End-to-end physics-informed deep neural network optimization of sub-Nyquist lenses.

In this paper, an approach for optimizing sub-Nyquist lenses using an end-to-end physics-informed deep neural network is presented. The simulation and optimization of these sub-Nyquist lenses is investigated for image quality, classification performance, or both. This approach integrates a diffractive optical model with a deep learning classifier, forming a unified optimization framework that facilitates simultaneous simulation and optimization. Lenses in this work span numerical apertures from approximately 0.1 to 1.0, and a total of 707 models are trained using the PyTorch-Lightning deep learning framework. Results demonstrate that the optimized lenses produce better image quality in terms of mean squared error (MSE) compared to analytical lenses by reducing the impact of diffraction order aliasing. When combined with the classifier, the optimized lenses show improved classification performance and reduced variability across the focal range. Additionally, the absence of correlation between the MSE measurement of image quality and classification performance suggests that images that appear good according to the MSE metric may not necessarily be beneficial for the classifier.

Burnout and compassion fatigue among Exercise Physiologists in mental healthcare.

BACKGROUND: Burnout and compassion fatigue (CF) are common among mental health practitioners. Accredited Exercise Physiologists (AEPs) provide clinical services to individuals experiencing mental illness, increasing their likelihood of experiencing burnout and CF. AIMS: To examine the prevalence of burnout and CF among AEPs working with people experiencing mental illness. METHODS: An anonymous online cross-sectional survey of AEPs working with people experiencing mental illness was distributed via the Exercise and Sports Science Australia Mental Health Special Interest Group Facebook page between July and November 2019. In addition to demographics and caseload data, respondents completed the Professional Quality of Life scale and Oldenburg Burnout Inventory (OLBI). Results are reported using descriptive statistics. RESULTS: Sixty-two AEPs (68%, n = 42 female) completed the survey. Most (n = 53, 86%) reported delivering services to consumers with severe mental health conditions. Less than half (n = 27, 44%) reported working in a dedicated mental health facility. Moderate levels of burnout and CF were experienced by 60% and 30% of respondents, respectively. CONCLUSIONS: The prevalence of moderate burnout and CF symptoms in AEPs is comparable with other mental health professionals. Strategies to preserve psychological well-being such as enhancing mental health training for undergraduates and formalized supervision structures discussed.

Bone marrow failure and extramedullary hematopoiesis in McCune-Albright syndrome.

In fibrous dysplasia/McCune-Albright syndrome (FD/MAS), bone and bone marrow are, to varying degrees, replaced by fibro-osseous tissue typically devoid of hematopoietic marrow. Despite the extensive marrow replacement in severely affected patients, bone marrow failure is not commonly associated with FD/MAS. We present a 14-year-old girl with FD/MAS, who developed pancytopenia and extramedullary hematopoiesis (EMH) with no identified cause, in the setting of iatrogenic thyrotoxicosis and hyperparathyroidism. Pancytopenia, requiring monthly blood transfusions, persisted despite multiple strategies to correct these endocrinopathies. Due to worsening painful splenomegaly, likely as a result of sequestration, splenectomy was performed. Following splenectomy, pancytopenia resolved and patient has since been transfusion-independent. We report the first detailed case of bone marrow failure and EMH in FD/MAS. The etiology of marrow failure is likely multifactorial and related to the loss of marrow reserve due to extensive polyostotic FD, exacerbated by iatrogenic thyrotoxicosis and hyperparathyroidism. Mini Abstract: A patient with fibrous dysplasia developed bone marrow failure and extramedullary hematopoiesis. The etiology likely involved loss of hematopoetic marrow space and uncontrolled endocrinopathies. Splenectomy was therapeutic.

Maresins: Specialized Proresolving Lipid Mediators and Their Potential Role in Inflammatory-Related Diseases.

Acute inflammatory responses are host-protective and normally self-limited; these responses can maintain cell homeostasis and promote defense against various infections and damage factors. However, when improperly managed or inappropriately activated, acute inflammation can lead to persistent and uncontrolled chronic inflammation, which is associated with many other chronic diseases including cardiovascular disease and metabolic disease. Recently, studies have shown that resolution of acute inflammation is a biosynthetically active process. Specialized proresolving lipid mediators (SPMs) known as resolvins and protectins are autacoids that resolve inflammation. A new family of anti-inflammatory and proresolving lipid mediators have recently been reported, known as maresins, which are biosynthesized from docosahexaenoic acid (DHA) by macrophages, have a conjugated double-bond system, and display strong anti-inflammatory and proresolving activity. Here, we review the biological actions, pathways, and mechanisms of maresins, which may play pivotal roles in the resolution of inflammation.

Sustaining competition for biosimilars on the pharmacy benefit: Use it or lose it.

Congress passed the Biologic Price Competition and Innovation Act of 2009, specifically to offer market competition as a counterweight to the rising costs of biologic medicines. As of April 15, 2024, 49 biosimilars have been approved by the US Food and Drug Administration in 15 biologic categories. Biosimilar competition has been undeniably successful: Through 2022, biosimilars have saved the US health system $23.6 billion, without significant care disruption or reduced quality. Through 2023, adalimumab biosimilar competition has added an additional $6.5 billion to this total, primarily through greater rebates from the reference manufacturer. Despite launching at discounts as great as 85%, adalimumab biosimilars have not been given preferred formulary positioning in the vast majority of cases and have thus gained only 3% of market share through 2023, largely because of payers' and pharmacy benefit managers' preference for rebates over discounts. This situation may negatively influence future biosimilar development, posing a threat to a biosimilar pipeline that represents hundreds of billions in savings over the next 10 years.

Impact of artificial accelerated ageing of PVC surfaces and surface degradation on disinfectant efficacy.

BACKGROUND: Standardized efficacy surface tests for disinfectants are performed on pristine surfaces. There is a growing interest in understanding the impact of surface ageing on disinfectant activity, owing for example to the increased usage of ultraviolet (UV) radiation and oxidative chemistries for surface decontamination. This acknowledges that general surface 'wear and tear' following UV radiation and oxidative biocide exposure may impact biocidal product efficacy. METHODS: PVC surfaces were aged through thermal and UV-A radiation (340 nm wavelength) following the use of standard ageing surface protocols to simulate natural surface degradation. Surface roughness, contact angle and scanning electron microscopy were performed to evaluate physical changes in PVC surfaces before and after artificial ageing. The efficacy of five pre-impregnated disinfectant wipes were evaluated using the ASTM E2967-15 on stainless-steel (control) and PVC surfaces (aged and non-aged). RESULTS: The type of formulation and the organism tested remained the most significant factors impacting disinfectant efficacy, compared with surface type. Both thermal ageing and UV-A exposure of PVC surfaces clearly showed signs of surface degradation, notably an increase in surface roughness. Physical changes were observed in the roughness of PVC after artificial ageing. A difference in disinfectant efficacy dependent on aged PVC surfaces was observed for some, but not all formulations. CONCLUSION: We showed that surface type and surface ageing can affect biocidal product efficacy, although in a non-predictable manner. More research is needed in this field to ascertain whether surface types and aged surfaces should be used in standardized efficacy testing.

Evaluating the antimicrobial efficacy of long-lasting hand sanitizers on skin.

BACKGROUND: The microbicidal efficacy of hand sanitizer formulations is usually measured through standardized quantitative suspension tests and fingerpad tests; these cannot evaluate long-lasting formulations or are impractical due to biological risks, high cost, or time required for testing. With increased numbers of long-lasting microbicidal activity claims of commercially available hand sanitizers, alternative testing strategies are required. AIM: To explore the use of a standardized ex-vivo pig skin model to reproducibly measure long-lasting efficacy of an alcohol-free hand sanitizer formulation. METHODS: The microbicidal efficacy of an alcohol-free hand sanitizer was tested against Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae, and the enveloped virus SARS-CoV-2 with quantitative suspension tests (EN13727 and EN14476) with a contact time of 5 min. The product was then tested over a 6 h period using an ex-vivo pig skin model with a modified version of PAS 2424 to simulate the impact of skin abrasion. FINDINGS: Quantitative suspension tests yielded a >5 log10 reduction for all organisms tested within a 5 min contact time. Pig skin tests showed reduced but consistent efficacy at all time points and indicated no significant impact of abrasion on efficacy. CONCLUSION: The use of the ex-vivo pig skin model provides a potentially viable and convenient model system to test long-lasting hand sanitizer formulations, providing a path for sustainable hand sanitizer formulation claims of activity on skin.

IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses.

Interferon-induced transmembrane protein 3 (IFITM3) is a restriction factor that limits viral pathogenesis and exerts poorly understood immunoregulatory functions. Here, using human and mouse models, we demonstrate that IFITM3 promotes MyD88-dependent, TLR-mediated IL-6 production following exposure to cytomegalovirus (CMV). IFITM3 also restricts IL-6 production in response to influenza and SARS-CoV-2. In dendritic cells, IFITM3 binds to the reticulon 4 isoform Nogo-B and promotes its proteasomal degradation. We reveal that Nogo-B mediates TLR-dependent pro-inflammatory cytokine production and promotes viral pathogenesis in vivo, and in the case of TLR2 responses, this process involves alteration of TLR2 cellular localization. Nogo-B deletion abrogates inflammatory cytokine responses and associated disease in virus-infected IFITM3-deficient mice. Thus, we uncover Nogo-B as a driver of viral pathogenesis and highlight an immunoregulatory pathway in which IFITM3 fine-tunes the responsiveness of myeloid cells to viral stimulation.

Dissociation of intracellular lysosomal rupture from the cell death caused by silica.

The relationship between intracellular lysosomal rupture and cell death caused by silica was studied in P388d(1) macrophages. After 3 h of exposure to 150 mug silica in medium containing 1.8 mM Ca(2+), 60 percent of the cells were unable to exclude trypan blue. In the absence of extracellular Ca(2+), however, all of the cells remained viable. Phagocytosis of silica particles occurred to the same extent in the presence or absence of Ca(2+). The percentage of P388D(1) cells killed by silica depended on the dose and the concentration of Ca(2+) in the medium. Intracellular lyosomal rupture after exposure to silica was measured by acridine orange fluorescence or histochemical assay of horseradish peroxidase. With either assay, 60 percent of the cells exposed to 150 mug silica for 3 h in the presence of Ca(2+) showed intracellular lysosomal rupture, was not associated with measureable degradation of total DNA, RNA, protein, or phospholipids or accelerated turnover of exogenous horseradish peroxidase. Pretreatment with promethazine (20 mug/ml) protected 80 percent of P388D(1) macrophages against silica toxicity although lysosomal rupture occurred in 60-70 percent of the cells. Intracellular lysosomal rupture was prevented in 80 percent of the cells by pretreatment with indomethacin (5 x 10(-5)M), yet 40-50 percent of the cells died after 3 h of exposure to 150 mug silica in 1.8 mM extracellular Ca(2+). The calcium ionophore A23187 also caused intracellular lysosomal rupture in 90-98 percent of the cells treated for 1 h in either the presence or absence of extracellular Ca(2+). With the addition of 1.8 mM Ca(2+), 80 percent of the cells was killed after 3 h, whereas all of the cells remained viable in the absence of Ca(2+). These experiments suggest that intracellular lysosomal rupture is not causally related to the cell death cause by silica or A23187. Cell death is dependent on extracellular Ca(2+) and may be mediated by an influx of these ions across the plasma membrane permeability barrier damaged directly by exposure to these toxins.

Who will take responsibility for obesity in Australia?

Obesity is increasing throughout the world. With its strong links to many health problems, the costs associated with obesity will strain future health budgets. Urgent action on obesity is needed and this needs to extend beyond treatment. Diets may work in the short term but their long-term success is poor. Bariatric surgery can be effective, but it is expensive and its long-term effects are unknown. Common sense dictates that attention should be focused on preventing obesity. Experience with other public health measures, such as reducing cigarette smoking, indicates that government intervention will be essential for success in preventing obesity. In practice, however, governments are reluctant to take responsibility for this multi-factorial problem that is exacerbated by modern lifestyles because it involves standing up to vested interests. The real need is to take action to alter food consumption patterns, change transport options and reform urban planning (including housing and workplace environments), so that healthy choices are easy and physical activity returns to being a normal part of everyday life.

Biosimilars in the USA: Will New Efforts to Spur Approvals and Access Spur Uptake and Cost Savings?

Unlike in Europe, US healthcare systems and payers are still awaiting significant savings related to biosimilar utilization. Costs related to biologic use continue to rise at double-digit rates, and biosimilars are seen as a major tool to control costs and increase access to biologic drugs. However, one 2018 report indicated that US$3.2 billion (only 3%) of biologic spending is subject to competition from biosimilar products. Although the European Medicines Agency did a great deal of pioneering work in biosimilar regulation, the US Food and Drug Administration is moving at approximately the same pace as the European Medicines Agency, based on the number of approvals at the same time after implementation of its regulatory pathway. Several unique factors in the USA have conspired to limit biosimilar access (e.g. delayed regulatory policies, extended patent litigation activities, federal reimbursement policies, the widespread use of rebate contracting, and limited competition). The US Federal Government is taking the initiative in an attempt to address these factors, and speed both biosimilar development and patient access. To date, the most significant cost savings in the US system associated with the introduction of biosimilars may be their ability to halt price increases of the reference product. The complexity of the healthcare delivery system, and how it is financed, will remain challenging to payers, manufacturers, health providers and patients as they seek ways to manage health expenditure growth.

The efficacy and safety of SGLT2 inhibitors for adjunctive treatment of type 1 diabetes: a systematic review and meta-analysis.

To assess the efficacy and safety of the SGLT-2 inhibitors as adjunct therapy to insulin in T1DM, clinical trials indexed in PubMed, Cochrane Library, EMbase from inception through April 5, 2016. A meta-analysis was conducted on trials of SGLT-2 inhibitors in patients with T1DM on insulin therapy using RevMan 5.3 software. Of the 371 articles identified, ten met eligibility criteria. Seven clinical trials including four randomized controlled trials and 581 patients were included. Compared with the control group, SGLT-2 inhibitors group had significantly reduced fasting plasma glucose by 0.69 mmol/L [1.32; 0.07], glycosylated hemoglobin A1C by 0.37% [0.54; 0.20], body weight by 2.54 kg [3.48; 1.60] and total daily insulin dose by 6.22 IU [8.04; 4.40]. The total incidence of adverse events (AEs), hypoglycemia, and genital and urinary infections were also similar to placebo, while an increased incidence of diabetic ketoacidosis (DKA) (n = 16) was seen in SGLT-2 inhibitors group. The present study demonstrates that SGLT-2 inhibitors are effective as adjunct therapy to insulin in T1DM, heralding improved glycemic control, reduced body weight and total daily insulin dose without an increase in total AEs, hypoglycemia, or genital and urinary infections. However, the risk of DKA should be carefully monitored in future clinical trials.

The evolutionary role of the pharmacy and therapeutics committee in technology assessment.

The origins of the Pharmacy and Therapeutics (P&T) Committee is intertwined with the evolution of the modern practice of pharmacy. Although the P&T Committee has been uniquely developed to help make coverage decisions, this implies that its technology assessment function, particularly with regard to medicines, has paved the way to more cost-effective and evidence-based practice. This article, which briefly traces the lineage of the first known "formulary" employed during the Revolutionary War to today's P&T Committee, argues that its true function--technology assessment--serves as the basis for coverage decisions throughout health systems.

Diabetic Kidney Disease and Hypertension.

Achieving blood pressure (BP) goals is an essential goal for both primary and secondary prevention of diabetic kidney disease (DKD). Even though there is universal agreement about the importance of controlling BP, there are many issues about many aspects of hypertension management for DKD patients. These issues include: what is the optimal BP for the prevention or slowing of progression of DKD patients; what is the best method for diagnosing hypertension and monitoring BP, and what are the best medicines to use to treat hypertension in DKD patients. In this review, these issues as well as others will be discussed.

Will the PCSK9 Inhibitors Be Employers' "Line in the Sand"?

After the introductions of sofosbuvir (Sovaldi) and ledipasvir plus sofosbuvir (Harvoni) for the treatment of hepatitis C, employers have become very sensitive to new, and especially unforeseen, factors that significantly raise healthcare costs. With the recent launch of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, self-insured and fully insured employers have been seeking information on this drug class and its potential for off-label use, which could amount to up to $23 billion in healthcare expenditures, according to a report from Prime Therapeutics. Based on their approved indications, 0.4% of commercial members may be eligible to use PCSK9 inhibitors, at a cost of $3.29 per member per month. Corporate employers are evaluating their options to manage the new expense associated with the novel PCSK9 inhibitors.

Payer Perspectives on PCSK9 Inhibitors: A Conversation with Stephen Gorshow, MD, and James T. Kenney, RPh, MBA.

The new proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can have significant budget effects, depending on the breadth of the US Food and Drug Administration (FDA)'s approved labeling. American Health & Drug Benefits asked Stephen Gorshow, MD, Regional Medical Director, UnitedHealthcare, and James T. Kenney, RPh, MBA, Manager, Specialty and Pharmacy Contracts, Harvard Pilgrim Health Care, to participate in a teleconference to better understand how payers are approaching the management of these agents.

Is a Biologic Produced 15 Years Ago a Biosimilar of Itself Today?

Much of the testing required for the regulatory approval of a biosimilar is focused on proving that the new drug is sufficiently similar to the reference biologic in structure, pharmacokinetics or pharmacodynamics, clinical efficacy, and safety. However, the reference drug may itself have gone through some changes in the years since its approval, including those caused by alterations in the manufacturing process. Do these changes increase the risk that the reference drug may cause unexpected outcomes? It is up to the US Food and Drug Administration to decide whether the changes merit the need for additional studies to confirm that the drug meets the structural or clinical outcomes standard for the reference agent. Although it is extremely rare, a change in the production of one biologic drug (ie, epoetin alfa) did result in unanticipated serious immunologic side effects.

Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries.

UNLABELLED: Infection with human cytomegalovirus (HCMV) profoundly affects cellular metabolism. Like in tumor cells, HCMV infection increases glycolysis, and glucose carbon is shifted from the mitochondrial tricarboxylic acid cycle to the biosynthesis of fatty acids. However, unlike in many tumor cells, where aerobic glycolysis is accompanied by suppression of mitochondrial oxidative phosphorylation, HCMV induces mitochondrial biogenesis and respiration. Here, we affinity purified mitochondria and used quantitative mass spectrometry to determine how the mitochondrial proteome changes upon HCMV infection. We found that the mitochondrial transcription and translation systems are induced early during the viral replication cycle. Specifically, proteins involved in biogenesis of the mitochondrial ribosome were highly upregulated by HCMV infection. Inhibition of mitochondrial translation with chloramphenicol or knockdown of HCMV-induced ribosome biogenesis factor MRM3 abolished the HCMV-mediated increase in mitochondrially encoded proteins and significantly impaired viral growth under bioenergetically restricting conditions. Our findings demonstrate how HCMV manipulates mitochondrial biogenesis to support its replication. IMPORTANCE: Human cytomegalovirus (HCMV), a betaherpesvirus, is a leading cause of morbidity and mortality during congenital infection and among immunosuppressed individuals. HCMV infection significantly changes cellular metabolism. Akin to tumor cells, in HCMV-infected cells, glycolysis is increased and glucose carbon is shifted from the tricarboxylic acid cycle to fatty acid biosynthesis. However, unlike in tumor cells, HCMV induces mitochondrial biogenesis even under aerobic glycolysis. Here, we have affinity purified mitochondria and used quantitative mass spectrometry to determine how the mitochondrial proteome changes upon HCMV infection. We find that the mitochondrial transcription and translation systems are induced early during the viral replication cycle. Specifically, proteins involved in biogenesis of the mitochondrial ribosome were highly upregulated by HCMV infection. Inhibition of mitochondrial translation with chloramphenicol or knockdown of HCMV-induced ribosome biogenesis factor MRM3 abolished the HCMV-mediated increase in mitochondrially encoded proteins and significantly impaired viral growth. Our findings demonstrate how HCMV manipulates mitochondrial biogenesis to support its replication.

Barriers to exercise prescription and participation in people with mental illness: the perspectives of nurses working in mental health.

ACCESSIBLE SUMMARY: Exercise is valuable in the treatment of mental illness, yet personal and organizational barriers limit widespread implementation by nurses in mental health settings. Using a self-report questionnaire, we sought to identify how often nurses prescribe exercise and their level of agreement with previously identified barriers to exercise prescription and participation for mental health consumers. Nurses disagree that many of the previously identified barriers should impede exercise prescription for people with mental illness. Nurses agree that many of the barriers expressed by mental health consumers might prevent exercise participation. Our study provides valuable new insight into the role of nurses in the provision of exercise for people with mental illness; however, it is limited to a small sample. Confirmation of these findings in larger, geographically and professionally diverse groups is needed. ABSTRACT: Evidence is mounting for the efficacy of exercise in the treatment of people with mental illness. Nurses working in mental health settings are well placed to provide exercise advice for people with mental illness. However, quantitative examinations of the barriers to exercise prescription experienced by nurses, or their views regarding the barriers to exercise participation experienced by people with mental illness, are lacking. In this study, 34 nurses completed the Exercise in Mental Illness Questionnaire-Health Professionals Version (EMIQ-HP). This survey examined the frequency of exercise prescription and the level of agreement with statements regarding barriers to exercise prescription for, and exercise participation by, people with mental illness. The level of agreement scores for statements for each section was summed, with a higher score indicating a higher level of agreement. Nurses disagree with many of the barriers to exercise prescription presented in the literature. The level of agreement scores did not differ between nurses who prescribe exercise 'Always', 'Most of the time', 'Occasionally' or 'Never'. We found a non-significant negative relationship between frequency of exercise prescription and summed level of agreement scores for barriers to exercise prescription. Consensus regarding barriers to exercise participation by mental health consumers is less clear. This study provides valuable new insight into the role of nurses in the provision of exercise for people with mental illness. Confirmation in larger samples is needed before translation of research to practice.

Reviewing the Unmet Needs of Patients with Multiple Sclerosis.

Significant innovations in the treatment of patients with multiple sclerosis (MS) have primarily addressed the frequency of flare-ups in relapsing-remitting MS (RRMS). Many advances have been made in this area, and the medical community may be on the verge of a serious discussion of what constitutes a truly effective MS treatment. Certainly, it is important to further delay MS flare-ups and more effectively treat RRMS symptoms. However, great strides in reducing or preventing MS-related disability and providing neuroprotection have been elusive. Many unmet needs are still voiced by patients with MS, clinicians, and caregivers. Current information on the need for progress in various areas is reviewed in this article, including psychosocial care, treatments for progressive MS, biomarker identification, functional outcome measures, individualization of treatment, reducing side effects of medications, and improving medication adherence.