bluuebunny/crossref_metadata_2025 huggingface dataset:
SENP6 induces microglial polarization and neuroinflammation through de-SUMOylation of Annexin-A1 after cerebral ischaemia–reperfusion injury
Authors: Mao Meng , Xia Qian , Zhan Gao-Feng , Chu Qin-Jun , Li Xing , Lian Hong-Kai
Published: July 2022

Background

Previous data have reported that Sentrin/SUMO-specific protease 6 (SENP6) is involved in ischaemic brain injury and induces neuronal apoptosis after cerebral ischaemia, but the role of SENP6 in microglia-induced neuroinflammation and its underlying mechanism remain poorly understood. This research systematically explored the function and potential mechanism of SENP6 in microglia-induced neuroinflammation after ischaemic stroke.

Results

We first identified an increased protein level of SENP6 in microglia after cerebral ischaemia. Then, we demonstrated that SENP6 promoted detrimental microglial phenotype polarization. Specifically, SENP6-mediated de-SUMOylation of ANXA1 targeted the IκB kinase (IKK) complex and selectively inhibited the autophagic degradation of IKKα in an NBR1-dependent manner, activating the NF-κB pathway and enhancing proinflammatory cytokine expression. In addition, downregulation of SENP6 in microglia effectively reduced cocultured neuronal damage induced by ischaemic stroke. More importantly, we employed an AAV-based technique to specifically knockdown SENP6 in microglia/macrophages, and in vivo experiments showed that SENP6 inhibition in microglia/macrophages notably lessened brain ischaemic infarct size, decreased neurological deficit scores, and ameliorated motor and cognitive function in mice subjected to cerebral ischaemia surgery.

Conclusion

We demonstrated a previously unidentified mechanism by which SENP6-mediated ANXA1 de-SUMOylation regulates microglial polarization and our results strongly indicated that in microglia, inhibition of SENP6 may be a crucial beneficial therapeutic strategy for ischaemic stroke.

Graphical Abstract
FBXL17/spastin axis as a novel therapeutic target of hereditary spastic paraplegia
Authors: Kang Hyun Mi , Kim Dae Hun , Kim Mijin , Min Yoohong , Jeong Bohyeon , Noh Kyung Hee , Lee Da Yong , Cho Hyun-Soo , Kim Nam-Soon , Jung Cho-Rok , Lim Jung Hwa
Published: July 2022

Background

Spastin significantly influences microtubule regulation in neurons and is implicated in the pathogenesis of hereditary spastic paraplegia (HSP). However, post-translational regulation of the spastin protein remains nebulous. The association between E3 ubiquitin ligase and spastin provides a potential therapeutic strategy.

Results

As evidenced by protein chip analysis, FBXL17 inversely correlated with SPAST-M1 at the protein level in vitro and, also in vivo during embryonic developmental stage. SPAST-M1 protein interacted with FBXL17 specifically via the BTB domain at the N-terminus of SPAST-M1. The SCFFBXL17 E3 ubiquitin ligase complex degraded SPAST-M1 protein in the nuclear fraction in a proteasome-dependent manner. SPAST phosphorylation occurred only in the cytoplasmic fraction by CK2 and was involved in poly-ubiquitination. Inhibition of SCFFBXL17 E3 ubiquitin ligase by small chemical and FBXL17 shRNA decreased proteasome-dependent degradation of SPAST-M1 and induced axonal extension. The SPAST Y52C mutant, harboring abnormality in BTB domain could not interact with FBXL17, thereby escaping protein regulation by the SCFFBXL17 E3 ubiquitin ligase complex, resulting in loss of functionality with aberrant quantity. Although this mutant showed shortening of axonal outgrowth, low rate proliferation, and poor differentiation capacity in a 3D model, this phenotype was rescued by inhibiting SCFFBXL17 E3 ubiquitin ligase.

Conclusions

We discovered that a novel pathway, FBXL17-SPAST was involved in pathogenicity of HSP by the loss of function and the quantitative regulation. This result suggested that targeting FBXL17 could provide new insight into HSP therapeutics.
Alternative transcription start sites contribute to acute-stress-induced transcriptome response in human skeletal muscle
Authors: Makhnovskii Pavel A. , Gusev Oleg A. , Bokov Roman O. , Gazizova Guzel R. , Vepkhvadze Tatiana F. , Lysenko Evgeny A. , Vinogradova Olga L. , Kolpakov Fedor A. , Popov Daniil V.
Published: July 2022

Background

More than half of human protein-coding genes have an alternative transcription start site (TSS). We aimed to investigate the contribution of alternative TSSs to the acute-stress-induced transcriptome response in human tissue (skeletal muscle) using the cap analysis of gene expression approach. TSSs were examined at baseline and during recovery after acute stress (a cycling exercise).

Results

We identified 44,680 CAGE TSS clusters (including 3764 first defined) belonging to 12,268 genes and annotated for the first time 290 TSSs belonging to 163 genes. The transcriptome dynamically changes during the first hours after acute stress; the change in the expression of 10% of genes was associated with the activation of alternative TSSs, indicating differential TSSs usage. The majority of the alternative TSSs do not increase proteome complexity suggesting that the function of thousands of alternative TSSs is associated with the fine regulation of mRNA isoform expression from a gene due to the transcription factor-specific activation of various alternative TSSs. We identified individual muscle promoter regions for each TSS using muscle open chromatin data (ATAC-seq and DNase-seq). Then, using the positional weight matrix approach we predicted time course activation of “classic” transcription factors involved in response of skeletal muscle to contractile activity, as well as diversity of less/un-investigated factors.

Conclusions

Transcriptome response induced by acute stress related to activation of the alternative TSSs indicates that differential TSSs usage is an essential mechanism of fine regulation of gene response to stress stimulus. A comprehensive resource of accurate TSSs and individual promoter regions for each TSS in muscle was created. This resource together with the positional weight matrix approach can be used to accurate prediction of TFs in any gene(s) of interest involved in the response to various stimuli, interventions or pathological conditions in human skeletal muscle.
Impact of the COVID-19 Pandemic on Exercise Physiology Services in Australia: A Retrospective Audit
Authors: Owen Patrick J. , Keating Shelley E. , Askew Christopher D. , Clanchy Kelly M. , Jansons Paul , Maddison Ralph , Maiorana Andrew , McVicar Jenna , Robinson Suzanne , Mundell Niamh L.
Published: July 2022

Introduction

The COVID-19 pandemic has led to a shift in healthcare towards telehealth delivery, which presents challenges for exercise physiology services. We aimed to examine the impact of the COVID-19 pandemic on the reach, efficacy, adoption and implementation of telehealth delivery for exercise physiology services by comparing Australian practises before (prior to 25 January 2020) and during the COVID-19 pandemic (after 25 January 2020).

Methods

This retrospective audit included 80 accredited exercise physiology clinicians. We examined relevant dimensions of the RE-AIM framework (reach, effectiveness, adoption and implementation) from the clinician perspective.

Results

During the COVID-19 pandemic, 91% (n = 73/80) of surveyed clinicians offered telehealth delivery service, compared to 25% (n = 20/80) prior. Mean (SD) telehealth delivery per week doubled from 5 (7) to 10 (8) hours. In-person delivery decreased from 23 (11) to 15 (11) hours per week. Typical reasons for not offering telehealth delivery were client physical/cognitive incapacity (n = 33/80, 41%) and safety (n = 24/80, 30%). Clinician-reported reasons for typical clients not adopting telehealth delivery were personal preference (n = 57/71, 80%), physical capacity (n = 35/71, 49%) and access to reliable delivery platforms (n = 27/71, 38%). Zoom (n = 54/71, 76%) and telephone (n = 53/71, 75%) were the most commonly used platforms. Of the reasons contributing to incomplete treatment, lack of confidence in delivery mode was sevenfold higher for telehealth compared to in-person delivery. No serious treatment-related adverse events were reported.

Conclusions

During the COVID-19 pandemic, telehealth delivery of exercise physiology services increased and in-person delivery decreased, which suggests the profession was adaptable and agile. However, further research determining comparative efficacy and cost-effectiveness is warranted.
Coacervate-mediated novel pancreatic cancer drug
Aleuria Aurantia
lectin delivery for augmented anticancer therapy
Authors: Kim Sungjun , Choi Yunyoung , Kim Kyobum
Published: July 2022

Background

Pancreatic cancer, one of the cancers with the highest mortality rate, has very limited clinical treatment. Cancer cells express abnormal glycans on the surface, and some lectins with a high affinity for the glycans induce apoptosis in cancer. In this study, the efficacy of
Aleuria Aurantia
lectin (AAL) for the treatment of pancreatic cancer was evaluated and the efficacy improvement through AAL delivery with mPEGylated coacervate (mPEG-Coa) was investigated.

Methods

AAL was treated with pancreatic cancer cells, PANC-1, and the expression level of caspase-3 and subsequent apoptosis was analyzed. In particular, the anticancer efficacy of AAL was compared with that of concanavalin A, one of the representative anticancer lectins. Then, methoxypolyethylene glycol-poly(ethylene arginylaspartate diglyceride), a polycation, was synthesized, and an mPEG-Coa complex was prepared with polyanion heparin. The AAL was incorporated into the mPEG-Coa and the release kinetics of the AAL from the mPEG-Coa and the cargo protection capacity of the mPEG-Coa were evaluated. Finally, improved anticancer ability through Coa-mediated AAL delivery was assessed.

Results

These results indicated that AAL is a potential effective pancreatic cancer treatment. Moreover, mPEG-Coa rapidly released AAL at pH 6.5, an acidic condition in the cancer microenvironment. The initial rapid release of AAL effectively suppressed pancreatic cancer cells, and the continuous supply of AAL through the Coa transporter effectively inhibited proliferation recurrence of cancer cells.

Conclusion

AAL is a potential novel drug for the treatment of pancreatic cancer therapeutic agent. In addition, a continuous supply of drugs above the therapeutic threshold using mPEG-Coa could improve therapeutic efficacy.
Urinary dipeptidyl peptidase-4 is a useful marker for tubulitis, and it is released from the tubular cells of kidney transplant recipients
Authors: Yamagishi Atsushi , Nishida Hayato , Ito Hiromi , Fukuhara Hiroki , Tsuchiya Norihiko
Published: July 2022

Background

Biomarkers are needed to diagnose kidney rejection in transplant recipients. We evaluated whether dipeptidyl peptidase-4 (DPP-4) could serve as a biomarker of rejection.

Methods

We determined DPP-4 concentrations and enzymatic activities in serum and urine, as well as DPP-4 expression in 49 kidney biopsy samples from 28 kidney transplant recipients. This study was approved by the ethical standards of the institutional research committee and comply with Helsinki declaration. All patients provided their informed consent. Donors were not from prisoners and were not paid or coerced.

Results

Serum and urinary DPP-4 activities closely correlated with DPP-4 concentrations, but were suppressed by DPP-4 inhibitors. Urinary DPP-4 concentrations increased with acute T cell-mediated rejection (ATCMR; p = 0.030) and higher Banff t and i scores (p < 0.001), and correlated with urinary protein/creatinine ratios (r = 0.450), and inversely with estimated glomerular filtration rate (r =  − 0.604). The area under the receiver operator characteristics curves for urinary DPP-4 concentrations with either Banff t3 or i3 scores were 0.811 (95% confidence interval: 0.687–0.934). The expression of DPP-4 in renal tubular cells was decreased in patients with ATCMR and higher in those with Banff t, i, ct, ci, ah, and ti scores, but was not associated with interstitial fibrosis/tubular atrophy.

Conclusions

We speculated that ATCMR leads to DPP-4 release from tubular cells into urine, resulting in a decrease in tubular cell expression. If so, then ATCMR would induce the elevation of urinary DPP-4 and could therefore serve as a biomarker of tubulitis.
Safeguarding equitable HIV service delivery at the health facility-level in a resource-limited setting during the pandemic
Authors: Tactacan-Abrenica Rosario Jessica , Almonte Dennis Gregg , Agrupis Kristal An , Malijan Greco Mark , Suzuki Shuichi , dela Cruz Ralph , Valdez Rich King , Arcangel Lalaine , Ariyoshi Koya , Smith Chris
Published: July 2022

The COVID-19 pandemic had a severe impact on delivering essential health services, including HIV service delivery. Among the challenges encountered and addressed by the HIV and AIDS Department of the San Lazaro Hospital were ensuring continued access to antiretroviral therapy and ensuring continuity of client education and empowerment. Two years into the pandemic, challenges still ensue, such as protecting health care providers from COVID-19 and regular clinical monitoring of clients. This highlights the importance of urgent action to strengthen the resilience of health systems at all its levels, not only to respond to sudden disturbances, but also to transform and evolve to be able to better face future pandemics.
How does face mask in COVID-19 pandemic disrupt face learning and recognition in adults with autism spectrum disorder?
Authors: Tso Ricky V. , Chui Celine O. , Hsiao Janet H.
Published: July 2022

Use of face masks is one of the measures adopted by the general community to stop the transmission of disease during this ongoing COVID-19 pandemic. This wide use of face masks has indeed been shown to disrupt day-to-day face recognition. People with autism spectrum disorder (ASD) often have predisposed impairment in face recognition and are expected to be more vulnerable to this disruption in face recognition. Here, we recruited typically developing adult participants and those with ASD, and we measured their non-verbal intelligence, autism spectrum quotient, empathy quotient, and recognition performances of faces with and without a face mask covering the lower halves of the face. When faces were initially learned unobstructed, we showed that participants had a general reduced face recognition performance for masked faces. In contrast, when masked faces were first learned, typically developing adults benefit with an overall advantage in recognizing both masked and unmasked faces; while adults with ASD recognized unmasked faces with a significantly more reduced level of performance than masked faces—this face recognition discrepancy is predicted by a higher level of autistic traits. This paper also discusses how autistic traits influence processing of faces with and without face masks.
Making decisions about health information on social media: a mouse-tracking study
Authors: Lowry Mark , Trivedi Neha , Boyd Patrick , Julian Anne , Treviño Melissa , Lama Yuki , Heley Kathryn , Perna Frank
Published: July 2022

Health misinformation is a problem on social media, and more understanding is needed about how users cognitively process it. In this study, participants’ accuracy in determining whether 60 health claims were true (e.g., “Vaccines prevent disease outbreaks”) or false (e.g., “Vaccines cause disease outbreaks”) was assessed. The 60 claims were related to three domains of health risk behavior (i.e., smoking, alcohol and vaccines). Claims were presented as Tweets or as simple text statements. We employed mouse tracking to measure reaction times, whether processing happens in discrete stages, and response uncertainty. We also examined whether health literacy was a moderating variable. The results indicate that information in statements and tweets is evaluated incrementally most of the time, but with overrides happening on some trials. Adequate health literacy scorers were equally certain when responding to tweets and statements, but they were more accurate when responding to tweets. Inadequate scorers were more confident on statements than on tweets but equally accurate on both. These results have important implications for understanding the underlying cognition needed to combat health misinformation online.
Isolation and evaluation of bacteria associated with entomopathogenic nematode Heterorhabditis spp. against the spider mite, Tetranychus truncatus Ehara (Acari: Tetranychidae)
Authors: Ashwini M. N. , Bhaskar Haseena , Mathew Deepu , Shylaja M. R. , Girija D.
Published: July 2022

Background

Entomopathogenic nematodes (EPNs) belonging to the Heterorhabditis spp. harbour symbiotically associated bacteria which are toxic to a wide range of insect pests. Isolation, purification, characterization and mass multiplication of such bacteria will be a promising strategy in the management of the pests. This study was carried out to isolate the EPN from different locations, isolate and purify the bacterial colonies, characterize the bacteria through morphological and molecular strategies and to test the efficacy of different bacteria in the control of polyphagous Tetranychus truncatus Ehara mites.

Results

EPNs were isolated from soil samples at 11 localities of Kerala State, India, and used to infect the Galleria mellonella L. larvae. Bacteria associated with the haemolymph of the infected larvae were isolated, which on NBTA medium have produced circular to irregular, entire, opaque and smooth colonies. Sequence characterization of the 16S rRNA revealed nine isolates namely: one symbiotic bacterium Photorhabdus luminescens, two Pseudomonas aeruginosa, five Ochrobactrum sp. and one Stenotrophomonas maltophilia. Phylogenetic analysis using the sequences has further confirmed the bacterial identity. Evaluation of the cell suspension (CS) and cell-free supernatant (CFS) of P. luminescens, P. aeruginosa and Ochrobactrum sp. for their adulticidal and ovicidal efficiencies on T. truncatus had identified significant adulticidal effects by P. luminescens, followed by P. aeruginosa. After 96 h of treatment, P. luminescens at 108 cells/ml resulted in a significantly higher mortality rate of adult mites (64.00 and 60.67%, respectively, for CFS and CS), compared to that resulted by P. aeruginosa (38.67 and 33.33%).

Conclusions

Results of this study showed that P. luminescens associated with the EPN Heterorhabditis spp. is a promising biocontrol agent for T. truncatus.
How low can you go? Examining the effects of brief online training and post-training consultation dose on implementation mechanisms and outcomes for measurement-based care
Authors: Lyon Aaron R. , Liu Freda F. , Connors Elizabeth H. , King Kevin M. , Coifman Jessica I. , Cook Heather , McRee Erin , Ludwig Kristy , Law Amy , Dorsey Shannon , McCauley Elizabeth
Published: July 2022

Background

Initial training and ongoing post-training consultation (i.e., ongoing support following training, provided by an expert) are among the most common implementation strategies used to change clinician practice. However, extant research has not experimentally investigated the optimal dosages of consultation necessary to produce desired outcomes. Moreover, the degree to which training and consultation engage theoretical implementation mechanisms—such as provider knowledge, skills, and attitudes—is not well understood. This study examined the effects of a brief online training and varying dosages of post-training consultation (BOLT+PTC) on implementation mechanisms and outcomes for measurement-based care (MBC) practices delivered in the context of education sector mental health services.

Methods

A national sample of 75 clinicians who provide mental health interventions to children and adolescents in schools were randomly assigned to BOLT+PTC or control (services as usual). Those in BOLT+PTC were further randomized to 2-, 4-, or 8-week consultation conditions. Self-reported MBC knowledge, skills, attitudes, and use (including standardized assessment, individualized assessment, and assessment-informed treatment modification) were collected for 32 weeks. Multilevel models were used to examine main effects of BOLT+PTC versus control on MBC use at the end of consultation and over time, as well as comparisons among PTC dosage conditions and theorized mechanisms (skills, attitudes, knowledge).

Results

There was a significant linear effect of BOLT+PTC over time on standardized assessment use (b = .02, p < .01), and a significant quadratic effect of BOLT+PTC over time on individualized assessment use (b = .04, p < .001), but no significant effect on treatment modification. BOLT + any level of PTC resulted in higher MBC knowledge and larger growth in MBC skill over the intervention period as compared to control. PTC dosage levels were inconsistently predictive of outcomes, providing no clear evidence for added benefit of higher PTC dosage.

Conclusions

Online training and consultation in MBC had effects on standardized and individualized assessment use among clinicians as compared to services as usual with no consistent benefit detected for increased consultation dosage. Continued research investigating optimal dosages and mechanisms of these established implementation strategies is needed to ensure training and consultation resources are deployed efficiently to impact clinician practices.

Trial registration

ClinicalTrials.gov NCT05041517. Retrospectively registered on 10 September 2021.
Attiny85 controlled watch winder for self-winding mechanical watches
Authors: Thothadri Madhavan
Published: July 2022

In mechanical self-winding movement, the center-anchored Rotating Weight rotates about its axis with physical motions of the hand. It thereby winds the mainspring only when worn and stops during lay-offs. A watch winder re-creates the physical motions to maintain the beat in the caliber, when not worn. The paper proposes a residential tourbillon watch winder for self-winding mechanical calibers. The main objectives of this paper are to minimize the working time of the winder and consequently optimize its power consumption. A significant trade-off between the winding and unwinding ratios of the mainspring is ensured, maintaining a higher former ratio using a single-phase 9 RPM Permanent Magnet Synchronous Motor. The proposed model states the sufficiency of the winder to work only for 60% of the time. The model uses Watchdog timer to rekindle Attiny85 Microcontroller from sleep mode for scheduling the working time of the winder. The disclosed model is deployed to a Seiko (7S26A) caliber and a Citizen (8200A) Caliber for a period of 26 days to validate the working. The results show that the proposed model with the Seiko caliber requires 41.1 h for winding while the commercial models require 70.99 h. Similarly with the Citizen Caliber, the proposed watch winder requires only 28.8 h which is 21.11 h less than the time required by commercial models.
Exploring patients' experience of peer-supported open dialogue and standard care following a mental health crisis: qualitative 3-month follow-up study
Authors: Sunthararajah Sailaa , Clarke Katherine , Razzaque Russell , Chmielowska Marta , Brandrett Benjamin , Pilling Stephen
Published: July 2022

Background

Experience of crisis care may vary across different care models.

Aims

To explore the experience of care in standard care and ‘open dialogue’ (a peer-supported community service focused on open dialogue and involving social networks for adults with a recent mental health crisis) 3 months after a crisis.

Method

We conducted semi-structured interviews with 11 participants (6 received open dialogue; 5 received treatment as usual (TAU)) in a feasibility study of open dialogue and analysed the data using a three-step inductive thematic analysis to identify themes that (a) were frequently endorsed and (b) represented the experiences of all participants.

Results

Four themes emerged: (a) feeling able to rely on and access mental health services; (b) supportive and understanding family and friends; (c) having a choice and a voice; and (d) confusion and making sense of experiences. Generally, there was a divergence in experience across the two care models. Open dialogue participants often felt able to rely on and access services and involve their family and friends in their care. TAU participants described a need to rely on services and difficulty when it was not met, needing family and friends for support and wanting them to be more involved in their care. Some participants across both care models experienced confusion after a crisis and described benefits of sense-making.

Conclusions

Understanding crisis care experiences across different care models can inform service development in crisis and continuing mental healthcare services.
Phase II LEAP-004 Study of Lenvatinib Plus Pembrolizumab for Melanoma With Confirmed Progression on a Programmed Cell Death Protein-1 or Programmed Death Ligand 1 Inhibitor Given as Monotherapy or in Combination
Authors: Arance Ana , de la Cruz-Merino Luis , Petrella Teresa M. , Jamal Rahima , Ny Lars , Carneiro Ana , Berrocal Alfonso , Márquez-Rodas Ivan , Spreafico Anna , Atkinson Victoria , Costa Svedman Fernanda , Mant Andrew , Khattak Muhammad A. , Mihalcioiu Catalin , Jang Sekwon , Cowey C. Lance , Smith Alan D. , Hawk Natalyn , Chen Ke , Diede Scott J. , Krepler Clemens , Long Georgina V.
Published: July 2022

PURPOSE

Effective treatments are needed for melanoma that progresses on inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). We conducted the phase II LEAP-004 study to evaluate the combination of the multikinase inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab in this population (ClinicalTrials.gov identifier: NCT03776136 ).

METHODS

Eligible patients with unresectable stage III-IV melanoma with confirmed progressive disease (PD) within 12 weeks of the last dose of a PD-1/L1 inhibitor given alone or with other therapies, including cytotoxic T-cell lymphocyte–associated antigen 4 (CTLA-4) inhibitors, received lenvatinib 20 mg orally once daily plus ≤ 35 doses of pembrolizumab 200 mg intravenously once every 3 weeks until PD or unacceptable toxicity. The primary end point was objective response rate (ORR) per RECIST, version 1.1, by independent central review.

RESULTS

A total of 103 patients were enrolled and treated. The median study follow-up was 15.3 months. ORR in the total population was 21.4% (95% CI, 13.9 to 30.5), with three (2.9%) complete responses and 19 (18.4%) partial responses. The median duration of response was 8.3 months (range, 3.2-15.9+). ORR was 33.3% in the 30 patients with PD on prior anti–PD-1 plus anti–CTLA-4 therapy. The median progression-free survival and overall survival in the total population were 4.2 months (95% CI, 3.8 to 7.1) and 14.0 months (95% CI, 10.8 to not reached), respectively. Grade 3-5 treatment-related adverse events occurred in 47 (45.6%) patients, most commonly hypertension (21.4%); one patient died from a treatment-related event (decreased platelet count).

CONCLUSION

Lenvatinib plus pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed PD on prior PD-1/L1 inhibitor-based therapy, including those with PD on anti–PD-1 plus anti–CTLA-4 therapy. The safety profile was as expected. These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.
CA-125 KELIM as a Potential Complementary Tool for Predicting Veliparib Benefit: An Exploratory Analysis From the VELIA/GOG-3005 Study
Authors: You Benoit , Sehgal Vasudha , Hosmane Balakrishna , Huang Xin , Ansell Peter J. , Dinh Minh H. , Bell-McGuinn Katherine , Luo Xizhi , Fleming Gini F. , Friedlander Michael , Bookman Michael A. , Moore Kathleen N. , Steffensen Karina D. , Coleman Robert L. , Swisher Elizabeth M.
Published: July 2022

PURPOSE

In VELIA trial, veliparib combined with carboplatin-paclitaxel, followed by maintenance (veliparib-throughout) was associated with improved progression-free survival (PFS) compared with carboplatin-paclitaxel alone in patients with high-grade ovarian carcinomas. We explored the prognostic value of the modeled cancer antigen (CA)-125 elimination rate constant K (KELIM), which is known to be an indicator of the intrinsic tumor chemosensitivity (the faster the rate of CA-125 decline, the higher the KELIM and the higher the chemosensitivity), and its association with benefit from veliparib.

PATIENTS AND METHODS

Individual KELIM values were estimated from longitudinal CA-125 kinetics. Patients were categorized as having favorable (≥ median) or unfavorable (< median) KELIM. The prognostic value of KELIM for veliparib-related PFS benefit was explored in cohorts treated with primary or interval debulking surgery, according to the surgery completeness, the disease progression risk group, and the homologous recombination (HR) status ( BRCA mutation, HR deficiency [HRD], or HR proficiency [HRP]).

RESULTS

The data from 854 of 1,140 enrolled patients were analyzed (primary debulking surgery, n = 700; interval debulking surgery, n = 154). Increasing KELIM values were associated with higher benefit from veliparib in HRD cancer, as were decreasing KELIM values in HRP cancer. The highest PFS benefit from veliparib was observed in patients with both favorable KELIM and BRCA mutation (hazard ratio, 0.28; 95% CI, 0.13 to 0.61) or BRCA wild-type HRD cancer (hazard ratio, 0.43; 95% CI, 0.26 to 0.70), consistent with the association between poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy and platinum sensitivity. In contrast, seventy-four percent of patients with a BRCA mutation and unfavorable KELIM progressed within 18 months while on veliparib. The patients with HRP cancer and unfavorable KELIM might have benefited from the veliparib chemosensitizing effect.

CONCLUSION

In addition to HRD/ BRCA status, the tumor primary chemosensitivity observed during the first-line chemotherapy might be another complementary determinant of poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy.
Universal quantum effect of two-body correlation in a weakly interacting Bose gas
Authors: Song Pham The
Published: July 2022

Based on the Cornwall-Jackiw-Tomboulis (CJT) effective action approach and the requirement to preserve the Goldstone theorem within two-loop approximation, we study the universal quantum effect, which is related to the two-body correlation, in a homogeneous weakly interacting Bose gas at zero temperature. We find the state equations that provide the condensate fraction, energy density, chemical potential, and sound speed. They are the series expansions of the gas parameter.
Medicaid and Accelerated Approval: Spending on Drugs with and without Proven Clinical Benefits
Authors: Sachs Rachel E. , Jazowski Shelley A. , Gavulic Kyle A. , Donohue Julie M. , Dusetzina Stacie B.
Published: July 2022

Many state Medicaid officials are concerned about rising prescription drug spending, particularly drugs approved through the Food and Drug Administration's (FDA) accelerated approval pathway. The authors examined how much of Medicaid programs' accelerated approval spending is attributable to products that have demonstrated clinical benefits versus those that have not. Their findings provide support for states' concerns that pharmaceutical companies often fail to complete their required postapproval confirmatory studies within the FDA's requested timeline. But the findings also highlight one issue that policy stakeholders have not yet devoted substantial attention to: the use of surrogate endpoints involved in the postapproval confirmatory studies for most of the products in this study's sample. The granularity of the study's results enabled an analysis of the impact of different policy recommendations on both the accelerated approval pathway and Medicaid programs. These findings inform the current policy debate, suggesting that policy stakeholders might focus attention on products converting their approval on the basis of surrogate outcomes rather than on clinical outcomes.
Improving Access to High-Value, High-Cost Medicines: The Use of Subscription Models to Treat Hepatitis C Using Direct-Acting Antivirals in the United States
Authors: Auty Samantha G. , Griffith Kevin N. , Shafer Paul R. , Gee Rebekah E. , Conti Rena M.
Published: July 2022

State payers may face financial incentives to restrict use of high-cost medications. Yet, restrictions on access to high-value medications may have deleterious effects on population health. Direct-acting antivirals (DAAs), available since 2013, can cure chronic infection with hepatitis C virus (HCV). With prices upward of $90,000 for a treatment course, states have struggled to ensure access to DAAs for Medicaid beneficiaries and the incarcerated, populations with a disproportionate share of HCV. Advance purchase commitments (APCs), wherein a payer commits to purchase a certain quantity of medications at lower prices, offer payers incentives to increase access to high-value medications while also offering companies guaranteed revenue. This article discusses the use of subscription models, a type of APC, to support increased access to high-value DAAs for treating HCV. First, the authors provide background information about HCV, its treatment, and state financing of prescription medications. They then review the implementation of HCV subscription models in two states, Louisiana and Washington, and the early evidence of their impact. The article discusses challenges to evaluating state-sponsored subscription models, and it concludes by discussing implications of subscription models that target DAAs and other high-value, high-cost medicines.
Pursuing Pharmacoequity: Determinants, Drivers, and Pathways to Progress
Authors: Chalasani Rohan , Krishnamurthy Sudarshan , Suda Katie J. , Newman Terri V. , Delaney Scott W. , Essien Utibe R.
Published: July 2022

The United States pays more for medical care than any other nation in the world, including for prescription drugs. These costs are inequitably distributed, as individuals from underrepresented racial and ethnic groups in the United States experience the highest costs of care and unequal access to high-quality, evidence-based medication therapy. Pharmacoequity refers to equity in access to pharmacotherapies or ensuring that all patients, regardless of race and ethnicity, socioeconomic status, or availability of resources, have access to the highest quality of pharmacotherapy required to manage their health conditions. Herein the authors describe the urgent need to prioritize pharmacoequity. This goal will require a bold and innovative examination of social policy, research infrastructure, patient and prescriber characteristics, as well as health policy determinants of inequitable medication access. In this article, the authors describe these determinants, identify drivers of ongoing inequities in prescription drug access, and provide a framework for the path toward achieving pharmacoequity.
Assessing US Pharmaceutical Policy and Pricing Reform Legislation in Light of European Price and Cost Control Strategies
Authors: Rodwin Marc A.
Published: July 2022

This article compares the pharmaceutical pricing policies employed by public and private insurers in the United States with seven price and spending control strategies employed in the United Kingdom, France, and Germany. Differences between American and European policies explain why American pharmaceutical prices and per capita spending are higher than in European nations. The article then analyzes two recent bills as examples of significant American reform ideas—H.R. 3, the Elijah E. Cummings Lower Drug Costs Now Act (introduced in 2019) and the Build Back Better Act (BBBA, introduced in 2021)—and compares them with European cost control strategies. Key drug price provisions of the BBBA were incorporated into the recently enacted Inflation Reduction Act (IRA). H.R. 3 would have used an international (mostly European) price index to cap U.S. prices; the BBBA would cap Medicare prices at a discount from average U.S. market prices. Neither bill would employ the key cost control strategies that European nations do. Both bills would have significantly less impact on prices than legislation that employs European-style cost controls. This article proposes steps that Congress could take in line with European strategies to lower purchase prices and costs for patients. These measures would have to overcome political obstacles that currently stymie reform.
Reforming the Medicare Part D Benefit Design: Financial Implications for Beneficiaries, Private Plans, Drug Manufacturers, and the Federal Government
Authors: Trish Erin , Kaiser Katrina M. , Celestin Jeanai , Joyce Geoffrey
Published: July 2022

Context: Reforming the Medicare Part D program—which provides prescription drug coverage to 49 million beneficiaries—has emerged as a key policy priority.

Methods: The authors evaluate prescription drug claims from a 100% sample of Medicare Part D beneficiaries to evaluate the current spending distribution across different payers for different types of beneficiaries across different benefit phases. They then model how these estimates would change under a proposal to redesign the Medicare Part D standard benefit.

Findings: Spending patterns differ for beneficiaries who do and do not qualify for low-income subsidies. Part D plans face limited liability for total spending under the current standard benefit design, amounting to 36% of total spending for beneficiaries who do not receive low-income subsidies and 28% of total spending for those who do. Proposed reforms would increase plan liability and significantly change the distribution of liability across plans, drug manufacturers, and the federal government.

Conclusions: Though the original goal of the Part D program was to create a market of competing private plans that provide prescription drug coverage to Medicare beneficiaries, the standard benefit design that was included in the original legislation reflected significant political compromises. Reforming the standard benefit design to give plans more skin in the game could significantly affect competition in the market, with differential impact across drug classes and types of beneficiaries.
A 4-Yr Mixed Longitudinal Study of Health Behaviors and Fat Mass Accrual during Adolescence and Early Adulthood
Authors: MCCONNELL-NZUNGA JENNIFER , GABEL LEIGH , MACDONALD HEATHER M. , RHODES RYAN E. , HOFER SCOTT M. , NAYLOR PATTI-JEAN , MCKAY HEATHER A.
Published: July 2022

Purpose

Physical activity (PA), sedentary time (SED), and energy intake (EI) are associated with fat mass accrual in children and youth. Previous studies relied primarily on cross-sectional designs and proxy measures of body composition such as body mass index. We aimed to prospectively investigate associations between PA, SED, EI, and total body fat mass accrual using dual-energy x-ray absorptiometry.

Methods

This analysis of the mixed longitudinal Healthy Bones III Study included data from 312 participants (138 boys age 9 to 21 yr at baseline). For each participant, we acquired a maximum of four annual total body dual-energy x-ray absorptiometry scans from which we determined fat mass (in kilograms; n = 748 observations). We assessed total PA, moderate-to-vigorous PA (MVPA) and SED with accelerometers (ActiGraph GT1M) and measured EI via 24-h dietary recall. We fit sex-specific multilevel models adjusting for maturity (years from age at peak height velocity (APHV)), weight status, ethnicity, total PA, MVPA, SED, and EI.

Results

Boys and girls demonstrated divergent trajectories of fat mass accrual; rate of fat mass accrual in girls was four times greater than boys at APHV and increased across adolescence, whereas boys’ fat mass plateaued after APHV. In boys, within-person change in MVPA negatively predicted fat mass independent of SED; each annual increase in MVPA of 6 min·d−1 was associated with a 0.21-kg lower fat mass. In girls, between-person average MVPA negatively predicted fat mass accrual independent of SED; greater MVPA of 4 min·d−1 across adolescence was associated with a 0.31-kg lower fat mass.

Conclusions

MVPA demonstrates an independent and negative effect on fat mass in boys and girls. Given different trajectories of fat mass accrual and movement behaviors between boys and girls, PA interventions aimed at preventing obesity in youth may benefit from a sex and gendered approach.
Repeatability and test–retest reproducibility of mean apparent diffusion coefficient measurements of focal and diffuse disease in relapsed multiple myeloma at 3T whole body diffusion-weighted MRI (WB-DW-MRI)
Authors: ElGendy Khalil , Barwick Tara D , Auner Holger W , Chaidos Aristeidis , Wallitt Kathryn , Sergot Antoni , Rockall Andrea
Published: July 2022

Objective:

To assess the test–retest reproducibility and intra/interobserver agreement of apparent diffusion coefficient (ADC) measurements of myeloma lesions using whole body diffusion-weighted MRI (WB-DW-MRI) at 3T MRI.

Methods:

Following ethical approval, 11 consenting patients with relapsed multiple myeloma were prospectively recruited and underwent baseline WB-DW-MRI. For a single bed position, axial DWI was repeated after a short interval to permit test–retest measurements.

Mean ADC measurement was performed by two experienced observers. Intra- and interobserver agreement and test–retest reproducibility were assessed, using coefficient of variation (CV) and interclass correlation coefficient (ICC) measures, for diffuse and focal lesions (small ≤10 mm and large >10 mm).

Results:

47 sites of disease were outlined (23 focal, 24 diffuse) in different bed positions (pelvis = 22, thorax = 20, head and neck = 5). For all lesions, there was excellent intraobserver agreement with ICC of 0.99 (0.98–0.99) and COV of 5%. For interobserver agreement, ICC was 0.89 (0.8–0.934) and COV was 17%. There was poor interobserver agreement for diffuse disease (ICC = 0.46) and small lesions (ICC = 0.54).

For test–retest reproducibility, excellent ICC (0.916) and COV (14.5%) values for mean ADC measurements were observed. ICCs of test–retest were similar between focal lesions (0.83) and diffuse infiltration (0.80), while ICCs were higher in pelvic (0.95) compared to thoracic (0.81) region and in small (0.96) compared to large (0.8) lesions.

Conclusion:

ADC measurements of focal lesions in multiple myeloma are repeatable and reproducible, while there is more variation in ADC measurements of diffuse disease in patients with multiple myeloma.

Advances in knowledge:

Mean ADC measurements are repeatable and reproducible in focal lesions in multiple myeloma, while the ADC measurements of diffuse disease in multiple myeloma are more subject to variation. The evidence supports the future potential role of ADC measurements as predictive quantitative biomarker in multiple myeloma.
Determinants of mortality risk among Indonesian patients with COVID-19
Authors: Efendi Ferry , Haryanto Joni , Has Eka Mishbahatul Mar'ah , Makhfudli Makhfudli , Indarwati Retno , Kuswanto Heri , Wahyuhadi Joni , Farabi Makhyan Jibril Al , Ho Ken Hok Man
Published: July 2022

Background: The mortality risk of the novel coronavirus disease 19 (COVID-19) remains a global concern. Particularly in Indonesia, patients aged 18–59 years have a high risk of death due to COVID-19. In this study, we analysed the determinants of mortality risk among patients with confirmed COVID-19.

Methods: A secondary analysis of data from the Indonesian COVID-19 dashboard, tracking COVID-19 cases from April 2020 to May 2021 was performed. Data of 22,314 patients with COVID-19 aged 18–59 years were analysed using descriptive analysis, chi-square test, and binary logistic regression to obtain adjusted odds ratios (AORs) with 95% confidence intervals (CIs).

Results: Factors associated with confirmed mortality risk among patients aged 18–59 years with COVID-19 included increasing age (AOR = 1.08; 95% CI = 1.07–1.09), hospitalised and on ventilator support (AOR = 130.75; 95% CI = 69.03–247.63), having severe disease (AOR = 15.24; 95% CI = 11.51–20.17), and travelling history (AOR = 1.36; 95% CI = 1.13–1.63).

Conclusions: These findings confirmed that the increasing risk of death due to COVID-19 was associated with increasing age, ventilator support during hospitalisation, developing severe disease, and having a travelling history. This suggests that curative strategies should be strengthened with a focus on improving clinical governance by prioritising patients with the above variables.
Case Report: Ovarian fibroma: typical presentation with Meigs’s Syndrome
Authors: Upreti Dipesh , Rohita Dipesh Kumar , Yadav Shailendra Kumar , Thapa Niku
Published: July 2022

Meigs’s syndrome is characterized by a triad of ovarian fibroma, ascites, and pleural effusion which can be managed surgically. Pleural effusion and ascites are usually transudative. Ovarian fibroma is an uncommon tumor. We herein report a case of Meigs’s syndrome in a 61-year-old woman who presented with complaints of abdominal pain for two-three months along with decreased appetite and constipation. On examination, there was decreased air entry in the right side of the chest, generalized abdominal distention, and a firm irregular mass was felt which was mobile and extending from upper border of symphysis pubis to just above the umbilicus on abdominal palpation. Chest X ray showed right sided pleural effusion, ultrasonogram (USG) abdominal and pelvis showed gross ascites, and a very large complex right ovarian cyst was confirmed by computed tomography (CT) scan. She underwent staging laparotomy with total abdominal hysterectomy, bilateral salpingo-oophorectomy and omental resection for biopsy. Biopsy showed right ovarian fibroma.
Nutritional knowledge of patients diagnosed with endocrinopathies
Authors: Grot Martina , Szajdewig Magdalena , Grajek Mateusz , Białek-Dratwa Agnieszka , Sobczyk Karolina
Published: July 2022

Background: Thyroid diseases including Hashimoto's chronic lymphocytic thyroiditis represent an increasing epidemiological problem of the 21st century. Thyroid disease is estimated to affect approximately 7.0-9.0 per cent of the population up to the age of 60 years, and as much as 10.0-12.0 per cent after the age of 60 years. Hashimoto's disease is much more common among women of childbearing age, but it is also increasingly common among children and adolescents. The number of reported cases of autoimmune thyroiditis is steadily increasing. The aim of this study was to assess the nutritional knowledge of female patients with Hashimoto's disease in selected closed online support groups for patients with thyroid disease.Materials and methods: A self-administered online survey questionnaire was used to conduct the study.Results: 321 women were enrolled in the study. The largest group of respondents, aged between 20 and 40 years, lived in cities with more than 100 000 inhabitants and had a university education. Hypothyroidism along with Hashimoto's disease was declared by the largest number of respondents. The respondents' main source of nutritional knowledge was the media; the level of knowledge was assessed as insufficient.Conclusions: There is a need to increase nutritional education among patients in order to reduce the incidence of disease complications, the development of other comorbidities and will allow for health-promoting effects during the pharmacotherapy process.
Goals and Values in Education and Upbringing – Historical Contexts
Authors: Kulbaka Jacek
Published: July 2022

The text contains information on the history of pedagogical thought. The author’s intention was to show universal goals and educational values and ideals throughout history (from antiquity to the present).