Miracle-dz/UniFAR-FTUs huggingface dataset:
Synaptic inputs to broad thorny ganglion cells in macaque retina

In primates, broad thorny retinal ganglion cells are highly sensitive to small, moving stimuli. They have tortuous, fine dendrites with many short, spine‐like branches that occupy three contiguous strata in the middle of the inner plexiform layer. The neural circuits that generate their responses to moving stimuli are not well‐understood, and that was the goal of this study. A connectome from central macaque retina was generated by serial block‐face scanning electron microscopy, a broad thorny cell was reconstructed, and its synaptic inputs were analyzed. It received fewer than 2% of its inputs from both ON and OFF types of bipolar cells; the vast majority of its inputs were from amacrine cells. The presynaptic amacrine cells were reconstructed, and seven types were identified based on their characteristic morphology. Two types of narrow‐field cells, knotty bistratified Type 1 and wavy multistratified Type 2, were identified. Two types of medium‐field amacrine cells, ON starburst and spiny, were also presynaptic to the broad thorny cell. Three types of wide‐field amacrine cells, wiry Type 2, stellate wavy, and semilunar Type 2, also made synapses onto the broad thorny cell. Physiological experiments using a macaque retinal preparation in vitro confirmed that broad thorny cells received robust excitatory input from both the ON and the OFF pathways. Given the paucity of bipolar cell inputs, it is likely that amacrine cells provided much of the excitatory input, in addition to inhibitory input.
Does the Intradiscal Injection of Platelet Rich Plasma Have Any Beneficial Role in the Management of Lumbar Disc Disease?

Study Design: Systematic review and meta-analysis. Objectives: We performed this meta-analysis to evaluate whether intradiscal Platelet Rich Plasma(PRP) injection has any beneficial role in the management of lumbar disc disease. Methods: We conducted independent and duplicate electronic database searches including PubMed, Embase, and Cochrane Library till September 2020 for studies investigating the role of intradiscal PRP in the management of lumbar disc disease. The analysis was performed in the R platform using OpenMeta[Analyst] software. Results: 13 studies including 2 RCTs, 5 prospective, and 6 retrospective studies involving 319 patients were included in the meta-analysis. A single-arm meta-analysis of the included studies showed a beneficial effect of the intervention in terms of pain relief outcomes like VAS score (p < 0.001), pain component of SF-36 (p = 0.003) while such improvement was not seen in functional outcome measures like ODI score (p = 0.071), the physical component of SF-36 (p = 0.130) with significant heterogeneity noted among the included studies. No structural improvement in magnetic resonance imaging was observed (p = 0.106). No additional procedure-related adverse events were noted in the included studies (p = 0.662). Conclusion: There is a paucity of high-quality studies to give conclusive evidence on the benefits of intradiscal PRP for lumbar disc disease. Although intradiscal PRP injection has shown some beneficial effect in controlling pain for lumbar disc disease, we could not find structural or functional improvement from the included studies. Hence, we recommend large double-blind double-arm randomized controlled studies to analyze the benefits of the intervention being analyzed.
Chemotherapy Induces Tumor-Associated Macrophages that Aid Adaptive Immune Responses in Ovarian Cancer

Neoadjuvant chemotherapy is shown to reduce the density of tumor-associated macrophages (TAM). In addition, chemotherapy reduces M2-related markers and increases proinflammatory signaling in TAMs, including inflammasome activation, thus highlighting an opportunity to improve antitumor responses. Neoadjuvant chemotherapy (NACT) may stimulate anticancer adaptive immune responses in high-grade serous ovarian cancer (HGSOC), but little is known about effects on innate immunity. Using omental biopsies from HGSOC, and omental tumors from orthotopic mouse HGSOC models that replicate the human tumor microenvironment, we studied the impact of platinum-based NACT on tumor-associated macrophages (TAM). We found that chemotherapy reduces markers associated with alternative macrophage activation while increasing expression of proinflammatory pathways, with evidence of inflammasome activation. Further evidence of a shift in TAM functions came from macrophage depletion via CSF1R inhibitors (CSF1Ri) in the mouse models. Although macrophage depletion in established disease had no impact on tumor weight or survival, CSF1Ri treatment after chemotherapy significantly decreased disease-free and overall survival. This decrease in survival was accompanied by significant inhibition of adaptive immune response pathways in the tumors. We conclude that chemotherapy skews the TAM population in HSGOC toward an antitumor phenotype that may aid adaptive immune responses, and therapies that enhance or sustain this during remission may delay relapse.
Non-small cell lung cancer with MET exon 14 skipping alteration responding to immunotherapy: a case report

Immunotherapy has been proved to be a promising candidate for advanced non-small cell lung cancer (NSCLC). Despite MET mutations are regarded as an independent factor of programmed death ligand 1 (PD-L1) high expression, the efficacy of immune checkpoint inhibitors (ICIs) across NSCLC harboring Mesenchymal-epithelial transition factor exon 14 skipping alteration (METex14) is still uncleared. Moreover, when the resistance of PD-1 antibody occurs, the questions of how to interpret the resistance and how to overcome the resistance are worth exploring. We report a case of NSCLC with METex14 developed a right femoral metastasis after responding well to neoadjuvant immunotherapy, a successful lobectomy, and adjuvant immunotherapy. The subsequent attempts of MET targeted inhibitor, concurrent chemoradiotherapy, and notably programmed cell death protein 1 (PD-1) antibody plus vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) failed to prevent disease progression. However, a regimen of anti-PD-1 plus anti-cytotoxic t-lymphocyte associated protein 4 (CTLA-4) reversed the progression to a complete response. This case shows that METex14 had a significant response to immunotherapy, which would be especially beneficial for those who developed targeted therapy resistance. Importantly, this is the first case reporting that salvage CTLA-4 antibody and PD-1 antibody could reverse the progression in NSCLC harboring METex14 when the anti-PD-1 resistance occurred.
Clinical predictors of heart block during atrioventricular nodal reentrant tachycardia ablation: A multicenter 18‐year experience

Catheter ablation is considered the first‐line treatment of symptomatic atrioventricular nodal reentrant tachycardia (AVNRT). It has been associated with a risk of heart block (HB) requiring a pacemaker. This study aims to determine potential clinical predictors of complete heart block as a result AVNRT ablation.
Dietary inflammatory index and pancreatic cancer risk: a systematic review and dose–response meta-analysis

Abstract Objective: The meta-analysis was conducted to test the link between pancreatic cancer (PC) risk and dietary inflammatory index (DII®) score. Design: Systematic review and meta-analysis. Setting: We searched PubMed, Embase, Web of Science and the Cochrane Library up to 22 November 2020 to identify the relevant studies. Studies that reported the risk estimates and the corresponding 95 % CI for the DII category and PC risk were included. The effect sizes were pooled using the random-effects model. Dose–response analysis was conducted where possible. Participants: Two prospective cohort studies of 634 705 participants (3152 incident cases), and four case–control studies of 2737 cases and 4861 controls. Results: Overall, the pooled risk ratio (RR) indicated that individuals in the highest category compared with the lowest category had an increased PC risk (RR = 1·45; 95 % CI 1·11, 1·90; P = 0·006). Meanwhile, significant heterogeneity was also revealed. The dose–response meta-analysis indicated that a 1-unit increase in the DII score was associated with the PC risk (RR = 1·08; 95 % CI 1·002, 1·166; P = 0·045; I2 = 94·1 %, P < 0·001). Nonlinear result showed an increased risk of moving from fewer to more inflammatory borders with increasing DII score (Pnonlinearity = 0·003; I2 = 76·5 %, P < 0·001). Subgroup analyses found that significant positive association between PC risk and DII score appeared to be in case–control studies (RR = 1·70; 95 % CI 1·16, 2·50; P = 0·007) and studies with ≤ 31 DII components (RR = 1·76; 95 % CI 1·14, 2·72; P = 0·011). Conclusion: These findings suggested dietary habits with high inflammatory features (high DII score) might increase PC risk.
Elucidation of the inhibitory activity of ivermectin with host nuclear importin α and several SARS-CoV-2 targets

Abstract Ivermectin (IVM) is an FDA-approved drug that has shown antiviral activity against a wide variety of viruses in recent years. IVM inhibits the formation of the importin-α/β1 heterodimeric complex responsible for the translocation and replication of various viral species proteins. Also, IVM hampers SARS-CoV-2 replication in vitro; however, the molecular mechanism through which IVM inhibits SARS-CoV-2 is not well understood. Previous studies have explored the molecular mechanism through which IVM inhibits importin-α and several potential targets associated with COVID-19 by using docking approaches and MD simulations to corroborate the docked complexes. This study explores the energetic and structural properties through which IVM inhibits importin-α and five targets associated with COVID-19 by using docking and MD simulations combined with the molecular mechanics generalized Born surface area (MMGBSA) approach. Energetic and structural analysis showed that the main protease 3CLpro reached the most favorable affinity, followed by importin-α and Nsp9, which shared a similar relationship. Therefore, in vitro activity of IVM can be explained by acting as an inhibitor of importin-α, dimeric 3CLpro, and Nsp9, but mainly over dimeric 3CLpro. Communicated by Ramaswamy H. Sarma
Requirements for Unobtrusive Monitoring to Support Home-Based Dementia Care: Qualitative Study Among Formal and Informal Caregivers

Background Due to a growing shortage in residential care, people with dementia will increasingly be encouraged to live at home for longer. Although people with dementia prefer extended independent living, this also puts more pressure on both their informal and formal care networks. To support (in)formal caregivers of people with dementia, there is growing interest in unobtrusive contactless in-home monitoring technologies that allow caregivers to remotely monitor the lifestyle, health, and safety of their care recipients. Despite their potential, these solutions will only be viable if they meet the expectations and needs of formal and informal caregivers of people with dementia. Objective The objective of this study was to explore the expected benefits, barriers, needs, and requirements toward unobtrusive in-home monitoring from the perspective of formal and informal caregivers of community-dwelling people with dementia. Methods A combination of semistructured interviews and focus groups was used to collect data among informal (n=19) and formal (n=16) caregivers of people with dementia. Both sets of participants were presented with examples of unobtrusive in-home monitoring followed by questions addressing expected benefits, barriers, and needs. Relevant in-home monitoring goals were identified using a previously developed topic list. Interviews and focus groups were transcribed and inductively analyzed. Requirements for unobtrusive in-home monitoring were elicited based on the procedure of van Velsen and Bergvall-Kåreborn. Results Formal and informal caregivers saw unobtrusive in-home monitoring as a support tool that should particularly be used to monitor (the risk of) falls, day and night rhythm, personal hygiene, nocturnal restlessness, and eating and drinking behavior. Generally, (in)formal caregivers reported cross-checking self-care information, extended independent living, objective communication, prevention and proactive measures, emotional reassurance, and personalized and optimized care as the key benefits of unobtrusive in-home monitoring. Main concerns centered around privacy, information overload, and ethical concerns related to dehumanizing care. Furthermore, 16 requirements for unobtrusive in-home monitoring were generated that specified desired functions, how the technology should communicate with the user, which services surrounding the technology were seen as needed, and how the technology should be integrated into the existing work context. Conclusions Despite the presence of barriers, formal and informal caregivers of people with dementia generally saw value in unobtrusive in-home monitoring, and felt that these systems could contribute to a shift from reactive to more proactive and less obtrusive care. However, the full potential of unobtrusive in-home monitoring can only unfold if relevant concerns are considered. Our requirements can inform the development of more acceptable and goal-directed in-home monitoring technologies to support home-based dementia care.
Blinatumomab following haematopoietic stem cell transplantation – a novel approach for the treatment of acute lymphoblastic leukaemia in infants

Blinatumomab with subsequent haematopoietic stem cell transplantation was applied in 13 infants with acute lymphoblastic leukaemia (ALL). Eight patients were treated in first remission due to slow clearance of minimal residual disease (MRD); one for MRD‐reappearance after long MRD negativity, one for primary refractory disease and three during relapse treatment. In slow MRD responders, complete MRD response was achieved prior to transplantation, with an 18‐month event‐free survival of 75%. In contrast, only one of five patients with relapsed/refractory ALL is still in complete remission. These data provide a basis for future studies of immunotherapy in very high‐risk infant ALL.
Delayed Endovascular Thrombectomy for Ischemic Stroke in a Young Woman with No Known Risk Factors: A Case Report

Patient: Female, 26-year-old Final Diagnosis: Internal carotid artery dissection Symptoms: Dysarthria • gaze palsy • hemiplegia • sensory loss Medication: — Clinical Procedure: Endovascular stenting and mechanical thrombectomy Specialty: Neurology • Radiology Objective: Unusual clinical course Background: National guidelines and consensus statements suggest a 24-hour window for endovascular recanalization in patients presenting with acute ischemic stroke due to large-vessel occlusion. However, the safety and efficacy of extending the window for intervention remains to be definitively established. Case Report: A healthy 26-year-old woman presented with headache, left-sided hemiplegia, and rightward gaze palsy 2 days after a minor trauma. Time last known well was approximately 50 hours prior to presentation. Computed tomography angiography revealed dissection of the distal right internal carotid artery and occlusion of the M1 segment of the right middle cerebral artery. Magnetic resonance imaging showed a small area of acute infarct in the right basal ganglia and right insular cortex, but suggested a large ischemic penumbra; this was confirmed with cerebral perfusion analysis. In light of the patient’s young age and potential for penumbral salvage, mechanical thrombectomy of an M1 thrombus and stenting of an internal carotid artery dissection were performed nearly 60 hours after the onset of symptoms. The patient demonstrated marked clinical improvement over the following days and was discharged home in excellent condition one week after presentation. Based on our clinical experience and other emerging data, we propose that extension of the 24-hour window for endovascular intervention may improve functional outcomes among select individuals. Conclusions: A 24-hour window for endovascular thrombectomy is appropriate for many patients presenting with acute ischemic stroke. However, in select individuals, extension of the window to 48 hours or beyond may improve functional outcomes.
Fecal microbiota transplantation in hepatic encephalopathy: a systematic review

Abstract Hepatic encephalopathy (HE) is a reversible neurocognitive dysfunction that ranges in severity from subclinical alterations to coma. Patients with chronic liver disease are predisposed to HE due to metabolic failure and portosystemic shunting of toxins, of which ammonia is believed to be the main toxic chemical. Fecal microbiota transplantation (FMT) may reduce ammonia synthesis by altering the gut microbiota composition to a taxon low in urease, diminish uptake of ammonia by reestablishing the integrity of the intestinal barrier and increase ammonia clearance by improving liver function. In this systematic review, we summarize the insights of the current literature examining FMT as a treatment for HE. PubMed and EMBASE were searched on 08 February 2021 using the MeSH terms ‘fecal microbiota transplantation & hepatic encephalopathy’ and the abbreviations ‘FMT & HE’. Eight studies fulfilled our inclusion criteria, comprising two randomized clinical trials, three case reports and three rodent studies. Thirty-nine patients with HE were treated with FMT. Thirty-nine rodents received FMT in laboratory tests. FMT improved neurocognitive test results in four human studies and two rodent studies. Microbiota originating from donors was found in human recipients one year post-FMT. Readmission of patients was lower after treatment with FMT compared to standard of care. FMT may improve neurocognitive function and reduce serious adverse events in patients with HE, but the studies conducted so far have been small and their long-term follow-up is limited. Large-scale, randomized and controlled trials are needed to validate and help standardize the clinical application of FMT in cases of HE.
Estrogen as a Safe Therapeutic Adjunct in Reducing the Inflammatory Storm in Trauma Hemorrhagic Shock Patients

Supplemental Digital Content is available in the text ABSTRACT Trauma is a major cause of death and disability throughout the world. It is a leading cause of death with or without sepsis in about 50% of patients. Limited therapeutic options are available besides definitive care with a mortality benefit. Preclinical studies have demonstrated the mortality benefit of estrogen in trauma hemorrhagic shock (THS). Based on encouraging results from preclinical studies, we hypothesized that early administration of estrogen in male THS patients may reduce the inflammatory storm, prevent sepsis-associated problems, and subsequently reduce mortality. The authors studied the safety of early administration of estrogen as a therapeutic adjunct in the emergency department (ED) and its effects on the inflammatory storm, prevention of sepsis, and mortality during the intensive care unit stay. Forty THS patients were recruited. THS patients were divided into experimental and placebo control groups based on the estrogen administration in the ED. Serum levels of cytokines and immune cells were measured at different time points on days 0, 3, 7, and 14 in both groups of THS patients. The experimental group received intravenous estrogen (25 mg) at a single time point in the ED beside standard of care as per advanced trauma life support guidelines. Patients did not develop any major or minor adverse events and showed favorable clinical outcomes in the experimental group. The levels of T regulatory cells, monocytes, and systemic cytokines significantly reduced and showed a balanced inflammatory response in THS patients who received estrogen. In conclusion, this preliminary study showed that intravenous estrogen therapy is safe and reduced the inflammatory insult due to trauma hemorrhagic shock. It may protect THS patients from sepsis-associated complications. Future clinical trials are required to study the efficacy and mechanistic pathway.
Alpha lipoic acid attenuates evoked and spontaneous pain following surgical skin incision in rats

ABSTRACT Our previous studies have implicated CaV3.2 isoform of T-type Ca2+ channels (T-channels) in the development of postsurgical pain. We have also previously established that different T-channel antagonists can alleviate in vivo postsurgical pain. Here we investigated the analgesic potential of another T-channel blocker and endogenous antioxidant molecule, α-lipoic acid (ALA), in a postsurgical pain model in rats. Our in vivo results suggest that single and repetitive intraperitoneal injections of ALA after surgery or preemptively, significantly reduced evoked mechanical hyperalgesia following surgical paw incision. Furthermore, repeated preemptive systemic injections of ALA effectively alleviated spontaneous postsurgical pain as determined by dynamic weight-bearing testing. We expect that our preclinical study may lead to further investigation of analgesic properties and mechanisms of analgesic action of ALA in patients undergoing surgery.
Exercise Training Improves Tumor Control by Increasing CD8+ T-cell Infiltration via CXCR3 Signaling and Sensitizes Breast Cancer to Immune Checkpoint Blockade

Optimized exercise therapy induces vessel normalization, boosts antitumor effector cell infiltration and function, and delays tumor growth in a CXCR3 pathway/CD8+ T cell–dependent manner. This results in sensitization of refractory breast cancer to immune checkpoint blockade. The mechanisms behind the antitumor effects of exercise training (ExTr) are not fully understood. Using mouse models of established breast cancer, we examined here the causal role of CD8+ T cells in the benefit acquired from ExTr in tumor control, as well as the ability of ExTr to improve immunotherapy responses. We implanted E0771, EMT6, MMTV-PyMT, and MCa-M3C breast cancer cells orthotopically in wild-type or Cxcr3−/− female mice and initiated intensity-controlled ExTr sessions when tumors reached approximately 100 mm3. We characterized the tumor microenvironment (TME) using flow cytometry, transcriptome analysis, proteome array, ELISA, and immunohistochemistry. We used antibodies against CD8+ T cells for cell depletion. Treatment with immune checkpoint blockade (ICB) consisted of anti–PD-1 alone or in combination with anti–CTLA-4. ExTr delayed tumor growth and induced vessel normalization, demonstrated by increased pericyte coverage and perfusion and by decreased hypoxia. ExTr boosted CD8+ T-cell infiltration, with enhanced effector function. CD8+ T-cell depletion prevented the antitumor effect of ExTr. The recruitment of CD8+ T cells and the antitumor effects of ExTr were abrogated in Cxcr3−/− mice, supporting the causal role of the CXCL9/CXCL11–CXCR3 pathway. ExTr also sensitized ICB-refractory breast cancers to treatment. Our results indicate that ExTr can normalize the tumor vasculature, reprogram the immune TME, and enhance the antitumor activity mediated by CD8+ T cells via CXCR3, boosting ICB responses. Our findings and mechanistic insights provide a rationale for the clinical translation of ExTr to improve immunotherapy of breast cancer.