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The localization and segmentation of the novel coronavirus disease of 2019 (COVID-19) lesions from computerized tomography (CT) scans are of great significance for developing an efficient computer-aided diagnosis system. Deep learning (DL) has emerged as one of the best choices for developing such a system. However, several challenges limit the efficiency of DL approaches, including data heterogeneity, considerable variety in the shape and size of the lesions, lesion imbalance, and scarce annotation. In this article, a novel multitask regression network for segmenting COVID-19 lesions is proposed to address these challenges. We name the framework MT-nCov-Net. We formulate lesion segmentation as a multitask shape regression problem that enables partaking the poor-, intermediate-, and high-quality features between various tasks. A multiscale feature learning (MFL) module is presented to capture the multiscale semantic information, which helps to efficiently learn small and large lesion features while reducing the semantic gap between different scale representations. In addition, a fine-grained lesion localization (FLL) module is introduced to detect infection lesions using an adaptive dual-attention mechanism. The generated location map and the fused multiscale representations are subsequently passed to the lesion regression (LR) module to segment the infection lesions. MT-nCov-Net enables learning complete lesion properties to accurately segment the COVID-19 lesion by regressing its shape. MT-nCov-Net is experimentally evaluated on two public multisource datasets, and the overall performance validates its superiority over the current cutting-edge approaches and demonstrates its effectiveness in tackling the problems facing the diagnosis of COVID-19.

Background No simple staging system has emerged for basal cell carcinomas (BCCs), since they do not follow the TNM process, and practitioners failed to agree on simple clinical or pathological criteria as a basis for a classification. Operational classification of BCCs is required for decision‐making, trials and guidelines. Unsupervised clustering of real cases of difficult‐to‐treat BCCs (DTT‐BCCs; part 1) has demonstrated that experts could blindly agree on a five groups classification of DTT‐BCCs based on five patterns of clinical situations. Objective Using this five patterns to generate an operational and comprehensive classification of BCCs. Method Testing practitioner's agreement, when using the five patterns classification to ensure that it is robust enough to be used in the practice. Generating the first version of a staging system of BCCs based on pattern recognition. Results Sixty‐two physicians, including 48 practitioners and the 14 experts who participated in the generation of the five different patterns of DTT‐BCCs, agreed on 90% of cases when classifying 199 DTT‐BCCs cases using the five patterns classification (part 1) attesting that this classification is understandable and usable in practice. In order to cover the whole field of BCCs, these five groups of DTT‐BCCs were added a group representing the huge number of easy‐to‐treat BCCs, for which sub‐classification has little interest, and a group of very rare metastatic cases, resulting in a four‐stage and seven‐substage staging system of BCCs. Conclusion A practical classification adapted to the specificities of BCCs is proposed. It is the first tumour classification based on pattern recognition of clinical situations, which proves to be consistent and usable. This EADO staging system version 1 will be improved step by step and tested as a decision tool and a prognostic instrument.

Salivary glands are considered the chief exocrine glands of the mouth and physiologically contribute to the maintenance of the homeostasis of the oral cavity. They consist of the parotid, submandibular and sublingual glands, which come in pairs and are collectively called the major glands, and the minor glands, which are much smaller and are dispersed throughout the buccal cavity. Salivary glands are distinguished by their size, amount of saliva secretion and their location in the oral cavity. Salivary glands pathophysiology has been a subject of interest in various worldwide metabolic disorders, including diabetes mellitus. Diabetes mellitus (DM), a global health concern, with a pathological imprint involved in vasculature, promotes microvascular and macrovascular complications among which periodontitis ranks sixth. Indeed, DM has also been directly associated with oral health lesions. Specifically, salivary glands in the context of diabetes have been a focal point of study and emphasis in the research field. There is evidence that relates salivary secretion content and diabetes progression. In this review, we present all the reported evidence of the deregulation of specific salivary proteins associated with the progression of diabetes in parallel with changes in salivary gland morphology, cellular architecture, and salivary secretion and composition more generally.

Light chain (AL) amyloidosis is characterized by deposition of immunoglobulin light chains (LC) as fibrils in target organs. Alongside the full-length protein, abundant LC fragments are always present in AL deposits. Herein, by combining gel-based and mass spectrometry analyses, we identified and compared the fragmentation sites of amyloid LCs from multiple organs of an AL λ amyloidosis patient (AL-55). The positions pinpointed here in kidney and subcutaneous fat, alongside those previously detected in heart of the same patient, were aligned and mapped on the LC's dimeric and fibrillar states. All tissues contain fragmented LCs along with the full-length protein; the fragment pattern is coincident across organs, although microheterogeneity exists. Multiple cleavage positions were detected; some are shared, whereas some are organ-specific, likely due to a complex of proteases. Cleavage sites are concentrated in "proteolysis-prone" regions, common to all tissues. Several proteolytic sites are not accessible on native dimers, while they are compatible with fibrils. Overall, data suggest that the heterogeneous ensemble of LC fragments originates in tissues, and is consistent with digestion of preformed fibrils, or with the hypothesis that initial proteolytic cleavage of the constant domain triggers the amyloidogenic potential of LCs, followed by subsequent proteolytic degradation. This work provides a unique set of molecular data on proteolysis from ex vivo amyloid, which allows discussing hypotheses on role and timing of proteolytic events occurring along amyloid formation and accumulation in AL patients.

Introduction Pembrolizumab provided durable responses and acceptable safety in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC) in the KEYNOTE-629 study. In this elderly, fragile population with disfiguring tumours, preservation of health-related quality of life (HRQoL) is critical. Here, we present pre-specified exploratory HRQoL analyses from the first interim analysis of KEYNOTE-629. Methods Patients with R/M cSCC not amenable to surgery or radiation therapy received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. HRQoL end points included change from baseline to week 12 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status (GHS)/QoL, functioning, symptom and European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) scores and change from baseline through week 48 in EORTC QLQ-C30 GHS/QoL and physical functioning scores. Improvement (≥ 10-point increase post-baseline with confirmation) was assessed using the exact binomial method. Results Analyses included 99 patients for EORTC QLQ-C30 and 100 for EQ-5D-5L. Compliance was > 80% at week 12. Mean scores were stable from baseline to week 12 for GHS/QoL (4.95 points; 95% confidence interval, −1.00 to 10.90) and physical functioning (−3.38 points; 95% confidence interval, −8.80 to 2.04). EORTC-QLQ-C30 functioning, symptom, and EQ-5D-5L scores remained stable at week 12. Post-baseline scores were improved in 29.3% of patients for GHS/QoL, 17.2% for physical functioning, and in a numerically higher proportion of responders versus non-responders (GHS/QoL, 55.6% versus 16.1%; physical functioning, 36.1% versus 7.1%). Conclusions In elderly patients with R/M cSCC, the clinical efficacy of pembrolizumab translates into a benefit validated by HRQoL preservation or improvement during treatment. Trial Registration ClinicalTrials.gov identifier: NCT03284424. Supplementary Information The online version contains supplementary material available at 10.1007/s13555-021-00598-6., Plain Language Summary Cutaneous squamous cell carcinoma (cSCC) is the second most common type of non-melanoma skin cancer. cSCC is usually caused by cumulative exposure to sunlight and often occurs in exposed parts of the body such as the head and neck. cSCC is most often seen in older people. If cSCC is detected early, it can be removed by surgery; however, if left untreated, the cancer can spread throughout the body and cause death. The disease itself and its treatment can be painful, cause scarring, or change the patient’s physical appearance. Hence, people with cSCC often have poor quality of life. It is therefore important to develop new drugs to help patients with cSCC live longer without worsening their quality of life. The phase 2 KEYNOTE-629 study investigated how well the drug pembrolizumab treated cSCC and whether it was safe. KEYNOTE-629 included patients who were mostly older and had advanced cSCC. The results showed that pembrolizumab was effective and safe. Here, we investigated how pembrolizumab affected the quality of life of these patients. To do this, we asked patients to answer questionnaires on important aspects of their experience, such as their general health status, physical functioning, emotional wellbeing, and symptoms. We found that patients who were treated with pembrolizumab had stable quality of life during treatment. Furthermore, patients whose cancer responded well to pembrolizumab were more likely to have an improved quality of life. These results support the use of pembrolizumab in patients with advanced cSCC. Supplementary Information The online version contains supplementary material available at 10.1007/s13555-021-00598-6.

The recent diagnosis of COVID-19 is based on real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and is regarded as the gold standard for confirmation of infection. It has already been widely recognized that deep learning techniques can potentially have a substantial role in streamlining and accelerating the diagnosis of COVID-19 patients. Numerous open dataset enterprises have been set up over the past weeks to help the researchers develop and check methods that could contribute to countering the Corona pandemic. In order to report the above unique problems in the diagnosis of COVID-19, pioneering techniques should be developed. This special issue focuses on novel deep learning imaging analysis techniques related to COVID-19.

[EN] Background: Essential anticancer medicines are an indispensable component of multidisciplinary treatment of paediatric malignancies. A European Society for Medical Oncology (ESMO) study reported inequalities in the availability of anticancer medicines for adult solid tumours and provided a model for the present survey. The aim of this survey was to assess the accessibility of essential medicines used in paediatric cancer patients aged 0 to 18 years across Europe from 2016 to 2018. Methods: A list of medicines was drawn with input from the European Society for Paediatric Oncology (SIOP Europe) Clinical Research Council referring to the World Health Organization Model List of Essential Medicines for Children (WHO EMLc) 2017. A survey was sent to nominated national clinician and pharmacist rapporteurs and parent associations in up to 37 countries; answers were obtained from 34 countries. Results: The full survey list contained 68 medicines, including 24 on the WHO EMLc 2017. Health professionals reported that 35% of all medicines were prescribed off-label in at least one country and that 44% were always available in >90% of countries. Only 63% of the EMLc 2017 medicines were reported as always available. The main determinant of unavailability was shortages, reported for 72% of medicines in at least one country. Out-of-pocket costs were reported in eight countries. Twenty-seven percent of orally administered medicines were never available in childfriendly formulations. Parents detailed individual efforts and challenges of facilitating ingestion of oral medicines as prescribed. Inequalities in access to pain control during procedures were reported by parents across Europe. Conclusions: Children and adolescents with cancer in Europe experience lack of access to essential medicines. Urgent actions are needed to address shortages, financial accessibility, availability of safe age-appropriate oral formulations, and pain management across Europe., This work was supported by the EU Health Programme (2014-2020) in the framework of the Joint Action on Rare Cancers [grant number 724161/JARC].

Background Laparoscopic liver resection (LLR) has been progressively developed along the past two decades. Liver surgery was one of the last frontiers reached by minimally invasive surgery. Surgical technique and equipment evolved to overcome technical limitations, making laparoscopic liver resections (LLR) safe and feasible. Surgeons developed skills in a stepwise approach, beginning with low complexity operations for benign diseases and reaching high-complexity surgeries for malignant cases and living donor organ harvesting. Objective s: The aim of the study is to compare short term results of laparoscopic versus open hepatectomy regarding to intra operative details and post-operative management and complications for achieving a safe hepatic resection for treatment of HCC in cirrhotic patients. Patients and Methods In this prospective study, a comparison between laparoscopic resection and open resection was done to compare short-term results between laparoscopic and open liver resection. This study was conducted on 30 patients with hepatocellular carcinoma. 15 patients (50%) were treated by laparoscopic liver resection (Group A) while the other 15 patients (50%) were treated by open liver resection (Group B). Results Regarding the demographic data, the presence of past history of medical condition and the preoperative laboratory results, no statistical significance was found. The mean operative time has statistically significant difference between the 2 groups, with decreased operative time in the laparoscopic group (P Conclusion Laparoscopic liver resection is a safe and feasible treatment option for HCC in cirrhotic patient needing minor resection at laparoscopic segments (II, III, IVa,V,VI). Laparoscopic liver resection for HCC has superior short- term and comparable oncological outcomes to open liver resection. LLR should be performed for carefully selected patients and by an expert surgical team.

Actinic cheilitis is a premalignant condition that can progress to squamous cell carcinoma with a higher propensity for metastasis than cutaneous squamous cell carcinoma. Optimal treatment for actinic cheilitis has not been established, and evidence-based estimates of clinical cure in the dermatology literature are limited. Here, we review and synthesize outcome data published for patients with actinic cheilitis after treatment with various modalities. A systematic review was conducted in MEDLINE, Embase and the Cochrane library for English, French and German-language studies and references of included articles from inception to 20 January 2020. Studies were included if they reported on at least six patients with biopsy-proven actinic cheilitis. After quality appraisal, results of studies with the strongest methodology criteria were synthesized. 18 studies of 411 patients (published 1985 to 2016) were included. The majority of the studies were case series. Carbon dioxide laser ablation and vermilionectomy were associated with the most favourable outcomes with fewest recurrences. Chemical peel and photodynamic therapy were associated with higher recurrence. Adverse effects generally resolved in the weeks following treatment and cosmetic outcomes were favourable overall. In conclusion, there is a lack of high-quality comparative studies evaluating different treatment options for actinic cheilitis. The included publications used various outcome measures; however, the majority reported on the recently defined core outcome sets. These results suggest that both carbon dioxide laser ablation and vermilionectomy are effective treatments for actinic cheilitis. Prospective head-to-head studies are needed to compare these treatment modalities and to assess patient preferences.

Background and objectivesPeripheral nerve blocks reduce postoperative pain and enhance recovery after total knee arthroplasty (TKA). This study aims to assess the benefits of addition of intravenous dexmedetomidine (DexM) to intravenous dexamethasone on the analgesic duration of quadruple nerve blocks.MethodsThis double-blind, randomized, controlled trial prospectively enrolled 90 patients scheduled for TKA under quadruple nerve blocks (sciatic, femoral, obturator, and lateral femoral cutaneous nerves blocks) with 70 mL, 0.32% ropivacaine. All patients received systemic dexamethasone 10 mg. Patients were randomized to receive DexM (2 µg/kg, intravenous) or placebo (1:1 ratio). The primary endpoint was the duration of analgesia defined as the time to first request for rescue analgesia (oxycodone).ResultsKaplan-Meier curves for the first analgesic request were similar between groups (log-rank test; p=0.27). Median (IQR) duration of analgesia was similar between placebo (1575 min (1211–1952)) and DexM (1470 min (1263–1700)) groups (p=0.56). Cumulative consumption of oxycodone at the 48th hour was 20 mg (10–30) and 30 mg (20–40) in placebo and DexM groups, respectively (p=0.14). The day after surgery, 93% and 89% of patients were able to walk in placebo and DexM groups, respectively (p=0.46). Intravenous DexM was associated with bradycardia, hypotension and longer recovery room stay (pConclusionsIn a multimodal analgesic regimen, addition of systemic DexM (2 µg/kg) to systemic dexamethasone does not prolong the analgesic duration of quadruple nerve block with ropivacaine 0.32% after TKA.Trial registration numberNCT03834129.

Aims: To show the benefit of chymotrypsin as an adjuvant therapy in cases of moderate parapneumonic pleural effusion in children. Study Design: Randomized controlled trial. Place and Duration of Study: Pulmonology Unit, Pediatric Department and Radiology Department, Tanta University Hospital, Egypt between Februray, 2019 to Februray, 2020. Methodology: Subjects comprised of 60 children randomized into three groups 20 children each (41 males, 19 females; age range 1-14 years) with moderate parapneumonic pleural effusion by chest ultrasound. Clinical as well as complete blood count, C-reactive protein and chest ultrasonography at time of presentation, after one week (first end point) and after two weeks (second end point). Management with antibiotics, analgesics, antipyretics, chest tube insertion and oral chymotrypsin in group 2 and intramuscular chymotrypsin in group 3. Results: There was statistically significant decrease in fluid thickness by chest u/s (mm) in group 2 (Mean ±SD= 6.400±3.872) and group 3 (Mean ±SD= 6.150±2.720) after one week and after two weeks group 2 (Mean ±SD= 15.3±4.658) while group 3 (Mean ±SD= 3.3±1.559) in comparsion to group 1 after one week (Mean ±SD= 16.100±10.351) and after two weeks (Mean ±SD= 11.35±7.066) ( P < 0.001), duration of hospitalization (days) and chest tube (days) were statistically significant lower in group 2 (Mean±SD= 15.200±4.112 ), (Mean±SD= 9.100±2.808) respectively and group 3 (Mean±SD= 14.050±3.300), (Mean±SD= 7.400±1.698 ), in relative to group 1 (Mean±SD= 18.65±3.329 ), (Mean±SD= 9.85±3.265 ), (P

Obstructive Sleep Apnea (OSA) syndrome is one of the most widespread diseases that difficult to be detected and remedied. In particular, the examination of OSA by using the traditional Polysomnography (PSG) is one of formidable complexity as it requires full observation in a laboratory overnight. Meanwhile, the number of available laboratories and beds is minimal comparing to the number of OSA patients. What's more, the unusual environment and restricted mobility of patients may result in deficient diagnosis results. The Internet of Things (IoT) is the most appropriate solution for the previous diagnosis obstacles by allowing doctors to synchronize patient status. Besides, several studies have been introduced to consolidate the performance of IoT interoperability via the fusion with Artificial Intelligence (AI) resulting in the Internet of Intelligent Things (IoIT). This paper presents a literature survey about the intensification of IoT technologies for smart monitoring of sleep quality and OSA diagnosis. Mainly, the most recent enabling IoT and support technologies such as (smart devices, fog computing, cloud, big data, and machine learning) are covered via the discussion of more recent works of literature published from 2016 to 2019. Also, the roles of AI in optimizing the efficiency of OSA smart diagnosis are presented. Besides, a new comprehensive IoIT optimization framework is presented which employing AI for optimizing the performance of intelligent diagnosis of OSA. Finally, the open issues and challenges in this field are argued. This paper is, therefore, a major contributor to the compilation of all IoT innovative and efficient AI methods that improving the quality of OSA diagnosis.

Immunoglobulin light chain (AL) amyloidosis is one of the most frequent systemic amyloidosis in Western countries. It is caused by a B-cell clone producing a misfolded light chain (LC) that deposits in organs.The review examines recent findings on pathophysiology and clinical management of AL amyloidosis. It contains an update on the recent hot topics as novel therapeutic approaches, definition of relapse, and hematologic response assessment. To review literature on AL amyloidosis, a bibliographic search was performed using PubMed.Due to the proteotoxicity of amyloidogenic LCs, the therapeutic goal is a rapid and profound decrease in their concentration. The standard treatment is a risk-adapted chemotherapy targeting the B-cell clone. Novel, promising drugs, as daratumumab, are currently under evaluation in newly-diagnosed and relapsed/refractory patients. New sensitive techniques, as mass spectrometry approach and bone marrow minimal residual disease assessment, are available to evaluate depth of response. After first-line therapy, increase in LC concentration may precede worsening of organ dysfunction and should be considered carefully. Further clarification of molecular mechanisms of the disease are shedding light on new possible therapeutic targets. Innovative treatment strategies and novel technologies will improve our ability to treat AL amyloidosis, preventing organ deterioration.

The purpose of this investigation was to encapsulate carvedilol, a model beta-blocker antihypertensive into nano-spanlastics, followed by incorporation into 1% CMC wafer to afford a mucoadhesive buccal drug delivery system, targeting to sidestep the first-pass metabolism, improving the drug absorption and pharmacological effect, achieving non-invasive buccal delivery for treating hypertension. Carvedilol-loaded nano-spanlastics were rendered by ethanol injection technique, using 23 factorial design. The effect of formulation variables was investigated on nano-spanlastic characteristics. The optimal nano-spanlastic formulation (S2; containing 20% Brij 97) exhibited particle size (239.8 ± 5 nm), entrapment efficiency (98. 16 ± 1.44%), deformability index (8.74 ± 0.42 g), and the flux after 24 h (Jmax) (22.5 ± 0.25 (μg/cm2/h) with enhancement ratio 2.87 as well as excellent stability after storage. Permeation study verified the preeminence of the S2 formula. A confocal laser scanning microscope showed deep penetration of S2 through sheep buccal mucosa formula compared to rhodamine B solution. S2-based wafer showed acceptable characters (pH, swelling, drug content, residence time, and release rate). In vivo studies (pharmacodynamic study and biochemical evaluation) showed considerable improvement in blood pressure, the profile of the lipid, oxidant stress biomarkers, and cardiac markers. Histopathological studies revealed the superiority of S2 wafer in the protection of heart tissues over Carvid®. The results achieved indicate that nano-spanlastic-based wafer offers a promising improving trans-buccal carvedilol delivery system.

Purpose : Few studies have examined the extent to which school-based vision screening is sufficient to achieve universal coverage among school-aged children in India. Method : A rural administrativ...

Key PointsDaratumumab is effective in treated light chain deposition disease. Daratumumab can prevent progression of renal failure in these patients.

Newly diagnosed AL amyloidosis patients were evaluated to develop a model for early assessment of treatment benefit at 6 months, integrating both hematologic (HR) and organ response (OR) assessment (testing cohort, Mayo: n = 473; validation cohort, Pavia: n = 575). Multiple OR were assessed as follows: All OR (AOR): response in all organs, mixed OR (MOR): response in some organs, no OR (NOR)]. AOR rates at 6 months improved with deepening HR; complete response (CR; 38%, 35%), very good partial response (VGPR; 30%, 26%), and partial response (PR; 16%, 21%), respectively. A composite HR/OR (CHOR) model was developed using incremental scoring based on hazard ratios with scores of 0–3 for HR (0—CR, 1—VGPR, 2—PR, 3—no response) and 0–2 for OR (0—AOR, 1—MOR, 2—NOR). Patients could be divided into two distinct CHOR groups (scores 0–3 and 4–5), with median OS in group 1 and group 2: Not reached vs. 34 months, p p

Background No simple classification system has emerged for 'advanced basal cell carcinomas', and more generally for all difficult-to-treat BCCs (DTT-BCCs), due to the heterogeneity of situations, TNM inappropriateness to BCCs, and different approaches of different specialists. Objective To generate an operational classification, using the unconscious ability of experts to simplify the great heterogeneity of the clinical situations into a few relevant groups, which drive their treatment decisions. Method Non-supervised independent and blinded clustering of real clinical cases of DTT-BCCs was used. Fourteen international experts from different specialties independently partitioned 199 patient cases considered 'difficult to treat' into as many clusters they want (≤10), choosing their own criteria for partitioning. Convergences and divergences between the individual partitions were analyzed using the similarity matrix, K-mean approach, and average silhouette method. Results There was a rather consensual clustering of cases, regardless of the specialty and nationality of the experts. Mathematical analysis showed that consensus between experts was best represented by a partition of DTT-BCCs into five clusters, easily recognized a posteriori as five clear-cut patterns of clinical situations. The concept of 'locally advanced' did not appear consistent between experts. Conclusion Although convergence between experts was not granted, this experiment shows that clinicians dealing with BCCs all tend to work by a similar pattern recognition based on the overall analysis of the situation. This study thus provides the first consensual classification of DTT-BCCs. This experimental approach using mathematical analysis of independent and blinded clustering of cases by experts can probably be applied to many other situations in dermatology and oncology.

The COVID‐19 pandemic is one of the most serious global challenges to delivering affordable and equitable treatment to children with cancer we have witnessed in the last few decades. This Special Report aims to summarize general principles for continuing multidisciplinary care during the SARS‐CoV‐2 (COVID‐19) pandemic. With contributions from the leadership of the International Society for Pediatric Oncology (SIOP), Children's Oncology Group (COG), St Jude Global program, and Childhood Cancer International, we have sought to provide a framework for healthcare teams caring for children with cancer during the pandemic. We anticipate the burden will fall particularly heavily on children, their families, and cancer services in low‐ and middle‐income countries. Therefore, we have brought together the relevant clinical leads from SIOP Europe, COG, and SIOP‐PODC (Pediatric Oncology in Developing Countries) to focus on the six most curable cancers that are part of the WHO Global Initiative in Childhood Cancer. We provide some practical advice for adapting diagnostic and treatment protocols for children with cancer during the pandemic, the measures taken to contain it (e.g., extreme social distancing), and how to prepare for the anticipated recovery period.

A substantial proportion of patients who have recovered from coronavirus disease-2019 (COVID-19) experience COVID-19–related symptoms even months after hospital discharge. We extensively immunologically characterized patients who recovered from COVID-19. In these patients, T cells were exhausted, with increased PD-1+ T cells, as compared with healthy controls. Plasma levels of IL-1β, IL-1RA, and IL-8, among others, were also increased in patients who recovered from COVID-19. This altered immunophenotype was mirrored by a reduced ex vivo T cell response to both nonspecific and specific stimulation, revealing a dysfunctional status of T cells, including a poor response to SARS-CoV-2 antigens. Altered levels of plasma soluble PD-L1, as well as of PD1 promoter methylation and PD1-targeting miR–15-5p, in CD8+ T cells were also observed, suggesting abnormal function of the PD-1/PD-L1 immune checkpoint axis. Notably, ex vivo blockade of PD-1 nearly normalized the aforementioned immunophenotype and restored T cell function, reverting the observed post–COVID-19 immune abnormalities; indeed, we also noted an increased T cell–mediated response to SARS-CoV-2 peptides. Finally, in a neutralization assay, PD-1 blockade did not alter the ability of T cells to neutralize SARS-CoV-2 spike pseudotyped lentivirus infection. Immune checkpoint blockade ameliorates post–COVID-19 immune abnormalities and stimulates an anti–SARS-CoV-2 immune response.

Self-talk is an effective mental training technique that has been shown to facilitate or debilitate an athlete's performance, depending on its valence. Although the effects of self-talk have been supported by observing change in sport performance, little is known about how self-talk can induce physiological changes. Specifically, it is important to understand if the type of self-talk (positive, neutral, or negative) and can influence stress-related parameters, such as perceived exertion, cardiorespiratory, and cortisol responses. The study's objective was therefore to investigate the top-down effect of positive and negative self-talk compared to a dissociative activity during an iso-metabolic running exercise on autonomic regulation of cardiorespiratory function. Twenty-nine well-trained male runners [38 ± 13 years, 177 ± 7 cm and 73 ± 7 kg] volunteered to participate in a randomized-group design study that included a negative self-talk (NST), a positive self-talk, and a dissociative group (DG). First, participants underwent an incremental running test on a treadmill to determine the maximal oxygen uptake (VO2max ). Next, participants received a mental training session on self-talk and created three positive and three negative self-talk statements. Finally, participants underwent a 60-min steady-state running exercise on a treadmill at 70% of VO2max , during which they were cued at 20-, 35-, and 50-min with their personal self-created positive or negative self-talk statements while the DG listened to a documentary. Cardiorespiratory parameters and rate of perceived exertion (RPE) were recorded throughout the 60-min endurance exercise. In addition, salivary cortisol samples were obtained at waking and after treatment. Although oxygen uptake, carbon dioxide production, RPE, and heart rate significantly changed overtime during the 60-min steady-state running exercise, no significant main treatment effect was found. However, RPE scores, minute ventilation, breathing frequency, and salivary cortisol were significantly higher in the NST group compared to the two other groups. These data suggest that NST [emotion-induced stress, as reflected by elevated cortisol] altered the breathing frequency response. In conclusion, manipulating self-talk alters hormonal response patterns, modulates cardiorespiratory function, and influences perceived exertion.

BackgroundThere is a clear need for targeted therapies to treat acute myeloid leukemia (AML), the most common acute leukemia in adults. CD123 (IL-3 receptor alpha chain) is an attractive target for AML treatment.1 However, cytotoxic antibody targeting CD123 proved insufficiently effective in a combination setting in phase II/III clinical trials.2 T-cell engagers targeting CD123 displayed some clinical efficacy but were often associated with cytokine release syndrome and neurotoxicity.3 Interest in the use of NK cells for therapeutic interventions has increased in recent years, as a potential safer alternative to T cells. Several NK-cell activating receptors, such as CD16a, NKG2D, and the natural cytotoxicity receptors NKp30 and NKp46, can be targeted to induce antitumor immunity. We previously reported the development of trifunctional NK-cell engagers (NKCEs) targeting a tumor antigen on cancer cells and co-engaging NKp46 and CD16a on NK cells.4MethodsWe report here the design, characterization and preclinical development of a novel trifunctional NK cell engager (NKCE) targeting CD123 on AML cells and engaging the activating receptors NKp46 and CD16a on NK cells. The CD123 NKCE therapeutic molecule was engineered with humanized antibodies targeting NKp464 and CD123.5 We compared CD123-NKCE and a cytotoxic ADCC-enhanced antibody (Ab) targeting CD123, in terms of antitumor activity in vitro, ex vivo and in vivo. Pharmacokinetic, pharmacodynamic and safety profile of CD123-NKCE were evaluated in non-human primate (NHP) studies.ResultsThe expression of the high affinity Fc gamma receptor CD64 on patient-derived AML cells inhibited the ADCC of the Ab targeting CD123 in vitro and ex vivo, but not the antitumor activity of CD123-NKCE. CD123-NKCE had potent antitumor activity against primary AML blasts and AML cell lines, promoted strong NK-cell activation and induced cytokine secretion only in the presence of AML target cells. Its antitumor activity in mouse model was greater than that of the comparator antibody. Moreover, CD123-NKCE had strong and prolonged pharmacodynamic effects in NHP when used at very low doses, was well-tolerated up to high 3 mg/kg dose and triggered only minor cytokine release.ConclusionsThe data for activity, safety, pharmacokinetics, and pharmacodynamics provided here demonstrate the superiority of CD123-NKCE over comparator cytotoxic antibody, in terms of antitumor activity in vitro, ex vivo, in vivo, and its favorable safety profile, as compared to T-cell therapies. These results constitute proof-of-principle for the efficacy of CD123-NKCE for controlling AML tumors in vivo, and provide consistent support for their clinical development.ReferencesEhninger A, Kramer M, Rollig C, et al. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer J 2014;4:e218.Montesinos P, Gail J Roboz GJ, et al. Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study. Leukemia 2021;35(1):62–74.Uy GL, Aldoss I, Foster MC, et al. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood 2021;137(6):751–762.Gauthier L, Morel A, Anceriz N, et al. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. Cell 2019;177(7):1701–13.Jin L, Lee EM, Ramshaw HS, et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell 2009;5:31–42.

COVID-19 stay threatening the health infrastructure worldwide. Computed tomography (CT) was demonstrated as an informative tool for the recognition, quantification, and diagnosis of this kind of disease. It is urgent to design efficient deep learning (DL) approach to automatically localize and discriminate COVID-19 from other comparable pneumonia on lung CT scans. Thus, this study introduces a novel two-stage DL framework for discriminating COVID-19 from community-acquired pneumonia (CAP) depending on the detected infection region within CT slices. Firstly, a novel U-shaped network is presented to segment the lung area where the infection appears. Then, the concept of transfer learning is applied to the feature extraction network to empower the network capabilities in learning the disease patterns. After that, multi-scale information is captured and pooled via an attention mechanism for powerful classification performance. Thirdly, we propose an infection prediction module that use the infection location to guide the classification decision and hence provides interpretable classification decision. Finally, the proposed model was evaluated on public datasets and achieved great segmentation and classification performance outperforming the cutting-edge studies.

To gain insight into complex biological endocrine glucose-insulin regulatory system where the interactions of components of the metabolic system and time-delay inherent in the biological system give rise to complex dynamics. The modeling has increased interest and importance in physiological research and enhanced the medical treatment protocols. This brief contains a new model using time delay differential equations, which give an accurate result by utilizing two explicit time delays. The bifurcation analysis has been conducted to find the main system parameters bifurcation values and corresponding system behaviors. The results found consistent with the biological experiments results.

Aims/hypothesis: Impaired wound healing significantly impacts morbidity and mortality in diabetic patients, necessitating the development of novel treatments to improve the wound healing process. We here investigated the topical use of acellular embryonic stem cell extracts (EXTs) in wound healing in diabetic db/db mice. Methods: Wounds were induced in diabetic db/db mice, which were subsequently treated with EXTs, with 3T3 fibroblast cell line protein extracts (3T3XTs) or with saline as a control. Pathology and mechanistic assays were then performed. Results: The in vivo topical administration of EXTs facilitates wound closure, contraction and re-epithelialization. Moreover, EXTs reduced the number of wound-infiltrating CD45+ inflammatory cells and increased the rate of repair and of angiogenesis as compared to controls. Interestingly, the EXT effect was partly enhanced by the use of a collagen-based biocompatible scaffold. In vivo, topical administration of EXTs increased the percentage of regulatory T cells in the wounded tissue, while in vitro EXT treatment reduced T cell-mediated IFN-γ production. Proteomic screening revealed 82 proteins differentially segregating in EXTs as compared to 3T3 extracts, with APEX1 identified as a key player for the observed immunomodulatory effect of EXTs. Conclusions: EXTs are endowed with immunoregulatory and anti-inflammatory properties; their use improves wound healing in diabetic preclinical models.