Experiences of women participating in a human papillomavirus-based screen-triage-and treat strategy for cervical cancer prevention in Malawi.

Objective: To explore the experiences of Malawian women who underwent a human papillomavirus (HPV)-based screen-triage-treat algorithm for cervical cancer (CxCa) prevention. This algorithm included GeneXpert® HPV testing of self-collected vaginal samples, visual inspection with acetic acid (VIA) and colposcopy for HPV-positive women, and thermal ablation of ablation-eligible women. Method: In-depth interviews were conducted with participants of a trial that evaluated the feasibility of a HPV-based screen-triage-treat algorithm among women living with HIV and HIV negative women in Lilongwe, Malawi. Participants were recruited from 3 groups: 1) HPV-negative; 2) HPV-positive/VIA-negative; 3) HPV-positive/VIA-positive and received thermal ablation. Interviews explored baseline knowledge of CxCa and screening, attitudes towards self-collection, and understanding of test results. Content analysis was conducted using NVIVO v12. Results: Thematic saturation was reached at 25 interviews. Advantages of HPV self-collection to participants were convenience of sampling, same-day HPV results and availability of same-day treatment. There was confusion surrounding HPV-positive/VIA-negative results, as some participants still felt treatment was needed. Counseling, and in particular anticipatory guidance, was key in helping participants understand complex screening procedures and results. Overall, participants expressed confidence in the HPV screen-triage-treat strategy. Discussion: HPV testing through self-collected samples is a promising tool to increase CxCa screening coverage. A multi-step screening algorithm utilizing HPV self-testing, VIA triage and thermal ablation treatment requires proper counseling and anticipatory guidance to improve patient understanding. Incorporating thorough counseling in CxCa screening programs can change women's perspectives about screening, build trust in healthcare systems, and influence healthcare seeking behavior towards routine screening and prevention.

Results from Two HPV-Based Cervical Cancer Screening-Family Planning Integration Models in Malawi: A Cluster Randomized Trial.

We conducted a cluster randomized trial of two models for integrating HPV self-collection into family-planning (FP) services at 16 health facilities in Malawi between March 2020-December 2021. Model 1 involved providing only clinic-based HPV self-collection, whereas Model 2 included both clinic-based and community-based HPV self-collection. An endline household survey was performed in sampled villages and households between October-December 2021 in the catchment areas of the health facilities. We analyzed 7664 surveys from 400 villages. Participants from Model 2 areas were more likely to have ever undergone cervical cancer screening (CCS) than participants from Model 1 areas, after adjusting for district, facility location (urban versus rural), and facility size (hospital versus health center) (adjusted odds ratio = 1.73; 95% CI: 1.29, 2.33). Among participants who had ever undergone CCS, participants from Model 2 were more likely to report having undergone HPV self-collection than participants from Model 1 (50.5% versus 22.8%, p = 0.023). Participants from Model 2 were more likely to be using modern FP (adjusted odds ratio = 1.01; 95% CI: 1.41, 1.98) than Model 1 participants. The integration of FP and HPV self-collection in both the clinic and community increases CCS and modern FP uptake more than integration at the clinic-level alone.

A novel cervical cancer screen-triage-treat demonstration project with HPV self-testing and thermal ablation for women in Malawi: Protocol for a single-arm prospective trial.

Cervical cancer is the leading cause of cancer mortality among Malawian women, despite being preventable through screening and preventive therapy. In 2004, Malawi implemented a national screening program, using visual inspection with acetic acid (VIA) and cryotherapy, but its success has been limited due to equipment and human resources challenges. Since the development of that program, new technologies for screening and treatment that are less resource-intensive and more scalable have become available. GeneXpert systems provide fast, accurate HPV results and are increasingly available in low-income countries. Self-collection for human papillomavirus (HPV) testing is a validated method for screening and improves uptake. Thermal ablation provides an alternative ablative treatment that is simpler to use than cryotherapy and can be performed with portable devices. Meanwhile, urine HPV testing methods provide promising options for primary screening. We designed a single-arm prospective study to investigate a novel HPV screen-triage-treat strategy among 1250 women in Lilongwe, Malawi. Our proposed strategy consists of (1) Xpert HPV testing of self-collected samples, (2) VIA and colposcopy for HPV-positive women, and (3) thermal ablation for HPV-positive/ablation-eligible women. We will collect cervical biopsies, Pap smears, and endocervical samples to validate the HPV results and VIA/colposcopy findings against endpoints of high-grade cervical intraepithelial neoplasia or cancer (CIN2+). We will evaluate same-day completion of our algorithm, its performance in triaging women for treatment, and 24-week treatment efficacy of thermal ablation. We will also explore the performance of HPV and methylation tests in urine samples, as compared to provider- and self-collected cervicovaginal samples.

Perceptions of cervical cancer and motivation for screening among women in Rural Lilongwe, Malawi: A qualitative study.

INTRODUCTION: Cervical cancer is the leading cause of cancer death among women in Malawi. Low awareness of cervical cancer and negative perceptions of screening can prevent women from participating in preventative strategies. We sought to explore perceptions and motivations for screening among women who participated in a cervical cancer screen-and-treat pilot study in rural Malawi. MATERIALS AND METHODS: We conducted a qualitative sub-study of a community-based cervical cancer screen-and-treat pilot study in rural Lilongwe between July-August 2017. From October 2017-February 2018, 17 women who underwent screening using visual inspection with acetic acid (VIA) and same-day thermal ablation treatment were recruited at their 12-week follow-up visit post treatment to participate in this qualitative sub-study. Semi-structured interview guides that explored baseline knowledge of cervical cancer, perceptions, and motivation for screening were used for in-depth interviews (IDIs). IDIs were conducted in the local language, Chichewa, translated and transcribed to English. Data was analyzed using NVivo® V12.0. RESULTS: Findings included fatalistic views on cancer, but limited knowledge specific to cervical cancer. Misconceptions of cervical cancer screening were common; however, there was a unique understanding of screening as prevention (i.e., finding and treating early disease to prevent progression to worsening disease). This understanding appeared to stem from HIV prevention concepts known to the community. Motivations for screening included desire to know one's health status, convenience of community-based screening, and peer encouragement. CONCLUSION: Despite limited knowledge of cervical cancer and misconceptions of screening, the concept of screening for prevention, desire to know one's health status, convenient access, and peers' influence were motivators for participation in screening. Cervical cancer screen-and-treat programs in high HIV prevalence areas should consider utilizing language that parallels HIV prevention language to communicate the need for cervical cancer screening and treatment and utilize prevention concepts that may already be familiar to women living there.

Prevalence of High-Risk Human Papillomavirus by RNA Assay in Home Self-Collected Samples Among Underscreened People in North Carolina.

BACKGROUND: Low-income and uninsured people with a cervix (PWC) are at the highest risk of being underscreened for cervical cancer. We evaluated the prevalence of high-risk human papillomavirus (hrHPV) on home self-collected samples, as well as rates of in-clinic follow-up and risk factors associated with hrHPV positivity in this at-risk population. METHODS: My Body My Test 3 was conducted between 2016 and 2019 in North Carolina among individuals aged 25 to 64 years, overdue for cervical cancer screening, and with incomes of <250% of the US Federal Poverty Level. Our analytic sample included participants randomized to the self-collection arm who returned self-collected cervicovaginal brush samples for HPV testing (n = 329). Samples were tested for 14 hrHPV types by an HPV RNA assay and further genotyped for HPV-16 and HPV-18/45. We examined behavioral risk factors for hrHPV positivity using logistic regression and between-subject t tests. RESULTS: High-risk HPV RNA prevalence was 16% (n = 52/329) in self-collected samples. Of the hrHPV-positive participants, 24 (46%) presented for in-clinic cervical cancer screening, compared with 56 (20%) of hrHPV-negative participants. Those with ≥2 sexual partners in the past year were twice as likely to be hrHPV positive in adjusted analyses (adjusted odds ratio, 2.00 [95% confidence interval, 1.03-3.88]). High-risk HPV-positive and HPV-negative participants had similar attitudes toward screening, with the exception of hrHPV-positive participants who reported a lower perceived risk of cervical cancer than those who were hrHPV negative (P < 0.05). CONCLUSION: The hrHPV RNA prevalence was similar to findings in other underscreened PWC in the United States. Efforts to reach underscreened PWC are critical for cervical cancer prevention. Future studies aimed at home self-collection should address methods of increasing clinic attendance and completion of treatment among those with HPV-positive results.

Valsartan- and melatonin-supported adipose-derived mesenchymal stem cells preserve renal function in chronic kidney disease rat through upregulation of prion protein participated in promoting PI3K-Akt-mTOR signaling and cell proliferation.

This study tested the hypothesis that valsartan (Val) and melatonin (Mel)-assisted adipose-derived mesenchymal stem cells (ADMSCs) preserved the residual renal function in chronic kidney disease (CKD) rat through promoting cellular-prior-protein (PrPC) to upregulate PI3K/Akt/mTOR signaling and cell proliferation. In vitro study demonstrated that as compared with CKD-derived-ADMSCs, Val/Mel/overexpression of PrPC-treated CKD derived-ADMSCs significantly upregulated cell proliferation and protein expressions of PrPC and phosphorylated (p)-PI3K/p-Akt/p-mTOR, and downregulated oxidative stress (all p < 0.001). Rats (n = 42) were categorized into group 1 (sham-operated-control), group 2 (CKD), group 3 (CKD + ADMSCs/1.2 ×106 cells) + Mel/20 mg/kg/day), group 4 (CKD + siRNA-PrPC-ADMSCs/1.2 ×106 cells), group 5 (CKD + ADMSCs/1.2 ×106 cells + Val/20 mg/kg/day) and group 6 (CKD + Val + Mel). By day 35, the kidney specimens were harvested and the result showed that the protein expression of PrPC was highest in group 1, lowest in groups 2/4 and significantly lower in group 6 than in groups 3/5, but it was similar in groups 3/5 (all p < 0.0001). The protein expressions of cell-stress-signaling (p-PI3K/p-Akt/p-mTOR) and cell-cycle activity (cyclin-D1/clyclin-E2/Cdk2/Cdk4) exhibited an identical pattern, whereas the protein expressions of oxidative-stress (NOX-1/NOX-2)/mitochondrial fission (PINK1/DRP1)/apoptosis (cleaved-capsase3/cleaved-PARP) and fibrosis (TFG-ß/Smad3) as well as creatinine/BUN levels, ratio of urine-protein to urine-creatine and kidney-injured score exhibited an opposite pattern of PrPC among the groups (all p < 0.0001). In conclusion, Mel/Val facilitated-ADMSCs preserved renal architecture and function in CKD rat through promoting PrPC to regulate the cell proliferation/oxidative-stress/cell-stress signalings.

Barriers to follow-up after an abnormal cervical cancer screening result and the role of male partners: a qualitative study.

INTRODUCTION: Cervical cancer is the leading cause of cancer deaths among women in Malawi, but preventable through screening. Malawi primarily uses visual inspection with acetic acid (VIA) for screening, however, a follow-up for positive screening results remains a major barrier, in rural areas. We interviewed women who underwent a community-based screen-and-treat campaign that offered same-day treatment with thermocoagulation, a heat-based ablative procedure for VIA-positive lesions, to understand the barriers in accessing post-treatment follow-up and the role of male partners in contributing to, or overcoming these barriers. METHODS: We conducted in-depths interviews with 17 women recruited in a pilot study that evaluated the safety and acceptability of community-based screen-and-treat programme using VIA and thermocoagulation for cervical cancer prevention in rural Lilongwe, Malawi. Ten of the women interviewed presented for post-treatment follow-up at the healthcare facility and seven did not. The interviews were analysed for thematic content surrounding barriers for attending for follow-up and role of male partners in screening. RESULTS: Transportation was identified as a major barrier to post-thermocoagulation follow-up appointment, given long distances to the healthcare facility. Male partners were perceived as both a barrier for some, that is, not supportive of 6-week post-thermocoagulation abstinence recommendation, and as an important source of support for others, that is, encouraging follow-up attendance, providing emotional support to maintaining post-treatment abstinence and as a resource in overcoming transportation barriers. Regardless, the majority of women desired more male partner involvement in cervical cancer screening. CONCLUSION: Despite access to same-day treatment, long travel distances to health facilities for post-treatment follow-up visits remained a major barrier for women in rural Lilongwe. Male partners were identified both as a barrier to, and an important source of support for accessing and completing the screen-and-treat programme. To successfully eliminate cervical cancer in Malawi, it is imperative to understand the day-to-day barriers women face in accessing preventative care.

Women's experiences in a community-based screen-and-treat cervical cancer prevention program in rural Malawi: a qualitative study.

BACKGROUND: Malawi has the world's highest cervical cancer incidence and mortality due to high rate of HIV coupled with inadequate screening and treatment services. The country's cervical cancer control program uses visual inspection with acetic acid (VIA) and cryotherapy, but screening is largely limited by poor access to facilities, high cost of cryotherapy gas, and high loss-to-follow-up. To overcome these limitations, we implemented a community-based screen-and-treat pilot program with VIA and thermocoagulation. Through a qualitative study, we explore the experiences of women who underwent this community-based pilot screening program. METHODS: We implemented our pilot program in rural Malawi and conducted an exploratory qualitative sub-study. We conducted in-depth interviews with women who were treated with thermocoagulation during the program. We used semi-structured interviews to explore screen-and-treat experience, acceptability of the program and attitudes towards self-sampling for HPV testing as an alternative screening method. Content analysis was conducted using NVIVO v12. RESULTS: Between July - August 2017, 408 participants eligible for screening underwent VIA screening. Thirty participants had VIA positive results, of whom 28 underwent same day thermocoagulation. We interviewed 17 of the 28 women who received thermocoagulation. Thematic saturation was reached at 17 interviews. All participants reported an overall positive experience with the community-based screen-and-treat program. Common themes were appreciation for bringing screening directly to their villages, surprise at the lack of discomfort, and the benefits of access to same day treatment immediately following abnormal screening. Negative experiences were rare and included discomfort during speculum exam, long duration of screening and challenges with complying with postprocedural abstinence. Most participants felt that utilizing self-collected HPV testing could be acceptable for screening in their community. CONCLUSIONS: Our exploratory qualitative sub-study demonstrated that the community-based screen-and-treat with VIA and thermocoagulation was widely accepted. Participants valued the accessible, timely, and painless thermocoagulation treatment and reported minimal side effects. Future considerations for reaching rural women can include community-based follow-up, cervical cancer education for male partners and self-sampling for HPV testing.

Aortic Thrombus in a Nonaneurysmal Ascending Aorta.

BACKGROUND: Ascending aortic thrombus (AAT) in a nonaneurysmal aorta is an extremely rare event and has potentially catastrophic complications, with a life-threatening risk of myocardial infarction and cerebral embolization. This systematic review aims to elucidate the clinical manifestations and to compare the outcomes of anticoagulation therapy versus open aortic surgery for AAT. METHODS: The MEDLINE/PubMed databases were extensively searched between 1995 and 2019. All relevant publications on AAT in adults were reviewed, and individual patient data were pooled in this meta-analysis. The primary outcome was AAT resolution. The adverse outcome variables were recurrent arterial embolic events, complications related to open aortic surgery, and mortality during the study period. Chi-squared test and logistic regression analysis were used to compare groups and identify any predictors of mortality. RESULTS: Overall, 107 patients from 101 articles were included, of whom 29 patients who received anticoagulation therapy and 59 who underwent open aortic surgery were included in the outcome analysis. Among 29 patients treated with initial anticoagulation therapy, the persistence of AAT was observed in 11 patients (38%) and recurrent arterial embolization was developed in 6 patients (21%). All 11 patients in the anticoagulation group underwent secondary aortic surgery for the persistence of AAT with uneventful postoperative course. Compared with patients treated with primary aortic surgery, patients treated with initial anticoagulation therapy had higher risk of recurrent embolization (P = 0.002). No significant difference existed in the mortality rates between the groups (P = 0.106). Hemodynamic instability was an independent predictor of mortality (P = 0.008). CONCLUSIONS: Anticoagulation therapy and open aortic surgery for AAT show similar results; however, open aortic surgery reliably removes AAT and reduces the risk of recurrent embolization compared with anticoagulation therapy. Furthermore, the preoperative hemodynamic status significantly influences the clinical outcome and is a strong predictor of prognosis.

Localization of goose haemorrhagic polyomavirus in naturally infected geese using in situ hybridization.

Goose haemorrhagic polyomavirus (GHPV) is the aetiological agent of haemorrhagic nephritis enteritis of geese (HNEG), a fatal disease that impacts geese and has been recorded only in Europe. The present study describes the first clinical cases of HNEG in Taiwan and the phylogenesis of Taiwanese GHPV, and it elucidates the pathogenesis of GHPV infection using in situ hybridization (ISH). The genomes of Taiwanese GHPV were highly similar to the previously reported strains. The diseased geese showed various degrees of vascular damage, especially in the digestive tract. The affected geese in the early stage showed transmural haemorrhagic enteritis in the intestine. In the middle to late stages, the most obvious lesion was hypoxic necrosis of renal tubules around intralobular central veins. Mineralization deposited in the kidney and systemic gout were also found. ISH revealed GHPV DNA in the vascular endothelial cells throughout the body, but not in the parenchymal cells of organs. Accordingly, the pathogenesis of GHPV infection was consistent with viral tropism in the endothelial cells. Specific attack of vascular endothelium by GHPV resulted in endothelial cell necrosis and subsequent increases of blood vessel permeability, as well as secondary circulation disorders, such as oedema, haemorrhage, and ischaemic necrosis in the adjacent parenchyma. RESEARCH HIGHLIGHTS Cell tropism of GHPV is determined by in situ hybridization. The tropism results in vascular dysfunction and subsequent pathobiology. Haemorrhagic nephritis and enteritis of geese described outside Europe for the first time.

Clinical course and outcome of patients with acute pulmonary embolism rescued by veno-arterial extracorporeal membrane oxygenation: a retrospective review of 21 cases.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (ECMO) is increasingly being utilized in patients with massive pulmonary embolism (PE). However, the efficacy and the safety remain uncertain. This study aimed to investigate clinical courses and outcomes in ECMO-treated patients with acute PE. METHODS: Twenty-one patients with acute PE rescued by ECMO from January 2012 to December 2019 were retrospectively analysed. Clinical features, laboratory biomarkers, and imaging findings of these patients were reviewed, and the relationship with immediate outcome and clinical course was investigated. RESULTS: Sixteen patients (76.2%) experienced refractory circulatory collapse requiring cardiopulmonary resuscitation (CPR) or ECMO support within 2 h after the onset of cardiogenic shock, and none could receive definitive reperfusion therapy before ECMO initiation. Before or during ECMO support, more than 90% of patients had imaging signs of right ventricular (RV) dysfunction. In normotension patients, the computed tomography (CT) value was a valuable predictor of rapid disease progression compared with cardiac troponin I level. Ultimately, in-hospital death occurred in ten patients (47.6%) and 90% of them died of prolonged CPR-related brain death. Cardiac arrest was a significant predictor of poor prognosis (p = 0.001). CONCLUSIONS: ECMO appears to be a safe and effective circulatory support in patients with massive PE. Close monitoring in intensive care unit is recommended in patients with RV dysfunction and aggressive use of ECMO may reduce the risk of sudden cardiac arrest and improve clinical outcome.

Xenogeneic and Allogeneic Mesenchymal Stem Cells Effectively Protect the Lung Against Ischemia-reperfusion Injury Through Downregulating the Inflammatory, Oxidative Stress, and Autophagic Signaling Pathways in Rat.

This study tested the hypothesis that both allogenic adipose-derived mesenchymal stem cells (ADMSCs) and human inducible pluripotent stem cell-derived MSCs (iPS-MSCs) offered a comparable effect for protecting the lung against ischemia-reperfusion (IR) injury in rodent through downregulating the inflammatory, oxidative stress, and autophagic signaling pathways. Adult male Sprague-Dawley rats (n = 32) were categorized into group 1 (sham-operated control), group 2 (IRI), group 3 [IRI + ADMSCs (1.0 × 106 cells)/tail-vein administration at 0.5/18/36 h after IR], and group 4 [IRI + iPS-MSCs (1.0 × 106 cells)/tail-vein administration at 0.5/18/36 h after IR], and lungs were harvested at 72 h after IR procedure. In vitro study demonstrated that protein expressions of three signaling pathways in inflammation (TLR4/MyD88/TAK1/IKK/I-κB/NF-κB/Cox-2/TNF-α/IL-1ß), mitochondrial damage/cell apoptosis (cytochrome C/cyclophilin D/DRP1/ASK1/APAF-1/mitochondrial-Bax/caspase3/8/9), and autophagy/cell death (ULK1/beclin-1/Atg5,7,12, ratio of LCB3-II/LC3B-I, p-AKT/m-TOR) were significantly higher in lung epithelial cells + 6h hypoxia as compared with the control, and those were significantly reversed by iPS-MSC treatment (all P < 0.001). Flow cytometric analysis revealed that percentages of the inflammatory cells in bronchioalveolar lavage fluid and circulation, and immune cells in circulation/spleen as well as circulatory early and late apoptotic cells were highest in group 2, lowest in group 1, and significantly higher in group 3 than in group 4 (all P < 0.0001). Microscopy showed the lung injury score and numbers of inflammatory cells and Western blot analysis showed the signaling pathways of inflammation, mitochondrial damage/cell apoptosis, autophagy, and oxidative stress exhibited an identical pattern of flow cytometric results among the four groups (all P < 0.0001). Both xenogeneic and allogenic MSCs protected the lung against IRI via suppressing the inflammatory, oxidative stress, and autophagic signaling.

Baseline factors identified for the prediction of good responders in patients with end-stage diffuse coronary artery disease undergoing intracoronary CD34+ cell therapy.

BACKGROUND: Treating patients with end-stage diffuse coronary artery disease (EnD-CAD) unsuitable for coronary intervention remains a clinical challenge. They usually express refractory angina and have a high risk of mortality. Although growing data have indicated cell therapy is an alternative solution to medical or invasive therapy, there are still lacking useful markers to predict whether heart function will improve in the EnD-CAD patients who underwent circulatory-derived CD34+ cell therapy. By utilizing the baseline variables and results from our previous phase I/II clinical trials, the aim of this study tried to elucidate the variables predictive of the "good response" to CD34+ cell therapy. METHODS: This retrospective study included 38 patients in phase I clinical trial (2011-2014), and 30 patients in phase II clinical trial (2013-2017). These patients were categorized into "good responders" and "non-responders" according to their 1-year improvement of LVEF ≥ 7.0% or < 7.0% after intracoronary CD34+ cell therapy. Univariate and multivariate logistic regression models were performed to identify potential independent predictors of a good responder to cell therapy, followed by Hosmer-Lemeshow (H-L) test for goodness of fit and prediction power. RESULTS: Among baseline data, multivariate analysis demonstrated that the history of a former smoker was independently predictive of good responders (p = 0.006). On the other hand, male gender, the baseline Canadian Cardiovascular Society angina score ≥ 3, and grades of LV diastolic dysfunction ≥ 2 were significantly negative predictors of good responders (all p < 0.01). After administration of subcutaneous granulocyte-colony stimulating factor (G-CSF), a higher post-G-CSF neutrophil count in addition to the above four baseline variables also played crucial roles in early prediction of good response to CD34+ cell therapy for EnD-CAD (all p < 0.03). The H-L test displayed a good prediction power with sensitivity 83.3%, specificity 85.3%, and accuracy 84.4%. CONCLUSIONS: Using the results of our phase I/II clinical trials, previous smoking habit, female sex, lower grades of angina score, and diastolic dysfunction were identified to be independently predictive of "good response" to CD34+ cell therapy in the patients with EnD-CAD. TRIAL REGISTRATION: This is a retrospective analysis based on phase I ( ISRCTN72853206 ) and II ( ISRCTN26002902 ) clinical trials.

P-cresyl sulfate causes mitochondrial hyperfusion in H9C2 cardiomyoblasts.

Increased circulating level of uraemic solute p-cresyl sulphate (PCS) in patients with chronic kidney disease (CKD) is known to increase myocardial burden relevant to mitochondrial abnormalities. This study aimed at investigating mitochondrial response to PCS in H9C2 cardiomyoblasts. H9C2 cardiomyoblasts were treated with four different concentrations of PCS (3.125, 6.25, 12.5 and 25.0 µg/mL) to study the changes in cell proliferation, cell size and mitochondrial parameters including morphology, respiration, biogenesis and membrane potential. The lowest effective dose of PCS (6.25 µg/mL) induced mitochondrial hyperfusion with enhanced mitochondrial connectivity, mitochondrial oxygen consumption rates, mitochondrial mass, mitochondrial DNA copy number and increased volume of cardiomyoblasts. After PCS treatment, phosphorylation of energy-sensing adenosine monophosphate-activated protein kinase (AMPK) was increased without induction of apoptosis. In contrast, mitochondrial mass was recovered after AMPK silencing. Additionally, mitochondrial hyperfusion and cell volume were reversed after cessation of PCS treatment. The results of the present study showed that low-level PCS not only caused AMPK-dependent mitochondrial hyperfusion but also induced cell enlargement in H9C2 cardiomyoblasts in vitro.

Human Umbilical Cord-Derived Mesenchymal Stem Cells for Acute Respiratory Distress Syndrome.

OBJECTIVES: To investigate the safety, feasibility, and possible adverse events of single-dose human umbilical cord-derived mesenchymal stem cells in patients with moderate-to-severe acute respiratory distress syndrome. DESIGN: Prospective phase I clinical trial. SETTING: Medical center in Kaohsiung, Taiwan. PATIENTS: Moderate-to-severe acute respiratory distress syndrome with a PaO2/FIO2 ratio less than 200. INTERVENTIONS: Scaling for doses was required by Taiwan Food and Drug Administration as follows: the first three patients received low-dose human umbilical cord-derived mesenchymal stem cells (1.0 × 10 cells/kg), the next three patients with intermediate dose (5.0 × 10 cells/kg), and the final three patients with high dose (1.0 × 10 cells/kg) between December 2017 and August 2019. MEASUREMENTS AND MAIN RESULTS: Nine consecutive patients were enrolled into the study. In-hospital mortality was 33.3% (3/9), including two with recurrent septic shock and one with ventilator-induced severe pneumomediastinum and subcutaneous emphysema. No serious prespecified cell infusion-associated or treatment-related adverse events was identified in any patient. Serial flow-cytometric analyses of circulating inflammatory biomarkers (CD14CD33/CD11b+CD16+/CD16+MPO+/CD11b+MPO+/CD14CD33+) and mesenchymal stem cell markers (CD26+CD45-/CD29+CD45-/CD34+CD45-/CD44+CD45-/CD73+CD45-/CD90+CD45-/CD105+CD45-/CD26+CD45-) were notably progressively reduced (p for trend < 0.001), whereas the immune cell markers (Helper-T-cell/Cytotoxity-T-cell/Regulatory-T-cell) were notably increased (p for trend < 0.001) after cell infusion. CONCLUSIONS: The result of this phase I clinical trial showed that a single-dose IV infusion of human umbilical cord-derived mesenchymal stem cells was safe with favorable outcome in nine acute respiratory distress syndrome patients.

Sequential drug delivery for liver diseases.

The liver performs critical physiological functions such as metabolism/detoxification and blood homeostasis/biliary excretion. A high degree of blood access means that a drug's resident time in any cell is relatively short. This short drug exposure to cells requires local sequential delivery of multiple drugs for optimal efficacy, potency, and safety. The high metabolism and excretion of drugs also impose both technical challenges and opportunities to sequential drug delivery. This review provides an overview of the sequential events in liver regeneration and the related liver diseases. Using selected examples of liver cancer, hepatitis B viral infection, fatty liver diseases, and drug-induced liver injury, we highlight efforts made for the sequential delivery of small and macromolecular drugs through different biomaterials, cells, and microdevice-based delivery platforms that allow fast delivery kinetics and rapid drug switching. As this is a nascent area of development, we extrapolate and compare the results with other sequential drug delivery studies to suggest possible application in liver diseases, wherever appropriate.

Estimating the costs of HIV clinic integrated versus non-integrated treatment of pre-cancerous cervical lesions and costs of cervical cancer treatment in Kenya.

OBJECTIVES: To estimate the modified societal costs of cervical cancer treatment in Kenya; and to compare the modified societal costs of treatment for pre-cancerous cervical lesions integrated into same-day HIV care compared to "non-integrated" treatment when the services are not coordinated on the same day. MATERIALS AND METHODS: A micro-costing study was conducted at Coptic Hope Center for Infectious Diseases and Kenyatta National Hospital from July 1-October 31, 2014. Interviews were conducted with 54 patients and 23 staff. Direct medical, non-medical (e.g., overhead), and indirect (e.g., time) costs were calculated for colposcopy, cryotherapy, Loop Electrosurgical Excision Procedure (LEEP), and treatment of cancer. All costs are reported in 2017 US dollars. RESULTS: Patients had a mean age of 41 and daily earnings of $6; travel time to the facility averaged 2.8 hours. From the modified societal perspective, per-procedure costs of colposcopy were $41 (integrated) vs. $91 (non-integrated). Per-procedure costs of cryotherapy were $22 (integrated) vs. $46 (non-integrated), whereas costs of LEEP were $50 (integrated) and $99 (non-integrated). This represents cost savings of $25 for cryotherapy and $50 for colposcopy and LEEP when provided on the same day as an HIV-care visit. Treatment for cervical cancer cost $1,345-$6,514, depending on stage. Facility-based palliative care cost $59/day. CONCLUSIONS: Integrating treatment of pre-cancerous lesions into HIV care is estimated to be cost-saving from a modified societal perspective. These costs can be applied to financial and economic evaluations in Kenya and similar urban settings in other low-income countries.

Short-interval exposure to ambient fine particulate matter (PM2.5) exacerbates the susceptibility of pulmonary damage in setting of lung ischemia-reperfusion injury in rodent: Pharmacomodulation of melatonin.

This study tested the hypothesis that exposure to ambient fine particulate matter (PM2.5) pollution increased susceptibility of rat lung to damage from acute ischemia-reperfusion (IR) injury that was reversed by melatonin (Mel) treatment. Male-adult SD rats (n = 30) were categorized into group 1 (normal control), group 2 (PM2.5 only), group 3 (IR only at day 8 after PM2.5 exposure), group 4 (PM2.5 + IR) and group 5 (PM2.5 + IR + Mel), and all animals were sacrificed by day 10 after PM2.5 exposure. Oxygen saturation (%) was significantly higher in group 1 than in other groups and significantly lower in group 4 than in groups 2, 3 and 5 but it did not differ among the latter three groups (p < 0.01). Pulmonary protein expressions of inflammation (MMP-9/TNF-α/NF-kB), oxidative stress (NOX-1/NOX-2/oxidized protein), apoptosis (mitochondrial-Bax/caspase-3/PARP) and fibrosis were lowest in group 1, highest in group 4, significantly higher in group 5 than in groups 2 and 3 (all p < 0.0001), but they did not differ between groups 2 and 3. Inflammatory cell infiltration in lung parenchyma, specific inflammatory cell surface markers (CD14+, F4/88+), allergic inflammatory cells (IgE+, eosinophil+), number of goblet cells, thickness of tracheal epithelial layer and fibrotic area exhibited an identical pattern of protein expressions to inflammation among the five groups (all p < 0.0001). In conclusion, lung parenchymal damage and a rigorous inflammatory response were identified in rodent even with short-term PM2.5 exposure.

Cleavable cellulosic sponge for functional hepatic cell culture and retrieval.

Interconnected macroporous hydrogel is hydrophilic; it exhibits soft tissue-like mechanical property and aqueous-stable macroporosity for 3D spheroid culture. There is an unmet need to develop cleavable macroporous hydrogel, for the ease of retrieving functional spheroids for further in vitro and in vivo applications. We have developed and comprehensively characterized a hydroxypropyl-cellulose-disulfide sponge by systematically identifying strategies and synthesis schemes to confer cleavability to the sponge under cell-friendly conditions. It preserved the essential advantages of the macroporous hydrogel to support 3D spheroid formation and maintenance of sensitive hepatocytes while allowing rapid cleavage and retrieval of functional spheroids. By culturing HepaRG as spheroids in the cleavable sponge, we have accelerated HepaRG differentiation to 9 days compared to 28 days in 2D culture. Cytochrome P450 basal activity reached significantly higher level, while albumin secretion and fluorescein diacetate staining indicated the same at day 5. The purity of albumin+ hepatocytes reached 92.9% versus 7.1% of CK19+ cholangiocytes at day 9, a much stronger preference for hepatocytes than the 60% albumin+ hepatocytes purity in 2D culture. HepaRG differentiated hepatocytes were retrieved by cleaving the sponge with 10 mM tris-(2-carboxyethyl)-phosphine (TCEP) within 30 min preserving viability, plateability and positive albumin staining of the hepatocyte spheroids. This cleavable macroporous hydrogel sponge will support the rapid development of various 3D spheroid- or organoid-based applications in basic research and drug testing.

Combined Adipose-Derived Mesenchymal Stem Cells and Low-Energy Extracorporeal Shock Wave Therapy Protect the Brain From Brain Death-Induced Injury in Rat.

This study tested the hypothesis that combined adipose-derived mesenchymal stem cell (ADMSC) and low-energy extracorporeal shock wave (ECSW) therapy could protect brain from brain death (BD)-induced injury. Adult male Sprague Dawley rats were categorized into group 1 (sham control), group 2 (BD), group 3 (BD + ECSW [0.15 mJ/mm2/300 impulses] applied to the skull surface 3 hours after BD induction), group 4 (BD + ADMSC [1.2 × 106 cell] by intravenous injection 3 hours after BD induction) and group 5 (BD + ECSW + ADMSC). By 6 hours after BD induction, circulating/spleen levels of immune cells (CD3/CD4+, CD8/CD4+, Treg+) and circulating levels of inflammatory cells (MPO/Ly6G/CD11a/b) and soluble mediators (TNF-α/IL-6) were lowest in group 1 and significantly progressively reduced from groups 2 to 5 (all p < 0.0001). Brain protein expressions of inflammatory (TNF-α/NF-κB/MMP-9/IL-1ß), apoptotic (caspase-3/PARP/mitochondrial-BAX), oxidative stress/DNA-damage (NOX-1/NOX-2/oxidized protein/γ-H2AX) biomarkers exhibited an identical pattern, whereas anti-oxidant (SIRT1/SIRT3) and mitochondrial-integrity (mitochondrial-cytochrome-C) biomarkers exhibited an opposite pattern to inflammatory biomarkers among the 5 groups (all p < 0.0001). The cellular expressions of inflammatory/brain-edema (F4/80/CD14+/GFAP/AQP4) biomarkers exhibited an identical pattern to inflammation among the 5 groups (all p < 0.0001). In conclusion, ECSW-ADMSC therapy is superior to either alone for attenuating brain from BD-induced damage.