A 52-Year-Old Woman With Dysarthria, Ataxia, Xanthelasmas, and Miliary Pulmonary Nodules.

CASE PRESENTATION: A 52-year-old woman with no significant medical history was referred to our hospital for expedited workup of progressive dysarthria and ataxia over the past year. Prior CT angiography of the head and neck showed no relevant neurologic findings but did reveal miliary lesions in the lung apices, which was later confirmed via dedicated CT chest scan (Fig 1). Review of systems was negative for any respiratory, constitutional, or rheumatologic symptoms, except for new xanthelasma-like lesions over her forehead. She previously had smoked with 20 pack-years and had no TB risk factors. MRI of the face showed a 21-mm mass within the left external temporal fascia. MRI of the head showed diffuse leptomeningeal enhancement, right frontal lobe enhancement, and cerebellar and brainstem T2/fluid-attenuated inversion recovery hyperintensity, which prompted her admission to hospital.

Mass spectrometry in IgG4-related disease diagnosis.

We compared liquid chromatography tandem mass spectrometry (LC-MS/MS) against Binding Site immunonephelometry (BSIN) with regards to these methods' abilities to diagnose IgG4-related disease (IgG4-RD). IgG subclasses were gathered from laboratory from December 2011 to December 2020. The IgG4-RD positive and negative patients were diagnosed according to the ACR/EULAR classification criteria by extensive chart review. Both methods' results were compared in terms of test characteristics. For BSIN, there were 43 IgG4-RD positive cases and 174 disease negative cases, while for LC-MS/MS, there were 102 IgG4-RD positive cases and 562 disease negative cases. The majority of IgG4-RD patients by BSIN and LC-MS/MS had an elevated IgG4 level, 81% and 86%, respectively. For BSIN, the ROC curve, cut-off value of 1.25 g/L, had a sensitivity of 81% and a specificity of 84%. For LC-MS/MS, the ROC curve, cut-off value of 1.25 g/L, had a sensitivity of 86% and a specificity of 84%. The responder index score to IgG4 level r-correlation value for BSIN and LC-MS/MS was 0.5 and 0.6, respectively. In our center, LC-MS/MS and BSIN are equivalent test methods in IgG4-RD diagnosis. IgG4 level does correlate with disease activity by the responder index. LC-MS/MS is a valid and equally reliable alternative to BSIN in the diagnosis of IgG4-related disease.

Inborn errors of immunity in adulthood.

Inborn errors of immunity (IEIs) are a group of conditions whereby parts of the immune system are missing or dysfunctional. Once thought to primarily be a pediatric disorder, it is now estimated that more than 50% of worldwide incident IEI cases are accounted for by adults. Delayed diagnosis, late symptom onset, and IEI phenocopies can all lead to adult-onset recognition of IEIs. Lack of awareness regarding the diversity of IEI manifestations in adults contributes to diagnostic and treatment delays. Prompt referral to immunology is critical so that patients can receive a precise molecular diagnosis and targeted therapy when available. This article serves as a primer on IEIs in adulthood, highlighting the pathophysiology, epidemiology and clinical features. We present clinical vignettes of three key IEIs to assist clinicians in building illness scripts on their presentations. We provide a framework for the laboratory evaluation of IEIs and their initial treatment, with the aim of improving recognition and management of these conditions.

Investigation of CO2 Absorption Rate in Gas/Liquid Membrane Contactors with Inserting 3D Printing Mini-Channel Turbulence Promoters.

The CO2 absorption by Monoethanolamine (MEA) solutions as chemical absorption was conducted in the membrane gas absorption module with inserting 3D mini-channel turbulence promoters of the present work. A mathematical modeling of CO2 absorption flux was analyzed by using the chemical absorption theory based on mass-transfer resistances in series. The membrane absorption module with embedding 3D mini-channel turbulence promoters in the current study indicated that the CO2 absorption rate improvement is achieved due to the diminishing concentration polarization effect nearby the membrane surfaces. A simplified regression equation of the average Sherwood number was correlated to express the enhanced mass-transfer coefficient of the CO2 absorption. The experimental results and theoretical predictions showed that the absorption flux improvement was significantly improved with implementing 3D mini-channel turbulence promoters. The experimental results of CO2 absorption fluxes were performed in good agreement with the theoretical predictions in aqueous MEA solutions. A further absorption flux enhancement up to 30.56% was accomplished as compared to the results in the previous work, which the module was inserted the promoter without mini channels. The influences of the MEA absorbent flow rates and inlet CO2 concentrations on the absorption flux and absorption flux improvement are also illustrated under both concurrent- and countercurrent-flow operations.

Classroom-Based Learning in an Academic Obstetrics and Gynecology Residency Training Program.

Objectives: Classroom-based learning such as academic half days (AHDs) are complementary to workplace learning in postgraduate medical education. This study examined three research questions: the purpose of AHDs, elements of an effective AHD, and factors that make AHD sustainable. Methods: We conducted a case study of the AHD in a large Obstetrics and Gynecology residency program at the University of British Columbia. Residents were interviewed in 2013 (n = 11) and 2018 (n = 7) and the program administrator was interviewed in 2018. The themes in each research question were identified by modified inductive analysis. Results: Residents expressed that the purposes of AHD included: providing organization and an overview for their knowledge acquisition; preparation for their Royal College specialty exam; and to provide a venue for peer support and mentorship. Elements of an effective AHD include the repetition of key concepts; formative assessments such as quizzes, a suitable balance of faculty input and resident active participation, and protection from clinical duty during AHD. Regarding the sustainability of AHD, themes included: addressing barriers to faculty participation, providing administrative support for logistical needs, and providing feedback to faculty. Conclusions: This work provides important insights into the purpose, effectiveness, and sustainability of AHDs for those who design and implement classroom learning for residents.

Pharmacokinetics, Safety, and Tolerability of Imipenem/Cilastatin/Relebactam in Children with Confirmed or Suspected Gram-Negative Bacterial Infections: A Phase 1b, Open-Label, Single-Dose Clinical Trial.

Imipenem/cilastatin/relebactam is approved for the treatment of serious gram-negative bacterial infections in adults. This study assessed the pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (with a fixed 2:1 ratio of imipenem/cilastatin to relebactam, and with a maximum dose of 15 mg/kg imipenem and 15 mg/kg cilastatin [≤500 mg imipenem and ≤500 mg cilastatin] and 7.5 mg/kg relebactam [≤250 mg relebactam]) in children with confirmed/suspected gram-negative bacterial infections receiving standard-of-care antibacterial therapy. In this phase 1, noncomparative study (ClinicalTrials.gov identifier, NCT03230916), PK parameters from 46 children were analyzed using both population modeling and noncompartmental analysis. The PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%fT>MIC) of ≥30% (MIC = 2 mcg/mL). For relebactam, the PK/PD target was a free drug area under the plasma concentration-time curve (AUC) normalized to MIC (at 2 mcg/mL) of ≥8.0 (equivalent to an AUC from time zero extrapolated to infinity of ≥20.52 mcg·h/mL). Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges for the geometric mean %fT>MIC and maximum concentration (Cmax ) across age cohorts were 56.5%-93.7% and 32.2-38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean Cmax and AUC from 0 to 6 hours across age cohorts were 16.9-21.3 mcg/mL and 26.1-55.3 mcg·h/mL, respectively. In total, 8/46 (17%) children experienced ≥1 adverse events (AEs) and 2/46 (4%) children experienced nonserious AEs that were deemed drug related by the investigator. Imipenem and relebactam exceeded plasma PK/PD targets; single doses of imipenem/cilastatin/relebactam were well tolerated with no significant safety concerns identified. These results informed imipenem/cilastatin/relebactam dose selection for further pediatric clinical evaluation.

Telehealth use and perceptions among prostate cancer survivors.

BACKGROUND: Reasons underlying disparities in telehealth use among cancer survivors are unknown. METHODS: We surveyed a sociodemographically diverse population-based cohort of 487 prostate cancer survivors regarding their use and perceptions of telehealth during the COVID-19 pandemic. RESULTS: Overall, only 28.5% of survivors had used telehealth at the time of survey and just 10% felt care through telehealth is comparable to that of an in-person visit. Still, over 55% felt telehealth is a good option for initial consultations or basic care and 15% felt more likely to use telehealth since the pandemic. After adjusting for other socioeconomic factors, survivors with lower education (≤high school vs. any college) had marginally lower use of telehealth (risk ratio [RR], 0.65 [95% CI, 0.42-1.01]) and lower probability of feeling more likely to use telehealth since the pandemic (RR, 0.39 [95% CI, 0.20-0.77]). CONCLUSIONS: Differences in survivor perceptions of telehealth by education level highlight new insights underlying disparities in telehealth use and potential targets for interventions.

Participant- and Disease-Related Factors as Independent Predictors of Treatment Outcomes in the RESTORE-IMI 2 Clinical Trial: A Multivariable Regression Analysis.

Background: In the RESTORE-IMI 2 trial, imipenem/cilastatin/relebactam (IMI/REL) was noninferior to piperacillin/tazobactam in treating hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. This post hoc analysis was conducted to determine independent predictors of efficacy outcomes in the RESTORE-IMI 2 trial, to assist in treatment decision making. Methods: A stepwise multivariable regression analysis was conducted to identify variables that were independently associated with day 28 all-cause mortality (ACM), favorable clinical response at early follow-up (EFU), and favorable microbiologic response at end of treatment (EOT). The analysis accounted for the number of baseline infecting pathogens and in vitro susceptibility to randomized treatment. Results: Vasopressor use, renal impairment, bacteremia at baseline, and Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II scores ≥15 were associated with a greater risk of day 28 ACM. A favorable clinical response at EFU was associated with normal renal function, an APACHE II score <15, no vasopressor use, and no bacteremia at baseline. At EOT, a favorable microbiologic response was associated with IMI/REL treatment, normal renal function, no vasopressor use, nonventilated pneumonia at baseline, intensive care unit admission at randomization, monomicrobial infections at baseline, and absence of Acinetobacter calcoaceticus-baumannii complex at baseline. These factors remained significant after accounting for polymicrobial infection and in vitro susceptibility to assigned treatment. Conclusions: This analysis, which accounted for baseline pathogen susceptibility, validated well-recognized patient- and disease-related factors as independent predictors of clinical outcomes. These results lend further support to the noninferiority of IMI/REL to piperacillin/tazobactam and suggests that pathogen eradication may be more likely with IMI/REL. Clinical Trials Registration: NCT02493764.

Academic half days, noon conferences and classroom-based education in postgraduate medical education: a scoping review.

BACKGROUND: Classroom-based education (CBE) is ubiquitous in postgraduate medical education (PGME), but to date no studies have synthesized the literature on the topic. We conducted a scoping review focusing on academic half days and noon conferences. METHODS: We searched 4 databases (MEDLINE [OVID], Embase [OVID], ERIC [EBSCO] and Web of Science) from inception to December 2021, performed reference and citation harvesting, and applied predetermined inclusion and exclusion criteria to our screening. We used 2 frameworks for the analysis: "experiences, trajectories and reifications" and "description, justification and clarification." RESULTS: We included 90 studies, of which 55 focused on resident experiences, 29 on trajectories and 6 on reification. We classified 44 studies as "description," 38 as "justification" and 8 as "clarification." In the description studies, 12 compared academic half days with noon conferences, 23 described specific teaching topics, and 9 focused on resources needed for CBE. Justification studies examined the effects of CBE on outcomes, such as examination scores (17) and use of teaching strategies in team-based learning, principles of adult learning and e-learning (15). Of the 8 clarification studies, topics included the role of CBE in PGME, stakeholder perspectives and transfer of knowledge between classroom and workplace. INTERPRETATION: Much of the existing literature is either a description of various aspects of CBE or justification of particular teaching strategies. Few studies exist on how and why CBE works; future studies should aim to clarify how CBE facilitates resident learning within the sociocultural framework of PGME.

Imipenem/cilastatin/relebactam efficacy, safety and probability of target attainment in adults with hospital-acquired or ventilator-associated bacterial pneumonia among patients with baseline renal impairment, normal renal function, and augmented renal clearance.

Objectives: To assess the relationship between renal function and efficacy/safety of imipenem/cilastatin/relebactam for the treatment of hospital-acquired/ventilator-associated pneumonia (HABP/VABP) from RESTORE-IMI 2 and determine the PTA. Methods: Adults with HABP/VABP were randomized 1:1 to IV imipenem/cilastatin/relebactam 1.25 g or piperacillin/tazobactam 4.5 g every 6 h for 7-14 days. Initial doses were selected by CLCR and adjusted thereafter, as appropriate. Outcomes included Day 28 all-cause mortality (ACM), clinical response, microbiological response and adverse events. Population pharmacokinetic modelling and Monte Carlo simulations assessed PTA. Results: The modified ITT population comprised those with normal renal function (n = 188), augmented renal clearance (ARC; n = 88), mild renal impairment (RI; n = 124), moderate RI (n = 109) and severe RI (n = 22). ACM rates were comparable between treatment arms among all baseline renal function categories. Clinical response rates were comparable between treatment arms for participants with RI and normal renal function but were higher (91.7% versus 44.4%) for imipenem/cilastatin/relebactam-treated versus piperacillin/tazobactam-treated participants with CLCR ≥250 mL/min (n = 21). Microbiologic response rates were comparable between treatment arms for participants with RI but higher among those treated with imipenem/cilastatin/relebactam in participants with CLCR ≥90 mL/min (86.6% versus 67.2%). Adverse events were comparable between treatment arms across renal function categories. Joint PTA was >98% for key pathogen MICs for susceptible pathogens (MIC ≤2 mg/L). Conclusions: Prescribing information-defined dose adjustments in participants with baseline RI and full dosing of imipenem/cilastatin/relebactam 1.25 g every 6 h for participants with normal renal function or augmented renal clearance achieved sufficiently high drug exposures and favourable safety and efficacy profiles.

VEXAS syndrome: A review of bone marrow aspirate and biopsies reporting myeloid and erythroid precursor vacuolation.

Myeloid and erythroid precursor vacuolation is a common dysplastic finding associated with myeloid malignancies, toxins, drug, and nutritional deficiencies. It has been described as a core morphologic feature in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. We sought to determine the number of cases attributable to VEXAS syndrome in bone marrow biopsies and aspirates (BAMB) reporting myeloid precursor vacuolation. We reviewed 1318 individual BAMB reports from January 2020 to July 2021 where "vacuole(s)," "vacuolation," or "vacuolated" was reported. Bone marrow biopsies with vacuolation confined to blasts or those completed as routine workup prior to stem cell transplant or post induction chemotherapy for AML (acute myeloid leukemia) were excluded. Myeloid and erythroid precursor vacuolation was noted in 219 reports representing 210 patients. The most common etiology was myelodysplastic syndrome (MDS) (38.6%), AML (16.7%), lymphoproliferative disorders and multiple myeloma (7.6%), drug or toxin exposure (5.2%) myeloproliferative neoplasm (MPN) or MPN/MDS overlap syndrome (4.3%). VEXAS syndrome was determined to be the etiology in 2.9% of patients. Two additional cases of VEXAS syndrome with bone marrow biopsies reported in the specified time frame did not explicitly report myeloid or erythroid precursor vacuolation but were identified based on clinical suspicion and repeat BAMB review. Myeloid and erythroid precursor vacuolation is a dysplastic feature attributable to VEXAS syndrome in at least 2.9% of cases. Standardized reporting of vacuolization, triaging of molecular sequencing and optimal treatment of this disorder are critical issues facing those seeing patients with suspected VEXAS syndrome.

Permeate Flux Enhancement in Air Gap Membrane Distillation Modules with Inserting Λ-Ribs Carbon-Fiber Open Slots.

A novel design of an air gap membrane distillation (AGMD) module was proposed to enhance the permeate flux improvement for the desalination of pure water productivity. The modeling equations for predicting permeate flux in the AGMD module by inserting Λ-ribs carbon-fiber open slots under various hydrodynamic angles were developed theoretically and experimentally. The temperature distributions of both hot and cold feed streams were represented graphically with the hot saline flow rate, inlet saline temperature, and carbon-fiber hydrodynamic angles as parameters. The results showed a good agreement between the experimental results and theoretical predictions. Designed by inserting Λ-ribs carbon-fiber open slots into the flow channel, the membrane distillation module was implemented to act as an eddy promoter and yield an augmented turbulence flow. The effect of Λ-ribs carbon-fiber open slots not only assured the membrane stability by preventing vibration but also increased the permeate flux by diminishing the temperature polarization of the thermal boundary layer. The permeate flux improvement by inserting Λ-ribs carbon-fiber open slots in the AGMD module provided the maximum relative increment of up to 15.6% due to the diminution of the concentration polarization effect. The experimental data was incorporated with the hydrodynamic angle of Λ-ribs carbon-fiber open slots to correlate the enhancement factor with the Nusselt numbers to confirm the theoretical predictions. The accuracy derivation between the experimental results and theoretical predictions was pretty good, within 9.95≤E≤1.85. The effects of operating and designing parameters of hot saline flow rate, inlet saline temperature, and hydrodynamic angle on the permeate flux were also delineated by considering both the power consumption increment and permeate flux enhancement.

A young woman with persistent sore throat, Epstein-Barr virus, lymphadenopathy, and aberrant CD4 + CD7- T-cells.

A young woman with persistent EBV viremia and lymphocytosis had an abnormal CD4- T cell population with aberrant loss of CD7. She had a diagnosis of chronic active EBV (CAEBV), a lymphoproliferative disorder for which she ultimately required allogeneic hematopoietic stem cell transplantation.

Progressive loss of hearing and balance in superficial siderosis due to occult spinal dural defects.

PURPOSE: Superficial siderosis, a progressive, debilitating, neurological disease, often presents with bilateral impairment of auditory and vestibular function. We highlight that superficial siderosis is often due to a repairable spinal dural defect of the type that can also cause spontaneous intracranial hypotension. METHODS: Retrospective chart review of five patients presenting with moderate to severe, progressive bilateral sensorineural hearing loss as well as vestibular loss. All patients had developed superficial siderosis from spinal dural defects: three after trauma, one after spinal surgery and one from a thoracic discogenic microspur. RESULTS: The diagnosis was made late in all five patients; despite surgical repair in four, hearing and vestibular loss failed to improve. CONCLUSIONS: In patients presenting with progressive bilateral sensorineural hearing loss, superficial siderosis should be considered as a possible cause. If these patients also have bilateral vestibular loss, cerebellar impairment and anosmia, then the diagnosis is likely and the inevitable disease progress might be halted by finding and repairing the spinal dural defect.