A descriptive study of the clinical impacts on COVID-19 survivors using telemonitoring (The TeleCOVID Study).

Background: There is increasing evidence that COVID-19 survivors are at increased risk of experiencing a wide range of cardiovascular complications post infection; however, there are no validated models or clear guidelines for remotely monitoring the cardiac health of COVID-19 survivors. Objective: This study aims to test a virtual, in-home healthcare monitoring model of care for detection of clinical symptoms and impacts on COVID-19 survivors. It also aims to demonstrate system usability and feasibility. Methods: This open label, prospective, descriptive study was conducted in South Western Sydney. Included in the study were patients admitted to the hospital with the diagnosis of COVID-19 between June 2021 and November 2021. Eligible participants after consent were provided with a pulse oximeter to measure oxygen saturation and a S-Patch EX to monitor their electrocardiogram (ECG) for a duration of 3 months. Data was transmitted in real-time to a mobile phone via Bluetooth technology and results were sent to the study team via a cloud-based platform. All the data was reviewed in a timely manner by the investigator team, for post COVID-19 related symptoms, such as reduction in oxygen saturation and arrhythmia. Outcome measure: This study was designed for feasibility in real clinical setting implementation, enabling the study team to develop and utilise a virtual, in-home healthcare monitoring model of care to detect post COVID-19 clinical symptoms and impacts on COVID-19 survivors. Results: During the study period, 23 patients provided consent for participation. Out of which 19 patients commenced monitoring. Sixteen patients with 81 (73.6%) valid tests were included in the analysis and amongst them seven patients were detected by artificial intelligence to have cardiac arrhythmias but not clinically symptomatic. The patients with arrhythmias had a higher occurrence of supraventricular ectopy, and most of them took at least 2 tests before detection. Notably, patients with arrhythmia had significantly more tests than those without [t-test, t (13) = 2.29, p < 0.05]. Conclusions: Preliminary observations have identified cardiac arrhythmias on prolonged cardiac monitoring in 7 out of the first 16 participants who completed their 3 months follow-up. This has allowed early escalation to their treating doctors for further investigations and early interventions.

Assessing Preference and Stability of Preference for Individuals with Neurocognitive Disorder.

Poor engagement can lead to a reduced quality of life for individuals with neurocognitive disorder (NCD). Research on determining preference and increasing engagement with this population is limited. The purpose of this study was to compare the accuracy of four preference assessment formats in identifying preferred activities and predicting engagement for six females with NCD and to measure the stability of preference and engagement over time. We compared the predictability of single-stimulus(SS) verbal and multimedia assessments, caregiver ranking (CR) assessments, and multiple-stimulus without-replacement (MSWO) assessments. Participants responded consistently on SS assessments, but we noted inconsistencies between the CR and MSWO assessments. SS assessments predicted engagement during engagement analyses, but rank-order assessments did not predict engagement for moderately ranked activities. The rank-order assessments predicted engagement for highly ranked activities for most participants and for low-ranked activities for two participants. We also evaluated the stability of preferences and engagement over time. Participants responded consistently on SS assessments and inconsistently on MSWO assessments across time. SS assessments consistently predicted engagement during engagement analyses for five participants, but when activity rank is considered, the MSWO was inconsistent in predicting engagement across time for most participants. These results suggest that SS assessments may be useful for identifying preferred activities and engagement, and preferences may remain stable for some individuals with NCD.

Natural history of infants with non-SCID T cell lymphopenia identified on newborn screen.

Newborn screening (NBS) for severe combined immunodeficiency (SCID) can identify infants with non-SCID T cell lymphopenia (TCL). The purpose of this study was to characterize the natural history and genetic findings of infants with non-SCID TCL identified on NBS. We analyzed data from 80 infants with non-SCID TCL in the mid-Atlantic region between 2012 and 2019. 66 patients underwent genetic testing and 41 (51%) had identified genetic variant(s). The most common genetic variants were thymic defects (33%), defects with unknown mechanisms (12%) and bone marrow production defects (5%). The genetic cohort had significantly lower median initial CD3+, CD4+, CD8+ and CD4/CD45RA+ T cell counts compared to the non-genetic cohort. Thirty-six (45%) had either viral, bacterial, or fungal infection; only one patient had an opportunistic infection (vaccine strain VZV infection). Twenty-six (31%) of patients had resolution of TCL during the study period.

Health workers' Perceptions and REsponses in implementing COVID-19 Immunisation StratEgy in South Western Sydney (PRECISE): an observational study.

OBJECTIVES: To understand the views and motivations of healthcare workers at a vaccination hub who received a COVID-19 vaccination in March-May 2021. STUDY DESIGN: This is an observational study via an anonymous electronic survey of seven questions focus on where survey recipients received information about the vaccine roll-out, their motivations for receiving the vaccine and their level of comfort in receiving the vaccine. SETTING: The Liverpool Vaccination Hub is located in South Western Sydney. PARTICIPANTS: Participants were healthcare workers who received the first dose of a COVID-19 vaccine in the Australian Government's Phase 1a and 1b priority categories. The majority of survey respondents (70%) were female (median aged between 35 and 44 years). The majority of survey respondents were clinical workers, such as nurse, paramedics and doctors. OUTCOME MEASURES: χ2 analysis was used for analysis of survey responses in univariate analysis. Logistic regression was used to analyse survey responses, adjusting for week, type of health worker and age. RESULTS: 4746 healthcare workers responded to the survey after receiving their first vaccine dose, a response rate of 23%. Over 90% of respondents said that COVID-19 vaccination information from their organisation was easily available. Most of them reported that they were comfortable receiving a COVID-19 vaccine. The majority of respondents were motivated to receive the vaccine due to concern about contracting COVID-19 themselves (75%), or concerns about transmitting it to other people such as patients (52%), family members (65%) or other community members (54%). Younger respondents were more likely to have preferred more information on vaccine safety (p<0.0001) and the effectiveness of the vaccine (p<0.0001). CONCLUSION: The majority of healthcare workers who received a COVID-19 vaccine reported that it was easy to find useful information about the vaccination roll-out and they had a positive experience being vaccinated.

Inositol polyphosphates and target of rapamycin kinase signalling govern photosystem II protein phosphorylation and photosynthetic function under light stress in Chlamydomonas.

Stress and nutrient availability influence cell proliferation through complex intracellular signalling networks. In a previous study it was found that pyro-inositol polyphosphates (InsP7 and InsP8 ) produced by VIP1 kinase, and target of rapamycin (TOR) kinase signalling interacted synergistically to control cell growth and lipid metabolism in the green alga Chlamydomonas reinhardtii. However, the relationship between InsPs and TOR was not completely elucidated. We used an in vivo assay for TOR activity together with global proteomic and phosphoproteomic analyses to assess differences between wild-type and vip1-1 in the presence and absence of rapamycin. We found that TOR signalling is more severely affected by the inhibitor rapamycin in a vip1-1 mutant compared with wild-type, indicating that InsP7 and InsP8 produced by VIP1 act independently but also coordinately with TOR. Additionally, among hundreds of differentially phosphorylated peptides detected, an enrichment for photosynthesis-related proteins was observed, particularly photosystem II proteins. The significance of these results was underscored by the finding that vip1-1 strains show multiple defects in photosynthetic physiology that were exacerbated under high light conditions. These results suggest a novel role for inositol pyrophosphates and TOR signalling in coordinating photosystem phosphorylation patterns in Chlamydomonas cells in response to light stress and possibly other stresses.

Recent Advances in Mass Spectrometry-Based Glycomic and Glycoproteomic Studies of Pancreatic Diseases.

Modification of proteins by glycans plays a crucial role in mediating biological functions in both healthy and diseased states. Mass spectrometry (MS) has emerged as the most powerful tool for glycomic and glycoproteomic analyses advancing knowledge of many diseases. Such diseases include those of the pancreas which affect millions of people each year. In this review, recent advances in pancreatic disease research facilitated by MS-based glycomic and glycoproteomic studies will be examined with a focus on diabetes and pancreatic cancer. The last decade, and especially the last five years, has witnessed developments in both discovering new glycan or glycoprotein biomarkers and analyzing the links between glycans and disease pathology through MS-based studies. The strength of MS lies in the specificity and sensitivity of liquid chromatography-electrospray ionization MS for measuring a wide range of biomolecules from limited sample amounts from many sample types, greatly enhancing and accelerating the biomarker discovery process. Furthermore, imaging MS of glycans enabled by matrix-assisted laser desorption/ionization has proven useful in complementing histology and immunohistochemistry to monitor pancreatic disease progression. Advances in biological understanding and analytical techniques, as well as challenges and future directions for the field, will be discussed.

Analysis of pancreatic extracellular matrix protein post-translational modifications via electrostatic repulsion-hydrophilic interaction chromatography coupled with mass spectrometry.

The pancreas is a vital organ with digestive and endocrine roles, and diseases of the pancreas affect millions of people yearly. A better understanding of the pancreas proteome and its dynamic post-translational modifications (PTMs) is necessary to engineer higher fidelity tissue analogues for use in transplantation. The extracellular matrix (ECM) has major roles in binding and signaling essential to the viability of insulin-producing islets of Langerhans. To characterize PTMs in the pancreas, native and decellularized tissues from four donors were analyzed. N-Glycosylated and phosphorylated peptides were simultaneously enriched via electrostatic repulsion-hydrophilic interaction chromatography and analyzed with mass spectrometry, maximizing PTM information from one workflow. A modified surfactant and chaotropic agent assisted sequential extraction/on-pellet digestion was used to maximize solubility of the ECM. The analysis resulted in the confident identification of 3650 proteins, including 517 N-glycoproteins and 148 phosphoproteins. We identified 214 ECM proteins, of which 99 were N-glycosylated, 18 were phosphorylated, and 9 were found to have both modifications. Collagens, a major component of the ECM, were the most highly glycosylated of the ECM proteins and several were also heavily phosphorylated, raising the possibility of structural and thus functional changes resulting from these modifications. To our knowledge, this work represents the first characterization of PTMs in pancreatic ECM proteins. This work provides a basal profile of PTMs in the healthy human pancreatic ECM, laying the foundation for future investigations to determine disease-specific changes such as in diabetes and pancreatic cancer, and potentially helping to guide the development of tissue replacement constructs. Data are available via ProteomeXchange with identifier PXD025048.

Label-Free Quantitative Phosphoproteomics for Algae.

The unicellular alga Chlamydomonas reinhardtii is a model photosynthetic organism for the study of microalgal processes. Along with genomic and transcriptomic studies, proteomic analysis of Chlamydomonas has led to an increased understanding of its metabolic signaling as well as a growing interest in the elucidation of its phosphorylation networks. To this end, mass spectrometry-based proteomics has made great strides in large-scale protein quantitation as well as analysis of posttranslational modifications (PTMs) in a high-throughput manner. An accurate quantification of dynamic PTMs, such as phosphorylation, requires high reproducibility and sensitivity due to the substoichiometric levels of modified peptides, which can make depth of coverage challenging. Here we present a method using TiO2-based phosphopeptide enrichment paired with label-free LC-MS/MS for phosphoproteome quantification. Three technical replicate samples in Chlamydomonas were processed and analyzed using this approach, quantifying a total of 1775 phosphoproteins with a total of 3595 phosphosites. With a median CV of 21% across quantified phosphopeptides, implementation of this method for differential studies provides highly reproducible analysis of phosphorylation events. While the culturing and extraction methods used are specific to facilitate coverage in algal species, this approach is widely applicable and can easily extend beyond algae to other photosynthetic organisms with minor modifications.

Phosphorus Availability Regulates TORC1 Signaling via LST8 in Chlamydomonas.

Target of rapamycin complex 1 (TORC1) is a central regulator of cell growth. It balances anabolic and catabolic processes in response to nutrients, growth factors, and energy availability. Nitrogen- and carbon-containing metabolites have been shown to activate TORC1 in yeast, animals, and plants. Here, we show that phosphorus (P) regulates TORC1 signaling in the model green alga Chlamydomonas (Chlamydomonas reinhardtii) via LST8, a conserved TORC1 subunit that interacts with the kinase domain of TOR. P starvation results in a sharp decrease in LST8 abundance and downregulation of TORC1 activity. A hypomorphic lst8 mutation resulted in decreased LST8 abundance, and it both reduced TORC1 signaling and altered the cellular response to P starvation. Additionally, we found that LST8 levels and TORC1 activity were not properly regulated in a mutant defective in the transcription factor PSR1, which is the major mediator of P deprivation responses in Chlamydomonas. Unlike wild-type cells, the psr1 mutant failed to downregulate LST8 abundance and TORC1 activity when under P limitation. These results identify PSR1 as an upstream regulator of TORC1 and demonstrate that TORC1 is a key component in P signaling in Chlamydomonas.

Inhibition of TOR in Chlamydomonas reinhardtii Leads to Rapid Cysteine Oxidation Reflecting Sustained Physiological Changes.

The target of rapamycin (TOR) kinase is a master metabolic regulator with roles in nutritional sensing, protein translation, and autophagy. In Chlamydomonas reinhardtii, a unicellular green alga, TOR has been linked to the regulation of increased triacylglycerol (TAG) accumulation, suggesting that TOR or a downstream target(s) is responsible for the elusive "lipid switch" in control of increasing TAG accumulation under nutrient limitation. However, while TOR has been well characterized in mammalian systems, it is still poorly understood in photosynthetic systems, and little work has been done to show the role of oxidative signaling in TOR regulation. In this study, the TOR inhibitor AZD8055 was used to relate reversible thiol oxidation to the physiological changes seen under TOR inhibition, including increased TAG content. Using oxidized cysteine resin-assisted capture enrichment coupled with label-free quantitative proteomics, 401 proteins were determined to have significant changes in oxidation following TOR inhibition. These oxidative changes mirrored characterized physiological modifications, supporting the role of reversible thiol oxidation in TOR regulation of TAG production, protein translation, carbohydrate catabolism, and photosynthesis through the use of reversible thiol oxidation. The delineation of redox-controlled proteins under TOR inhibition provides a framework for further characterization of the TOR pathway in photosynthetic eukaryotes.

Clopidogrel Hypersensitivity: Pathogenesis, Presentation and Diagnosis.

This paper provides an overview of the pathogenesis, presentation and diagnosis of clopidogrel hypersensitivity. The majority of clopidogrel hypersensitivity cases are due to a T cell mediated Gell and Coombs Type IV reaction. History, histology, and patch testing have shown consistency with a T cell mediated mechanism. Clopidogrel reactions most commonly present as a mild delayed maculopapular erythematous rash 5 to 10 days after introduction of the drug, and do not always require discontinuation of the drug. Severe cutaneous, systemic, and immediate adverse reactions to clopidogrel are rare. For the diagnosis of clopidogrel hypersensitivity, drug causality can be determined using patch testing, or for mild reactions, recurrence of symptoms after drug reintroduction, although neither are required for diagnosis.

Three-dimensional image analysis for staging chronic rhinosinusitis.

BACKGROUND: Traditional methods of staging chronic rhinosinusitis (CRS) through imaging do not differentiate between degrees of partial mucosal sinus inflammation, thus limiting their utility as imaging biomarkers. We hypothesized that software-aided, quantitative measurement of sinus inflammation would generate a metric of disease burden that would correlate with clinical parameters in patients with suspected sinus disease. METHODS: Adults with rhinologic complaints undergoing computed tomography imaging were recruited at an urban, academic, tertiary care center (n = 45 with Lund-Mackay [LM] scores ≥4). Three-dimensional (3D) volumetric image analysis was performed using a semiautomated method to obtain a "Chicago-modified Lund-Mackay" (Chicago MLM) score, which provides a continuous scale to quantify extent of opacification. Linear regression was used to test the association of the Chicago MLM score with concurrent symptoms (Total Nasal Symptom Score [TNSS]) and disease-specific quality of life, based on the Sinonasal Outcome Test-22 (SNOT-22). RESULTS: Chicago MLM scores were significantly associated with both symptoms (p = 0.037) and disease-specific quality of life (p = 0.007). Inflammation in the ethmoid and sphenoid sinuses appeared to influence these associations. These findings were even more robust when analysis was limited to patients with more severe disease (LM >6). CONCLUSION: The quantitative measurement of sinus inflammation by computer-aided 3D analysis correlates modestly with both symptoms and disease-specific quality of life. Posterior sinuses appear to have the greatest impact on these findings, potentially providing an anatomic target for clinicians to base therapy. The Chicago MLM score is a promising imaging biomarker for clinical and research use.

Computer-assisted staging of chronic rhinosinusitis correlates with symptoms.

BACKGROUND: The Lund-Mackay (LM) staging system for chronic rhinosinusitis (CRS) does not correlate with clinical parameters, likely due to its coarse scale. We developed a "Modified Lund Mackay" (MLM) system, which uses a three-dimensional (3D), computerized method to quantify the volume of mucosal inflammation in the sinuses, and sought to determine whether the MLM would correlate with symptoms and disease-specific quality of life. METHODS: We obtained Total Nasal Symptom Score (TNSS) and 22-item Sino-Nasal Outcome Test (SNOT-22) data from 55 adult subjects immediately prior to sinus imaging. The volume of each sinus occupied by mucosal inflammation was measured using MATLAB algorithms created using customized, image analysis software after manual outlining of each sinus. Linear regression was used to model the relationship between the MLM and the SNOT-22 and TNSS. Correlation between the LM and MLM was tested using Spearman's rank correlation coefficient. RESULTS: Adjusting for age, gender, and smoking, a higher symptom burden was associated with increased sinonasal inflammation as captured by the MLM (ß = 0.453, p < 0.013). As expected due to the differences in scales, the LM and MLM scores were significantly different (p < 0.011). No association between MLM and SNOT-22 scores was found. CONCLUSION: The MLM is one of the first imaging-based scoring systems that correlates with sinonasal symptoms. Further development of this custom software, including full automation and validation in larger samples, may yield a biomarker with great utility for both treatment of patients and outcomes assessment in clinical trials.

Intolerance of uncertainty, cognitive complaints, and cancer-related distress in prostate cancer survivors.

OBJECTIVE: Prostate cancer survivors have reported cognitive complaints following treatment, and these difficulties may be associated with survivors' ongoing cancer-related distress. Intolerance of uncertainty may exacerbate this hypothesized relationship by predisposing individuals to approach uncertain situations such as cancer survivorship in an inflexible and negative manner. We investigated whether greater cognitive complaints and higher intolerance of uncertainty would interact in their relation to more cancer-related distress symptoms. METHODS: This cross-sectional, questionnaire-based study included 67 prostate cancer survivors who were 3 to 5 years post treatment. Hierarchical multiple regression analyses tested the extent to which intolerance of uncertainty, cognitive complaints, and their interaction were associated with cancer-related distress (measured with the Impact of Event Scale-Revised; IES-R) after adjusting for age, education, physical symptoms, and fear of cancer recurrence. RESULTS: Intolerance of uncertainty was positively associated with the IES-R avoidance and hyperarousal subscales. More cognitive complaints were associated with higher scores on the IES-R hyperarousal subscale. The interaction of intolerance of uncertainty and cognitive complaints was significantly associated with IES-R intrusion, such that greater cognitive complaints were associated with greater intrusive thoughts in survivors high in intolerance of uncertainty but not those low in it. CONCLUSIONS: Prostate cancer survivors who report cognitive difficulties or who find uncertainty uncomfortable and unacceptable may be at greater risk for cancer-related distress, even 3 to 5 years after completing treatment. It may be beneficial to address both cognitive complaints and intolerance of uncertainty in psychosocial interventions.

Clinical considerations for working with patients with advanced cancer.

Advanced cancer is a life-limiting condition, but improvements in medical care are contributing to longer survival among some patients. As a result, it is likely that mental health professionals will be called upon to assist more patients with advanced cancer. The present paper reviews the psychological literature and from it draws clinical considerations for working with individuals affected by advanced cancer. It begins with a brief description of advanced cancer and the medical attributes of an advanced cancer diagnosis, and then catalogues salient medical, psychological, existential, and interpersonal challenges faced by this patient population. The review concludes with recommendations for treatment planning including an overview of some of the more recently tested and widely available interventions. It is hoped that this review will serve as a resource for professionals working with patients affected by advanced cancer.

Body image predicts quality of life in men with prostate cancer.

OBJECTIVE: Most men diagnosed with prostate cancer in the USA will survive. Of the many aspects of survivorship affected by prostate cancer, body image receives limited attention despite some indication that it may be important to men with the disease. The present study investigated how body image changes over time and the relations between changes in body image and quality of life (QOL) in men with prostate cancer. METHODS: In a longitudinal design, patients (N = 74) completed questionnaires before treatment (T1) and at 1 month (T2) and 2 years (T3) following treatment completion. RESULTS: Growth curve modeling indicated that there was no significant change over time in group-level body image scores. However, hormone treatment was associated with a negative trajectory of change over 2 years. Also, analysis of individual difference scores indicated that ≥50% of patients demonstrated change of at least 0.5 standard deviation between time points. Hierarchical regression indicated that change in body image between T1 and T2 was significantly associated with change in QOL between T1 and T3, while controlling for demographic variables, treatment, treatment-related functioning, and general and treatment-specific positive expectations. In predicting change in body image between T1 and T2, treatment-specific positive expectation was the only significant predictor. CONCLUSIONS: The present study demonstrates that body image is an important component of the prostate cancer experience. Findings suggest that body image has a meaningful association with QOL among prostate cancer survivors.

Peptide-activated double-negative T cells can prevent autoimmune type-1 diabetes development.

Autoimmune diseases may develop because of defective maturation, activation, differentiation and function of regulatory T cells. Previous studies have shown that exposure to donor antigen activates peripheral TCRalphabeta+CD3+CD4-CD8-NK1.1-, double-negative (DN) T cells, which specifically suppress anti-donor T cells and enhance survival of skin and heart grafts from allogeneic and xenogeneic donors. However, the role of DN T cells in preventing T cell-mediated autoimmune disease is unknown. Here, we analyzed the ability of DN T cells to recognize peptides expressed on self MHC and to suppress peptide-reactive CD8+ T cells, using the P14 mouse model that expresses a transgenic TCR specific for gp33 peptide presented on self MHC class I-Db. We found that injection of gp33 peptide resulted in increased DN and decreased CD8+ T cell numbers in the lymph nodes when compared to untreated mice. Injection of gp33, but not TCR-non-specific AV peptide, increased expression of T cell activation markers on DN T cells. Moreover, gp33-activated DN T cells suppressed proliferation of syngeneic CD8+ T cells via killing activated CD8+ T cells in an antigen-specific fashion in vitro. Furthermore, transferring gp33-activated DN T cells inhibited the development of autoimmune diabetes, suggesting that DN T cells may provide a novel therapy for T cell-mediated autoimmune diseases.