Multiple Ion Charge Extraction (MICE) for High-Throughput Charge Detection Mass Spectrometry.

Charge detection mass spectrometry (CD-MS) is a single-particle technique, where the masses of individual ions are determined from simultaneous measurements of their mass-to-charge ratio (m/z) and charge. The ions are trapped in an electrostatic linear ion trap (ELIT) and oscillate back and forth through a conducting cylinder connected to a charge-sensitive amplifier. The oscillating ions generate a periodic signal that is processed with fast Fourier transforms (FFTs) to obtain the oscillation frequency (which is related to m/z) and magnitude (which is proportional to the charge). The simultaneous trapping of two or more ions is a way to increase throughput. However, when multiple ions are trapped, it is possible that some of them have overlapping oscillation frequencies, which can lead to an error in the charge determination. To avoid this error, results from overlapping ions are usually discarded. When measurements are performed with many trapped ions, the most abundant m/z species are discarded at a higher rate, which affects the relative abundances in the mass distribution. Here, we report the development of a post-processing method called multiple ion charge extraction (MICE) that uses a statistical approach to assign charges to ions with overlapping frequencies. MICE recovers single-ion information from high signal measurements and makes the relative abundances more resilient to the signal intensity. This approach corrects for high signal m/z biasing, allowing analysis to be faster and more reliable. Using MICE, CD-MS measurements were made at rates of 120 ions/s with little m/z biasing.

Severe pulmonary hypertension-interstitial lung disease presenting as right ventricular failure: stabilisation with intravenous prostacyclin and maintenance with inhaled prostacyclin.

Background: Pulmonary hypertension (PH) leads to increased morbidity and mortality in interstitial lung disease (ILD). While the INCREASE trial highlighted the use of inhaled prostacyclin in PH-ILD patients, such therapy may be inadequate when right ventricular failure (RVF) is also present. In this study, we report the use of intravenous prostacyclin in three PH-ILD patients to stabilise right ventricular (RV) function, with a subsequent transition to maintenance therapy with inhaled prostacyclin. Methods: We evaluated three consecutive PH-ILD patients with RVF. RV afterload and pulmonary vascular resistance (PVR) were treated with intravenous prostacyclin during the induction phase of the therapy. Patients transitioned from intravenous prostacyclin to the maintenance phase of the treatment with inhaled prostacyclin once three transition criteria were met: cardiac index (CI) >2 L·min-1·m-2, PVR <7 Wood units (WU) and tricuspid annular plane systolic excursion (TAPSE) change >1 mm or TAPSE >1.6 cm. Results: Pre-treatment parameters for the three patients were a mean PVR of 14.3 WU, a mean Fick CI of 1.8 L·min-1·m-2 and a mean TAPSE of 1.4 cm. The average intravenous prostacyclin dose at the time of transition to maintenance therapy was 20.7 ng·kg-1·m-2 of treprostinil. At 3-months follow-up, the mean PVR was 6.3 WU, Fick CI 2.2 L·min-1·m-2 and TAPSE 1.7 cm. Conclusion: This case series of three PH-ILD patients with RVF introduces the concept of an initial intravenous prostacyclin induction phase, followed by a transition to maintenance therapy with inhaled prostacyclin. Further development of this treatment algorithm with a refinement of the transition criteria, potential testing in a clinical trial and a longer-term follow-up period is warranted to improve the outcomes of advanced PH-ILD patients with concomitant RVF.

Assessing the optimal MAP target in pre-capillary PH patients with RV failure: A retrospective analysis.

Right ventricular failure (RVF) in pre-capillary pulmonary hypertension (PH) is associated with high morbidity and mortality. While mean arterial pressure (MAP) goals have been well established in critical care literature, the optimal MAP target for patients with RVF secondary to pre-capillary PH remains unknown. The objective of this study was to evaluate the difference in outcomes between patients who were managed with different MAP targets. We retrospectively analyzed records of 60 patients who were admitted to the intensive care unit for decompensated RVF secondary to pre-capillary PH. The records were stratified into two groups: 30 patients who were treated with a static MAP goal of either 65 or 70 mmHg (MAP65/70) and 30 patients who received a dynamic MAP goal (MAPCVP) determined by invasively obtained central venous pressure or right atrial pressure. The dynamic MAP group had a statistically significant decrease in in-hospital mortality and incidence of acute kidney injury compared to the static MAP cohort.

The PH-ILD Detection tool: External validation and use in patients with ILD.

Pulmonary hypertension (PH) results in increased morbidity and mortality in patients with interstitial lung disease (ILD). Early recognition of PH in this population is essential for planning diagnostic testing, initiating therapy, and evaluating for lung transplantation. The previously developed PH-ILD Detection tool has significant potential in the evaluation and treatment of ILD patients; the aim of this study was to validate the tool in an independent, multicenter cohort of patients. We conducted a retrospective review of prospectively collected data from 161 ILD patients. Patients were stratified into low- (n = 78, 48.4%), intermediate- (n = 54, 33.5%), and high-risk (n = 29, 18.0%) groups based on the score obtained with the tool. Intermediate- and high-risk patients underwent follow-up echocardiogram (TTE); 49.4% (n = 41) had an abnormal TTE suggestive of underlying PH. These patients underwent right heart catheterization; PH-ILD was diagnosed in 73.2% (n = 30) of these cases. The PH-ILD Detection tool has a sensitivity of 93.3%, specificity of 90.9%, and area-under-the-curve of 0.921 for diagnosing PH in ILD patients, validating the findings from the original study and establishing the tool as a fundamental resource for early recognition of PH in ILD patients.

Should Virtual Objective Structured Clinical Examination (OSCE) Teaching Replace or Complement Face-to-Face Teaching in the Post-COVID-19 Educational Environment: An Evaluation of an Innovative National COVID-19 Teaching Programme.

Background The COVID-19 pandemic brought about drastic changes to medical education and examinations, with a shift to online lectures and webinars. Additionally, social restrictions in the United Kingdom (UK) inhibited students' ability to practice for objective structured clinical examination (OSCE) with their peers. Methods The Virtual OSCE buddy scheme (VOBS) provided a means to practice OSCE skills virtually by linking groups of 2-6 final-year medical students with a junior doctor who had recently passed their exams. Sessions were held virtually, tailored to the needs of each group, in a 3-month period prior to examinations. The scheme ran across two examination periods, 2020/21 and 2021/22, including a total of 13 universities throughout the UK. Results In 2020/21, 96% (n=227) of students described improved confidence in OSCE scenarios. Furthermore, 90% (n=213) reported improvement in communication, 89% (n=211) in diagnosis and clinical reasoning and 86% (n=203) in history-taking skills. Examination and procedural skills proved more challenging to practice virtually, with improvement reported by 31% (n=73) and 15% (n=36) of students, respectively. Ninety-three per cent (n=58) of buddies reported improved lesson planning abilities and 90% (n=57) felt more confident in their teaching. In 2021/22, 90% (n=133) of students felt more prepared for their OSCE. In key skills, improvement was reported by 87% (n=128) in communication, 84% (n=124) in diagnosis and clinical reasoning and 83% (n=123) in history-taking. In this cohort, 40% (n=59) reported improvement in examination skills and 24% (n=36) in procedural skills. Ninety per cent (n=83) of buddies reported an improvement in teaching skills, with 93% (n=85) increasing their confidence to teach. Conclusion VOBS demonstrates the benefits to students and teachers of near-peer OSCE teaching. Given the virtual nature, the main drawback is the inability to practice hands-on examination and procedural skills. This scheme provides insight to educators planning virtual teaching programmes in the future. With the evolution of technology, virtual examination and procedure practice may be possible in the near future. VOBS would suggest that currently, virtual OSCE teaching should be used to complement face-to-face teaching.

Pulmonary hypertension in patients with interstitial lung disease: a tool for early detection.

Pulmonary hypertension (PH) complicates the treatment of interstitial lung disease (ILD) patients resulting in poor functional status and worse outcomes. Early recognition of PH in ILD is important for initiating therapy and considering lung transplantation. However, no standard exists regarding which patients to screen for PH-ILD or the optimal method to do so. The aim of this study was to create a risk assessment tool that could reliably predict PH in ILD patients. We developed a PH-ILD Detection tool that incorporated history, exam, 6-min walk distance, diffusion capacity for carbon monoxide, chest imaging, and cardiac biomarkers to create an eight-component score. This tool was analyzed retrospectively in 154 ILD patients where each patient was given a score ranging from 0 to 12. The sensitivity (SN) and specificity (SP) of the PH-ILD Detection tool and an area-under-the-curve (AUC) were calculated. In this cohort, 74 patients (48.1%) had PH-ILD. A score of ≥6 on the PH-ILD Detection tool was associated with a diagnosis of PH-ILD (SN: 86.5%; SP: 86.3%; area-under-the-curve: 0.920, p < 0.001). The PH-ILD Detection tool provides high SN and SP for detecting PH in ILD patients. With confirmation in larger cohorts, this tool could improve the diagnosis of PH in ILD and may suggest further testing with right heart catheterization and earlier intervention with inhaled treprostinil and/or lung transplant evaluation.

Epoprostenol-associated ascites in pulmonary arterial hypertension.

The development of ascites in pulmonary arterial hypertension (PAH) in the absence of pre-existing hepatic dysfunction is usually associated with decompensated right heart failure or cardiac cirrhosis. Ascites in PAH has rarely been associated with intravenous epoprostenol, a synthetic form of the prostaglandin PGI2.

COVID-19: A Curious Abettor in the Occurrence of Stevens-Johnson Syndrome.

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are immune-mediated life-threatening skin diseases. The condition is known to be caused by various infections, drugs (mainly antibiotics), or can be idiopathic. Amidst the novel coronavirus 2019 (COVID-19) pandemic, there is an increasing number of SJS/TEN cases being reported. Viral infections are known to have decreased the threshold of drug reactions by inducing a pro-inflammatory state in the body. We report a case of TEN secondary to tamsulosin use in the setting of COVID-19 infection. There is only one documented case of tamsulosin-induced SJS, and no documented case of TEN secondary to tamsulosin use. Our patient was a 26-year-old male who presented to the hospital after a recent history of COVID-19 infection with a diffuse maculo-vesicular rash with bullae, involving the mucosa. The patient had recent use of tamsulosin on the day of presentation and there were bullae and erythematous rashes present in the oral mucosa as well as significant conjunctival erythema with pain on ocular movement on physical examination. His rash progressively worsened, involving greater than 30% of his body. A biopsy was done that showed full-thickness necrosis indicative of toxic epidermal necrolysis (TEN). We hypothesize that in our patient COVID-19 infections lowered the threshold for the development of SJS/TEN.

Predictors to forgo resuscitative effort during Covid-19 critical illness at the height of the pandemic : A retrospective cohort study.

BACKGROUND: Early in the Covid-19 pandemic, there was uncertainty regarding critical illness prognosis and challenges to traditional face-to-face family meetings. Ethnic minority populations have suffered disproportionately worse outcomes during the pandemic, which may in part relate to differences in end-of-life decision-making. AIM: Characterize patterns of and factors associated with decisions to forgo resuscitative efforts, as measured by do-not-resuscitate orders, during critical illness with Covid-19. DESIGN: Retrospective cohort with medical record abstraction. SETTING/PARTICIPANTS: Adult patients diagnosed with SARS-Cov-2 virus via polymerase chain reaction and admitted to the intensive care unit at an academic hospital, which cares for the city's underserved communities, between March 1 and June 7, 2020 who underwent invasive mechanical ventilation for at least 48 hours. RESULTS: In this cohort (n = 155), 45% were black people, and 51% spoke English as their primary language. Median time to first goals-of-care conversation was 3.9 days (IQR 1.9-7.6) after intensive care unit admission. Overall 61/155 patients (39%) transitioned to do-not-resuscitate status, and 50/62 (82%) patients who died had do-not-resuscitate orders. Multivariate analysis shows age and palliative care involvement as the strongest predictors of decision to instate do-not-resuscitate order. There was no association between race, ethnicity, or language and decisions to forego resuscitation. CONCLUSIONS: During this time of crisis and uncertainty with limited resources and strained communication, time to first goals of care conversation was shorter than in pre-pandemic studies, but rates of foregoing resuscitation remained similar, with no differences observed by race, ethnicity, or language. This study suggests that early palliative care involvement and non-traditional communications, including videoconferencing, to facilitate goals of care conversations could have mitigated potential disparities in end-of-life decision making patterns during the pandemic.

Exploring Machine Teaching with Children.

Iteratively building and testing machine learning models can help children develop creativity, flexibility, and comfort with machine learning and artificial intelligence. We explore how children use machine teaching interfaces with a team of 14 children (aged 7-13 years) and adult co-designers. Children trained image classifiers and tested each other's models for robustness. Our study illuminates how children reason about ML concepts, offering these insights for designing machine teaching experiences for children: (i) ML metrics (e.g. confidence scores) should be visible for experimentation; (ii) ML activities should enable children to exchange models for promoting reflection and pattern recognition; and (iii) the interface should allow quick data inspection (e.g. images vs. gestures).

ICU outcomes in Covid-19 patients with obesity.

The reviews of this paper are available via the supplemental material section.

E-cigarette, or vaping, product use-associated lung injury: a review.

BACKGROUND: E-cigarette, or Vaping, Product Use-Associated Lung Injury (EVALI) is a disease entity related to the use of battery-operated or superheating devices that create an aerosolized form of nicotine and tetrahydrocannabinol (THC) and/or other substances for inhalation. METHODS: We performed a literature review to document epidemiology, pathogenesis and risk factors, diagnosis, clinical presentation, evaluation and management of EVALI. RESULTS: In the summer of 2019, an outbreak of EVALI cases brought this disease entity into the national spotlight. Since being recognized as a serious pulmonary disease with public health implications, more than 2600 cases have been reported to CDC with 68 deaths as of February 2020. The pathophysiology of EVALI remains unknown. Substances such as Vitamin E acetate have been implicated as a possible causes of lung injury. The CDC has established case definitions of "confirmed EVALI" cases to help guide identification of the disease and assist in surveillance. While clinical judgement by healthcare providers is imperative in the identification of EVALI cases, the heterogeneous presentations of EVALI make this difficult as well. Ultimately most investigative studies should be aimed at ruling out other disease processes that can present similarly. Treatment is centered around removing the offending substance and providing supportive care. CONCLUSIONS: EVALI is a serious pulmonary disease with public health implications. Diagnosis requires a high degree of suspicion to diagnose and exclusion of other possible causes of lung disease. It may be beneficial to involve a pulmonary specialist early in the management of this disease which is generally supportive care.

Assessing the Respiratory Effects of Air Pollution from Biomass Cookstoves on Pregnant Women in Rural India.

BACKGROUND: In India, biomass fuel is burned in many homes under inefficient conditions, leading to a complex milieu of particulate matter and environmental toxins known as household air pollution (HAP). Pregnant women are particularly vulnerable as they and their fetus may suffer from adverse consequences of HAP. Fractional exhaled nitric oxide (FeNO) is a noninvasive, underutilized tool that can serve as a surrogate for airway inflammation. We evaluated the prevalence of respiratory illness, using pulmonary questionnaires and FeNO measurements, among pregnant women in rural India who utilize biomass fuel as a source of energy within their home. METHODS: We prospectively studied 60 pregnant women in their 1st and 2nd trimester residing in villages near Nagpur, Central India. We measured FeNO levels in parts per billion (ppb), St. George's Respiratory Questionnaire (SGRQ-C) scores, and the Modified Medical Research Council (mMRC) Dyspnea Scale. We evaluated the difference in the outcome distributions between women using biomass fuels and those using liquefied petroleum gas (LPG) using two-tailed t-tests. RESULTS: Sixty-five subjects (32 in Biomass households; 28 in LPG households; 5 unable to complete) were enrolled in the study. Age, education level, and second-hand smoke exposure were comparable between both groups. FeNO levels were higher in the Biomass vs. LPG group (25.4 ppb vs. 8.6 ppb; p-value = 0.001). There was a difference in mean composite SGRQ-C score (27.1 Biomass vs. 10.8 LPG; p-value < 0.001) including three subtotal scores for Symptoms (47.0 Biomass vs. 20.2 LPG; p-value< 0.001), Activity (36.4 Biomass vs. 16.5 LPG; p-value < 0.001) and Impact (15.9 Biomass vs. 5.2 LPG; p-value < 0.001). The mMRC Dyspnea Scale was higher in the Biomass vs. LPG group as well (2.9 vs. 0.5; p < 0.001). CONCLUSION: Increased FeNO levels and higher dyspnea scores in biomass-fuel-exposed subjects confirm the adverse respiratory effects of this exposure during pregnancy. More so, FeNO may be a useful, noninvasive biomarker of inflammation that can help better understand the physiologic effects of biomass smoke on pregnant women. In the future, larger studies are needed to characterize the utility of FeNO in a population exposed to HAP.

Use of ultrasound-measured internal jugular vein collapsibility index to determine static intracardiac pressures in patients with presumed pulmonary hypertension.

BACKGROUND: Bedside ultrasound helps to estimate volume status in critically ill patients and has traditionally relied on diameter, respiratory variation, and collapsibility of the inferior vena cava (IVC) to reflect fluid status. We evaluated collapsibility of the internal jugular vein (IJ) with ultrasound and correlated it with concomitant right heart catheterization (RHC) measurements in patients with presumed pulmonary hypertension. METHODS AND RESULTS: We studied 71 patients undergoing RHC for evaluation of pulmonary hypertension. Using two-dimensional ultrasound (Sonosite, Washington, USA), we measured the diameter of the IJ at rest, during respiratory variation, and during manual compression. Collapsibility index during respiration (respiratory CI) and during manual compression (compression CI) was calculated. We correlated mean right atrial pressure (mRAP) and pulmonary artery occlusion pressure (PAOP) defined by RHC measurements with respiratory and compression CI. A secondary goal was examining correlations between CI calculations and B-type natriuretic peptide (BNP) levels. Baseline characteristics demonstrated female predominance (n = 51; 71.8%), mean age 59.5 years, and BMI 27.3. There were significant correlations between decrease in compression CI and increase in both mRAP (Spearman: - 0.43; p value = 0.0002) and PAOP (Spearman: - 0.35; p value = 0.0027). In contrast, there was no significant correlation between respiratory CI and either mRAP (Spearman: - 0.14; p value = 0.35) or PAOP (Spearman:- 0.12; p value = 0.31). We also observed significant negative correlation between compression CI and BNP (Spearman: - 0.31; p value = 0.01) but not between respiratory CI and BNP (Spearman: - 0.12; p value = 0.35). CONCLUSION: Increasing use of ultrasound has led to innovative techniques for estimating volume status. While prior ultrasound studies have used clinical parameters to estimate fluid status, our study used RHC measurements and demonstrated that compression CI potentially reflects directly measured mRAP and PAOP.

Barriers to frostbite treatment at an academic medical center.

The treatment of frostbite injuries has undergone a radical change over the past decade with a shift from supportive therapy and observation towards early and aggressive medical intervention with thrombolytics and vasodilators. Institutions that have implemented evidence-based protocols have significantly decreased their amputation rates (Bruen et al., 2007; Lindford et al., 2017a; Twomey et al., 2005). We present the case of a middle-aged male treated for frostbite of multiple fingers on both hands. Because there was no treatment protocol at our institution, there were multiple delays in the patient's care including imaging and initiation of intravenous (IV) prostanoids. This case illustrates the deleterious effects of delays in treatment and strongly suggests that all facilities located in areas of cold exposure should have protocols in place for such an occurrence.