Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

The tale of TILs in breast cancer : a report from the International Immuno-Oncology Biomarker Working Group

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed deathligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.The National Health and Medical Research Council of Australia; the Cure; the Royal Australasian College of Physicians; the NIH/NCI ; the National Breast Cancer Foundation of Australia Endowed Chair; the Breast Cancer Research Foundation, New York and the Breast Cancer Research Foundation (BCRF).www.nature.com/npjbcanceram2022Immunolog

Enablers and barriers to adopt the locally developed Masi mechanical ventilator amid COVID-19 pandemic in Peru

Background: Limited supply of resources during the COVID-19 emergency encouraged the local development of the Masi mechanical ventilator (MV). Despite the efforts to promote Masi, adopting this innovation faced multiple obstacles, regardless of its performance. We explored the perceptions among healthcare personnel towards incorporating Masi to provide ventilatory support to COVID-19 patients during the second wave in Peru (January to June 2021). Methods: We conducted twelve in-depth virtual interviews. Topics included experience when handling Masi, the impact of the training received, confidence in the device, barriers perceived, and enablers identified. All participants provided verbal informed consent. Results: Most of the participants were male physicians. Participants belonged to seven hospitals that exhibited a wide range of healthcare capacities. Globally, the adoption of Masi MV was driven by the scarcity of ventilatory devices in the wards and reinforced by appropriate training and prompt technical support. Participants reported that Masi's structural and operational features played both advantages and disadvantages. Hospital infrastructure readiness, availability of commercial MVs, mistrust in its simple appearance, and resistance to change among healthcare personnel were perceived as barriers, while low-cost, prompt technical support and user-friendliness were valuable enablers. The first two enablers were observed in participants regardless of their attitude towards Masi. Despite the small number of participants for this qualitative study, it is important to note that the sample size was sufficient to reach saturation, as the topics discussed with participants became redundant and did not yield new information. Conclusions: The perceptions among healthcare personnel to incorporate Masi as a mechanical ventilator for COVID-19 patients showed that communication, training and experience, and peer encouragement were essential to secure its use and sustainability of the technology. A priori judgments and perceptions unrelated to the performance of the novel device were observed, and its proper management may define its further implementation. Altogether our study suggests that along with strengthening local technological development, strategies to improve their adoption process must be considered as early as possible in medical innovations

Gut Microbiota Dynamics in Natural Populations of Pintomyia evansi under Experimental Infection with Leishmania infantum

Pintomyia evansi is recognized by its vectorial competence in the transmission of parasites that cause fatal visceral leishmaniasis in rural and urban environments of the Caribbean coast of Colombia. The effect on and the variation of the gut microbiota in female P. evansi infected with Leishmania infantum were evaluated under experimental conditions using 16S rRNA Illumina MiSeq sequencing. In the coinfection assay with L. infantum, 96.8% of the midgut microbial population was composed mainly of Proteobacteria (71.0%), followed by Cyanobacteria (20.4%), Actinobacteria (2.7%), and Firmicutes (2.7%). In insect controls (uninfected with L. infantum) that were treated or not with antibiotics, Ralstonia was reported to have high relative abundance (55.1–64.8%), in contrast to guts with a high load of infection from L. infantum (23.4–35.9%). ASVs that moderately increased in guts infected with Leishmania were Bacillus and Aeromonas. Kruskal–Wallis nonparametric variance statistical inference showed statistically significant intergroup differences in the guts of P. evansi infected and uninfected with L. infantum (p Leishmania infection. This assay also showed a negative effect of the antibiotic treatment and L. infantum infection on the gut microbiota diversity. Endosymbionts, such as Microsporidia infections (Leishmania infection, whereas Arsenophonus was only found in guts with a high load of Leishmania infection and treated with antibiotics. Finally, this is the first report that showed the potential role of intestinal microbiota in natural populations of P. evansi in susceptibility to L. infantum infection

Antimicrobial Susceptibility of Bacteria and Yeasts Isolated from the Milk of Dairy Cattle Presenting with Subclinical Mastitis in Puebla, Mexico

"This study was designed to identify the bacteria and yeasts from the milk samples of dairy cattle presenting with subclinical mastitis and evaluate their antimicrobial susceptibility. We collected a total of 52 milk samples from cows across three farms in San Salvador El Seco (Puebla, Mexico). Microbial isolation was performed using microbiological techniques followed by taxonomic identification of bacteria and yeasts. Antimicrobial susceptibility was evaluated using the guidelines provided by the Clinical Laboratory Standard Institute (CLSI). 1 We identified three genera and six species of yeasts including Candida glabrata, C. krusei, C. lipolytica, Cryptococcus laurentii, Rhodotorula rubra, and R. glutinis and five species of bacteria, including Staphylococcus saprophyticus, S. aureus, S. hominis, S. epidermidis, and Streptococcus disgalactiae. All of the yeast strains were sensitive to amphotericin B; 1/23 (4.3%) were resistant to ketoconazole and nystatin, 10/23 (43%) were resistant to fluconazole, and 13/23 (53%) were resistant to 5-fluorocytosine. The dominant genus isolated was Candida, with the most abundant groups being C glabrata and C. krusei. Resistance to 5-fluorocytosine was observed in all yeasts except C. lipolytica, while both S. aureus and S. epidermidis were resistant to oxacillin and dicloxacillin. S. hominis was resistant to gentamicin"

Metatranscriptomic investigation of single Ixodes pacificus ticks reveals diverse microbes, viruses, and novel mRNA-like endogenous viral elements.

Ticks are increasingly important vectors of human and agricultural diseases. While many studies have focused on tick-borne bacteria, far less is known about tick-associated viruses and their roles in public health or tick physiology. To address this, we investigated patterns of bacterial and viral communities across two field populations of western black-legged ticks (Ixodes pacificus). Through metatranscriptomic analysis of 100 individual ticks, we quantified taxon prevalence, abundance, and co-occurrence with other members of the tick microbiome. In addition to commonly found tick-associated microbes, we assembled 11 novel RNA virus genomes from Rhabdoviridae, Chuviridae, Picornaviridae, Phenuiviridae, Reoviridae, Solemovidiae, Narnaviridae and two highly divergent RNA virus genomes lacking sequence similarity to any known viral families. We experimentally verified the presence of these in I. pacificus ticks across several life stages. We also unexpectedly identified numerous virus-like transcripts that are likely encoded by tick genomic DNA, and which are distinct from known endogenous viral element-mediated immunity pathways in invertebrates. Taken together, our work reveals that I. pacificus ticks carry a greater diversity of viruses than previously appreciated, in some cases resulting in evolutionarily acquired virus-like transcripts. Our findings highlight how pervasive and intimate tick-virus interactions are, with major implications for both the fundamental biology and vectorial capacity of I. pacificus ticks.ImportanceTicks are increasingly important vectors of disease, particularly in the United States where expanding tick ranges and intrusion into previously wild areas has resulted in increasing human exposure to ticks. Emerging human pathogens have been identified in ticks at an increasing rate, and yet little is known about the full community of microbes circulating in various tick species, a crucial first step to understanding how they interact with each and their tick host, as well as their ability to cause disease in humans. We investigated the bacterial and viral communities of the Western blacklegged tick in California and found 11 previously uncharacterized viruses circulating in this population

Microfluidic Synthesis of Biodegradable Polyethylene-Glycol Microspheres for Controlled Delivery of Proteins and DNA Nanoparticles

Polymeric microspheres represent an injectable platform for controlling the release of a variety of biologics; microspheres may be combined in a modular fashion to achieve temporal release of two or more biomolecules. Microfluidics offers a versatile platform for synthesizing uniform polymeric microspheres harboring a variety of biologics under relatively mild conditions. Poly­(ethylene glycol) (PEG) is a bioinert polymer that can be easily tailored to encapsulate and control the release of biologics. In this study, we report the microfluidic synthesis of biodegradable PEG-based microparticles for controlled release of growth factors or DNA nanoparticles. Simple changes in microfluidic design increased the rate of microparticle formation and controlled the size of the microspheres. Mesh size and degradation rate were controlled by varying the PEG polymer weight percent from 7.5 to 15% (w/v), thus tuning the release of growth factors and DNA nanoparticles, which retained their bioactivity in assays of cell proliferation and DNA transfection, respectively. This platform may provide a useful tool for synthesizing microspheres for use as injectable carriers to achieve coordinated growth-factor or DNA nanoparticle release in therapeutic applications