bluuebunny/crossref_metadata_2025 huggingface dataset:
Portable continuous wave Doppler ultrasound for primary healthcare in South Africa: can the EUnetHTA Core Model guide evaluation before technology adoption?
Authors: Mueller Debjani , Pattinson Robert C. , Hlongwane Tsakane M. , Busse Reinhard , Panteli Dimitra
Published: February 2021

Background

This study had a threefold aim: to test the value of stakeholder involvement in HTA to reduce evidence gaps and interpret findings; and to assess a medical device by applying the EUnetHTA Core Model (CM) in South Africa and thus ultimately provide a first overview of evidence for potential widespread adoption of the technology in a primary health care (PHC) setting. Used in primary healthcare setting for obstetric use, the technology under assessment is a low-cost continuous wave Doppler ultrasound (DUS).

Methods

The scoping of the assessment was defined by involving policy makers in selecting the domains and corresponding questions relevant to the ultrasound and its use. Additionally, hospital managers were invited to respond to dichotomous questions on the criteria for procurement. To substantiate evidence obtained from an initial literature review, different stakeholders were identified and consulted. The evidence generated fromall steps was used to populate the high-ranked assessment elements of the CM.

Results

The HTA on continuous-wave DUS incorporated the evidence on organizational, ethical, and social value of its use together with effectiveness, safety, and cost-effectiveness of the technology. The domains on “health problem” and “safety” had a higher rank than the rest of the nine domains. Unexplained fetal mortality is the largest single contributor to perinatal deaths in South Africa. Pregnant women in PHC setting were examined using a continuous-wave DUS, after their routine antenatal visit. The healthcare professionals interviewed, indicated the benefit in the use of continuous-wave DUS in the PHC setting and the need for training.

Conclusions

Collection and generation of evidence based on the HTA CM and the chosen decision criteria provided a generalized but structured guidance on the methodology. Several questions were not applicable for the technology and the context of its use and elimination of those that are inappropriate for the African context, resulted in a pragmatic solution. Engaging and consulting local stakeholders was imperative to understand the context, reduce evidence gaps, and address the uncertainties in the evidence, ultimately paving the way for technology adoption. Given the ongoing studies and the evolving evidence base, the potential of this technology should be reassessed.
Cost-effectiveness analysis of text messaging to support health advice for smoking cessation
Authors: Cobos-Campos Raquel , Mar Javier , Apiñaniz Antxon , de Lafuente Arantza Sáez , Parraza Naiara , Aizpuru Felipe , Orive Gorka
Published: February 2021

Background

Smoking in one of the most serious public health problems. It is well known that it constitutes a major risk factor for chronic diseases and the leading cause of preventable death worldwide. Due to high prevalence of smokers, new cost-effective strategies seeking to increase smoking cessation rates are needed.

Methods

We performed a Markov model-based cost-effectiveness analysis comparing two treatments: health advice provided by general practitioners and nurses in primary care, and health advice reinforced by sending motivational text messages to smokers’ mobile phones. A Markov model was used in which smokers transitioned between three mutually exclusive health states (smoker, former smoker and dead) after 6-month cycles. We calculated the cost-effectiveness ratio associated with the sending of motivational messages. Health care and society perspectives (separately) was adopted. Costs taken into account were direct health care costs and direct health care cost and costs for lost productivity, respectively. Additionally, deterministic sensitivity analysis was performed modifying the probability of smoking cessation with each option.

Results

Sending of text messages as a tool to support health advice was found to be cost-effective as it was associated with increases in costs of €7.4 and €1,327 per QALY gained (ICUR) for men and women respectively from a healthcare perspective, significantly far from the published cost-effectiveness threshold. From a societal perspective, the combined programmed was dominant.

Conclusions

Sending text messages is a cost-effective approach. These findings support the implantation of the combined program across primary care health centres.
Land use mix and physical activity in middle-aged and older adults: a longitudinal study examining changes in land use mix in two Dutch cohorts
Authors: Noordzij J. M. , Beenackers M. A. , Groeniger J. Oude , Timmermans E. J. , Motoc I. , Huisman M. , van Lenthe F. J.
Published: February 2021

Background

With urbanization and aging increasing in coming decades, societies face the challenge of keeping aging populations active. Land use mix (LUM) has been associated with cycling and walking, but whether changes in LUM relate to changes in cycling/walking is less known.

Objectives

Our objective was to study the effect of LUM on cycling/walking in two Dutch aging cohorts using data with 10 years of follow-up.

Methods

Data from 1183 respondents from the Health and Living Conditions of the Population of Eindhoven and Surroundings (GLOBE) study and 918 respondents from the Longitudinal Aging Study Amsterdam (LASA) were linked to LUM in 1000-m sausage network buffers at three time-points. Cycling/walking outcomes were harmonized to include average minutes spent cycling/walking per week. Data was pooled and limited to respondents that did not relocate between follow-up waves. Associations between LUM and cycling/walking were estimated using a Random Effects Within-Between (REWB) model that allows for the estimation of both within and between effects. Sensitivity analyses were performed on smaller (500-m) and larger (1600-m) buffers.

Results

We found evidence of between-individual associations of LUM in 1000-m buffers and walking (β: 11.10, 95% CI: 0.08; 21.12), but no evidence of within-associations in 1000-m buffers. Sensitivity analyses using 500-m buffers showed similar between-associations, but negative within-associations (β: -35.67, 95% CI: − 68.85; − 2.49). We did not find evidence of between-individual associations of LUM in any buffer size and cycling, but did find evidence of negative within-associations between LUM in 1600-m buffers and cycling (β: -7.49, 95% CI: − 14.31; − 0.66).

Discussion

Our study found evidence of positive associations between LUM and average walking time, but also some evidence of negative associations between a change in LUM and cycling/walking. LUM appears to be related to cycling/walking, but the effect of changes in LUM on cycling/walking is unclear.
Avelumab treatment in Italian patients with metastatic Merkel cell carcinoma: experience from an expanded access program
Authors: Grignani Giovanni , Chiarion Sileni Vanna , Pinto Carmine , Depenni Roberta , Fazio Nicola , Galli Luca , Giuffrida Dario , Carnaghi Carlo , Ciliberto Domenico , Corsi Domenico C. , Queirolo Paola , Benincasa Elena , Venturini Filippo , Fazzi Gennaro , Costa Nuno , Ascierto Paolo Antonio
Published: February 2021

Background

The incidence of Merkel cell carcinoma (MCC), a rare form of skin cancer with a poor prognosis, has increased in Italy in recent decades. Avelumab, an anti-programmed death ligand 1 monoclonal antibody, is approved for the treatment of metastatic MCC (mMCC) based on the results of the phase 2 JAVELIN Merkel 200 trial. The global avelumab expanded access program (EAP) was designed to provide compassionate use of avelumab prior to approval for patients with mMCC who had limited treatment options. We report findings from a subgroup of Italian patients enrolled in the avelumab EAP.

Methods

Eligible patients had mMCC and progressive disease following ≥ 1 prior line of chemotherapy or were ineligible for chemotherapy or clinical trial participation. Patients received avelumab 10 mg/kg intravenously every 2 weeks. Treating physicians were provided with an initial 3-month supply of avelumab; resupply was permitted if the patient achieved a complete response, partial response, stable disease, or other clinical benefit per physician assessment. Safety and efficacy data for the EAP were reported at the treating physician’s discretion.

Results

Between April 1, 2016, and September 14, 2018, 109 requests for avelumab were received from Italy, and 102 were approved. All but 1 of the approved patients had received ≥ 1 prior line of therapy. At data cutoff (March 22, 2019), 95 patients had been supplied with avelumab and response data were available for 55 patients. The objective response rate in response-evaluable patients was 29.1%, including 6 patients (10.9%) who achieved a complete response and 10 patients (18.2%) who achieved a partial response; in the total population supplied with avelumab (n = 95), the proportion who had an objective response was 16.8%. The median duration of treatment in responding patients was 9.7 months (range, 3.5–41.7 months). The most frequently reported treatment-related adverse events were infusion-related reaction (single preferred term; n = 3 [3.2%]) and pyrexia (n = 2 [2.1%]).

Conclusions

Results from Italian patients enrolled in the avelumab EAP are consistent with the findings of the JAVELIN Merkel 200 trial and confirm the efficacy and safety of avelumab treatment in this population.
Translational research in Uganda: linking basic science to bedside medicine in a resource limited setting
Authors: Kwizera Richard , Mande Emmanuel , Omali Denis , Okurut Samuel , Nabweyambo Sheila , Nabatanzi Rose , Nakanjako Damalie , Meya David B.
Published: February 2021

Background

Translational research is a process of applying knowledge from basic biology and clinical trials to techniques and tools that address critical medical needs. Translational research is less explored in the Ugandan health system, yet, it is fundamental in enhancing human health and well-being. With the current high disease burden in Uganda, there are many opportunities for exploring, developing and utilising translational research.

Main body

In this article, we described the current state, barriers and opportunities for translational research in Uganda. We noted that translational research is underutilised and hindered by limited funding, collaborations, laboratory infrastructure, trained personnel, equipment and research diversity. However, with active collaborations and funding, it is possible to set up and develop thriving translational research in Uganda. Researchers need to leverage existing international collaborations to enhance translational research capacity development.

Conclusion

Expanding the integration of clinical and translational research in Uganda health care system will improve clinical care.
On inflammatory hypothesis of depression: what is the role of IL-6 in the middle of the chaos?
Authors: Roohi Elnaz , Jaafari Nematollah , Hashemian Farshad
Published: February 2021

Many patients with major depressive disorder (MDD) are reported to have higher levels of multiple inflammatory cytokines including interleukin 6 (IL-6). Recent studies both pre-clinical and clinical have advocated for the functional role of IL-6 in development of MDD and suggested a great potential for targeting this cytokine to open new avenues in pharmacotherapy of depression. The purpose of the present narrative review was to provide an integrated account of how IL-6 may contribute to development of depression. All peer-reviewed journal articles published before July 2020 for each area discussed were searched by WOS, PubMed, MEDLINE, Scopus, Google Scholar, for original research, review articles, and book chapters. Publications between 1980 and July 2020 were included. Alterations in IL-6 levels, both within the periphery and the brain, most probably contribute to depression symptomatology in numerous ways. As IL-6 acts on multiple differing target tissues throughout the body, dysregulation of this particular cytokine can precipitate a multitude of events relevant to depression and blocking its effects can prevent further escalation of inflammatory responses, and potentially pave the way for opening new avenues in diagnosis, treatment, and prevention of this debilitating disorder.
“As a woman who watches how my family is… I take the difficult decisions”: a qualitative study on integrated family planning and childhood immunisation services in five African countries
Authors: Hoyt Jenna , Krishnaratne Shari , Hamon Jessie K. , Boudarene Lydia , Chantler Tracey , Demissie Shiferaw Dechasa , Landegger Justine , Moseti Easterlina , Marcus Seth , Kambanje Misozi , Pryor Shannon , Spilotros Nathaly , Gnintoungbe Marius , Curry Dora , Webster Jayne
Published: February 2021

Background

Family planning (FP) has the potential to improve maternal and child health outcomes and to reduce poverty in sub-Saharan Africa. However, substantial unmet need for modern contraceptive methods (MCMs) persists in this region. Current literature highlights multi-level barriers, including socio-cultural norms that discourage the use of MCMs. This paper explores women’s choices and decision-making around MCM use and examines whether integrating FP services with childhood immunisations influenced women’s perceptions of, and decision to use, an MCM.

Methods

94 semi-structured interviews and 21 focus group discussions with women, health providers, and community members (N = 253) were conducted in health facilities and outreach clinics where an intervention was delivering integrated FP and childhood immunisation services in Benin, Ethiopia, Kenya, Malawi and Uganda. Data were coded using Nvivo software and an analytical framework was developed to support interpretative and thematic analyses on women’s decision-making about MCM use.

Results

Most women shared the reproductive desire to space or limit births because of the perceived benefits of improved health and welfare for themselves and for their children, including the economic advantages. For some, choices about MCM use were restricted because of wider societal influences. Women’s decision to use MCMs was driven by their reproductive desires, but for some that was stymied by fears of side effects, community stigma, and disapproving husbands, which led to clandestine MCM use. Health providers acknowledged that women understood the benefits of using MCMs, but highlighted that the wider socio-cultural norms of their community often contributed to a reluctance to use them. Integration of FP and childhood immunisation services provided repeat opportunities for health providers to counter misinformation and it improved access to MCMs, including for women who needed to use them covertly.

Conclusions

Some women chose to use MCMs without the approval of their husbands, and/or despite cultural norms, because of the perceived health and economic benefits for themselves and for their families, and because they lived with the consequences of short birth intervals and large families. Integrated FP and childhood immunisation services expanded women’s choices about MCM use and created opportunities for women to make decisions autonomously.
Development of a reverse transcription droplet digital PCR (RT-ddPCR) assay for sensitive detection of simian immunodeficiency virus (SIV)
Authors: Long Samuel , Berkemeier Brian
Published: February 2021

Background

Simian immunodeficiency virus (SIV)-infected rhesus macaques constitute an excellent model of human HIV infection. Sensitive detection of SIV RNA in cell and tissue samples from infected animals subjected to treatment regimens becomes especially critical in determining which therapeutic attempts are successful, and consequently, which interventions should be prioritized in HIV cure research.

Results

In this report, we describe the design and testing of a Raindance ddPCR platform-based, sensitive SIV reverse transcription droplet digital PCR (RT-ddPCR) assay by exploring the combinations of various priming conditions and reverse transcriptases, and testing one-step vs. two-step procedures, to eliminate background signal(s) and enable detection and quantification of low level target signals.

Conclusions

Similar reaction conditions and assay validation procedures can be explored for potential development of additional assays for other applications that require sensitive detection of low-level targets in RNA samples.
Sociodemographic and lifestyle correlates of exclusive breastfeeding practices among mothers on antiretroviral therapy in the Eastern Cape, South Africa
Authors: Goon Daniel Ter , Ajayi Anthony Idowu , Adeniyi Oladele Vincent
Published: February 2021

Background

Exclusive breastfeeding (EBF) is associated with a reduction of postnatal HIV transmission and optimal infant growth. Given that the factors influencing exclusive breastfeeding are multi-factorial and context-specific, we examined the prevalence and factors associated with exclusive breastfeeding practice in the first 6 months among mothers on antiretroviral therapy in the Eastern Cape, South Africa.

Methods

This was a cross-sectional study conducted between January to May 2018, on 469 parturient women enlisted in the prevention of mother-to-child HIV transmission cohort study in the Eastern Cape. Mothers were asked to recall whether they breastfed their infant exclusively with breast milk from birth and if so, to state how long they did. We collected relevant sociodemographic, lifestyle, and maternal information by interview. Bivariate and multivariable logistic regression analyses were fitted to determine the sociodemographic and lifestyle factors associated with exclusive breastfeeding practice.

Results

The prevalence of six-month exclusive breastfeeding, measured since birth, was 32.0%. E Exclusive breastfeeding’s prevalence was significantly higher among married women (36.8%), unemployed women (36.6%), non-smokers (32.7%), and those who never drank alcohol (37.0%). Unemployed women (adjusted odds ratio [AOR] 1.66, 95% Confidence Interval [CI] 1.08–2.56) and those with grade 12 or less level of education (AOR 2.76, 95% CI 1.02–7.49) had a higher likelihood of practising EBF for 6 months since birth while mothers who consumed alcohol (AOR 0.54, 95% CI 0.34–0.85) were less likely to practice EBF for 6 months.

Conclusions

The prevalence of six-month exclusive breastfeeding in the study, although comparable with sub-Saharan Africa and worldwide prevalence, remains suboptimal. Advocacy campaigns on EBF must target alcohol cessation and the creation of a favourable workplace environment for lactating mothers.
Increased serum QUIN/KYNA is a reliable biomarker of post-stroke cognitive decline
Authors: Cogo Adrien , Mangin Gabrielle , Maïer Benjamin , Callebert Jacques , Mazighi Mikael , Chabriat Hughes , Launay Jean-Marie , Huberfeld Gilles , Kubis Nathalie
Published: February 2021

Background

Strokes are becoming less severe due to increased numbers of intensive care units and improved treatments. As patients survive longer, post-stroke cognitive impairment (PSCI) has become a major health public issue. Diabetes has been identified as an independent predictive factor for PSCI. Here, we characterized a clinically relevant mouse model of PSCI, induced by permanent cerebral artery occlusion in diabetic mice, and investigated whether a reliable biomarker of PSCI may emerge from the kynurenine pathway which has been linked to inflammatory processes.

Methods

Cortical infarct was induced by permanent middle cerebral artery occlusion in male diabetic mice (streptozotocin IP). Six weeks later, cognitive assessment was performed using the Barnes maze, hippocampi long-term potentiation using microelectrodes array recordings, and neuronal death, white matter rarefaction and microglia/macrophages density assessed in both hemispheres using imunohistochemistry. Brain and serum metabolites of the kynurenin pathway were measured using HPLC and mass fragmentography. At last, these same metabolites were measured in the patient’s serum, at the acute phase of stroke, to determine if they could predict PSCI 3 months later.

Results

We found long-term spatial memory was impaired in diabetic mice 6 weeks after stroke induction. Synaptic plasticity was completely suppressed in both hippocampi along with increased neuronal death, white matter rarefaction in both striatum, and increased microglial/macrophage density in the ipsilateral hemisphere. Brain and serum quinolinic acid concentrations and quinolinic acid over kynurenic acid ratios were significantly increased compared to control, diabetic and non-diabetic ischemic mice, where PSCI was absent. These putative serum biomarkers were strongly correlated with degradation of long-term memory, neuronal death, microglia/macrophage infiltration and white matter rarefaction. Moreover, we identified these same serum biomarkers as potential predictors of PSCI in a pilot study of stroke patients.

Conclusions

we have established and characterized a new model of PSCI, functionally and structurally, and we have shown that the QUIN/KYNA ratio could be used as a surrogate biomarker of PSCI, which may now be tested in large prospective studies of stroke patients.
Factors influencing post-ICU psychological distress in family members of critically ill patients: a linear mixed-effects model
Authors: Naef Rahel , von Felten Stefanie , Ernst Jutta
Published: February 2021

Background

Adverse responses to critical illness, such as symptoms of depression, anxiety or posttraumatic stress, are relatively common among family members. The role of risk factors, however, remains insufficiently understood, but may be important to target those family members most in need for support. We therefore examined the association of patient-, family member- and care-related factors with post-ICU psychological distress in family members in a general population of critical ill patients.

Methods

We conducted a prospective, single-centre observational study in a twelve-bed surgical ICU in a 900-bed University Hospital in Switzerland. Participants were family members of patients treated in ICU who completed the Family Satisfaction in ICU-24 Survey, the Hospital Anxiety Depression Scale, Impact of Event Scale-Revised-6, and a demographic form within the first 3 months after their close other’s ICU stay. Data were analysed using linear mixed-effects models, with depression, anxiety, and posttraumatic stress as outcome measures.

Results

A total of 214 family members (53% return rate) returned a completed questionnaire. We found that higher levels of satisfaction were significantly associated with lower levels of depression, anxiety and posttraumatic stress. There was no statistically significant association between family member characteristics and any measure of psychological distress. Among the included patient characteristics, younger patient age was associated with higher levels of depression, and patient death was associated with higher levels of depression and posttraumatic stress.

Conclusions

Our results suggest that satisfaction with ICU care is strongly associated with family well-being post-ICU. Family members of younger patients and of those who die seem to be most at risk for psychological distress, requiring specific support, whereas family member characteristics may have less relevance.
Effects of test experience, closed-arm wall color, and illumination level on behavior and plasma corticosterone response in an elevated plus maze in male C57BL/6J mice: a challenge against conventional interpretation of the test
Authors: Shoji Hirotaka , Miyakawa Tsuyoshi
Published: February 2021

The elevated plus maze test is a widely used test for assessing anxiety-like behavior and screening novel therapeutic agents in rodents. Previous studies have shown that a variety of internal factors and procedural variables can influence elevated plus maze behavior. Although some studies have suggested a link between behavior and plasma corticosterone levels, the relationships between them remain unclear. In this study, we investigated the effects of experience with a battery of behavioral tests, the wall color of the closed arms, and illumination level on the behavior and plasma corticosterone responses in the elevated plus maze in male C57BL/6J mice. Mice were either subjected to a series of behavioral tests, including assessments of general health and neurological function, a light/dark transition test, and an open field test, or left undisturbed until the start of the elevated plus maze test. The mice with and without test battery experience were allowed to freely explore the elevated plus maze. The other two independent groups of naïve mice were tested in mazes with closed arms with different wall colors (clear, transparent blue, white, and black) or different illumination levels (5, 100, and 800 lx). Immediately after the test, blood was collected to measure plasma corticosterone concentrations. Mice with test battery experience showed a lower percentage of open arm time and entries and, somewhat paradoxically, had lower plasma corticosterone levels than the mice with no test battery experience. Mice tested in the maze with closed arms with clear walls exhibited higher open arm exploration than mice tested in the maze with closed arms with black walls, while there were no significant differences in plasma corticosterone levels between the different wall color conditions. Illumination levels had no significant effects on any measure. Our results indicate that experience with other behavioral tests and different physical features of the maze affect elevated plus maze behaviors. Increased open arm time and entries are conventionally interpreted as decreased anxiety-like behavior, while other possible interpretations are considered: open arm exploration may reflect heightened anxiety and panic-like reaction to a novel situation under certain conditions. With the possibility of different interpretations, the present findings highlight the need to carefully consider the test conditions in designing experiments and drawing conclusions from the behavioral outcomes in the elevated plus maze test in C57BL/6J mice.
GABAergic neuron-specific whole-brain transduction by AAV-PHP.B incorporated with a new GAD65 promoter
Authors: Hoshino Chiaki , Konno Ayumu , Hosoi Nobutake , Kaneko Ryosuke , Mukai Ryo , Nakai Junichi , Hirai Hirokazu
Published: February 2021

GABAergic interneurons play a critical role in tuning neural networks in the central nervous system, and their defects are associated with neuropsychiatric disorders. Currently, the mDlx enhancer is solely used for adeno-associated virus (AAV) vector-mediated transgene delivery into cortical interneurons. Here, we developed a new inhibitory neuron-specific promoter (designated as the mGAD65 promoter), with a length of 2.5 kb, from a mouse genome upstream of exon 1 of the Gad2 gene encoding glutamic acid decarboxylase (GAD) 65. Intravenous infusion of blood–brain barrier-penetrating AAV-PHP.B expressing an enhanced green fluorescent protein under the control of the mGAD65 promoter transduced the whole brain in an inhibitory neuron-specific manner. The specificity and efficiency of the mGAD65 promoter for GABAergic interneurons, which was assessed at the motor cortex, were almost identical to or slightly higher than those of the mDlx enhancer. Immunohistochemical analysis revealed that the mGAD65 promoter preferentially transduced parvalbumin (PV)-expressing interneurons. Notably, the mGAD65 promoter transduced chandelier cells more efficiently than the mDlx enhancer and robustly labeled their synaptic boutons, called the cartridge, targeting the axon initial segments of excitatory pyramidal neurons. To test the ability of the mGAD65 promoter to express a functional molecule, we virally expressed G-CaMP, a fluorescent Ca2+ indicator, in the motor cortex, and this enabled us to monitor spontaneous and drug-induced Ca2+ activity in GABAergic inhibitory neurons. These results suggest that the mGAD65 promoter is useful for AAV-mediated targeting and manipulation of GABAergic neurons with the dominance of cortical PV-expressing neurons, including chandelier cells.
Daratumumab monotherapy for patients with relapsed or refractory natural killer/T-cell lymphoma, nasal type: an open-label, single-arm, multicenter, phase 2 study
Authors: Huang Huiqiang , Zhu Jun , Yao Ming , Kim Tae Min , Yoon Dok Hyun , Cho Seok-Goo , Eom Hyeon Seok , Lim Soon Thye , Yeh Su-peng , Song Yuqin , Kwong Yok Lam , Kim Jin Seok , Jin Jie , Shi Yuankai , Kim HyeJin , Qing Min , Zhou Tianyuan , Gao Grace , Dong Zongqi , Qi Ming , Kim Won Seog
Published: February 2021

Background

Natural killer/T-cell lymphoma (NKTCL) is a disease with limited treatment options and poor outcomes. Daratumumab monotherapy demonstrated clinical activity in a single-patient case report. We present data from the primary analysis of a phase 2 study of daratumumab monotherapy in relapsed or refractory (R/R) NKTCL.

Methods

This phase 2 study with Simon’s two-stage design evaluated daratumumab in patients with histologically confirmed extranodal NKTCL, nasal type, per WHO classification that was refractory to or relapsed after ≥ 1 line of chemotherapy, who were not candidates for other treatment modalities. All patients received daratumumab 16 mg/kg intravenously once weekly for Cycles 1 and 2, every other week for Cycles 3 through 6, and every 4 weeks thereafter until progression or unacceptable toxicity; all cycles were 28 days. The primary end point was objective response rate (ORR) based on blinded independent central review per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma (Lugano classification).

Results

In total, 32 Asian patients received daratumumab. The ORR was 25.0% (95% confidence interval [CI] 11.5–43.4); all 8 responders had a partial response; and the median duration of response was 55.0 days (95% CI 29–339). At 10.2 months of median follow-up, median progression-free survival (PFS) was 53.0 days (95% CI 43–106); the 4-month PFS rate was 13.0%. Median overall survival (OS) was 141.0 days (95% CI 94–438); the 6-month OS rate was 42.9%. Nineteen (59.4%) patients had grade 3/4 treatment-emergent adverse events (TEAEs); the most common was thrombocytopenia (25.0%; n = 8). TEAEs leading to death occurred in 4 patients (death, respiratory failure, septic shock, and pneumonia); all were unrelated to daratumumab.

Conclusions

In patients with R/R NKTCL, daratumumab monotherapy was well tolerated with no new safety concerns and achieved an ORR of 25.0%. However, no patients achieved complete response, and duration of response was short.

Trial registration ClinicalTrials.gov, NCT02927925. Registered 7 October 2016.
Correction to: Novel and emerging therapies for B cell lymphoma
Authors: Ayyappan Sabarish , Maddocks Kimi
Published: February 2021

An amendment to this paper has been published and can be accessed via the original article.
Favorable response to carbamazepine therapy in genetically proven myoclonus-dystonia child
Authors: Aljabri Mohammed F. , Kamal Naglaa M. , Alghamdi Abdulrhman , Alghamdi Hamdan , Alomairi Naif
Published: February 2021

Background

Myoclonus dystonia (MDS) is a dominantly inherited genetic disorder caused by loss-of-function mutations in the epsilon sarcoglycan gene (SGCE).

Case presentation

We here in report a twenty months old Saudi boy who presented to us with a concern that the child is unable to walk properly. On assessment, he was flexing his left arm and left leg that usually followed by a back-ward fall. Diagnosis of dystonia induced with initiation of movement was suggested that later on proven genetically to be pathogenic mutation of sarcoglycan gene. Carbamazepine therapy was initiated with dramatic response. Response was maintained at 4 years follow up.

Conclusions

Our patient and the other previously reported cases might highlight the response of SGCE mutations to carbamazepine therapy.
Comparative validation of the BOADICEA and Tyrer-Cuzick breast cancer risk models incorporating classical risk factors and polygenic risk in a population-based prospective cohort of women of European ancestry
Authors: Pal Choudhury Parichoy , Brook Mark N. , Hurson Amber N. , Lee Andrew , Mulder Charlotta V. , Coulson Penny , Schoemaker Minouk J. , Jones Michael E. , Swerdlow Anthony J. , Chatterjee Nilanjan , Antoniou Antonis C. , Garcia-Closas Montserrat
Published: February 2021

Background

The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and the Tyrer-Cuzick breast cancer risk prediction models are commonly used in clinical practice and have recently been extended to include polygenic risk scores (PRS). In addition, BOADICEA has also been extended to include reproductive and lifestyle factors, which were already part of Tyrer-Cuzick model. We conducted a comparative prospective validation of these models after incorporating the recently developed 313-variant PRS.

Methods

Calibration and discrimination of 5-year absolute risk was assessed in a nested case-control sample of 1337 women of European ancestry (619 incident breast cancer cases) aged 23–75 years from the Generations Study.

Results

The extended BOADICEA model with reproductive/lifestyle factors and PRS was well calibrated across risk deciles; expected-to-observed ratio (E/O) at the highest risk decile :0.97 (95 % CI 0.51 − 1.86) for women younger than 50 years and 1.09 (0.66 − 1.80) for women 50 years or older. Adding reproductive/lifestyle factors and PRS to the BOADICEA model improved discrimination modestly in younger women (area under the curve (AUC) 69.7 % vs. 69.1%) and substantially in older women (AUC 64.6 % vs. 56.8%). The Tyrer-Cuzick model with PRS showed evidence of overestimation at the highest risk decile: E/O = 1.54(0.81 − 2.92) for younger and 1.73 (1.03 − 2.90) for older women.

Conclusion

The extended BOADICEA model identified women in a European-ancestry population at elevated breast cancer risk more accurately than the Tyrer-Cuzick model with PRS. With the increasing availability of PRS, these analyses can inform choice of risk models incorporating PRS for risk stratified breast cancer prevention among women of European ancestry.
Transcutaneous electrical acupoint stimulation for high-normal blood pressure: study protocol for a randomized controlled pilot trial
Authors: Wang Yu , Shi Guang-Xia , Tian Zhong-Xue , Liu Jun-Hong , Qi You-Sheng , Tu Jian-Feng , Yang Jing-Wen , Wang Li-Qiong , Liu Cun-Zhi
Published: February 2021

Background

High-normal blood pressure (BP) is associated with increased all-cause, cardiovascular mortality and frequently progresses to hypertension. Transcutaneous electrical acupoint stimulation (TEAS) might be a non-pharmaceutical therapy option to control BP. This trial aims to determine the effectiveness and safety of TEAS combined with lifestyle modification for high-normal BP.

Methods/design

This prospective, randomized, and parallel clinical trial will be conducted in a community service center in China. Sixty participants with high-normal BP will be randomly allocated to receive TEAS plus lifestyle modification (intervention group) or lifestyle modification alone (control group) in a 1:1 ratio. In addition to lifestyle modification, the intervention group will receive TEAS at four acupoints for 30 min, 4 times weekly for 12 weeks for a total of 48 sessions at home. The control group will receive same lifestyle modification but no TEAS. The primary outcome will be the change in mean systolic blood pressure at 12 weeks from the baseline measurement. Secondary outcomes include the change of mean diastolic blood pressure, proportion of subjects with progression to hypertension, quality of life, body mass index, and waist circumference. Adverse events during the trial will be monitored.

Discussion

This trial will explore the feasibility and provide potential evidence for the effectiveness and safety of TEAS plus lifestyle modification for high-normal BP. Furthermore, this pilot trial is being undertaken to determine the feasibility of a full scale definitive randomized controlled trial. The results of this study will be published in a peer-reviewed journal.

Trial registration

Chinese Clinical Trial Registry, ChiCTR 1900024982. Registered on August 6, 2019.
MR CLEAN-NO IV: intravenous treatment followed by endovascular treatment versus direct endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion—study protocol for a randomized clinical trial
Authors:   for the MR CLEAN-NO IV Investigators, Treurniet Kilian M. , LeCouffe Natalie E. , Kappelhof Manon , Emmer Bart J. , van Es Adriaan C. G. M. , Boiten Jelis , Lycklama Geert J. , Keizer Koos , Yo Lonneke S. F. , Lingsma Hester F. , van Zwam Wim H. , de Ridder Inger , van Oostenbrugge Robert J. , van der Lugt Aad , Dippel Diederik W. J. , Coutinho Jonathan M. , Roos Yvo B. W. E. M. , Majoie Charles B. L. M.
Published: February 2021

Background

Endovascular treatment (EVT) has greatly improved the prognosis of acute ischemic stroke (AIS) patients with a proximal intracranial large vessel occlusion (LVO) of the anterior circulation. Currently, there is clinical equipoise concerning the added benefit of intravenous alteplase administration (IVT) prior to EVT. The aim of this study is to assess the efficacy and safety of omitting IVT before EVT in patients with AIS caused by an anterior circulation LVO.

Methods

MR CLEAN-NO IV is a multicenter randomized open-label clinical trial with blinded outcome assessment (PROBE design). Patients ≥ 18 years of age with a pre-stroke mRS < 3 with an LVO confirmed on CT angiography/MR angiography eligible for both IVT and EVT are randomized to receive either IVT (0.9 mg/kg) followed by EVT, or direct EVT in a 1:1 ratio. The primary objective is to assess superiority of direct EVT. Secondarily, non-inferiority of direct EVT compared to IVT before EVT will be explored. The primary outcome is the score on the modified Rankin Scale at 90 days. Ordinal regression with adjustment for prognostic variables will be used to estimate treatment effect. Secondary outcomes include reperfusion graded with the eTICI scale after EVT and stroke severity (National Institutes of Health Stroke Scale) at 24 h. Safety outcomes include intracranial hemorrhages scored according to the Heidelberg criteria. A total of 540 patients will be included.

Discussion

IVT prior to EVT might facilitate early reperfusion before EVT or improved reperfusion rates during EVT. Conversely, among other potential adverse effects, the increased risk of bleeding could nullify the beneficial effects of IVT. MR CLEAN-NO IV will provide insight into whether IVT is still of added value in patients eligible for EVT.

Trial registration

www.isrctn.com:ISRCTN80619088. Registered on 31 October 2017.
Effectiveness of C1-INH therapy in angiotensin converting enzyme inhibitor induced angioedema
Authors: Kovaltchouk Uliana , Zhang Boyang , Jain Vipul , Kalicinsky Chrystyna
Published: February 2021

Introduction

Angiotensin Converting Enzyme Inhibitors (ACEI) are a common cause of Emergency Room presentation for angioedema. Although no treatment guidelines exist, C1 esterase inhibitor concentrate (C1-INH) is used on an off label basis for management of ACEI acquired angioedema (ACEI AAE).

Objective

To evaluate the efficacy of C1-INH in management of ACEI AAE at our local centers.

Results

Nine patients, from 3 academic sites, were identified through Allergy Service consultation data and records from Diagnostic Services Manitoba, Canada from 2010–2020. The majority of the patients (n = 8/9) required endotracheal intubation prior to the initiation of C1-INH. Overall, approximately 56% of patients (n = 5/9) had resolution of angioedema ranging between 12 and 17 h, with a median time of 13.5 h, and no recurrence after the administration of C1-INH concentrate. One patient had transient symptom resolution in 14 h, however, recurrence of angioedema required re-intubation. The remainder of patients (n = 4/9), had resolution of angioedema between 22 and 72 h, with a median time of 33.75 h.

Conclusion

Our findings demonstrate continued ambivalence of the efficacy and role of C1-INH concentrate in the treatment of ACEI AAE, secondary to multiple uncontrolled confounding factors. Further research into characterizing a subgroup of intubated patients in our study that responded to C1-INH concentrate needs to be completed.
Primary breast tuberculosis: imaging findings of a rare disease
Authors: Baykan Ali H. , Sayiner Hakan S. , Inan Ibrahim , Aydin Elcin , Erturk Sukru M.
Published: February 2021

Breast tuberculosis is a rare form of extrapulmonary tuberculosis which tends to affect females of reproductive age, and is much rarer in males, postmenopausal women, and pre-pubescent girls. It is difficult to diagnose because it can mimic benign conditions such as a fibroadenoma, as well as malignant diseases like a carcinoma. It is also particularly difficult to distinguish breast tuberculosis from granulomatous mastitis, so other possible diagnoses should be ruled out first. The diagnosis of breast tuberculosis has three essential pillars: clinical examination, radiological evaluations, and histopathological sampling. Radiological evaluations are not only critical in diagnosis but are also important in the planning of the treatment and during the follow-up. This paper aims to review the imaging findings and the differential diagnosis of breast tuberculosis.
Vancomycin induced cardiac arrest: a case report
Authors: Khakurel Sharad , Rawal Sangam
Published: February 2021

Background

Rapid intravenous administration of vancomycin may manifest with histaminergic responses with clinical features ranging from mild rashes, pruritus and even shock. This case reports of a child, who was accidentally given intravenous vancomycin within minutes and hadacardiac arrest.

Case presentation

A 9-year-old Asian girl who was scheduled for a limb salvage surgery, received vancomycin preoperatively. As a result of rapid infusion of the drug, the patient developed flushing, pruritus and had respiratory distress with hypotension leading to asystole. However, prompt detection and immediate cardiopulmonary resuscitation revived the patient in time following which sound recovery ensued. We recognised inadvertent brisk infusion of vancomycin as the culprit with strong suspicion of Red Man Syndrome.

Conclusion

Red Man Syndrome, though rarely encountered, can always be life threatening. With a surge in the use of vancomycin, adverse effects associated with its use also rises. So a comprehensive knowledge regarding its rationale use, adverse effects and its prompt management in personnel prescribing it, can be life saving.
SGLT2 inhibition alleviated hyperglycemia, glucose intolerance, and dumping syndrome-like symptoms in a patient with glycogen storage disease type Ia: a case report
Authors: Katayama Daisuke , Baba Hiroo , Kuwabara Takashige , Kido Jun , Mitsubuchi Hiroshi , Matsumoto Shirou , Nakamura Kimitoshi
Published: February 2021

Background

Glycogen storage disease (GSD) type Ia is a glycogenesis disorder with long-term complications such as hepatomegaly and renal dysfunction and is caused by congenital loss of glucose-6-phosphatase (G6Pase) expression. G6Pase is essential for the final step of gluconeogenesis and glycogenolysis, and its deficiency causes clinical hypoglycemia in the fasting state during infancy. Contrastingly, patients also show blood glucose trends and glucose intolerance similar to those in type II diabetes. Owing to the contrasting presentation of hypoglycemia with glucose intolerance, glucose control in patients remains a challenge, requiring management of both fasting hypoglycemia and post-prandial hyperglycemia.

Case presentation

The patient was a 45-year old Asian (Japanese) woman who showed disease onset at 3 years of age, when hypoglycemia and hepatomegaly were observed, and GDS type Ia was diagnosed by the lack of G6Pase activity. Over the past 45 years, she presented hyperglycemia and dumping syndrome like symptoms (a feeling of fullness, even after eating just a small amount, abdominal cramping, nausea, sweating, flushing, or light-headedness and rapid heartbeat) at 2 hours after food intake. Her liver and kidney dysfunction also worsened over time. Treatment with exercise combined with a sodium-glucose co-transporter 2 inhibitor and an alpha glucosidase inhibitor alleviated her glucose intolerance and dumping syndrome-like symptoms, without increasing hypoglycemic events.

Conclusion

This case suggests SGLT2 inhibitor as a promising candidate for treating glucose intolerance in GSD type Ia without worsening of hypoglycemia.
Mesenchymal stem cells modified by FGF21 and GLP1 ameliorate lipid metabolism while reducing blood glucose in type 2 diabetic mice
Authors: Xue Binghua , Xiao Xiuxiao , Yu Tingting , Xiao Xinhua , Xie Jing , Ji Qiuhe , Wang Li , Na Tao , Meng Shufang , Qian Lingjia , Duan Haifeng
Published: February 2021

Objective

The purpose of this study was to investigate the therapeutic effects of genetically modified mesenchymal stem cells (MSCs) in the treatment of type 2 diabetes mellitus (T2DM) in order to identify a new method for treating diabetes that differs from traditional medicine and to provide a new means by which to fundamentally improve or treat diabetes.

Methods

MSCs derived from adipose tissue were modified to overexpress FGF21 and GLP1, which was achieved through lentiviral particle transduction. The cells were transplanted into BKS.Cg-Dock7m+/+Leprdb/Nju mice (T2DM mouse model). Injections of physiological saline (0.1 mL) and liraglutide (0.5 mg/kg) were used as negative and positive controls, respectively. ELISA or Western blotting was used for protein analysis, and quantitative real-time PCR was used for gene expression analysis.

Results

Genetic modification had no effects on the morphology, differentiation ability, or immunophenotype of MSCs. Moreover, MSC-FGF21+GLP1 cells exhibited significantly increased secretion of FGF21 and GLP1. In the T2DM mouse model, the transplantation of MSC-FGF21+GLP1 cells ameliorated the changes in blood glucose and weight, promoted the secretion of insulin, enhanced the recovery of liver structures, and improved the profiles of lipids. Moreover, FGF21 and GLP1 exerted synergistic effects in the regulation of glucolipid metabolism by controlling the expression of insulin, srebp1, and srebp2.

Conclusion

Stem cell treatment based on MSCs modified to overexpress the FGF21 and GLP1 genes is an effective approach for the treatment of T2DM.
3D skin models in domestic animals
Authors: Souci Laurent , Denesvre Caroline
Published: February 2021

The skin is a passive and active barrier which protects the body from the environment. Its health is essential for the accomplishment of this role. Since several decades, the skin has aroused a strong interest in various fields (for e.g. cell biology, medicine, toxicology, cosmetology, and pharmacology). In contrast to other organs, 3D models were mostly and directly elaborated in humans due to its architectural simplicity and easy accessibility. The development of these models benefited from the societal pressure to reduce animal experiments. In this review, we first describe human and mouse skin structure and the major differences with other mammals and birds. Next, we describe the different 3D human skin models and their main applications. Finally, we review the available models for domestic animals and discuss the current and potential applications.