Clinician Ordering and Management Patterns of Urine Toxicology Results at a Cancer Center.

CONTEXT: Opioid therapy is a cornerstone for treatment of cancer-related pain, but standardized management practices for patients with cancer and aberrant urine drug test (UDT) results are lacking. OBJECTIVES: To identify the prevalence of UDT ordering (both screening and definitive testing) in the oncology setting and to examine clinician management practices for patients with cancer on opioid therapy with aberrant definitive UDT results. METHODS: We conducted a retrospective chart review of patients with cancer on opioid therapy at an academic cancer center in the United States. Outcomes included UDT ordering patterns and clinician management practices in response to aberrant definitive UDT results. RESULTS: Our study revealed an overall UDT ordering rate of 3.7% among 10,371 patients with cancer on opioid therapy. Among 143 patients for whom definitive UDTs were ordered, oncologists only ordered 14 (9.8%) UDTs, while palliative care ordered the majority (n = 129; 90.2%). Fifty-five (38.5%) patients had aberrant results, and the most common aberrancy was presence of illicit drugs 22 [15.4%]. Clinicians rarely made medication changes (20 [36.4%]) when UDT results were aberrant, and in the setting of possible fentanyl use (n = 8), only 3 (37.5%) patients were started/switched to methadone, and none were started/switched to buprenorphine. CONCLUSION: Overall UDT ordering was infrequent for patients with cancer on opioid therapy, especially by oncologists, and clinicians rarely made prescribing changes when definitive UDT results were aberrant. More definitive guidance related to UDT ordering and opioid management are needed for patients with cancer and aberrant UDT results.

Myeloid C-type lectin receptors in innate immune recognition.

C-type lectin receptors (CLRs) expressed by myeloid cells constitute a versatile family of receptors that play a key role in innate immune recognition. Myeloid CLRs exhibit a remarkable ability to recognize an extensive array of ligands, from carbohydrates and beyond, and encompass pattern-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and markers of altered self. These receptors, classified into distinct subgroups, play pivotal roles in immune recognition and modulation of immune responses. Their intricate signaling pathways orchestrate a spectrum of cellular responses, influencing processes such as phagocytosis, cytokine production, and antigen presentation. Beyond their contributions to host defense in viral, bacterial, fungal, and parasitic infections, myeloid CLRs have been implicated in non-infectious diseases such as cancer, allergies, and autoimmunity. A nuanced understanding of myeloid CLR interactions with endogenous and microbial triggers is starting to uncover the context-dependent nature of their roles in innate immunity, with implications for therapeutic intervention.

Diagnostic accuracy of the Enferplex Bovine TB antibody test using individual milk samples from cattle.

Bovine tuberculosis is usually diagnosed using tuberculin skin tests or at post-mortem. Recently, we have developed a serological test for bovine tuberculosis in cattle which shows a high degree of accuracy using serum samples. Here, we have assessed the performance of the test using individual bovine milk samples. The diagnostic specificity estimate using the high sensitivity setting of the test was 99.7% (95% CI: 99.2-99.9). This estimate was not altered significantly by tuberculin boosting. The relative sensitivity estimates of the test using the high sensitivity setting in milk samples from comparative skin test positive animals was 90.8% (95% CI: 87.1-93.6) with boosting. In animals with lesions, the relative sensitivity was 96.0% (95% CI: 89.6-98.7). Analysis of paired serum and milk samples from skin test positive animals showed correlation coefficients ranging from 0.756-0.955 for individual antigens used in the test. Kappa analysis indicated almost perfect agreement between serum and milk results, while McNemar marginal homogeneity analysis showed no statistically significant differences between the two media. The positive and negative likelihood ratio were 347.8 (95% CI: 112.3-1077.5) and 0.092 (95% CI: 0.07-0.13) respectively for boosted samples from skin test positive animals. The results show that the test has high sensitivity and specificity in individual milk samples and thus milk samples could be used for the diagnosis of bovine tuberculosis.

PyPop: a mature open-source software pipeline for population genomics.

Python for Population Genomics (PyPop) is a software package that processes genotype and allele data and performs large-scale population genetic analyses on highly polymorphic multi-locus genotype data. In particular, PyPop tests data conformity to Hardy-Weinberg equilibrium expectations, performs Ewens-Watterson tests for selection, estimates haplotype frequencies, measures linkage disequilibrium, and tests significance. Standardized means of performing these tests is key for contemporary studies of evolutionary biology and population genetics, and these tests are central to genetic studies of disease association as well. Here, we present PyPop 1.0.0, a new major release of the package, which implements new features using the more robust infrastructure of GitHub, and is distributed via the industry-standard Python Package Index. New features include implementation of the asymmetric linkage disequilibrium measures and, of particular interest to the immunogenetics research communities, support for modern nomenclature, including colon-delimited allele names, and improvements to meta-analysis features for aggregating outputs for multiple populations. Code available at: https://zenodo.org/records/10080668 and https://github.com/alexlancaster/pypop.

Evaluation of Three Cytomegalovirus IgG Lateral Flow Assays for Rapid Determination of CMV Serostatus.

Background: Cytomegalovirus (CMV) serostatus is a major determinant of CMV infection, disease risk, and transplant outcomes. Current clinical serology assays are limited by relatively slow turnaround time, design for batched testing, need for trained personnel, and/or specialized equipment. Rapid diagnostic assays in development have a role in emerging settings, such as critically ill patients, but have not been systematically evaluated. Methods: We assessed the performance of 3 rapid lateral flow assays (LFAs) for the detection of CMV immunoglobulin (Ig)G antibodies compared with a reference commercially available CMV IgG enzyme-linked immunosorbent assay in residual serum samples from 200 consecutive adults who underwent clinical CMV serology testing. Samples with discrepant results between the LFA and reference assay were tested by a second reference assay. A subset of serum samples was assessed for interoperator variability. Operating characteristics of the QooLabs LFA were separately assessed in plasma samples. Results: The sensitivity and specificity of the individual LFA assays using serum varied significantly: 86%/83%, 99/93%, and 57/97%, for Healgen, QNow automated reader, and nanoComposix, respectively, compared with the reference assay. Results for the QNow assay were comparable between automated and manual reads. Among a subset of 10 serum samples assessed by 5 individual operators, 44 of 50 (88%) results were concordant. Among 50 plasma samples assessed by the QooLabs LFA, the sensitivity and specificity were 72% and 96%. Conclusions: The ease of performance, rapid turnaround time, and good operating characteristics provide the rationale for further evaluation of the Qoolabs QNow LFA in specialized settings where rapid assessment of CMV serostatus would be advantageous.

Cryptococcus neoformans rapidly invades the murine brain by sequential breaching of airway and endothelial tissues barriers, followed by engulfment by microglia.

Cryptococcus neoformans causes lethal meningitis and accounts for approximately 10%-15% of AIDS-associated deaths worldwide. There are major gaps in our understanding of how this fungus invades the mammalian brain. To investigate the dynamics of C. neoformans tissue invasion, we mapped fungal localization and host cell interactions in infected brain, lung, and upper airways using mouse models of systemic and airway infection. To enable this, we developed an in situ imaging pipeline capable of measuring large volumes of tissue while preserving anatomical and cellular information by combining thick tissue sections, tissue clarification, and confocal imaging. We confirm high fungal burden in mouse upper airway after nasal inoculation. Yeast in turbinates were frequently titan cells, with faster kinetics than reported in mouse lungs. Importantly, we observed one instance of fungal cells enmeshed in lamina propria of the upper airways, suggesting penetration of airway mucosa as a possible route of tissue invasion and dissemination to the bloodstream. We extend previous literature positing bloodstream dissemination of C. neoformans, by finding viable fungi in the bloodstream of mice a few days after intranasal infection. As early as 24 h post systemic infection, the majority of C. neoformans cells traversed the blood-brain barrier, and were engulfed or in close proximity to microglia. Our work presents a new method for investigating microbial invasion, establishes that C. neoformans can breach multiple tissue barriers within the first days of infection, and demonstrates microglia as the first cells responding to C. neoformans invasion of the brain.IMPORTANCECryptococcal meningitis causes 10%-15% of AIDS-associated deaths globally. Still, brain-specific immunity to cryptococci is a conundrum. By employing innovative imaging, this study reveals what occurs during the first days of infection in brain and in airways. We found that titan cells predominate in upper airways and that cryptococci breach the upper airway mucosa, which implies that, at least in mice, the upper airways are a site for fungal dissemination. This would signify that mucosal immunity of the upper airway needs to be better understood. Importantly, we also show that microglia, the brain-resident macrophages, are the first responders to infection, and microglia clusters are formed surrounding cryptococci. This study opens the field to detailed molecular investigations on airway immune response, how fungus traverses the blood-brain barrier, how microglia respond to infection, and ultimately how microglia monitor the blood-brain barrier to preserve brain function.

No position-specific interference from prior lists in cued recognition: A challenge for position coding (and other) theories of serial memory.

Position-specific intrusions of items from prior lists are rare but important phenomena that distinguish broad classes of theory in serial memory. They are uniquely predicted by position coding theories, which assume items on all lists are associated with the same set of codes representing their positions. Activating a position code activates items associated with it in current and prior lists in proportion to their distance from the activated position. Thus, prior list intrusions are most likely to come from the coded position. Alternative "item dependent" theories based on associations between items and contexts built from items have difficulty accounting for the position specificity of prior list intrusions. We tested the position coding account with a position-cued recognition task designed to produce prior list interference. Cuing a position should activate a position code, which should activate items in nearby positions in the current and prior lists. We presented lures from the prior list to test for position-specific activation in response time and error rate; lures from nearby positions should interfere more. We found no evidence for such interference in 10 experiments, falsifying the position coding prediction. We ran two serial recall experiments with the same materials and found position-specific prior list intrusions. These results challenge all theories of serial memory: Position coding theories can explain the prior list intrusions in serial recall and but not the absence of prior list interference in cued recognition. Item dependent theories can explain the absence of prior list interference in cued recognition but cannot explain the occurrence of prior list intrusions in serial recall.

Ocular accommodation and wavelength: The effect of longitudinal chromatic aberration on the stimulus-response curve.

The longitudinal chromatic aberration (LCA) of the eye creates a chromatic blur on the retina that is an important cue for accommodation. Although this mechanism can work optimally in broadband illuminants such as daylight, it is not clear how the system responds to the narrowband illuminants used by many modern displays. Here, we measured pupil and accommodative responses as well as visual acuity under narrowband light-emitting diode (LED) illuminants of different peak wavelengths. Observers were able to accommodate under narrowband light and compensate for the LCA of the eye, with no difference in the variability of the steady-state accommodation response between narrowband and broadband illuminants. Intriguingly, our subjects compensated more fully for LCA at nearer distances. That is, the difference in accommodation to different wavelengths became larger when the object was placed nearer the observer, causing the slope of the accommodation response curve to become shallower for shorter wavelengths and steeper for longer ones. Within the accommodative range of observers, accommodative errors were small and visual acuity normal. When comparing between illuminants, when accommodation was accurate, visual acuity was worst for blue narrowband light. This cannot be due to the sparser spacing for S-cones, as our stimuli had equal luminance and thus activated LM-cones roughly equally. It is likely because ocular LCA changes more rapidly at shorter wavelength and so the finite spectral bandwidth of LEDs corresponds to a greater dioptric range at shorter wavelengths. This effect disappears for larger accommodative errors, due to the increased depth of focus of the eye.

The gated cascade diffusion model: An integrated theory of decision making, motor preparation, and motor execution.

This article introduces an integrated and biologically inspired theory of decision making, motor preparation, and motor execution. The theory is formalized as an extension of the diffusion model, in which diffusive accumulated evidence from the decision-making process is continuously conveyed to motor areas of the brain that prepare the response, where it is smoothed by a mechanism that approximates a Kalman-Bucy filter. The resulting motor preparation variable is gated prior to reaching agonist muscles until it exceeds a particular level of activation. We tested this gated cascade diffusion model by continuously probing the electrical activity of the response agonists through electromyography in four choice tasks that span a variety of domains in cognitive sciences, namely motion perception, numerical cognition, recognition memory, and lexical knowledge. The model provided a good quantitative account of behavioral and electromyographic data and systematically outperformed previous models. This work represents an advance in the integration of processes involved in simple decisions and sheds new light on the interplay between decision and motor systems. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Disrupted limbic-prefrontal effective connectivity in response to fearful faces in lifetime depression.

BACKGROUND: Multiple brain imaging studies of negative emotional bias in major depressive disorder (MDD) have used images of fearful facial expressions and focused on the amygdala and the prefrontal cortex. The results have, however, been inconsistent, potentially due to small sample sizes (typically N<50). It remains unclear if any alterations are a characteristic of current depression or of past experience of depression, and whether there are MDD-related changes in effective connectivity between the two brain regions. METHODS: Activations and effective connectivity between the amygdala and dorsolateral prefrontal cortex (DLPFC) in response to fearful face stimuli were studied in a large population-based sample from Generation Scotland. Participants either had no history of MDD (N=664 in activation analyses, N=474 in connectivity analyses) or had a diagnosis of MDD during their lifetime (LMDD, N=290 in activation analyses, N=214 in connectivity analyses). The within-scanner task involved implicit facial emotion processing of neutral and fearful faces. RESULTS: Compared to controls, LMDD was associated with increased activations in left amygdala (PFWE=0.031,kE=4) and left DLPFC (PFWE=0.002,kE=33), increased mean bilateral amygdala activation (ß=0.0715,P=0.0314), and increased inhibition from left amygdala to left DLPFC, all in response to fearful faces contrasted to baseline. Results did not appear to be attributable to depressive illness severity or antidepressant medication status at scan time. LIMITATIONS: Most studied participants had past rather than current depression, average severity of ongoing depression symptoms was low, and a substantial proportion of participants were receiving medication. The study was not longitudinal and the participants were only assessed a single time. CONCLUSIONS: LMDD is associated with hyperactivity of the amygdala and DLPFC, and with stronger amygdala to DLPFC inhibitory connectivity, all in response to fearful faces, unrelated to depression severity at scan time. These results help reduce inconsistency in past literature and suggest disruption of 'bottom-up' limbic-prefrontal effective connectivity in depression.

The pathogenesis of experimental Emergomycosis in mice.

Emergomyces africanus is a recently identified thermally-dimorphic fungal pathogen that causes disseminated infection in people living with advanced HIV disease. Known as emergomycosis, this disseminated disease is associated with very high case fatality rates. Over the last decade, improved diagnostics and fungal identification in South Africa resulted in a dramatic increase in the number of reported cases. Although the true burden of disease is still unknown, emergomycosis is among the most frequently diagnosed dimorphic fungal infections in Southern Africa; and additional species in the genus have been identified on four continents. Little is known about the pathogenesis and the host's immune response to this emerging pathogen. Therefore, we established a murine model of pulmonary infection using a clinical isolate, E. africanus (CBS 136260). Both conidia and yeast forms caused pulmonary and disseminated infection in mice with organisms isolated in culture from lung, spleen, liver, and kidney. Wild-type C57BL/6 mice demonstrated a drop in body weight at two weeks post-infection, corresponding to a peak in fungal burden in the lung, spleen, liver, and kidney. An increase in pro-inflammatory cytokine production was detected in homogenized lung supernatants including IFN-γ, IL-1ß, IL-6, IL12-p40 and IL-17 at three- and four-weeks post-infection. No significant differences in TNF, IL-12p70 and IL-10 were observed in wild-type mice between one and four-weeks post-infection. Rag-1-deficient mice, lacking mature T-and B-cells, had an increased fungal burden associated with reduced IFN-γ production. Together our data support a protective T-helper type-1 immune response to E. africanus infection. This may provide a possible explanation for the susceptibility of only a subset of people living with advanced HIV disease despite hypothesized widespread environmental exposure. In summary, we have established a novel murine model of E. africanus disease providing critical insights into the host immune components required for eliminating the infection.

A CO2 sensing module modulates ß-1,3-glucan exposure in Candida albicans.

Microbial species capable of co-existing with healthy individuals, such as the commensal fungus Candida albicans, exploit multifarious strategies to evade our immune defenses. These strategies include the masking of immunoinflammatory pathogen-associated molecular patterns (PAMPs) at their cell surface. We reported previously that C. albicans actively reduces the exposure of the proinflammatory PAMP, ß-1,3-glucan, at its cell surface in response to host-related signals such as lactate and hypoxia. Here, we show that clinical isolates of C. albicans display phenotypic variability with respect to their lactate- and hypoxia-induced ß-1,3-glucan masking. We have exploited this variability to identify responsive and non-responsive clinical isolates. We then performed RNA sequencing on these isolates to reveal genes whose expression patterns suggested potential association with lactate- or hypoxia-induced ß-1,3-glucan masking. The deletion of two such genes attenuated masking: PHO84 and NCE103. We examined NCE103-related signaling further because NCE103 has been shown previously to encode carbonic anhydrase, which promotes adenylyl cyclase-protein kinase A (PKA) signaling at low CO2 levels. We show that while CO2 does not trigger ß-1,3-glucan masking in C. albicans, the Sch9-Rca1-Nce103 signaling module strongly influences ß-1,3-glucan exposure in response to hypoxia and lactate. In addition to identifying a new regulatory module that controls PAMP exposure in C. albicans, our data imply that this module is important for PKA signaling in response to environmental inputs other than CO2.IMPORTANCEOur innate immune defenses have evolved to protect us against microbial infection in part via receptor-mediated detection of "pathogen-associated molecular patterns" (PAMPs) expressed by invading microbes, which then triggers their immune clearance. Despite this surveillance, many microbial species are able to colonize healthy, immune-competent individuals, without causing infection. To do so, these microbes must evade immunity. The commensal fungus Candida albicans exploits a variety of strategies to evade immunity, one of which involves reducing the exposure of a proinflammatory PAMP (ß-1,3-glucan) at its cell surface. Most of the ß-1,3-glucan is located in the inner layer of the C. albicans cell wall, hidden by an outer layer of mannan fibrils. Nevertheless, some ß-1,3-glucan can become exposed at the fungal cell surface. However, in response to certain specific host signals, such as lactate or hypoxia, C. albicans activates an anticipatory protective response that decreases ß-1,3-glucan exposure, thereby reducing the susceptibility of the fungus to impending innate immune attack. Here, we exploited the natural phenotypic variability of C. albicans clinical isolates to identify strains that do not display the response to ß-1,3-glucan masking signals observed for the reference isolate, SC5314. Then, using genome-wide transcriptional profiling, we compared these non-responsive isolates with responsive controls to identify genes potentially involved in ß-1,3-glucan masking. Mutational analysis of these genes revealed that a sensing module that was previously associated with CO2 sensing also modulates ß-1,3-glucan exposure in response to hypoxia and lactate in this major fungal pathogen of humans.

Do patients who read visit notes on the patient portal have a higher rate of "loop closure" on diagnostic tests and referrals in primary care? A retrospective cohort study.

OBJECTIVES: The 2021 US Cures Act may engage patients to help reduce diagnostic errors/delays. We examined the relationship between patient portal registration with/without note reading and test/referral completion in primary care. MATERIALS AND METHODS: Retrospective cohort study of patients with visits from January 1, 2018 to December 31, 2021, and order for (1) colonoscopy, (2) dermatology referral for concerning lesions, or (3) cardiac stress test at 2 academic primary care clinics. We examined differences in timely completion ("loop closure") of tests/referrals for (1) patients who used the portal and read ≥1 note (Portal + Notes); (2) those with a portal account but who did not read notes (Portal Account Only); and (3) those who did not register for the portal (No Portal). We estimated the predictive probability of loop closure in each group after adjusting for socio-demographic and clinical factors using multivariable logistic regression. RESULTS: Among 12 849 tests/referrals, loop closure was more common among Portal+Note-readers compared to their counterparts for all tests/referrals (54.2% No Portal, 57.4% Portal Account Only, 61.6% Portal+Notes, P < .001). In adjusted analysis, compared to the No Portal group, the odds of loop closure were significantly higher for Portal Account Only (OR 1.2; 95% CI, 1.1-1.4), and Portal+Notes (OR 1.4; 95% CI, 1.3-1.6) groups. Beyond portal registration, note reading was independently associated with loop closure (P = .002). DISCUSSION AND CONCLUSION: Compared to no portal registration, the odds of loop closure were 20% higher in tests/referrals for patients with a portal account, and 40% higher in tests/referrals for note readers, after controlling for sociodemographic and clinical factors. However, important safety gaps from unclosed loops remain, requiring additional engagement strategies.

Characterizing the Neurobiological Mechanisms of Action of Exercise and Cognitive-Behavioral Interventions for Rheumatoid Arthritis Fatigue: A Magnetic Resonance Imaging Brain Study.

OBJECTIVE: Chronic fatigue is a major clinical unmet need among patients with rheumatoid arthritis (RA). Current therapies are limited to nonpharmacological interventions, such as personalized exercise programs (PEPs) and cognitive-behavioral approaches (CBAs); however, most patients still continue to report severe fatigue. To inform more effective therapies, we conducted a magnetic resonance imaging (MRI) brain study of PEPs and CBAs, nested within a randomized controlled trial (RCT), to identify their neurobiological mechanisms of fatigue reduction in RA. METHODS: A subgroup of patients with RA (n = 90), participating in an RCT of PEPs and CBAs for fatigue, undertook a multimodal MRI brain scan following randomization to either usual care (UC) alone or in addition to PEPs and CBAs and again after the intervention (six months). Brain regional volumetric, functional, and structural connectivity indices were curated and then computed employing a causal analysis framework. The primary outcome was fatigue improvement (Chalder fatigue scale). RESULTS: Several structural and functional connections were identified as mediators of fatigue improvement in both PEPs and CBAs compared to UC. PEPs had a more pronounced effect on functional connectivity than CBAs; however, structural connectivity between the left isthmus cingulate cortex (L-ICC) and left paracentral lobule (L-PCL) was shared, and the size of mediation effect ranked highly for both PEPs and CBAs (ßAverage = -0.46, SD 0.61; ßAverage = -0.32, SD 0.47, respectively). CONCLUSION: The structural connection between the L-ICC and L-PCL appears to be a dominant mechanism for how both PEPs and CBAs reduce fatigue among patients with RA. This supports its potential as a substrate of fatigue neurobiology and a putative candidate for future targeting.

Enferplex bovine TB antibody test and bovine TB diagnosis: letter to the editor.

Bovine tuberculosis is usually diagnosed using tuberculin skin and interferon gamma tests. However, it is clear these tests miss infected animals due to poor sensitivity. The Enferplex Bovine TB antibody test has been validated by the World Organisation for Animal Health as fit for purpose in diagnosing bovine TB. A recent paper by Madden and colleagues (Veterinary Research Communications published online 17 August 2023) presented data on the future risk of Enferplex test antibody positive animals developing bovine TB. We argue in this communication that this does not make sense. Also, the study design did not include measuring antibodies at the point of censure of the animals and hence the survival analysis performed was meaningless. Most significantly, the study misses the point that skin and interferon gamma tests fail to detect a significant proportion of infected animals identified by the Enferplex test.

Low Rate of Completion of Recommended Tests and Referrals in an Academic Primary Care Practice with Resident Trainees.

BACKGROUND: A frequent, preventable cause of diagnostic errors involves failure to follow up on diagnostic tests, referrals, and symptoms-termed "failure to close the diagnostic loop." This is particularly challenging in a resident practice where one third of physicians graduate annually, and rates of patient loss due to these transitions may lead to more opportunities for failure to close diagnostic loops. The aim of this study was to determine the prevalence of failure of loop closure in a resident primary care clinic compared to rates in the faculty practice and identify factors contributing to failure. METHODS: This retrospective cohort study included all patient visits from January 1, 2018, to December 31, 2021, at two academic medical center-based primary care practices where residents and faculty practice in the same setting. The primary outcome was prevalence of failure to close the loop for (1) dermatology referrals, (2) colonoscopy, and (3) cardiac stress testing. The primary predictor was resident vs. faculty status of the ordering provider. The authors present an unadjusted analysis and the results of a multivariable logistic regression analysis incorporating all patient factors to determine their association with loop closure. RESULTS: Of 12,282 orders for referrals and tests for the three studied areas, 1,929 (15.7%) were ordered by a resident physician. Of resident orders for all three tests, 52.9% were completed within the designated time vs. 58.4% for orders placed by attending physicians (p < 0.01). In an unadjusted analysis by test type, a similar trend was seen for colonoscopy (51.4% completion rate for residents vs. 57.5% for attending physicians, p < 0.01) and for cardiac stress testing (55.7% completion rate for residents vs. 61.2% for attending physicians), though a difference was not seen for dermatology referrals (64.2% completion rate for residents vs. 63.7% for attending physicians). In an adjusted analysis, patients with resident orders were less likely than attendings to close the loop for all test types combined (odds ratio 0.88, 95% confidence interval 0.79-0.98), with low rates of test completion for both physician groups. CONCLUSION: Loop closure for three diagnostic interventions was low for patients in both faculty and resident primary care clinics, with lower loop closure rates in resident clinics. Failure to close diagnostic loops presents a safety challenge in primary care and is of particular concern for training programs.

Zinc prevents vaginal candidiasis by inhibiting expression of an inflammatory fungal protein.

Candida causes an estimated half-billion cases of vulvovaginal candidiasis (VVC) every year. VVC is most commonly caused by Candida albicans, which, in this setting, triggers nonprotective neutrophil infiltration, aggressive local inflammation, and symptomatic disease. Despite its prevalence, little is known about the molecular mechanisms underpinning the immunopathology of this fungal infection. In this study, we describe the molecular determinant of VVC immunopathology and a potentially straightforward way to prevent disease. In response to zinc limitation, C. albicans releases a trace mineral binding molecule called Pra1 (pH-regulated antigen). Here, we show that the PRA1 gene is strongly up-regulated during vaginal infections and that its expression positively correlated with proinflammatory cytokine concentrations in women. Genetic deletion of PRA1 prevented vaginal inflammation in mice, and application of a zinc solution down-regulated expression of the gene and also blocked immunopathology. We also show that treatment of women suffering from recurrent VVC with a zinc gel prevented reinfections. We have therefore identified a key mediator of symptomatic VVC, giving us an opportunity to develop a range of preventative measures for combatting this disease.

Completion Rates and Timeliness of Diagnostic Colonoscopies for Rectal Bleeding in Primary Care.

BACKGROUND: Rectal bleeding is the most common presenting symptom of colorectal cancer, and guidelines recommend timely follow-up, usually with colonoscopy to ensure timely diagnoses of colorectal cancer. OBJECTIVE: Identify loop closure rates and vulnerable process points for patients with rectal bleeding. DESIGN: Retrospective cohort study, using medical record review of patients aged ≥ 40 with index diagnosis of rectal bleeding at 2 primary practices-an urban academic practice and affiliated community health center, between January 1, 2018, and December 31, 2020. Patients were classified as having completed recommended follow-up workup ("closed loop") vs. not ("open loop"). Open loop patient cases were categorized into six types of process failures. PARTICIPANTS: A total of 837 patients had coded diagnoses of rectal bleeding within study window. Sixty-seven were excluded based on prior colectomy, clinical presentation more consistent with upper GI bleed, no rectal bleeding documented on chart review, or expired during the follow-up period, leaving 770 patients included. MAIN MEASURES: Primary outcomes were percentages of patient cases classified as "open loops" and distribution of these cases into six categories of process failure that were identified. KEY RESULTS: 22.3% of patients (N = 172) failed to undergo timely recommended workup for rectal bleeding. Largest failure categories were patients for whom no procedure was ordered (N = 62, 36%), followed by patients with procedures ordered but never scheduled (N = 44, 26%) or scheduled but subsequently cancelled or not kept (N = 31, 18%). While open loops increased after the onset of the COVID-19 pandemic, this difference was not significant within our study period. CONCLUSIONS: Significant numbers of patients presenting to primary care with rectal bleeding fail to undergo recommended workup. The majority either have no procedure ordered, or procedure ordered but never scheduled or cancelled and not kept, suggesting these are important failure modes to target in future interventions. Ensuring reliable ordering and processes for timely scheduling and completion of procedures represent critical areas for improving the diagnostic process for patients with rectal bleeding in primary care.

Completion of Recommended Tests and Referrals in Telehealth vs In-Person Visits.

Importance: Use of telehealth has increased substantially in recent years. However, little is known about whether the likelihood of completing recommended tests and specialty referrals-termed diagnostic loop closure-is associated with visit modality. Objectives: To examine the prevalence of diagnostic loop closure for tests and referrals ordered at telehealth visits vs in-person visits and identify associated factors. Design, Setting, and Participants: In a retrospective cohort study, all patient visits from March 1, 2020, to December 31, 2021, at 1 large urban hospital-based primary care practice and 1 affiliated community health center in Boston, Massachusetts, were evaluated. Main Measures: Prevalence of diagnostic loop closure for (1) colonoscopy referrals (screening and diagnostic), (2) dermatology referrals for suspicious skin lesions, and (3) cardiac stress tests. Results: The study included test and referral orders for 4133 patients (mean [SD] age, 59.3 [11.7] years; 2163 [52.3%] women; 203 [4.9%] Asian, 1146 [27.7%] Black, 2362 [57.1%] White, and 422 [10.2%] unknown or other race). A total of 1151 of the 4133 orders (27.8%) were placed during a telehealth visit. Of the telehealth orders, 42.6% were completed within the designated time frame vs 58.4% of those ordered during in-person visits and 57.4% of those ordered without a visit. In an adjusted analysis, patients with telehealth visits were less likely to close the loop for all test types compared with those with in-person visits (odds ratio, 0.55; 95% CI, 0.47-0.64). Conclusions: The findings of this study suggest that rates of loop closure were low for all test types across all visit modalities but worse for telehealth. Failure to close diagnostic loops presents a patient safety challenge in primary care that may be of particular concern during telehealth encounters.