PPP1R15A-expressing monocytic MDSCs promote immunosuppressive liver microenvironment in fibrosis-associated hepatocellular carcinoma.

Background & Aims: Recent studies demonstrated the importance of fibrosis in promoting an immunosuppressive liver microenvironment and thereby aggressive hepatocellular carcinoma (HCC) growth and resistance to immune checkpoint blockade (ICB), particularly via monocyte-to-monocytic myeloid-derived suppressor cell (M-MDSC) differentiation triggered by hepatic stellate cells (HSCs). We thus aimed to identify druggable targets in these immunosuppressive myeloid cells for HCC therapy. Methods: M-MDSC signature genes were identified by integrated transcriptomic analysis of a human HSC-monocyte culture system and tumor-surrounding fibrotic livers of patients with HCC. Mechanistic and functional studies were conducted using in vitro-generated and patient-derived M-MDSCs. The therapeutic efficacy of a M-MDSC targeting approach was determined in fibrosis-associated HCC mouse models. Results: We uncovered over-expression of protein phosphatase 1 regulatory subunit 15A (PPP1R15A), a myeloid cell-enriched endoplasmic reticulum stress modulator, in human M-MDSCs that correlated with poor prognosis and ICB non-responsiveness in patients with HCC. Blocking TGF-ß signaling reduced PPP1R15A expression in HSC-induced M-MDSCs, whereas treatment of monocytes by TGF-ß upregulated PPP1R15A, which in turn promoted ARG1 and S100A8/9 expression in M-MDSCs and reduced T-cell proliferation. Consistently, lentiviral-mediated knockdown of Ppp1r15a in vivo significantly reduced ARG1+S100A8/9+ M-MDSCs in fibrotic liver, leading to elevated intratumoral IFN-γ+GZMB+CD8+ T cells and enhanced anti-tumor efficacy of ICB. Notably, pharmacological inhibition of PPP1R15A by Sephin1 reduced the immunosuppressive potential but increased the maturation status of fibrotic HCC patient-derived M-MDSCs. Conclusions: PPP1R15A+ M-MDSC cells are involved in immunosuppression in HCC development and represent a novel potential target for therapies. Impact and implications: Our cross-species analysis has identified PPP1R15A as a therapeutic target governing the anti-T-cell activities of fibrosis-associated M-MDSCs (monocytic myeloid-derived suppressor cells). The results from the preclinical models show that specific inhibition of PPP1R15A can break the immunosuppressive barrier to restrict hepatocellular carcinoma growth and enhance the efficacy of immune checkpoint blockade. PPP1R15A may also function as a prognostic and/or predictive biomarker in patients with hepatocellular carcinoma.

Role of Mass Transport in Electrochemical CO2 Reduction to Methanol Using Immobilized Cobalt Phthalocyanine.

Electrochemical CO2 reduction (CO2R) using heterogenized molecular catalysts usually yields 2-electron reduction products (CO, formate). Recently, it has been reported that certain preparations of immobilized cobalt phthalocyanine (CoPc) produce methanol (MeOH), a 6-electron reduction product. Here, we demonstrate the significant role of intermediate mass transport in CoPc selectivity to methanol. We first developed a simple, physically mixed, polymer (and polyfluoroalkyl, PFAS)-free preparation of CoPc on multiwalled carbon nanotubes (MWCNTs) which can be integrated onto Au electrodes using a poly(3,4-ethylenedioxythiophene) polystyrenesulfonate (PEDOT:PSS) adhesion layer. After optimization of catalyst preparation and loading, methanol Faradaic efficiencies and partial current densities of 36% (±3%) and 3.8 (±0.5) mA cm-2, respectively, are achieved in the CO2-saturated aqueous electrolyte. The electrolyte flow rate has a large effect. A linear flow velocity of 8.5 cm/min produces the highest MeOH selectivity, with higher flow rates increasing CO selectivity and lower flow rates increasing the hydrogen evolution reaction, suggesting that CO is an unbound intermediate. Using a continuum multiphysics model assuming CO is the intermediate, we show qualitative agreement with the optimal inlet flow rate. Polymer binders were not required to achieve a high Faradaic efficiency for methanol using CoPc and MWCNTs. We also investigated the role of formaldehyde as an intermediate and the role of strain, but definitive conclusions could not be established.

Building blocks for a happy life: Longitudinal associations between early life income, mentorship and later well-being.

Longitudinal data from the Panel Study of Income Dynamics (PSID; N = 2996) were used to test hypotheses about the link between well-being and financial and social developmental resources. Results suggest that higher average family income from birth to age 18, and personal and professional mentoring received between 17 and 30, were positively associated with indicators of positive well-being and negatively related to negative indicators of well-being. Interactions between early life family income and mentoring during emerging adulthood were not significant predictors of any of the well-being outcomes. In all cases, the magnitudes of the coefficients became larger when simultaneously accounting for early life income, emerging adulthood mentoring, and their interactions-suggesting that financial and social resources in earlier life are independently linked to later life well-being. Findings highlight that mentoring received in emerging adulthood benefits downstream hedonic and eudemonic well-being, regardless of financial resources.

Lipid metabolism in the immune niche of tumor-prone liver microenvironment.

The liver is a common primary site not only for tumorigenesis, but also for cancer metastasis. Advanced cancer patients with liver metastases also show reduced response rates and survival benefits when treated with immune checkpoint inhibitors. Accumulating evidence has highlighted the importance of the liver immune microenvironment in determining tumorigenesis, metastasis-organotropism, and immunotherapy resistance. Various immune cells such as T cells, natural killer and natural killer T cells, macrophages and dendritic cells, and stromal cells including liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, and hepatocytes are implicated in contributing to the immune niche of tumor-prone liver microenvironment. In parallel, as the major organ for lipid metabolism, the increased abundance of lipids and their metabolites is linked to processes crucial for nonalcoholic fatty liver disease and related liver cancer development. Furthermore, the proliferation, differentiation, and functions of hepatic immune and stromal cells are also reported to be regulated by lipid metabolism. Therefore, targeting lipid metabolism may hold great potential to reprogram the immunosuppressive liver microenvironment and synergistically enhance the immunotherapy efficacy in the circumstance of liver metastasis. In this review, we describe how the hepatic microenvironment adapts to the lipid metabolic alterations in pathologic conditions like nonalcoholic fatty liver disease. We also illustrate how these immunometabolic alterations promote the development of liver cancers and immunotherapy resistance. Finally, we discuss the current therapeutic options and hypothetic combination immunotherapies for the treatment of advanced liver cancers.

Holographic Hintways: A systems feasibility and usability study of augmented reality cueing for gait adaptation.

BACKGROUND: Through providing on-demand visual and auditory cues while walking,augmented reality (AR) can theoretically cue spatiotemporal gait adaptations in, populations such as those with Parkinson's disease. However, given the novelty of the, technology, the type and extent of gait adaptations in response to such a cueing, system are unknown. Before such systems can be incorporated into rehabilitation, approaches, it is important to understand how people interact with the technology. RESEARCH QUESTIONS: What are the effects of visual and auditory cues delivered, through AR on spatiotemporal walking patterns and variability in a healthy, young, population? Is there a relationship between system usability and gait variability? , METHODS: Twenty healthy, young participants walked in four different cueing conditions using an AR headset: No Cues (NC) (i.e., natural gait), Auditory (A), Visual (V), and Auditory + Visual (AV). Inertial measurement units recorded spatiotemporal gait data at 200 Hz, a System Usability Survey was administered afterward, and linear regression models were developed to examine whether gait variability is predictive of system usability. RESULTS: All cueing conditions exhibited a significantly slower cadence compared to, NC trials. Cadence variability was significantly higher for A trials compared to V and, NC. V trials exhibited significantly decreased stride lengths compared to NC. Increased, reported system usability was significantly correlated with decreased stance phase, time variability across A trials. SIGNIFICANCE: Our findings support that holographic spatial-visual and auditory cues, are promising to evoke spatiotemporal gait adaptations. Results also support the, notion that the type of system and cue delivery design may impact gait outcomes.,Before an AR cueing system can be applied to a specific population in future, interventions, a more holistic approach towards finding the relationship between this, technology and its users is needed.

Chinese expert consensus on Bruton tyrosine kinase inhibitors in the treatment of B-cell malignancies.

Targeted therapy with Bruton tyrosine kinase (BTK) inhibitors have revolutionized the treatment of patients with various B-cell malignancies. BTK inhibitors such as ibrutinib, zanubrutinib, orelabrutinib, and acalabrutinib have shown good clinical efficacy and better safety profiles than those of traditional chemotherapy and chemoimmunotherapy regimens. Multiple studies on new BTK inhibitors are ongoing, which may provide more therapeutic options for the treatment of B-cell malignancies. Considering the unmet need of evidence on BTK inhibitors in all clinical settings and to standardize the use of BTK inhibitors available in mainland China, Taiwan, Hong Kong, and Macau regions, this consensus has been formulated for the treatment of various B-cell malignancies based on the clinical practice and available evidences on the use of BTK inhibitors. The recommendations of this consensus will provide guidance to physicians and clinical researchers on the effective treatment of B-cell malignancies with BTK inhibitors.

Hepatitis B virus reactivation in seronegative occult hepatitis B patient receiving ibrutinib therapy.

BACKGROUND: Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment for several mature B-cell malignancies. Reactivation of hepatitis B virus (HBV) is a well-described complication in patients with chronic HBV infection or prior HBV exposure undergoing cytotoxic or immunosuppressive chemotherapy for hematologic malignancies. This phenomenon has been frequently reported with rituximab. However, published data on the risk of HBV reactivation induced by ibrutinib are scarce. Cases of HBV reactivation in hematologic patients receiving ibrutinib therapy have recently been described, but limited only to overt hepatitis B patients or seropositive occult hepatitis B patients. CASE PRESENTATION: We report the first case of HBV reactivation during ibrutinib treatment in an asymptomatic 82-year-old woman with seronegative occult hepatitis B patient (i.e., negative for HBsAg, anti-HBc and anti-HBs). Four months after ibrutinib treatment, her liver function test (LFT) was deranged, with seroconversion to HBsAg positivity. Serum hepatitis B virus DNA was quantified to be 1.92 × 108 IU/ml. Antiviral treatment was initiated, and viral load was gradually suppressed with improvement in LFT. CONCLUSIONS: Our case illustrated that in populations with a high incidence of HBV exposure, systematic screening for HBV exposure is essential prior to ibrutinib treatment, followed by serial monitoring of serologic and molecular markers of hepatitis B. There is a need for an international consensus to support the recommendation of antiviral prophylaxis against HBV reactivation in patients using ibrutinib.

In too deep? A systematic literature review of fully-immersive virtual reality and cybersickness among older adults.

BACKGROUND: Virtual reality technology holds great promise in improving the health and well-being of older adults; however, this technology is associated with potential risks that may outweigh the benefits. The purpose of this systematic review is to synthesize and critique the existing literature on fully-immersive virtual reality interventions for older adults and the associated risk of cybersickness. METHODS: We searched eight databases for studies that utilized fully-immersive virtual reality, stated the population as older adults, provided outcomes related to cybersickness, and were written or translated into the English language. Our search generated 332 articles, 39 of which were selected for inclusion in this systematic synthesis and appraisal. RESULTS: We found that the majority of studies utilized a one-time session. The studies generally had weak sample generalizability and methodological design, but strong data collection and participant retention. The studies nearly all used the Simulator Sickness Questionnaire to measure cybersickness, but the scoring for the Simulator Sickness Questionnaire varied or was not mentioned. Most included studies reported only minor cybersickness among older adult participants. CONCLUSION: Researchers might conclude that the benefits of virtual reality interventions outweigh the risk of cybersickness in this population. Going forward, researchers should concentrate on the efficacy of virtual reality interventions among older adults, using larger samples and randomized controlled study design, along with measuring dosage effects.

Simulation of vertical dispersion and pollution impact of artificial light at night in urban environment.

The use of artificial light at night (ALAN) enables social and commercial activities for urban living. However, the excessive usage of lighting causes nuisance and waste of energy. Light is provided to illuminate target areas on the street level where activities take place, yet light can also cause trespass to residents at the floors above. While regulations are beginning to cover light design, simulation tools for the outdoor environment have also become more popular for assessing the design condition. Simulation tools allow visualisation of the impact of the selected light sources on those who are affected. However, this cause-and-effect relationship is not easy to determine in the complex urban environment. The current work offers a simple methodology that takes site survey results and correlates them with the simulation model to determine lighting impact on the investigated area in 3D. Four buildings in two mixed commercial and residential streets in Hong Kong were studied. Data collection from each residential building requires lengthy work and permission from each household. Therefore, a valid lighting simulation model could help determine the light pollution impact in the area. A light model using DIALux is developed and calibrated by correlating the simulated data with the actual measured data. The correlation value R2 achieved ranged from 0.95 to 0.99, verifying the accuracy of this model and matched from 340 lx to 46 lx for the lower to higher floors of one building and 10 lx to 4 lx for floors of another building. This model can also be applied to human health research, by providing light-level data on residential windows in an area or determining the environmental impact of a development project.

Clinico-pathological correlations and outcomes of de novo glomerular diseases in patients after haematopoietic stem cell transplantation.

Background: Various glomerular pathologies have been reported in patients who have undergone haematopoietic stem cell transplantation (HSCT), but the data on clinico-pathological correlations and clinical outcome remain limited. Methods: We analysed the clinical and histopathological data of patients who had biopsy-proven de novo glomerular diseases after HSCT since 1999. Results: A total of 2204 patients underwent HSCT during the period 1999-2021, and 31 patients (1.4%) developed de novo glomerular diseases after a mean duration of 2.8 ± 2.7 years after HSCT. Fifteen of these patients (48.4%) had graft-versus-host-disease prior to or concomitant with renal abnormalities. Proteinuria and eGFR at the time of kidney biopsy were 4.1 ± 5.3 g/day and 50.8 ± 25.4 mL/min/1.73 m2, respectively. Kidney histopathologic diagnoses included thrombotic microangiopathy (TMA) (38.7%), membranous nephropathy (MN) (25.8%), mesangial proliferative glomerulonephritis (12.9%), minimal change disease (9.7%), focal segmental glomerulosclerosis (9.7%) and membranoproliferative glomerulonephritis (3.2%). Immunosuppressive treatment was given to patients who presented with nephrotic-range proteinuria and/or acute kidney injury, while renin-angiotensin-aldosterone blockade was given to all patients with proteinuria ≥1 g/day, with complete and partial response rates of 54.8% and 19.4%, respectively. One patient with TMA progressed to end-stage kidney disease after 24 weeks, and two patients, one with TMA and one with MN, (6.4%) progressed to chronic kidney disease (CKD) Stage ≥3. Kidney and patient survival rates were 96.6% and 83.5%, respectively, at 5 years. Conclusion: De novo glomerular diseases with diverse histopathologic manifestations affect 1.4% of patients after HSCT, and approximately 10% develop progressive CKD.

In situ x-ray absorption investigations of a heterogenized molecular catalyst and its interaction with a carbon nanotube support.

A highly active heterogenized molecular CO2 reduction catalyst on a conductive carbon support is investigated to identify if its improved catalytic activity can be attributed to strong electronic interactions between catalyst and support. The molecular structure and electronic character of a [Re+1(tBu-bpy)(CO)3Cl] (tBu-bpy = 4,4'-tert-butyl-2,2'-bipyridine) catalyst deposited on multiwalled carbon nanotubes are characterized using Re L3-edge x-ray absorption spectroscopy under electrochemical conditions and compared to the homogeneous catalyst. The Re oxidation state is characterized from the near-edge absorption region, while structural changes of the catalyst are assessed from the extended x-ray absorption fine structure under reducing conditions. Chloride ligand dissociation and a Re-centered reduction are both observed under applied reducing potential. The results confirm weak coupling of [Re(tBu-bpy)(CO)3Cl] with the support, since the supported catalyst exhibits the same oxidation changes as the homogeneous case. However, these results do not preclude strong interactions between a reduced catalyst intermediate and the support, preliminarily investigated here using quantum mechanical calculations. Thus, our results suggest that complicated linkage schemes and strong electronic interactions with the initial catalyst species are not required to improve the activity of heterogenized molecular catalysts.

Synthesis, structure and reactivity of µ3-SnH capped trinuclear nickel cluster.

Treatment of the trichlorotin-capped trinuclear nickel cluster, [Ni3(dppm)3(µ3-Cl)(µ3-SnCl3)], 1, with 4 eq. NaHB(Et)3 yields a µ3-SnH capped trinuclear nickel cluster, [Ni3(dppm)3(µ3-H)(µ3-SnH)], 2 [dppm = bis(diphenylphosphino)methane]. Single-crystal X-ray diffraction, nuclear magnetic resonance (NMR) spectroscopy, and computational studies together support that cluster 2 is a divalent tin hydride. Complex 2 displays a wide range of reactivity including oxidative addition of bromoethane across the Sn center. Addition of 1 eq. iodoethane to complex 2 releases H2 (g) and generates an ethyltin-capped nickel cluster with a µ3-iodide, [Ni3(dppm)3(µ3-I)(µ3-Sn(CH2CH3))], 4. Notably, insertion of alkynes into the Sn-H bond of 2 can be achieved via addition of 1 eq. 1-hexyne to generate the 1-hexen-2-yl-tin-capped nickel cluster, [Ni3(dppm)3(µ3H)(µ3-Sn(C6H11))], 5. Addition of H2 (g) to 5 regenerates the starting material, 2, and hexane. The formally 44-electron cluster 2 also displays significant redox chemistry with two reversible one-electron oxidations (E = -1.3 V, -0.8 V vs. Fc0/+) and one-electron reduction process (E = -2.7 V vs. Fc0/+) observed by cyclic voltammetry.

PM-IRRAS and DFT investigation of the surface orientation of new Ir piano-stool complexes attached to Au(111).

Surface immobilization of organometallic catalysts is a promising approach to developing new catalytic systems that combine molecular catalysts with heterogenous surfaces to probe surface mechanisms. The orientation of the catalyst relative to the surface is one important parameter that must be considered in such hybrid systems. In this work, we synthesize three new sulfide-modified Ir piano-stool complexes with sulfide-modified bipyridine and phenylpyridine ligands for the attachment to Au(111) surfaces. Self-assembled monolayers made from (Cp*Ir(2,2'-bipyridine-4-sulfide)Cl)2[Cl]2 (C1m) and [Cp*Ir(2-phenylpyridine-4-sulfide)Cl]2 (C2m) were characterized by combining polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS) with DFT calculations of the minimum energy orientations of the complexes on the surface. We find that the bipyridine and phenylpyridine ligands are oriented at between 73-77° relative to the surface normal, irrespective of the orientation of the other ligands. Additionally, DFT and PM-IRRAS support that there is no orientation preference for C1m and C2m, with both orientations present on the surface.

Supportive care and symptom management in patients with advanced hematological malignancies: a literature review.

BACKGROUND AND OBJECTIVE: Recent advances have led to cure or long-term disease control for patients with hematological malignancy (HM). Unfortunately, some of them still have poor prognoses and are often associated with significant symptom burden and poor quality of life for patients and families. These patients usually require supportive care including red blood cell and platelet transfusion, due to disease itself and the oncological treatment, apart from their symptom management. However, there is currently lack of the literatures review in these aspects. The objective of this review is to summarize practical supportive care recommendations for physicians or nurses practicing in palliative care (PC)/hematology-oncology unit, starting with core approaches in use of blood products for anemia and thrombocytopenia, management of tumor lysis syndrome, PC and oncology nursing care. METHODS: Evidence for this review was obtained from a search of the Cochrane database, PubMed, guidelines of European Society of Medical Oncology, British society of Hematology, American Society of Clinical Oncology, National Comprehensive Cancer Network and peer-reviewed journal articles. KEY CONTENT AND FINDINGS: For asymptomatic cancer patients who are anaemic, a threshold of haemoglobin level of 7 g/dL is considered to be safe and generally favored for blood transfusion. 'Single-unit' red cell transfusion is safer and at least as effective as 'double-unit' transfusion. Prophylactic platelet transfusion should be given to stable patients without bleeding and with platelet count less than 10×109/L. In febrile patients, the threshold is lifted to 20×109/L. There are also recommendations for the use of blood products during COVID-19 pandemic. In general, HM patients were more prone to painful infections when compared with solid cancer patients. Thus, antibiotics to treat underlying infections should be applied whenever possible and as required to control pain. CONCLUSIONS: This narrative review showed the recent literatures in the supportive care and symptom management of advanced HM patients. However, it is limited by some of the 'evidence-based' recommendations for interventions (including symptom management) based on early phase of HM populations rather than those receiving end-of-life care.

A Case of Spontaneous Perinephric Hematoma From Rivaroxaban.

Spontaneous perinephric hematoma is an uncommon but serious condition that is typically caused by tumor hemorrhage or vascular disease such as polyarteritis nodosa. We describe a 78-year-old Chinese gentleman with underlying chronic kidney disease, renal cysts, non-obstructive renal stones, hypertension, ischemic heart disease, and atrial fibrillation who was on rivaroxaban and clopidogrel. He developed spontaneous perinephric hematoma complicated by acute kidney injury, anemia, and myocardial infarction who underwent angioembolization and packed cell transfusion. He did not have further bleeding episodes, and his kidney function improved before discharge.

Bendamustine treatment of haematological malignancies: significant risks of opportunistic viral, fungal and bacterial infections.

OBJECTIVES: Bendamustine is a standard treatment for low-grade B-cell lymphomas, and considered safe in clinical trials. Its safety in routine practice might be different. METHODS: We retrospectively analyzed the infection complications in an unselected cohort of patients treated with bendamustine over a nine-year period. Patients were regularly monitored for blood counts and cytomegalovirus (CMV) reactivation by antigen assay and polymerase chain reaction. They received granulocyte colony stimulating factor for neutropenia, and routine anti-pneumocystis and optional anti-fungal prophylaxis. RESULTS: There were 179 men and 127 women at a median age of 61.5 (20-90) years, 52% receiving bendamustine for relapsed/refractory disease. Malignancies included low-grade B-cell lymphomas (54%), myeloma (10%), T-cell lymphomas (11%), Hodgkin lymphoma (2%) and other lymphoid neoplasms (23%). Most patients had good performance status (Eastern Cooperative Oncology Group score: 0-1, 72%). CMV reactivation occurred in 58 patients (19%) at a median age of 68 (39-85) years. Univariate analysis showed CMV reactivation to be significantly associated with elevated lactate dehydrogenase (P = 0.045), decreased albumin (P = 0.003) and older age (reactivation versus no reactivation: 66.3 ± 11.4 versus 59.4 ± 14.5 years, P = 0.0016). Age remained the only significant risk on multivariate analysis. CMV reactivation resulted in retinitis (N = 4), ependymitis/ventriculitis (N = 1) and duodenitis/colitis (N = 1). Invasive fungal disease occurred in five patients (candidemia, N = 2; aspergillosis N = 1; cryptococcemia, N = 1; scedosporiosis, N-1). Nineteen patients had culture positive septicaemia. CONCLUSION: Our observations showed that even with a vigorous anti-infective strategy, bendamustine treatment was still associated with significant risks of bacterial and opportunistic viral and fungal infections.

Eltrombopag as frontline treatment of aplastic anaemia in routine practice: implications on cost and efficacy.

The thrombopoietin mimetic eltrombopag (EPAG) is efficacious in clinical trials of newly diagnosed moderate (M), severe (S) and very severe (vS) aplastic anaemia (AA). Its use in routine practice and resource-constrained settings is not well described. Twenty-five men and 38 women at a median age of 54 (18-86) years with newly diagnosed AA treated consecutively in a 7-year period with EPAG (N = 6), EPAG/cyclosporine (CsA) (N = 33) and EPAG/CsA/anti-thymocyte globulin (ATG) (N = 24) were analyzed. Because EPAG was not reimbursed, peak doses ranged from 25 to 200 mg/day depending on affordability. EPAG/CsA-treated patients were older (median age: 61 years) with less severe AA (MAA, N = 15; SAA, N = 14; vSAA, N = 4), whereas EPAG/CsA/ATG-treated patients were younger (median age: 44 years) with more severe AA (MAA, N = 2; SAA, N = 12, vSAA, N = 10). The overall/trilineage response rates were 83%/50% for EPAG-treated patients; 79%/42% for EPAG/CsA-treated patients and 75%/63% for EPAG/CsA/ATG-treated patients. Adverse events included grade 1 liver derangement (N = 7) and grade 1 dyspepsia (N = 3). The 5-year overall survivals/failure-free survivals were 62%/80% for the entire cohort; 55%/75% for EPAG/CsA-treated patients and 82%/78% for EPAG/CsA/ATG-treated patients. EPAG showed robust efficacy in AA in routine practice. However, EPAG dosage and combinations remain to be optimized for AA of different severities.

The COVID Positive Pathway: a collaboration between public health agencies, primary care, and metropolitan hospitals in Melbourne.

OBJECTIVES: To assess the capacity of the COVID Positive Pathway, a collaborative model of care involving the Victorian public health unit, hospital services, primary care, community organisations, and the North Western Melbourne Primary Health Network, to support people with coronavirus disease 2019 (COVID-19) isolating at home. DESIGN, SETTING, PARTICIPANTS: Cohort study of adults in northwest Melbourne with COVID-19, 3 August - 31 December 2020. MAIN OUTCOME MEASURES: Demographic and clinical characteristics, and social and welfare needs of people cared for in the Pathway, by care tier level. RESULTS: Of 1392 people referred to the Pathway by the public health unit, 858 were eligible for enrolment, and 711 consented to participation; 647 (91%) remained in the Pathway until they had recovered and isolation was no longer required. A total of 575 participants (81%) received care in primary care, mostly from their usual general practitioners; 155 people (22%) received care from hospital outreach services, and 64 (9%) needed high tier care (hospitalisation). Assistance with food and other basic supplies was required by 239 people in the Pathway (34%). CONCLUSIONS: The COVID Positive Pathway is a feasible multidisciplinary, tiered model of care for people with COVID-19. About 80% of participants could be adequately supported by primary care and community organisations, allowing hospital services to be reserved for people with more severe illness or with risk factors for disease progression. The principles of this model could be applied to other health conditions if regulatory and funding barriers to information-sharing and care delivery by health care providers can be overcome.

Learning from work-from-home issues during the COVID-19 pandemic: Balance speaks louder than words.

During the 2019 novel coronavirus disease (COVID-19) pandemic, many employees have switched to working from home. Despite the findings of previous research that working from home can improve productivity, the scale, nature, and purpose of those studies are not the same as in the current situation with the COVID-19 pandemic. We studied the effects that three stress relievers of the work-from-home environment-company support, supervisor's trust in the subordinate, and work-life balance-had on employees' psychological well-being (stress and happiness), which in turn influenced productivity and engagement in non-work-related activities during working hours. In order to collect honest responses on sensitive questions or negative forms of behavior including stress and non-work-related activities, we adopted the randomized response technique in the survey design to minimize response bias. We collected a total of 500 valid responses and analyzed the results with structural equation modelling. We found that among the three stress relievers, work-life balance was the only significant construct that affected psychological well-being. Stress when working from home promoted non-work-related activities during working hours, whereas happiness improved productivity. Interestingly, non-work-related activities had no significant effect on productivity. The research findings provide evidence that management's maintenance of a healthy work-life balance for colleagues when they are working from home is important for supporting their psychosocial well-being and in turn upholding their work productivity.