preventable, CLABSIs accounted for only 22 (14%) of these 157 preventable HOB events. In multivariable analysis, neutropenia, and sepsis as an indication for blood culture were associated with decreased odds of HOB preventability, whereas hospital stay ≥7 days and presence of a urinary catheter were associated with increased likelihood of preventability. CONCLUSIONS: HOB may have utility as a healthcare-associated infection metric in LMIC settings because it captures preventable bloodstream infections beyond NHSN-reportable CLABSIs.

Hippocampal Resting State Functional Connectivity Associated with Physical Activity in Periadolescent Children.

Periadolescence is a neurodevelopmental period characterized by structural and functional brain changes that are associated with cognitive maturation. The development of the functional connectivity of the hippocampus contributes to cognitive maturation, especially memory processes. Notably, hippocampal development is influenced by lifestyle factors, including physical activity. Physical activity has been associated with individual variability in hippocampal functional connectivity. However, this relationship has not been characterized in a developmental cohort. In this study, we aimed to fill this gap by investigating the relationship between physical activity and the functional connectivity of the hippocampus in a cohort of periadolescents aged 8-13 years (N = 117). The participants completed a physical activity questionnaire, reporting the number of days per week they performed 60 min of physical activity; then, they completed a resting-state functional MRI scan. We observed that greater physical activity was significantly associated with differences in hippocampal functional connectivity in frontal and temporal regions. Greater physical activity was associated with decreased connectivity between the hippocampus and the right superior frontal gyrus and increased connectivity between the hippocampus and the left superior temporal sulcus. Capturing changes in hippocampal functional connectivity during key developmental periods may elucidate how lifestyle factors including physical activity influence brain network connectivity trajectories, cognitive development, and future disease risk.

Adalimumab serum levels and anti-drug antibodies: associations to treatment response and drug survival in inflammatory joint diseases.

OBJECTIVES: To explore associations between serum adalimumab level, treatment response and drug survival in order to identify therapeutic drug levels for therapeutic drug monitoring of adalimumab. Also, to assess occurrence and risk factors of anti-drug antibody (ADAb) formation. METHODS: Non-trough adalimumab and ADAb levels were measured by automated fluorescence assays in serum collected after 3 months of adalimumab treatment in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) included in the observational NOR-DMARD study. Treatment response was evaluated after 3 months, and drug survival during long-term follow-up. RESULTS: In 340 patients (97 RA, 69 PsA, 174 axSpA), median adalimumab level was 7.3 mg/l (IQR 4.0-10.3). 33 (10%) patients developed ADAb. Findings were comparable across diagnoses. In RA and PsA, adalimumab levels ≥6.0 mg/l were associated with treatment response (Odds Ratio [OR] 2.2 [95% CI 1.0, 4.4]) and improved drug survival (Hazard Ratio [HR] 0.49 [0.27, 0.80]). In axSpA, a therapeutic level could not be identified, but higher adalimumab levels were associated with response. Factors associated with ADAb formation were previous bDMARD use, no methotrexate comedication and use of adalimumab originator compared with GP2017. CONCLUSION: Higher adalimumab levels were associated with better response and improved drug survival for all diagnoses, with a suggested lower threshold of 6.0 mg/l for RA/PsA. This finding, the large variability in drug levels among patients receiving standard adalimumab dose, and the high proportion of patients developing ADAb, encourages further investigations into the potential role of therapeutic drug monitoring of adalimumab.

Trends in Opioid Medication Adherence During the COVID-19 Pandemic: Retrospective Cohort Study.

BACKGROUND: The recent pandemic had the potential to worsen the opioid crisis through multiple effects on patients' lives, such as the disruption of care. In particular, good levels of adherence with respect to medication for opioid use disorder (MOUD), recognized as being important for positive outcomes, may be disrupted. OBJECTIVE: This study aimed to investigate whether patients on MOUD experienced a drop in medication adherence during the recent COVID-19 pandemic. METHODS: This retrospective cohort study used Medicaid claims data from 6 US states from 2018 until the start of 2021. We compared medication adherence for people on MOUD before and after the beginning of the COVID-19 pandemic in March 2020. Our main measure was the proportion of days covered (PDC), a score that measures patients' adherence to their MOUD. We carried out a breakpoint analysis on PDC, followed by a patient-level beta regression analysis with PDC as the dependent variable while controlling for a set of covariates. RESULTS: A total of 79,991 PDC scores were calculated for 37,604 patients (age: mean 37.6, SD 9.8 years; sex: n=17,825, 47.4% female) between 2018 and 2021. The coefficient for the effect of COVID-19 on PDC score was -0.076 and was statistically significant (odds ratio 0.925, 95% CI 0.90-0.94). CONCLUSIONS: The COVID-19 pandemic was negatively associated with patients' adherence to their medication, which had declined since the beginning of the pandemic.

Impact of measurement and feedback on chlorhexidine gluconate bathing among intensive care unit patients: A multicenter study.

OBJECTIVE: To assess whether measurement and feedback of chlorhexidine gluconate (CHG) skin concentrations can improve CHG bathing practice across multiple intensive care units (ICUs). DESIGN: A before-and-after quality improvement study measuring patient CHG skin concentrations during 6 point-prevalence surveys (3 surveys each during baseline and intervention periods). SETTING: The study was conducted across 7 geographically diverse ICUs with routine CHG bathing. PARTICIPANTS: Adult patients in the medical ICU. METHODS: CHG skin concentrations were measured at the neck, axilla, and inguinal region using a semiquantitative colorimetric assay. Aggregate unit-level CHG skin concentration measurements from the baseline period and each intervention period survey were reported back to ICU leadership, which then used routine education and quality improvement activities to improve CHG bathing practice. We used multilevel linear models to assess the impact of intervention on CHG skin concentrations. RESULTS: We enrolled 681 (93%) of 736 eligible patients; 92% received a CHG bath prior to survey. At baseline, CHG skin concentrations were lowest on the neck, compared to axillary or inguinal regions (P < .001). CHG was not detected on 33% of necks, 19% of axillae, and 18% of inguinal regions (P < .001 for differences in body sites). During the intervention period, ICUs that used CHG-impregnated cloths had a 3-fold increase in patient CHG skin concentrations as compared to baseline (P < .001). CONCLUSIONS: Routine CHG bathing performance in the ICU varied across multiple hospitals. Measurement and feedback of CHG skin concentrations can be an important tool to improve CHG bathing practice.

Cancer development in patients hospitalized with systemic lupus erythematosus: A population-level data linkage study.

AIM: To explore the association between systemic lupus erythematosus (SLE) with the risk of cancer development and subsequent 5-year mortality in Western Australia (WA). METHODS: Population-level, data linkage study of SLE patients (n = 2111) and general population comparators (n = 21 110) hospitalized between 1980 and 2014. SLE patients (identified by ICD-9-CM: 695.4, 710.0, and ICD-10-AM: L93.0, M32.0) were nearest matched (10:1) for age, sex, Aboriginality, and temporality. Follow up was from time zero (index SLE hospitalization) to cancer development, death or 31 December 2014. We assessed the risk of cancer development and subsequent 5-year mortality between SLE patients and comparators with univariate and multivariate-adjusted Cox proportional hazards regression models. RESULTS: SLE patients had similar multivariate-adjusted risk (adjusted hazard ratio [aHR] 1.03, 95% confidence interval [CI] 0.93-1.15; p = .583) of cancer development. Cancer development risk was higher in SLE patients <40 years old (aHR 1.58, 95% CI 1.29-1.94; p < .001), and from 1980 to 1999 (aHR 1.16, 95% CI 1.02-1.31; p < .001). SLE patients had higher risk of developing cancer of the oropharynx (aHR 2.13, 95% CI 1.30-3.50), vulvo-vagina (aHR 3.22, 95% CI 1.34-7.75), skin (aHR 1.20, 95% CI 1.01-1.43), musculoskeletal tissues (aHR 2.26, 95% CI 1.16-4.40), and hematological tissues (aHR 1.78 95% CI 1.25-2.53), all p < .05. After cancer development, SLE patients had increased risk of 5-year mortality (aHR 1.31, 95% CI 1.06-1.61); highest in patients <50 years old (aHR 2.03, 95% CI 1.03-4.00), and in those with reproductive system and skin cancers. CONCLUSIONS: Hospitalized SLE patients had increased risk of multiple cancer sub-types. Following cancer development, SLE patients had increased risk of 5-year mortality. There is scope to improve cancer prevention and surveillance in SLE patients. TRIAL REGISTRATION: Not applicable. This low-risk risk study used de-identified administrative linked health data.