Digital roots: harnessing digital platforms in advancing traditional and complementary medicine for cancer care in Sub-Saharan Africa.

The rise in cancer rates in Sub-Saharan Africa (SSA), combined with limited access to Western pharmaceuticals, has sparked growing adoption of traditional and complementary medicine (T&CM) for cancer treatment in the region. However, many challenges exist, including the lack of reliable evidence-based research on these products, scarcity of standardized documentation as part of cancer registries, limited physician expertise, and negative effects on mortality. Nonetheless, herbal medicines also present opportunities for further research, development, and stakeholder education, potentially benefiting the regional healthcare systems in SSA countries and global health as whole. Recent trends highlight the willingness of patients to use mobile-based applications that provide accurate information on herbal therapeutics, reflecting the increasing adoption of internet and smart/mobile phone services in SSA. To maximize the potential benefits of traditional and complementary medicine, it is necessary to bridge the trust gap between the public, local practitioners, and Western healthcare providers. Sustained funding and policy support are needed to complement these initiatives. Our preliminary survey hopes to inspire the community and policymakers to embrace innovative solutions, fostering a forward-looking approach to cancer care in SSA.

Comparative Evaluation of Astigmatic Changes Induced by Superior and Temporal Corneal Incisions in Sutureless Phacoemulsification Surgery: A Case Series.

Background In cataract surgery, the effect of corneal incision astigmatism has been widely recognized for many years. The incision's size, shape, and location can all impact the patient's postoperative visual outcomes. Currently, phacoemulsification is considered the most preferred surgical technique for cataract extraction. However, there is still some debate about whether temporal incisions, which are smaller and considered nearly astigmatic neutral, result in more astigmatism than other incisions. As a result, it is important to continue studying the refractive changes induced by corneal incisions made at different sites during phacoemulsification surgery. Aim and objective To compare the incidence, extent, and course of postoperative astigmatic changes associated with superior versus temporal clear corneal incisions for sutureless phacoemulsification cataract surgery. Materials and method In this prospective study, 50 patients of the civil hospital in Gujrat with cataracts who underwent sutureless, small incision (2.8 mm) phacoemulsification surgery were included. The preoperative evaluation comprised visual acuity assessment, refraction, keratometry, fundus examination, and intraocular lens (IOL) power calculation. The superior incision was made in 25 patients, and the temporal incision was made in another 25 patients. Patients were examined preoperatively on day 1, at one week (day 7), after one month (day 30), and after two months (day 60). Result Postoperatively, two months (on day 60) postoperatively, in group A (superior approach), the mean surgically induced astigmatism (SIA) was 0.39±0.34 SD diopters, and in group B (temporal approach), it was 0.5±0.42 SD diopters. A significant statistical difference was not seen between these two groups. Conclusion Surgically induced astigmatism was minimal and comparable with both superior and temporal approaches to clear corneal incisions for phacoemulsification surgery.

Clostridium Bifermentans Infection of a Prosthetic Knee Joint in a Patient With Human Immunodeficiency Virus: A Case Report.

We reported a case of Clostridium bifermentans (C. bifermentans) infection in the prosthetic knee joint of a human immunodeficiency virus (HIV) patient, who presented with swelling, discomfort, pain, and redness in the right lower extremity. An uncommon yet potentially lethal human illness triggered by C. bifermentans. Foreign material is especially susceptible to local infection because of the local immunodeficiency close to the implant. Intravenous (IV) cefepime and IV ampicillin/sulbactam were administered to the patient. The idea of performing surgery to eradicate the infection was under consideration, but its necessity remained uncertain, and the decision to proceed with surgery had not been finalized.

Restoration of ß-GC trafficking improves the lysosome function in Gaucher disease.

Lysosomes function as a primary site for catabolism and cellular signaling. These organelles digest a variety of substrates received through endocytosis, secretion and autophagy with the help of resident acid hydrolases. Lysosomal enzymes are folded in the endoplasmic reticulum (ER) and trafficked to lysosomes via Golgi and endocytic routes. The inability of hydrolase trafficking due to mutations or mutations in its receptor or cofactor leads to cargo accumulation (storage) in lysosomes, resulting in lysosome storage disorder (LSD). In Gaucher disease (GD), the lysosomes accumulate glucosylceramide because of low ß-glucocerebrosidase (ß-GC) activity that causes lysosome enlargement/dysfunction. We hypothesize that improving the trafficking of mutant ß-GC to lysosomes may improve the lysosome function in GD. RNAi screen using high throughput based ß-GC activity assay followed by reporter trafficking assay utilizing ß-GC-mCherry led to the identification of nine potential phosphatases. Depletion of these phosphatases in HeLa cells enhanced the ß-GC activity by increasing the folding and trafficking of Gaucher mutants to the lysosomes. Consistently, the lysosomes in primary fibroblasts from GD patients restored their ß-GC activity upon the knockdown of these phosphatases. Thus, these studies provide evidence that altering phosphatome activity is an alternative therapeutic strategy to restore the lysosome function in GD.

Pseudophosphatase STYXL1 depletion enhances glucocerebrosidase trafficking to lysosomes via ER stress.

Pseudophosphatases are catalytically inactive but share sequence and structural similarities with classical phosphatases. STYXL1 is a pseudophosphatase that belongs to the family of dual-specificity phosphatases and is known to regulate stress granule formation, neurite formation and apoptosis in different cell types. However, the role of STYXL1 in regulating cellular trafficking or the lysosome function has not been elucidated. Here, we show that the knockdown of STYXL1 enhances the trafficking of ß-glucocerebrosidase (ß-GC) and its lysosomal activity in HeLa cells. Importantly, the STYXL1-depleted cells display enhanced distribution of endoplasmic reticulum (ER), late endosome and lysosome compartments. Further, knockdown of STYXL1 causes the nuclear translocation of unfolded protein response (UPR) and lysosomal biogenesis transcription factors. However, the upregulated ß-GC activity in the lysosomes is independent of TFEB/TFE3 nuclear localization in STYXL1 knockdown cells. The treatment of STYXL1 knockdown cells with 4-PBA (ER stress attenuator) significantly reduces the ß-GC activity equivalent to control cells but not additive with thapsigargin, an ER stress activator. Additionally, STYXL1-depleted cells show the enhanced contact of lysosomes with ER, possibly via increased UPR. The depletion of STYXL1 in human primary fibroblasts derived from Gaucher patients showed moderately enhanced lysosomal enzyme activity. Overall, these studies illustrated the unique role of pseudophosphatase STYXL1 in modulating the lysosome function both in normal and lysosome-storage disorder cell types. Thus, designing small molecules against STYXL1 possibly can restore the lysosome activity by enhancing ER stress in Gaucher disease.

Expanding radiotherapy access in Sub-Saharan Africa: an analysis of travel burdens and patient-related benefits of hypofractionation.

Purpose: The purpose of this project was to examine the travel burdens for radiotherapy patients in Nigeria, Tanzania, and South Africa, and to assess the patient-related benefits of hypofractionated radiotherapy (HFRT) for breast and prostate cancer patients in these countries. The outcomes can inform the implementation of the recent Lancet Oncology Commission recommendations on increasing the adoption of HFRT in Sub-Saharan Africa (SSA) to enhance radiotherapy access in the region. Methods: Data were extracted from electronic patient records at the NSIA-LUTH Cancer Center (NLCC) in Lagos, Nigeria and the Inkosi Albert Luthuli Central Hospital (IALCH) in Durban, South Africa, from written records at the University of Nigeria Teaching Hospital (UNTH) Oncology Center in Enugu, Nigeria, and from phone interviews at Ocean Road Cancer Institute (ORCI) in Dar Es Salaam, Tanzania. Google Maps was used to calculate the shortest driving distance between a patient's home address and their respective radiotherapy center. QGIS was used to map the straight-line distances to each center. Descriptive statistics were used to compare transportation costs, time expenditures, and lost wages when using HFRT versus conventionally fractionated radiotherapy (CFRT) for breast and prostate cancer. Results: Patients in Nigeria (n=390) traveled a median distance of 23.1 km to NLCC and 86.7 km to UNTH, patients in Tanzania (n=23) traveled a median distance of 537.0 km to ORCI, and patients in South Africa (n=412) traveled a median distance of 18.0 km to IALCH. Estimated transportation cost savings for breast cancer patients in Lagos and Enugu were 12,895 Naira and 7,369 Naira, respectively and for prostate cancer patients were 25,329 and 14,276 Naira, respectively. Prostate cancer patients in Tanzania saved a median of 137,765 Shillings in transportation costs and 80.0 hours (includes travel, treatment, and wait times). Mean transportation cost savings for patients in South Africa were 4,777 Rand for breast cancer and 9,486 Rand for prostate cancer. Conclusion: Cancer patients in SSA travel considerable distances to access radiotherapy services. HFRT decreases patient-related costs and time expenditures, which may increase radiotherapy access and alleviate the growing burden of cancer in the region.

Challenges and opportunities for implementing hypofractionated radiotherapy in Africa: lessons from the HypoAfrica clinical trial.

The rising cancer incidence and mortality in sub-Saharan Africa (SSA) warrants an increased focus on adopting or developing approaches that can significantly increase access to treatment in the region. One such approach recommended by the recent Lancet Oncology Commission for sub-Saharan Africa is hypofractionated radiotherapy (HFRT), which can substantially increase access to radiotherapy by reducing the overall duration of time (in days) each person spends being treated. Here we highlight challenges in adopting such an approach identified during the implementation of the HypoAfrica clinical trial. The HypoAfrica clinical trial is a longitudinal, multicentre study exploring the feasibility of applying HFRT for prostate cancer in SSA. This study has presented an opportunity for a pragmatic assessment of potential barriers and facilitators to adopting HFRT. Our results highlight three key challenges: quality assurance, study harmonisation and machine maintenance. We describe solutions employed to resolve these challenges and opportunities for longer term solutions that can facilitate scaling-up use of HFRT in SSA in clinical care and multicentre clinical trials. This report provides a valuable reference for the utilisation of radiotherapy approaches that increase access to treatment and the conduct of high-quality large-scale/multi-centre clinical trials involving radiotherapy. Trial registration: Not available yet.

Empowering Women's Health: A Global Perspective on Artificial Intelligence and Robotics.

In our rapidly evolving world, technology stands at the forefront, driving remarkable advancements across various sectors. One of the most notable changes is the use of Artificial Intelligence (AI) and robotics in healthcare, starting a revolution that has the power to change women's health all over the world. Developed nations are already witnessing the benefits. However, a significant portion of the global population in underdeveloped regions is lagging behind, resulting in a noticeable disparity. This is particularly evident in women's healthcare, an area already facing global inequities. As we witness a digital revolution, we examine the progressive steps taken in women's healthcare. AI and robotics are key to this transformation. The services range from using data to predict cancer trends to tailor-made medicine and technologies in reproduction. This editorial addresses the existing gaps and the digital divide, exploring the necessity for an inclusive approach in technology design and implementation to ensure equitable healthcare access.  Furthermore, it highlights the imperative role of multi-sectoral collaborations to foster innovation while mitigating risks. The clear goal is to build a future where all women, no matter where they live, can get good healthcare, helped by AI and robotics, bringing in a time of healthcare for all. It's crucial for everyone involved to come together to make a healthcare system that everyone can use, helping women everywhere with the help of new technology.

Utilization of cancer immunotherapy in sub-Saharan Africa.

Introduction: The Lancet Oncology Commission for sub-Saharan Africa (SSA) predicts that cancer deaths will double from 520,158 per year to more than 1 million per year by the year 2040. These striking figures indicate a need to urgently evaluate cancer treatment infrastructure and resources in the region. Studies have found immunotherapy to be effective for the treatment of advanced-stage cancer, which almost 70% of patients in SSA present with. Despite immunotherapy's significant therapeutic potential, its utilization in SSA is not well documented. The purpose of this study was to evaluate the landscape of immunotherapy in SSA. Methods: A Qualtrics survey assessing the existing infrastructure and training for safe immunotherapy administration was developed and distributed online via email and WhatsApp to 3,231 healthcare providers across SSA, with a target audience of healthcare providers serving patients with cancer. The survey contained 22 questions evaluating the accessibility, use, knowledge, and training on immunotherapy in SSA. Responses were collected between January and February 2023. Microsoft Excel was used to summarize and visually present the distribution of responses as counts and proportions. Results: 292 responses were included from 28 countries in SSA. 29% of all respondents indicated their clinic has easy access to cancer immunotherapy and 46% indicated their clinic currently practices it. Of clinics that practiced immunotherapy (n = 133), 12% used genomic sequencing to assess the tumor mutational burden biomarker, and 44% assessed expression of the PD-L1 biomarker prior to immunotherapy administration. 46% of all respondents were familiar with immunotherapy. 11% indicated being adequately trained to administer it. Of these (n=33), 52% indicated also being trained to manage immune-related adverse events related to immunotherapy administration. Conclusion: Immunotherapy utilization and training is low in SSA and insufficient for the rising cancer burden. Increased accessibility and usage of biomarker testing to predict immunotherapy response, incorporation of immunotherapy training into continuous medical education, and increased access to immunotherapy drugs may be prerequisites for expanded utilization of immunotherapy in SSA.

Risk factors for COVID-19 associated mucormycosis in India: A case control study.

The coronavirus disease 2019 (COVID-19) pandemic had led to an increase in a surge of mucormycosis in COVID-19 patients, especially in India. Diabetes and irrational usage of corticosteroids to treat COVID-19 were some of the factors implicated for COVID-19-associated mucormycosis (CAM). We designed this case-control study to identify risk factors for mucormycosis in COVID-19 patients. The study was conducted at a private tertiary care center in western India. Data were extracted from records of COVID 19 patients (January-May 2021) and divided into two groups: Those with proven or probable mucormycosis, and those without mucormycosis with a ratio of 1:3. A binary logistic regression analysis was done to assess potential risk factors for CAM. A total of 64 CAM and 205 controls were included in the analysis. Age and sex distribution were similar in cases and controls with the majority of males in both the groups (69.9%) and the mean age was 56.4 (±13.5) years. We compared the comorbidities and treatment received during acute COVID-19, specifically the place of admission, pharmacotherapy (steroids, tocilizumab, remdesivir), and the requirement of oxygen as a risk factor for CAM. In a multivariate analysis, risk factors associated with increased odds of CAM were new-onset diabetes (vs. non-diabetics, adjusted odds ratio [OR] 48.66, 95% confidence interval [CI] 14.3-166), pre-existing diabetes (vs. non-diabetics, aOR 2.93, 95%CI 1.4-6.1), corticosteroid therapy (aOR 3.64, 95%CI 1.2-10.9) and home isolation (vs. ward admission, aOR 4.8, 95%CI 2-11.3). Diabetes, especially new-onset, along with corticosteroid usage and home isolation were the predominant risk factors for CAM. LAY SUMMARY: This study revealed new-onset diabetes, pre-existing diabetes, corticosteroid therapy, and home isolation as risk factors for COVID-19-associated mucormycosis. Avoiding the use of corticosteroids in non-severe COVID-19 disease coupled with proper blood sugar monitoring and control will help to reduce the CAM burden.

Crystal structure of 4-bromo-N-(propyl-carbamo-yl)benzene-sulfonamide.

The title compound, C10H13BrN2O3S, 1, contains a sulfonyl urea moiety, which possesses potential therapeutic functions (e.g., anti-diabetic and herbicidal). The geometry of 1 is similar to its closely related analogues, chlorpropamide and tolbutamide. This compound crystallizes in the monoclinic space group C2/c, having one mol-ecule in its asymmetric unit. The crystal structure of 1, recorded at 296 K, shows inter-molecular N-H⋯O and C-H⋯O-type infinite hydrogen-bonded chains involving the sulfonyl urea moiety. Hirshfeld surface analysis and the two-dimensional fingerprint plots confirmed hydrogen bonding as the dominant feature in the crystal packing.

Endodontic Emergencies Encountered in a Tertiary Dental Hospital during the Periods of Prelockdown, Lockdown, and Sequential Unlock Phases of the First Wave of COVID-19 in Ahmedabad City, India.

INTRODUCTION: With the worldwide spread of SARS-CoV-2 infection, temporary suspension of all the elective dental procedures and an urgent shift to nonaerosol producing dental treatments were observed. This study provides a detailed description of emergency treatments provided in the Department of Endodontics at a tertiary healthcare centre during the period of prelockdown, lockdown, and sequential unlocking from March 1, 2020, to October 31, 2020. METHODS: Access to General and Departmental OPD data along with treatment records was obtained and was segregated based on age, sex, and treatments performed. Treatments were divided into aerosol generating procedures (AGPs) and non-AGPs and further subdivided into palliative treatment (PT), pulp capping (PC), incision and drainage (ID), temporary filling (TF), pulpectomy (PU), and pulpotomy (PO). Data was analysed and subjected to chi-square test. RESULTS: A total of 15052 patients approached general OPD during the period of 8 months of which 5698 (37.86%) were endodontic in origin and treatments offered were PT 858 (15.05%), PO 1560 (27.37%), PU 2018 (35.42%), TF 500 (8.78%), ID 164 (2.88%), and PC 598 (10.94%). Also, more females (57.28% (3264/5698)) visited the department as compared to males (42.72% (2434/5698)). CONCLUSION: The pandemic had turned the tables on over the people around the world, and it has become extremely necessary to rule out the emergencies needed to treat the patients accordingly shifting more towards non-AGPs compared to AGPs among the various age groups of the society.

Crystal structure of tert-butyl 4-[4-(4-fluoro-phen-yl)-2-methyl-but-3-yn-2-yl]piperazine-1-carboxyl-ate.

The title sterically congested piperazine derivative, C20H27FN2O2, was prepared using a modified Bruylants approach. A search of the Cambridge Structural Database identified 51 compounds possessing an N-tert-butyl piperazine substructure. Of these only 14 were asymmetrically substituted on the piperazine ring and none with a synthetically useful second nitro-gen. Given the novel chemistry generating a pharmacologically useful core, determination of the crystal structure for this compound was necessary. The piperazine ring is present in a chair conformation with di-equatorial substitution. Of the two N atoms, one is sp 3 hybridized while the other is sp 2 hybridized. Inter-molecular inter-actions resulting from the crystal packing patterns were investigated using Hirshfeld surface analysis and fingerprint analysis. Directional weak hydrogen-bond-like inter-actions (C-H⋯O) and C-H⋯π inter-actions with the dispersion inter-actions as the major source of attraction are present in the crystal packing.

Dual inhibition of MEK1/2 and MEK5 suppresses the EMT/migration axis in triple-negative breast cancer through FRA-1 regulation.

Triple-negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. Constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway has been linked to chemoresistance and metastatic progression through distinct mechanisms, including activation of epithelial-to-mesenchymal transition (EMT) when cells adopt a motile and invasive phenotype through loss of epithelial markers (CDH1), and acquisition of mesenchymal markers (VIM, CDH2). Although MAPK/ERK1/2 kinase inhibitors (MEKi) are useful antitumor agents in a clinical setting, including the Food and Drug Administration (FDA)-approved MEK1,2 dual inhibitors cobimetinib and trametinib, there are limitations to their clinical utility, primarily adaptation of the BRAF pathway and ocular toxicities. The MEK5 (HGNC: MAP2K5) pathway has important roles in metastatic progression of various cancer types, including those of the prostate, colon, bone and breast, and elevated levels of ERK5 expression in breast carcinomas are linked to a worse prognoses in TNBC patients. The purpose of this study is to explore MEK5 regulation of the EMT axis and to evaluate a novel pan-MEK inhibitor on clinically aggressive TNBC cells. Our results show a distinction between the MEK1/2 and MEK5 cascades in maintenance of the mesenchymal phenotype, suggesting that the MEK5 pathway may be necessary and sufficient in EMT regulation while MEK1/2 signaling further sustains the mesenchymal state of TNBC cells. Furthermore, additive effects on MET induction are evident through the inhibition of both MEK1/2 and MEK5. Taken together, these data demonstrate the need for a better understanding of the individual roles of MEK1/2 and MEK5 signaling in breast cancer and provide a rationale for the combined targeting of these pathways to circumvent compensatory signaling and subsequent therapeutic resistance.

Molecular Mechanisms of Epithelial to Mesenchymal Transition Regulated by ERK5 Signaling.

Extracellular signal-regulated kinase (ERK5) is an essential regulator of cancer progression, tumor relapse, and poor patient survival. Epithelial to mesenchymal transition (EMT) is a complex oncogenic process, which drives cell invasion, stemness, and metastases. Activators of ERK5, including mitogen-activated protein kinase 5 (MEK5), tumor necrosis factor α (TNF-α), and transforming growth factor-ß (TGF-ß), are known to induce EMT and metastases in breast, lung, colorectal, and other cancers. Several downstream targets of the ERK5 pathway, such as myocyte-specific enhancer factor 2c (MEF2C), activator protein-1 (AP-1), focal adhesion kinase (FAK), and c-Myc, play a critical role in the regulation of EMT transcription factors SNAIL, SLUG, and ß-catenin. Moreover, ERK5 activation increases the release of extracellular matrix metalloproteinases (MMPs), facilitating breakdown of the extracellular matrix (ECM) and local tumor invasion. Targeting the ERK5 signaling pathway using small molecule inhibitors, microRNAs, and knockdown approaches decreases EMT, cell invasion, and metastases via several mechanisms. The focus of the current review is to highlight the mechanisms which are known to mediate cancer EMT via ERK5 signaling. Several therapeutic approaches that can be undertaken to target the ERK5 pathway and inhibit or reverse EMT and metastases are discussed.

Evaluating the Facilitators, Barriers, and Medical Outcomes Commensurate with the Use of Assistive Technology to Support People with Dementia: A Systematic Review Literature.

Background: Assistive technologies (AT) have been used to improve the daily living conditions of people living with dementia (PWD). Research supports the positive impact of the use of AT such as decreased burden on caregivers and behavioral support for people with dementia. Four reviews in the last six years have analyzed AT and PWD, but none have incorporated the dimension of medical outcomes. Objectives: The purpose of this review is to identify the facilitators, barriers, and medical outcomes commensurate with the use of AT with PWD. Method: This review queried The Cumulative Index of Nursing and Allied Health Literature (CINAHL), Web of Science, Science Direct, and PubMed databases for peer-reviewed publications in the last five years for facilitators, barriers, and medical outcomes commensurate with the use of AT with PWD. The study is reported and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and the Kruse Protocol for conducting a systematic review. Results: 48 studies were analyzed. Fourteen types of AT, 17 facilitators, 17 barriers, and 16 medical outcomes were identified in the literature. The two most frequently mentioned ATs were cognitive stimulators (9/48, 19%) and social robots (5/48, 10%). The two most frequently mentioned facilitators were caregivers want AT (8/68, 12%) and enables increased independence (7/68, 10%). The top two barriers were cost (8/75, 11%) and PWD reject AT (8/75, 11%). The top medical outcomes were improved cognitive abilities (6/69, 9%), increased activities of daily living (ADLs), and increased autonomy (each at 5/69, 7%): Zero negative outcomes were reported. Conclusion: The systematic review revealed the positive relations that occur when PWD and their caregivers use AT. Although many reservations surrounding the use of AT exist, a majority of the literature shows a positive effect of its use. Research supports a strong support for AT by caregivers due to many positive medical outcomes, but also a reticence to adopt by PWD. If ATs for PWD are a way to reduce stress on caregivers, barriers of cost and complexity need to be addressed through health policy or grants.

Regulation of Lipoprotein Homeostasis by Self-Assembling Peptides.

High levels of serum low-density lipoprotein (LDL) cholesterol contribute to atherosclerosis, a key risk factor of cardiovascular diseases. PCSK9 is a circulatory enzyme that downregulates expression of hepatic LDL receptors, concomitantly increasing serum LDL-C. This work investigates a small, self-assembling peptide, EPep2-8, as a peptide inhibitor of PCSK9. EPep2-8 is a multidomain peptide comprising a self-assembling domain, E2, conjugated to a bioactive domain, Pep2-8, previously shown to inhibit PCSK9. The E2 domain facilitates self-assembly of EPep2-8 into long, nanofibrous polymers with an underlying supramolecular ß-sheet secondary structure. Intermolecular interactions between nanofibers drive EPep2-8 to form a thixotropic and cytocompatible hydrogel in aqueous and charge-neutral solutions. These properties enable EPep2-8 to be delivered as an in situ depot for regulation of lipoprotein homeostasis. In surface plasmon resonance studies, EPep2-8 bound specifically to PCSK9 with an apparent, noncovalent, and irreversible dissociation, significantly improving the binding affinity of Pep2-8 alone (KD = 667 ± 48 nM). Increased binding affinity of EPep2-8 is primarily due to the superstoichiometric interaction of the peptide with PCSK9. Promisingly, EPep2-8 retains bioactivity in vitro, engendering dose-dependent uptake of LDL-C in hepatocytes. This mechanism of self-assembly on a target site may be a simple method to improve the affinity of peptide inhibitors.

Correction: Keratinocyte differentiation promotes ER stress-dependent lysosome biogenesis.

Following publication of this article, the authors realized there was an error in Figure 2b that needed correction. The TFEB panel of Figure 2b (total lysate) appears to be the same as the TFEB panel of Figure 2e (cytosolic fraction); the TFE3 panels of Figure 2b (total lysate) appear to be the same as the TFE3 panels of Figure 2e (cytosolic fraction) which happened during image assembly.This error did not impact the scientific conclusions of the article.

Tobacco pack display at hospitality venues after the introduction of standardised tobacco packaging in New Zealand: a field observation study.

OBJECTIVES: In March 2018, New Zealand (NZ) introduced standardised tobacco packaging that also featured new pictorial warnings, with implementation completed by early June 2018. We evaluated how the new packaging affected tobacco pack displays in outdoor areas of hospitality venues. DESIGN: Before-and-after descriptive field observation study. SETTING: Central city area of the capital city of NZ (Wellington). PARTICIPANTS: Observations of people smoking and tobacco packs were made at 56 hospitality venues with outdoor tables (2422 separate venue observations), after the introduction of standardised tobacco packaging. Comparisons were made with a prior study in the same setting, from a time when tobacco packaging still featured brand imagery. RESULTS: A total of 8191 patrons, 1113 active smokers and 889 packs and pouches (522 of known orientation) were observed over 2422 venue observations. There were 0.80 visible packs per active smoker in 2018, compared with 1.26 in 2014 (risk ratio (RR)=0.64, 95% CI 0.60 to 0.67, p<0.0001). The new packs in 2018 were also less likely to be displayed face-up, compared with packs in 2014, which had brand imagery on the front face (RR=0.77, 95% CI 0.72 to 0.83, p<0.0001). Pack and pouch display (RR=3.09 in 2014 and 3.10 in 2018) and active smoking (RR=3.16 in 2014 compared with 3.32 in 2018) were higher at venues without children present, compared with venues with children present (this finding was consistent over time). CONCLUSIONS: The reduction in the number of visible packs per active smoker, along with the reduction in face-up positioning of packs, suggests that smokers found the new standardised packs less attractive. Countries introducing standardised packaging should consider evaluating social display of tobacco packaging.

Premature ventricular contractions activate vagal afferents and alter autonomic tone: implications for premature ventricular contraction-induced cardiomyopathy.

Mechanisms behind development of premature ventricular contraction (PVC)-induced cardiomyopathy remain unclear. PVCs may adversely modulate the autonomic nervous system to promote development of heart failure. Afferent neurons in the inferior vagal (nodose) ganglia transduce cardiac activity and modulate parasympathetic output. Effects of PVCs on cardiac parasympathetic efferent and vagal afferent neurotransmission are unknown. The purpose of this study was to evaluate effects of PVCs on vagal afferent neurotransmission and compare these effects with a known powerful autonomic modulator, myocardial ischemia. In 16 pigs, effects of variably coupled PVCs on heart rate variability (HRV) and vagal afferent neurotransmission were evaluated. Direct nodose neuronal recordings were obtained in vivo, and cardiac-related afferent neurons were identified based on their response to cardiovascular interventions, including ventricular chemical and mechanical stimuli, left anterior descending (LAD) coronary artery occlusion, and variably coupled PVCs. On HRV analysis before versus after PVCs, parasympathetic tone decreased (normalized high frequency: 83.6 ± 2.8 to 72.5 ± 5.3; P < 0.05). PVCs had a powerful impact on activity of cardiac-related afferent neurons, altering activity of 51% of neurons versus 31% for LAD occlusion (P < 0.05 vs. LAD occlusion and all other cardiac interventions). Both chemosensitive and mechanosensitive neurons were activated by PVCs, and their activity remained elevated even after cessation of PVCs. Cardiac afferent neural responses to PVCs were greater than any other intervention, including ischemia of similar duration. These data suggest that even brief periods of PVCs powerfully modulate vagal afferent neurotransmission, reflexly decreasing parasympathetic efferent tone.NEW & NOTEWORTHY Premature ventricular contractions (PVCs) are common in many patients and, at an increased burden, are known to cause heart failure. This study determined that PVCs powerfully modulate cardiac vagal afferent neurotransmission (exerting even greater effects than ventricular ischemia) and reduce parasympathetic efferent outflow to the heart. PVCs activated both mechano- and chemosensory neurons in the nodose ganglia. These peripheral neurons demonstrated adaptation in response to PVCs. This study provides additional data on the potential role of the autonomic nervous system in PVC-induced cardiomyopathy.