Inhibition of lysine acetyltransferase KAT6 in ER+HER2- metastatic breast cancer: a phase 1 trial.

Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER+) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER+ human epidermal growth factor receptor-negative (HER2-) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3-4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144-fulvestrant combination (n = 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2-46.1%) and the median PFS was 10.7 (5.3-not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER+HER2- mBC. These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration: NCT04606446 .

The ADnet Bayesian belief network for alder decline: Integrating empirical data and expert knowledge.

The globalization in plant material trading has caused the emergence of invasive pests in many ecosystems, such as the alder pathogen Phytophthora ×alni in European riparian forests. Due to the ecological importance of alder to the functioning of rivers and the increasing incidence of P. ×alni-induced alder decline, effective and accessible decision tools are required to help managers and stakeholders control the disease. This study proposes a Bayesian belief network methodology to integrate diverse information on the factors affecting the survival and infection ability of P. ×alni in riparian habitats to help predict and manage disease incidence. The resulting Alder Decline Network (ADnet) management tool integrates information about alder decline from scientific literature, expert knowledge and empirical data. Expert knowledge was gathered through elicitation techniques that included 19 experts from 12 institutions and 8 countries. An original dataset was created covering 1189 European locations, from which P. ×alni occurrence was modeled based on bioclimatic variables. ADnet uncertainty was evaluated through its sensitivity to changes in states and three scenario analyses. The ADnet tool indicated that mild temperatures and high precipitation are key factors favoring pathogen survival. Flood timing, water velocity, and soil type have the strongest influence on disease incidence. ADnet can support ecosystem management decisions and knowledge transfer to address P. ×alni-induced alder decline at local or regional levels across Europe. Management actions such as avoiding the planting of potentially infected trees or removing man-made structures that increase the flooding period in disease-affected sites could decrease the incidence of alder disease in riparian forests and limit its spread. The coverage of the ADnet tool can be expanded by updating data on the pathogen's occurrence, particularly from its distributional limits. Research on the role of genetic variability in alder susceptibility and pathogen virulence may also help improve future ADnet versions.

Fear in general populations: A cross-sectional study on perceived fear of common diseases, COVID-19, life events, and environmental threats in 30 countries.

Background: In this study, we assessed the general population's fears towards various diseases and events, aiming to inform public health strategies that balance health-seeking behaviours. Methods: We surveyed adults from 30 countries across all World Health Organization (WHO) regions between July 2020 and August 2021. Participants rated their fear of 11 factors on an 11-point Likert scale. We stratified the data by age and gender and examined variations across countries and regions through multidimensional preference analysis. Results: Of the 16 512 adult participants, 62.7% (n = 10 351) were women. The most feared factor was the loss of family members, reported by 4232 participants (25.9%), followed by cancer (n = 2248, 13.7%) and stroke (n = 1416, 8.7%). The highest weighted fear scores were for loss of family members (mean (x̄) = 7.46, standard deviation (SD) = 3.04), cancer (x̄ = 7.00, SD = 3.09), and stroke (x̄ = 6.61, SD = 3.24). The least feared factors included animals/insects (x̄ = 3.72, SD = 2.96), loss of a mobile phone (x̄ = 4.27, SD = 2.98), and social isolation (x̄ = 4.83, SD = 3.13). Coronavirus disease 2019 (COVID-19) was the sixth most feared factor (x̄ = 6.23, SD = 2.92). Multidimensional preference analyses showed distinct fears of COVID-19 and job loss in Australia and Burundi. The other countries primarily feared loss of family members, cancer, stroke, and heart attacks; this ranking was consistent across WHO regions, economic levels, and COVID-19 severity levels. Conclusions: Fear of family loss can improve public health messaging, highlighting the need for bereavement support and the prevention of early death-causing diseases. Addressing cancer fears is crucial to encouraging the use of preventive services. Fear of non-communicable diseases remains high during health emergencies. Top fears require more resources and countries with similar concerns should collaborate internationally for effective fear management.

Internet Gaming Disorder and the Incidence of Suicide-Related Ideation and Behaviors in College Students.

OBJECTIVES: The longitudinal associations between DSM-5 Internet Gaming Disorder (IGD) and suicide-related ideation and behaviors have not been explored. In this study, we therefore seek to examine the association between baseline IGD and incident suicide ideation, plans, and attempts. METHODS: This is a prospective cohort study of 2586 Mexican college students followed up from September 2018 to June 2022. We estimated hazards ratios modeling incidence of suicide ideation, plans, and attempts by fitting proportional hazards Cox models with person-time scaled in years. RESULTS: Among 2140 students without suicide ideation at baseline, there were 467 incident cases in 3987.6 person-years; ideation incidence rates were 179 cases per 1000 person-years among students with IGD and 114 cases per 1000 person-years among those without IGD. Incidence rates for suicide plans were 67 and 39 per 1000 among IGD and non-IGD students, and 15 and 10 per 1000, respectively for attempts. After controlling for age, sex, and mood, anxiety, and substance use disorders, IGD was associated with an 83% increased risk of suicide ideation. Although incidence rate estimates for plans and attempts were higher among students with IGD, results were not statistically significant. CONCLUSIONS: This study helps to raise awareness of the increased risk of at least suicidal ideation in people experiencing IGD. Clinicians treating patients with IGD may encounter complaints of suicide ideation over time, and even reports of suicidal behavior that should not be disregarded. Identifying these patients and treating/referring them for underlying suicidality should form part of IGD treatment.

Photobiomodulation Therapy in the Management of Late Complications After Facial Filling.

The aim of the present study is to report a clinical case of a patient diagnosed with a late adverse reaction to the injection of filler material - persistent and intermittent delayed swelling (PIDS) - in which photobiomodulation therapy (PBMT) with low-power laser was used for edema reduction. This is an observational, descriptive, and retrospective work of a case report. The female patient, aged 73 years old, had undergone dermal filler six years before and complained of increased volume in the face region (glabellar region, labiomental sulcus, and nasolabial folds) and was submitted to ultrasound and anatomopathological analysis. PBMT using a low-power laser (660 nm and 808 nm, simultaneous irradiation, in contact, 2 J/point, 100 mW) proved to be effective for the non-invasive approach of late adverse reaction to dermal filler, such as PIDS, a common complication related to the use of dermal fillers.

Emotional Distress and Physical Activity Engagement in U.S. Veterans With Chronic Obstructive Pulmonary Disease: A Qualitative Study.

BACKGROUND: Physical activity is recommended as part of guideline-based care for managing chronic obstructive pulmonary disease (COPD) at all stages of the disease. However, physical activity interventions are less effective in individuals with co-occurring emotional distress (i.e., depression and/or anxiety symptoms). Interventions that dually promote improved physical and mental health in COPD are needed. The first step for intervention development is understanding individuals' experience of these factors. PURPOSE: To understand the experience of emotional distress in U.S. Veterans diagnosed with COPD and to explore how emotional distress impacts physical activity engagement. METHODS: Structured interviews informed by the cognitive and behavioral models of psychopathology were conducted with 29 United States Veterans with COPD (89.66% male, age 67.72 ± 6.55 years, 93.10% White) at the VA Boston Healthcare System. Interviews were audio recorded, transcribed, and underwent thematic analysis. RESULTS: Three major themes encapsulating 17 codes emerged through thematic analysis: (i) the experience of emotional distress in Veterans with COPD; (ii) the complex relationship between emotional distress, physical activity engagement, and COPD; (iii) contextual and personal factors. CONCLUSIONS: Veterans' interpretation of their COPD symptoms as unpredictable and uncontrollable and COPD-related physical limitations influenced their experience of emotional distress, while the experience of emotional distress both promoted and deterred physical activity engagement. Veterans were motivated to engage in physical activity despite experiencing emotional distress when they faced a responsibility in daily life. They identified motivational strategies and self-regulation techniques to manage emotional distress and to foster physical activity.

Promoting physical activity is important for maintaining functioning in persons with chronic obstructive pulmonary disease (COPD), but physical activity interventions do not help all individuals. One reason may be the presence of co-occurring clinically significant depression and/or anxiety symptoms (i.e., emotional distress). Behavioral interventions that can address both physical activity and emotional distress at the same time are needed and may translate to improved outcomes. To inform intervention development, the current qualitative study explored the relationship between emotional distress and physical activity engagement, as well as contextual influencers (i.e., social support) in 29 U.S. Veterans with COPD and emotional distress. Participants completed a structured interview guided by the cognitive behavioral model of psychopathology. Three major themes encapsulating 17 codes emerged through thematic analysis: (i) the experience of emotional distress in Veterans with COPD; (ii) the complex relationship between emotional distress, physical activity engagement, and COPD; (iii) contextual and personal factors. The experience of emotional distress both promoted and deterred physical activity. Family, friends, and environmental factors (i.e., seasonal changes) impacted the experience of emotional distress and physical activity engagement. The findings inform intervention development that is patient-centered and dually address physical activity and emotional distress.

Opportunistic atrial fibrillation screening in primary care in Ireland: results of a pilot screening programme.

BACKGROUND: Atrial fibrillation (AF), a common, frequently asymptomatic cardiac arrhythmia, is a major risk factor for stroke. Identification of AF enables effective preventive treatment to be offered, potentially reducing stroke risk by up to two-thirds. There is international consensus that opportunistic AF screening is valuable though uncertainty remains about the optimum screening location and method. Primary care has been identified as a potential location for AF screening using one-lead ECG devices. METHODS: A pilot AF screening programme is in primary care in the south of Ireland. General practitioners (GPs) were recruited from Cork and Kerry. GPs invited patients ≥65 years to undergo AF screening. The screening comprised a one-lead ECG device, Kardia Mobile, blood pressure check and ascertainment of smoking status. Possible AF on one-lead ECG was confirmed with a 12-lead ECG. GPs also recorded information including medical history, current medication and onward referral. The Keele Decision Support tool was used to assess patients for oral anticoagulation (OAC). RESULTS: 3555 eligible patients, attending 52 GPs across 34 GP practices, agreed to undergo screening. 1720 (48%) were female, 1780 (50%) were hypertensive and 285 (8%) were current smokers. On the one-lead ECG, 3282 (92%) were in normal sinus rhythm, 101 (3%) had possible AF and among 124 (4%) the one-lead ECG was unreadable or unclassified. Of the 101 patients with possible AF, 45 (45%) had AF confirmed with 12-lead ECG, an incidence rate of AF of 1.3%. Among the 45 confirmed AF cases, 27 (60%) were commenced on OAC therapy by their GP. CONCLUSION: These findings suggest that AF screening in primary care may prove useful for early detection of AF cases that can be assessed for treatment. One-lead ECG devices may be useful in the detection of paroxysmal AF in this population and setting. Current OAC of AF may be suboptimal.

Electrophysiological responses to appetitive and consummatory behavior in the rostral nucleus tractus solitarius in awake, unrestrained rats.

As the intermediate nucleus in the brainstem receiving information from the tongue and transmitting information upstream, the rostral portion of the nucleus tractus solitarius (rNTS) is most often described as a "taste relay". Although recent evidence implicates the NTS in a broad neural circuit involved in regulating ingestion, there is little information about how cells in this structure respond when an animal is eating solid food. Here, single cells in the rNTS were recorded in awake, unrestrained rats as they explored and ate solid foods (Eating paradigm) chosen to correspond to the basic taste qualities: milk chocolate for sweet, salted peanuts for salty, Granny Smith apples for sour and broccoli for bitter. A subset of cells was also recorded as the animal licked exemplars of the five basic taste qualities: sucrose, NaCl, citric acid, quinine and MSG (Lick paradigm). Results showed that most cells were excited by exploration of a food-filled well, sometimes responding prior to contact with the food. In contrast, cells that were excited by food well exploration became significantly less active while the animal was eating the food. Most cells were broadly tuned across foods, and those cells that were recorded in both the Lick and Eating paradigms showed little correspondence in their tuning across paradigms. The preponderance of robust responses to the appetitive versus the consummatory phase of ingestion suggests that multimodal convergence onto cells in the rNTS may be used in decision making about ingestion.

Accelerated MRI reconstructions via variational network and feature domain learning.

We introduce three architecture modifications to enhance the performance of the end-to-end (E2E) variational network (VarNet) for undersampled MRI reconstructions. We first implemented the Feature VarNet, which propagates information throughout the cascades of the network in an N-channel feature-space instead of a 2-channel feature-space. Then, we add an attention layer that utilizes the spatial locations of Cartesian undersampling artifacts to further improve performance. Lastly, we combined the Feature and E2E VarNets into the Feature-Image (FI) VarNet, to facilitate cross-domain learning and boost accuracy. Reconstructions were evaluated on the fastMRI dataset using standard metrics and clinical scoring by three neuroradiologists. Feature and FI VarNets outperformed the E2E VarNet for 4 × , 5 × and 8 × Cartesian undersampling in all studied metrics. FI VarNet secured second place in the public fastMRI leaderboard for 4 × Cartesian undersampling, outperforming all open-source models in the leaderboard. Radiologists rated FI VarNet brain reconstructions with higher quality and sharpness than the E2E VarNet reconstructions. FI VarNet excelled in preserving anatomical details, including blood vessels, whereas E2E VarNet discarded or blurred them in some cases. The proposed FI VarNet enhances the reconstruction quality of undersampled MRI and could enable clinically acceptable reconstructions at higher acceleration factors than currently possible.

Postmortem mitochondria function in longissimus lumborum of Angus and Brahman steers.

Mitochondria function and integrity may impact postmortem metabolism and meat quality development. Adaptations in heat tolerant Brahman may persist to limit cellular stress postmortem. Our objective was to evaluate glycolysis, pH decline, and mitochondria function in longissimus lumborum (LL) from Angus and Brahman steers (N = 28) early postmortem (1 to 6 h) and after rigor (24 h). We evaluated metabolites of anaerobic glycolysis, ATP, pH, and temperature, and determined mitochondria oxygen consumption rate (OCR) in permeabilized fibers. The main effects of breed (b) and time (t) and the interaction were tested. Brahman LL contained greater ATP during the first 6 h postmortem; Brahman also tended to exhibit a slower pH decline (b × t, P = 0.07) and more rapid temperature decline (b × t, P < 0.001), but metabolites of anaerobic glycolysis were not different. Mitochondria in Brahman and Angus LL were well-coupled and respired at 1 h postmortem. However, outer membrane integrity became increasingly compromised postmortem (t, P < 0.001). Brahman tended to exhibit greater electron transport system capacity (b, P < 0.1) and had greater capacity for oxidative phosphorylation (complex I and II substrates) at 6 h compared with Angus (P < 0.001). In totality, greater ATP, slower pH decline, and enhanced mitochondria capacity indicate that Brahman possess mitochondrial properties or cellular adaptations that help protect the cell during energy stress postmortem. Slower pH and more rapid temperature decline in LL from Brahman may also help preserve mitochondria function postmortem.

More Than Skin Deep: Patient-Provider Racial and Ethnic Concordance and Discordance in Collegiate Athletics and Concussion Management.

CONTEXT: There is strong evidence that racial and ethnic disparities exist in multiple arenas of health and wellness. The causes of racial and ethnic differences in healthcare are multi- dimensional, one factor that may impact injury/illness communication, interactions, and outcomes is patient-provider racial and ethnic concordance. At present, it is unclear what role patient-provider racial and ethnic concordance and discordance plays in facilitating concussion care for collegiate athletes. OBJECTIVE: Investigate the presence of athlete-athletic trainer (AT) racial and ethnic concordance and discordance amongst diagnosed concussion cases, and examine if racial and ethnic concordance and discordance influences time (in days) until diagnosis, symptom resolution, or return-to-sport clinical milestones in collegiate athletes. DESIGN: Retrospective cohort study. SETTING: Collegiate athletics. PATIENTS OR OTHER PARTICIPANTS: A total of 694 concussion cases [38.6% (n=268) sustained by women, 61.4% (n=426) sustained by men] that occurred within the 2015-2016 through 2019- 2020 sport seasons at 9 institutions. MAIN OUTCOME MEASURE(S): The number of days from date of injury to diagnosis, symptom resolution, and return-to-sport; and from date of diagnosis to symptom resolution and return-to- sport. RESULTS: Overall, 68.4% (n=475) of concussion cases had patient-provider racial and ethnic concordance and 31.6% (n =219) were discordant. All concordant pairs included a White athlete and White AT. Time to diagnosis differed between the concordant and discordant groups (median[IQR]=1[0,2] versus 0[0,1], respectively) only in the model adjusted for sex, sport-type, and availability of an AT (OR[CI95]=1.46[1.07, 1.85]). There were no other group differences. CONCLUSIONS: One-third of concussion cases had athlete-AT racial and ethnic discordance. While this group was diagnosed with a concussion 1-day sooner than the concordant group, no differences were observed for any concussion recovery milestones. These findings suggest that patient-provider racial and ethnic concordance may play a minor role in concussion recognition or reporting, but not necessarily in the management and recovery thereafter.

Community Engagement, Equity, and Cross-Sector Public Health Practice.

In this topical review, we integrate 3 concepts-public health practice, community engagement, and cross-sector governance-to consider the following question: What is the underlying relationship between public health and cross-sector governance according to which the field can understand the role of community engagement in achieving health equity? We begin with an overview of public health practice and the practice of community engagement. Next, we position these practices in the broader turn toward cross-sector governance. The integration of these themes reveals that common tools for community engagement fail to address questions about how services should be funded, how resources should be distributed, and which members of the community have a claim to services. We therefore suggest that distinguishing between community engagement for equity and equitable community engagement is a first step toward deepening dialogue about the role of public health in achieving health equity.

Exploring bereavement processes among BLACK adolescent male CO-VICTIMS of homicide.

Black adolescent males are disproportionally impacted by violence exposure and violent loss. The primary aim of this study was to explore the bereavement experiences of Black adolescent males who have lost a friend or family member to murder. Participants were Black adolescent males between the ages of 14-19 years. This was a purposive sample recruited from a community-based study that took place in urban neighborhoods in Pittsburgh, Pennsylvania. Participants who completed their final survey for the parent study were recruited from January to June 2017. Participants completed a brief computerized survey and those who responded affirmatively to a screening question about losing a friend or family member to murder were invited to a qualitative interview. Interviews were audio recorded, transcribed, and coded to identify key themes. Among the 31 youth interviewed, 30 had lost more than one person to murder. Four primary themes emerged from their narratives: (1) self-preservation through isolation, (2) finding sanctuary through shared narratives of loss, (3) freedom from the mind, and (4) post-traumatic growth (i.e., motivation, healing, resilience). Findings suggest that interventions that provide sanctuary for youth that are culturally relevant and create opportunities for youth to process violent loss may aid in promoting opportunities for youth to grieve and heal from violent loss.

Synthetic abnormal mast cell particles successfully mimic neoplastic mast cells by flow cytometry.

Clinical flow cytometry laboratories require quality control materials for assay development, validation, and performance monitoring, including new reagent lot qualification. However, finding suitable controls for populations with uncommonly expressed antigens or for rare populations, such as mast cells, can be difficult. To that end, we evaluated synthetic abnormal mast cell particles (SAMCP), developed together with, and manufactured by, Slingshot Biosciences. The SAMCP's were designed to phenotypically mimic abnormal neoplastic mast cells: they were customized to have the same light scatter and autofluorescence properties of mast cells, along with surface antigen levels of CD45, CD33, CD117, CD2, CD25, and CD30 consistent with that seen in mast cell disease. We evaluated several performance characteristics of these particles using ARUP's high sensitivity clinical mast cell assay, including limit of detection, off-target activity and FMO controls, precision, scatter properties of the particles utilizing several different cytometer platforms, and particle antigen stability. The phenotype of the SAMCP mimicked abnormal mast cells, and they could be distinguished from normal native mast cells. FMO controls demonstrated specificity of each of the markers, and no off-target binding was detected. The limit of detection of the particles spiked into normal bone marrow was found to be ≤0.003% in a limiting dilution assay. The mast cell particles were found to perform similarly on Becton Dickinson Lyric, Cytek Aurora, and Beckman Coulter Navios and CytoFLEX platforms. Within run and between run precision were less than 10% CV. SAMCP were stable up to 13 days with minimal loss of antigen fluorescence intensity. The SAMCP's were able to successfully mimic neoplastic mast cells based on the results of our high sensitivity mast cell flow cytometry panel. These synthetic cell particles represent an exciting and innovative technology, which can fulfill vital needs in clinical flow cytometry such as serving as standardized control materials for assay development and performance monitoring.

Deep-learning-based motion correction using multichannel MRI data: a study using simulated artifacts in the fastMRI dataset.

Deep learning presents a generalizable solution for motion correction requiring no pulse sequence modifications or additional hardware, but previous networks have all been applied to coil-combined data. Multichannel MRI data provide a degree of spatial encoding that may be useful for motion correction. We hypothesize that incorporating deep learning for motion correction prior to coil combination will improve results. A conditional generative adversarial network was trained using simulated rigid motion artifacts in brain images acquired at multiple sites with multiple contrasts (not limited to healthy subjects). We compared the performance of deep-learning-based motion correction on individual channel images (single-channel model) with that performed after coil combination (channel-combined model). We also investigate simultaneous motion correction of all channel data from an image volume (multichannel model). The single-channel model significantly (p < 0.0001) improved mean absolute error, with an average 50.9% improvement compared with the uncorrected images. This was significantly (p < 0.0001) better than the 36.3% improvement achieved by the channel-combined model (conventional approach). The multichannel model provided no significant improvement in quantitative measures of image quality compared with the uncorrected images. Results were independent of the presence of pathology, and generalizable to a new center unseen during training. Performing motion correction on single-channel images prior to coil combination provided an improvement in performance compared with conventional deep-learning-based motion correction. Improved deep learning methods for retrospective correction of motion-affected MR images could reduce the need for repeat scans if applied in a clinical setting.

The impact of a mixed reality technology-driven health enhancing physical activity program among community-dwelling older adults: a study protocol.

Background: Physical inactivity and a sedentary lifestyle among community-dwelling older adults poses a greater risk for progressive physical and cognitive decline. Mixed reality technology-driven health enhancing physical activities such as the use of virtual coaches provide an emerging and promising solution to support healthy lifestyle, but the impact has not been clearly understood. Methods and analysis: An observational explanatory sequential mixed-method research design was conceptualized to examine the potential impact of a user-preferred mixed reality technology-driven health enhancing physical activity program directed toward purposively selected community-dwelling older adults in two senior centers in the Philippines. Quantitative components of the study will be done through a discreet choice experiment and a quasi-experimental study. A total of 128, or 64 older adults in each center, will be recruited via posters at community senior centers who will undergo additional screening or health records review by a certified gerontologist to ensure safety and proper fit. Treatments (live coaching with video-based exercise and mixed reality technology-driven exercise) will be assigned to each of the two senior center sites for the quasi-experiment. The participants from the experimental group shall be involved in the discreet choice experiment, modeling, and usability evaluations. Finally, a qualitative sample of participants (n = 6) as key informants shall be obtained from the experimental group using purposive selection. Discussion: This study protocol will examine the health impact of a promising mixed reality program in health promotion among older adults. The study utilizes a human-centered mixed method research design in technology development and evaluation in the context of developing nations.Clinical trial registration: ClinicalTrials.gov, identifier NCT06136468.

Direct sub-atmospheric pressure ionization mass spectrometry: Evaporation/sublimation-driven ionization is amazing, fundamentally, and practically.

This paper covers direct sub-atmospheric pressure ionization mass spectrometry (MS). The discovery, applications, and mechanistic aspects of novel ionization processes for use in MS that are not based on the high-energy input from voltage, laser, and/or high temperature but on sublimation/evaporation within a region linking a higher to lower pressure and modulated by heat and collisions, are discussed, including how this new reality has guided a series of discoveries, instrument developments, and commercialization. A research focus, inter alia, is on how best to understand, improve, and use these novel ionization processes, which convert volatile and nonvolatile compounds from solids (sublimation) or liquids (evaporation) into gas-phase ions for analysis by MS providing reproducible, accurate, sensitive, and prompt results. Our perception on how these unprecedented versus traditional ionization processes/methods relate to each other, how they can be made to coexist on the same mass spectrometer, and an outlook on new and expanded applications (e.g., clinical, portable, fast, safe, and autonomous) is presented, and is based on ST's Opening lecture presentation at the Nordic Mass spectrometry Conference, Geilo, Norway, January 2023. Focus will be on matrix-assisted ionization (MAI) and solvent-assisted ionization (SAI) MS covering the period from 2010 to 2023; a potential paradigm shift in the making.

Estimates of SARS-CoV-2 Hospitalization and Fatality Rates in the Prevaccination Period, United States.

Few precise estimates of hospitalization and fatality rates from COVID-19 exist for naive populations, especially within demographic subgroups. We estimated rates among persons with SARS-CoV-2 infection in the United States during May 1-December 1, 2020, before vaccines became available. Both rates generally increased with age; fatality rates were highest for persons >85 years of age (24%) and lowest for children 1-14 years of age (0.01%). Age-adjusted case hospitalization rates were highest for African American or Black, not Hispanic persons (14%), and case-fatality rates were highest for Asian or Pacific Islander, not Hispanic persons (4.4%). Eighteen percent of hospitalized patients and 44.2% of those admitted to an intensive care unit died. Male patients had higher hospitalization (6.2% vs. 5.2%) and fatality rates (1.9% vs. 1.5%) than female patients. These findings highlight the importance of collecting surveillance data to devise appropriate control measures for persons in underserved racial/ethnic groups and older adults.

Elevated C5-hydroxy acylcarnitine in an infant girl as a result of holocarboxylase synthetase deficiency.

CONTEXT: Elevated 3-hydroxyisovaleryl-/2-methyl-3-hydroxybutyryl (C5-OH) acylcarnitine in blood can result from several genetic enzyme deficiencies: 3-methylcrotonyl CoA carboxylase deficiency, 3-hydroxy 3-methylglutaryl-CoA lyase deficiency, beta-ketothiolase deficiency, 2-methyl 3-hydroxybutyryl-CoA dehydrogenase deficiency, primary 3-methylglutaconic aciduria, multiple biotin-dependent carboxylase deficiencies and biotin metabolism disorders. Biochemical tests help differentiate these causes while molecular tests are usually required for definitive diagnosis. CASE DESCRIPTION: We reported an infant girl with newborn screen findings of elevated C5-OH acylcarnitine. She had further confirmational biochemical testing including plasma acylcarnitines, urine organic acids and urine acylglycines. Patient's urine organic acid profile showed markedly increased 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. Urine acylglycine test reported a large increase of 3-methylcrotonylglycine and plasma acylcarnitine test repeated the finding of elevated C5-OH acylcarnitine together with propionyl acylcarnitine elevation. These results point to multiple biotin-dependent carboxylase deficiency. Molecular tests revealed a homozygous mutation in the holocarboxylase synthetase gene that is consistent with her biochemical test findings. This case demonstrated the critical role of newborn screen in identifying inborn errors of metabolism that may otherwise be missed and lead to severe morbidity later in life. It also showcased that both biochemical and molecular tests are essential tools in the diagnosis.

A miniaturised semi-dynamic in-vitro model of human digestion.

Reliable in-vitro digestion models that are able to successfully replicate the conditions found in the human gastrointestinal tract are key to assess the fate and efficiency of new formulations aimed for oral consumption. However, current in-vitro models either lack the capability to replicate crucial dynamics of digestion or require large volumes of sample/reagents, which can be scarce when working with nanomaterials under development. Here, we propose a miniaturised digestion system, a digestion-chip, based on incubation chambers integrated on a polymethylmethacrylate device. The digestion-chip incorporates key dynamic features of human digestion, such as gradual acidification and gradual addition of enzymes and simulated fluids in the gastric phase, and controlled gastric emptying, while maintaining low complexity and using small volumes of sample and reagents. In addition, the new approach integrates real-time automated closed-loop control of two key parameters, pH and temperature, during the two main phases of digestion (gastric and intestinal) with an accuracy down to ± 0.1 °C and ± 0.2 pH points. The experimental results demonstrate that the digestion-chip successfully replicates the gold standard static digestion INFOGEST protocol and that the semi-dynamic digestion kinetics can be reliably fitted to a first kinetic order model. These devices can be easily adapted to dynamic features in an automated, sensorised, and inexpensive platform and will enable reliable, low-cost and efficient assessment of the bioaccessibility of new and expensive drugs, bioactive ingredients or nanoengineered materials aimed for oral consumption, thereby avoiding unnecessary animal testing.