Dry eye disease (DED) is a multifactorial disorder with recognized pathology, but not entirely known pathomechanism. It is suggested to represent a continuum with neuropathic corneal pain with the paradox that DED is a pain-free disease in most cases, although it is regarded as a pain condition. The current paper puts into perspective that one gateway from physiology to pathophysiology could be a Piezo2 channelopathy, opening the pathway to a potentially quad-phasic non-contact injury mechanism on a multifactorial basis and with a heterogeneous clinical picture. The primary non-contact injury phase could be the pain-free microinjury of the Piezo2 ion channel at the corneal somatosensory nerve terminal. The secondary non-contact injury phase involves harsher corneal tissue damage with C-fiber contribution due to the lost or inadequate intimate cross-talk between somatosensory Piezo2 and peripheral Piezo1. The third injury phase of this non-contact injury is the neuronal sensitization process with underlying repeated re-injury of the Piezo2, leading to the proposed chronic channelopathy. Notably, sensitization may evolve in certain cases in the absence of the second injury phase. Finally, the quadric injury phase is the lingering low-grade neuroinflammation associated with aging, called inflammaging. This quadric phase could clinically initiate or augment DED, explaining why increasing age is a risk factor. We highlight the potential role of the NGF-TrkA axis as a signaling mechanism that could further promote the microinjury of the corneal Piezo2 in a stress-derived hyperexcited state. The NGF-TrkA-Piezo2 axis might explain why female sex represents a risk factor for DED. Dry eye disease (DED) is one of the most frequent ophthalmologic disorders, affecting up to 50% of the population, and is considered a complex, multifactorial and heterogeneous disease with recognized underlying pathology but not entirely known pathomechanism -tropomyosin receptor kinase A (TrkA) axis signaling plays a role in promoting the development of this dose-limiting and threshold-driven Piezo2 channelopathy that may explain the sex difference in the epidemiology of DED.Piezo proteins are the largest membrane proteins known so far, with numerous transmembrane segments , acts by a dual-action mechanism, meaning inhibition of both cyclooxygenase and lipoxygenase pathways. Diclofenac not only has a favorable effect on DOMS, suggested to be caused by Piezo2 microinjury  antagonist preincubation of neural wound media diminishes the secondary calcium waves is in line with the theory of Sonkodi that Piezo2 channelopathy activates NMDA receptors , leading to increased transport to the central nerve terminals of these pseudounipolar trigeminal neurons, constituting a critical mechanism in sensitization , with concomitant NMDA receptor activation, could lead to the activation of microglia and opening of the pathway to neuropathic pain  is capable of suppressing DED symptoms by stimulating tear secretion  is critically involved in this sterile inflammatory process by reacting to the release of endogenous stimuli , that spermidine depletion-induced opioid-like withdrawal could be an additional stress source during stress-derived fatiguing repetitive forced lengthening contractions (Sonkodi et al. Neuropathic pain is an important hallmark of NCP and has been considered as a lesion or disease of the somatosensory nervous system (Galor et al. Additional discussion of peripheral and central sensitization of corneal pain and their progressiveness is not the subject of this manuscript, only the aforementioned critical pathways. However, comprehensive reviews about sensitization are presented by Galor et al. (Galor et al. Again it is worth noting that increasing age has been considered a risk factor for DED (Chiang et al. Female sex is considered a risk factor for DED (The epidemiology of dry eye disease Later, Sonkodi et al. even implicated the Piezo2 channelopathy in these proprioceptive terminal microinjuries leading to non-contact injuries (Sonkodi et al. Importantly, Nakamachi et al. also found that PACAP-null female animals were more affected than males (Nakamachi et al. DED is the most common ophthalmologic disorder, with a substantial economic burden and impaired quality of life. This paper proposes a critical pathophysiological role of corneal somatosensory Piezo2 channelopathy at the nerve terminals in the development of DED. This microinjury could open a gateway to a potential quad-phasic non-contact injury mechanism on a multifactorial basis and with a heterogeneous clinical picture. Furthermore, the NGF-TrkA-Piezo2 axis may be the critical signaling explaining the sex difference with female predisposition in DED.


Oil pollution in the ocean has been a great threaten to human health and the ecological environment, which has raised global concern. Therefore, it is of vital importance to develop simple and efficient techniques for oil–water separation. In this work, a facile and low-cost laser-heat surface treatment method was employed to fabricate superwetting copper (Cu) foam. Nanosecond laser surface texturing was first utilized to generate micro/nanostructures on the skeleton of Cu foam, which would exhibit superhydrophilicity/superoleophilicity. Subsequently, a post-process heat treatment would reduce the surface energy, thus altering the surface chemistry and the surface wettability would be converted to superhydrophobicity/superoleophilicity. With the opposite extreme wetting scenarios in terms of water and oil, the laser-heat treated Cu foam can be applied for oil–water separation and showed high separation efficiency and repeatability. This method can provide a simple and convenient avenue for oil–water separation. Oil pollution in the ocean, including oil spills and oil diffusion, has become more severe in recent years with the increasing demand of maritime oil transportation, and has raised global concerns since it can also cause significant damage to the ecological environment and human health ,2,3. TheInspired by the plants and animals in nature, a superwetting surface that exhibits either superhydrophobicity  or superIn recent decades, pulsed laser processing using either an ultra-fast pulsed laser  or a nanIn this work, a laser-heat surface treatment method was developed to prepare superhydrophobic/superoleophilic Cu foam for efficient oil water separation. A UV nanosecond laser was firstly employed to induce micro/nanostructures on Cu foam, and subsequently the laser-textured Cu foam was subjected to heat treatment in a conventional oven for 2 h and then ultrasonically cleaned. The surface morphology of the Cu foam was investigated by scanning electron microscope (SEM), and the surface chemistry of the Cu foam was analyzed by energy-dispersive X-ray spectroscopy (EDS). The surface wettability of the Cu foam in terms of both water and oil was studied by water contact angle (WCA) and oil contact angle (OCA) measurements. The influences of some key laser processing parameters, including power, scanning speed and line spacing on the surface morphology and surface wettability of the Cu foam subject to laser-heat surface treatment, was systematically investigated. Finally, the oil–water separation performance of the laser-heat treated Cu foam was evaluated by the oil–water separation test.Cu foam with a thickness of 0.19 mm and PPI (pores per linear inch) of 110 was chosen as the experimental material and was purchased from Kunshan GuangJiaYuan New Materials Co. Ltd., Kunshan, China. The test samples were first cut into square pieces with a dimension of 12 × 12 × 0.19 mm, and subsequently, all the samples were ultrasonically cleaned with acetone, ethanol and deionized (DI) water in sequence to eliminate contaminants on the surface. The samples were then stored in ambient air for further treatment and analysis. The soybean oil used in the oil–water separation test was obtained from Linyi Shansong Biological Products Co., Ltd., Linyi, China.The process schematic for the laser-heat surface treatment method developed in this work can be found in The laser-textured Cu foam exhibited superhydrophilicity and superoleophilicity. To achieve rapid wettability conversion from superhydrophilicity to superhydrophobicity, a post-process treatment was applied, as shown in The surface morphology of the untreated Cu foam and the laser-heat treated Cu foams was observed using a field emission scanning electron microscope . The surface chemistry of the untreated Cu foam, laser-textured Cu foam and laser-heat treated Cu foam was evaluated using energy-dispersive X-ray spectroscopy . The surface wettability was examined via a water contact angle (WCA) measurement and an oil contact angle (OCA) measurement using a contact angle goniometer  furnished with a high-resolution CMOS camera. During each WCA or OCA measurement, a water droplet or an oil droplet with a volume of ~4 µL was dropped onto the sample. The optical shadowgraph was captured for each measurement, and image analysis software was utilized to determine the WCA or OCA value. Five WCA or OCA measurements were conducted for each sample, and the average WCA or OCA value was reported.A self-designed experimental setup was utilized for the oil–water separation test, as shown in equation :(1)η=m1mThe surface morphology of the untreated Cu foam and laser-heat treated Cu foams was first examined by visual inspection. The surface morphology of the untreated Cu foam and laser-heat treated Cu foams was further investigated by SEM, as shown in Since scanning speed and line spacing are also key parameters for laser surface texturing, their effects on the surface morphology formation of the laser-heat treated Cu foam was also investigated. The surface wettability of the Cu foam was evaluated by contact angle measurements in terms of both water and oil. The effect of the laser processing parameters on the wettability transition of the laser-heat treated Cu foam was further investigated. Since the laser-heat treated Cu foam will exhibit superoleophilicity with an OCA of 0° after any type of treatment, only the WCA measurement results are shown and discussed in this section. From 2–, –CH3 and C=C, should have been absorbed onto the laser-heat treated Cu foam [For metallic materials, researchers pointed out that the surface chemistry of the metallic materials can be modified by laser-induced material vaporization and oxidation , or heat Cu foam . Since t Cu foam . The app Cu foam , the sur Cu foam , and thuThe EDS elemental mapping data was also obtained to reveal the elemental distributions of the detected elements on each Cu foam. The oil–water separation performance of the laser-heat treated Cu foam was evaluated by an oil–water separation test. The separation efficiency and repeatability of the laser-heat treated Cu foam were further investigated and analyzed. The separation efficiency of the laser-heat treated Cu foams processed with different laser processing parameters can be found in Nanosecond laser surface texturing can significantly modify the skeleton structure of the Cu foam by inducing micro/nanostructures on top. The laser processing parameters will also greatly influence the density and size of the micro/nanostructures, and thus should be carefully controlled.The surface energy of the laser-textured Cu foam was reduced by heat treatment, which should be attributed to the combined effects of adsorption of hydrophobic airborne carbon-containing groups and the generation of a Si-based PDMS layer.The Cu foam exhibited superhydrophilicity/superoleophilicity directly upon laser surface texturing and was converted to superhydrophobicity/superoleophilicity subsequent to heat treatment. The wettability transition was ascribed to laser-induced micro/nanostructures and the reduction of surface energy.The laser-heat treated Cu foam showed good performance for oil–water separation with good separation efficiency up to 94.6%, and the oil–water separation process can be repeated.In this work, a simple, efficient and convenient laser-heat surface treatment method was developed to fabricate superwetting Cu foam that can be used for oil–water separation. The surface morphology, surface wettability surface chemistry and oil–water separation performance of the laser-heat treated Cu foams were studied and analyzed. Some main findings can be summarized as below:Overall, the developed method is quite facile and convenient, can potentially be utilized for diverse applications where oil–water separation is needed.


The covid-19 pandemic has had a large impact on the daily lives of adolescents, even in Sweden where the restrictions were relatively mild. The aim of this study was to examine if there had been a change in mental health outcomes and if these changes were related to changes in physical activity patterns before and during the pandemic.In this longitudinal study, data were collected in the autumn 2019 and in follow-up measurements in the spring 2021. Physical activity and sedentary time were measured for seven consecutive days by accelerometry (Actigraph). The mental health outcomes, health-related quality of life (HRQoL) and psychosomatic health were measured with questionnaires (KIDSCREEN-10 and PSP). ANCOVA analyses were applied to estimate the associations between change in physical activity patterns and mental health outcomes.In total, 585 boys (45%) and girls (55%), aged 13-14 years (baseline) from 34 schools around Stockholm, were included in the study. Between 2019-2021 there was a decrease in HRQoL (p > 0.001) and increase in psychosomatic problems (p > 0.001) among both boys and girls. There was a significant positive relationship between change in MVPA and change in HRQoL .The results suggest that the COVID-19 pandemic has impaired the mental health of Swedish adolescents but increased physical activity was related to positive changes in the mental health outcome HRQoL.Funding: The Public Health Authority and Skandia


Accessory mitral valve tissue (AMVT) is a rare congenital cardiac anomaly that mainly diagnosed in the first decade of life. However, asymptomatic cases may not be diagnosed even up to adulthood. We report a fetus with AMVT to show the diagnostic ability of the fetal echocardiography for detection of this pathology in the prenatal period.AMVT was diagnosed in a 26-week-old male fetus with persistent dysrhythmia. Dysrhythmia could not be aborted and controlled by sotalol till the third trimester evaluation. Apical left ventricular (LV) diverticulum was the additional finding in his fetal echocardiogram. After birth, he was in sinus rhythm and echocardiography confirmed the presence of AMVT, however, without any evidence of LV apical diverticulum.The diagnosis of AMVT in the prenatal period is possible by fetal echocardiography.The online version contains supplementary material available at 10.1186/s43044-022-00263-z. Accessory mitral valve tissue (AMVT) is a rare congenital cardiac anomaly. This anomaly is mainly diagnosed in the first decade of life, but it may remain undiagnosed until adulthood . A largeA 30-year-old pregnant woman  was referred to us at 26 weeks of gestation because of her fetus dysrhythmia. Extrasystoles of bigeminy premature ventricular contractions (PVCs) were the cause of dysrhythmia  and the synchronous left ventricular diverticulum (LVD) contraction with the main LV chamber at 26 weeks of gestation.


Osteonecrosis of the metaphysis is often rare as it is a highly vascular region. Here we report an unusual case of non-traumatic osteonecrosis of the humerus predominantly involving the metaphysis in a post covid elderly female. The patient had a pathological fracture of humerus during the post-operative period of intertrochanteric femur fracture surgery. She was evaluated for the causes of pathological fracture and the fracture was managed with hemi replacement of the shoulder because of the extensive bone loss. The pathology here could only be explained as some sequelae of hyper inflammatory state associated with COVID-19 infection. The possible differentials are also discussed here. This case report will help clinicians to consider COVID-19 infection as a cause for non-traumatic osteonecrosis among other reported causes of osteonecrosis. The rapidly spreading COVID-19 infection has been a major challenge especially in India with a high population density. The manifestations of the disease are still evolving and are under close scientific scrutiny. Recent evidences suggest that COVID-19 adversely affects different human body systems as a part of “long COVID-19”, such as Guillain-Barré syndrome, lung fibrosis, pulmonary thromboembolism, cardiomyopathy, sensory dysfunction and stroke . The lonPatient information: sixty years old female, a known case of type 2 diabetes mellitus and hypertension admitted in a tertiary centre with fever and breathlessness 2 months prior to admission in our facility. She was diagnosed with SARS-CoV-2 (COVID-19) infection and was on IV steroids, Remdisivir and other supportive measures. She developed post covid pneumonia which later progressed to sepsis and acute kidney injury. High Resolution Computed Tomography (HRCT) chest was suggestive of post covid sequelae with superadded secondary infection. A bronchoscopy was done and the bronchoalveolar lavage showed the growth of Burkholderia pseudomallei. Blood culture revealed growth of B. pseudomallei, Vancomycin resistant enterococcus faecalis and Pseudomonas, for which culture specific IV antibiotics  were given. She was then referred to a local facility for continuation of IV antibiotics. During her stay in that hospital, she had a fall and sustained displaced intertrochanteric fracture of right proximal femur  grade three bedsores over sacrum. Her right lower limb was shortened and externally rotated due to the fracture. The trochanteric femur fracture was managed with proximal femoral nailing (PFN A2).Timeline: on 3rd post-operative day , she complained of pain over her left shoulder and restriction of shoulder movements with no definite history of trauma to her shoulder. There was a mild swelling over the proximal arm with no skin discolouration or local rise of temperature. She was afebrile.Diagnostic approach: a radiograph of the left shoulder and humerus ( humerus  showed p humerus  confirmeTherapeutic intervention: considering the differentials of infection, malignancy, secondary hyperparathyroidism and melioidosis of bone, we planned for open biopsy and fixation of the humerus fracture through deltopectoral approach. Intraoperatively, the bone was found excessively friable without much soft tissue involvement or pus collection. Another unicortical lytic lesion was seen at the diaphysis which was further away from the metaphyseal lytic lesion. Since the bone was excessively friable and due to poor bone stock at the head and neck, osteosynthesis was abandoned and a cemented hemi replacement was done. The bone and tissue (d tissue  were send tissue . PostopeFollow-up: with FDG PET scan showed no evidence of malignancy or distant metastasis. She had regular follow-up with X-rays (h X-rays  and blooConsent: we confirm that the patient has given informed consent for the case report to be published.Osteonecrosis has been reported in various pathologies like pancreatitis, sickle cell disease, caisson´s disease and other hypercoagulable states . The exaInterestingly, during SARS-CoV-2 infection, ORF3a induces Mito-ROS production to activate HIF-1Þ, which in turn enhances the viral infection and aggravates inflammatory responses . The proBased on the clinical, radiological, histopathological and microbiological analysis, we presume that the osteonecrosis involving the metaphysis of humerus in our case is predominantly due to COVID-19 induced hyper inflammatory response. Our case report will help clinicians to consider COVID-19 infection as a cause for non-traumatic osteonecrosis among other reported causes of osteonecrosis.


Viruses are naturally endowed with the capacity to transfer genetic material between cells. Following early skepticism, engineered viruses have been used to transfer genetic information into thousands of patients, and genetic therapies are currently attracting large investments. Despite challenges and severe adverse effects along the way, optimized technologies and improved manufacturing processes are driving gene therapy toward clinical translation. Fueled by the outbreak of AIDS in the 1980s and the accompanying focus on human immunodeficiency virus (HIV), lentiviral vectors derived from HIV have grown to become one of the most successful and widely used vector technologies. In 2022, this vector technology has been around for more than 25 years. Here, we celebrate the anniversary by portraying the vector system and its intriguing properties. We dive into the technology itself and recapitulate the use of lentiviral vectors for ex vivo gene transfer to hematopoietic stem cells and for production of CAR T-cells. Furthermore, we describe the adaptation of lentiviral vectors for in vivo gene delivery and cover the important contribution of lentiviral vectors to basic molecular research including their role as carriers of CRISPR genome editing technologies. Last, we dwell on the emerging capacity of lentiviral particles to package and transfer foreign proteins. Acquired immunodeficiency syndrome (AIDS) was first diagnosed in 1981. The first reports describing five men from the Los Angeles area who suffered from serious infections caused by severe immunosuppression . The hitThe fast track to discovery of HIV-1 as the causing agent of AIDS was built on early pioneering studies of genetically simpler retroviruses, which are now classified as alpha- and gamma-retroviruses. Most importantly, in back-to-back publications published 50 years ago, Howard Temin and David Baltimore rewrote the central dogma by documenting that virions derived from two tumor-causing RNA viruses, Rous sarcoma virus (RSV) and Rauscher murine leukemia virus (R-MLV), carried a virally encoded enzyme capable of converting single-stranded RNA into DNA , 7. Evenpol gene encoding the RT to a region near the 5′-end, where they stumbled upon the RNA motifs directing incorporation of viral RNA into virions.The molecular characterization of simple retroviruses, like murine leukemia virus (MLV), did not only support the swift identification of HIV-1 as the causative agent of AIDS. It also paved the way for new concepts of gene therapy, which would start taking shape in the early 1980s and embark on a thrilling and often bumpy roller coaster ride through good and bad times for the next forty years. Along for the ride came vector technologies based on HIV in the late 1990’s, but it all started with work by the labs of Baltimore and Temin, who had now moved up the retroviral genome from the cis-acting defect in RSVs carrying a deletion at a similar position in the genome . T. TWAS geid cells   now totals more than 1.5 million integration sites. Most recently, Kohn and co-workers identified 724,685 unique lentiviral integration sites in nine X-CGD patients . Analyseoduction . This dooduction . Togethevegfa gene as a feasible treatment of age-related macular degeneration [For most diseases, it is not an option to handle cells ex vivo and transfer therapeutic genes in culture flasks. Wisely, Friedmann and Roblin urged to caution in treating human disease by administering genes directly to patients when they first framed the concepts of gene therapy almost 50 years ago . Indeed,neration .Whereas delivery of transgenes to cells in vivo has mostly been achieved using lentiviral vectors pseudotyped with VSV-G due its broad tissue-specificity and high transduction capacity, an intriguing aspect of in vivo lentiviral vector delivery is the ability to replace VSV-G with alternative surface proteins, thereby altering vector tropism. Girard-Gagnepain and coworkers demonstrated incorporation of the baboon endogenous retrovirus glycoprotein on the surface of virions, resulting in increased vector transduction efficacy in human CD34 + HSCs, B-cells, and T-cells compared to VSV-G-pseudotyped lentiviral vectors . As an aFor liver-directed gene therapy, AAV-based vectors have shown immense clinical potential leading for example to sustained therapeutic expression of highly active factor IX in AAV-treated hemophilia B patients . HoweverThe clinical potential of lentiviral vectors has been particularly apparent in the generation of chimeric antigen receptors (CAR) T-cells, which have shown an impressive potential for treatment of hematological malignancies –121. CARAnother area where CAR-T cells has shown clinical efficacy is in the treatment of neuroblastoma using anti-GD2 CAR T-cells. However, compared to the response in B-cell malignancies, clinical translation of CAR T-cell therapy in solid tumors such as neuroblastoma has not been quite as successful reflecting various challenges related to solid tumors, including the lack of highly expressed tumor-specific antigens as well as immunosuppressive tumor microenvironments, leading to exhaustion and dysfunction of infused CAR-T cells –133. HowGiven that the design of state-of-the-art lentiviral vectors has not changed dramatically since the development of the third-generation lentiviral vectors, virtually all efforts including lentiviral vectors for production of CAR T-cells have been based on the third-generation packaging system with the SIN configuration. However, early version second-generation lentiviral vectors were indeed used in studies that went on to clinical trials . Given tGenome editing based on a rapidly growing family of CRISPR technologies has revolutionized molecular biology and is quickly being transformed into promising tools for site-directed gene modification and gene therapy . CRISPR Streptococcus pyogenes Cas9 (SpCas9) fused to a marker gene through a 2A self-cleaving peptide  is efficient, safe, and well-studied, and these vectors are being investigated for co-delivery of Cas9 and sgRNA expression cassettes –139 as wide Fig. . An earlide Fig. A. In a cGenomic insertion of SpCas9- and sgRNA-encoding lentiviral vectors is an essential feature of novel lentiviral CRISPR-based strategies for interrogating gene function. By combining the properties of lentiviral vectors to integrate with CRISPR-directed gene knockout, it is possible to create genome-wide lentiviral CRISPR libraries consisting of thousands of different lentiviral vectors each encoding a unique sgRNA targeting a single gene . LentiviFor specific purposes, it may be attractive to deliver the CRISPR components without integrating the SpCas9 and sgRNA genes in the genome Fig. B. Early The therapeutic focus of gene therapy has always been on delivery of genetic information to cells and tissues. However, with the discovery of genome editing technologies based on the administration of genome editing tool kits, the ultimate goal may not necessarily be long-term expression of transgenes but rather potent, but short-term activity of proteins at work in the genome. Not unexpectedly, attempts of translating CRISPR editing methodologies into therapies have so far, as noted above, found inspiration in the potent gene delivery technologies, which have been developed and optimized over the last 40 years. However, to reduce off-target cleavage events and avoid toxic effects, these techniques may require strict regulation of gene expression, allowing production of Cas9 and sgRNA to be shut-down after successful genetic intervention, and may not eventually be the best agents for therapeutic CRISPR administration.Whereas nucleofection of recombinant Cas9 protein complexed with chemically modified sgRNAs has become a preferred strategy for ex vivo genome editing of stem cells , there iSomewhere back in time, viruses evolved to transport their own genetic information and carry the proteins required to process the genetic information in host cells. We now know that viruses interact with cellular factors not only to fight cellular antiviral responses, but also to traverse the cytoplasm and gain access to the nucleus and potentially to attractive landing sites in the genome. Such early steps of viral evolution have shaped viruses and provided properties that may either support or hamper their use as vector technologies for safe clinical gene therapy. HIV-derived lentiviral vectors were endowed with a desirable integration profile facilitating the landing of transgene cassettes in regions of transcriptional activity without severely impacting endogenous gene expression. Emerging evidence from clinical trials bear witness of a safe and potent vector technology with obvious clinical benefit in both gene and cell therapies. At the same time, new ways of exploiting lentiviral delivery for genome-wide screening and genome editing are sprouting. Lentiviral vectors are in their prime—and remain state-of-the-art after 25 years.


Patient-reported outcome measures, including satisfaction with treatment decisions, provide important information in addition to clinical outcomes, survival and decision-making in lung cancer surgery. We investigated associations between preoperative clinical and socio-demographic factors and patient-reported satisfaction 6 weeks after radical treatment for early-stage non-small cell lung cancer (NSCLC).We conducted a sub-group analysis of the prospective observational longitudinal study of 225 participants in two treatment groups—surgical (VATS) and radiotherapy (SABR). The Patient Satisfaction Questionnaire-18 (PSQ-18) was used to measure patient satisfaction 6 weeks after treatment. Clinical variables, Index of Multiple Deprivation decile and Decision self-efficacy scores were used in regression analysis. Variables with a p level < 0.1 were used as independent predictors in generalised linear logistic regression analyses.As expected, the two groups differed in pre-treatment clinical features. The SABR group experienced more grade 1–2 complications than the VATS group. No differences were found between the groups in any subscale of the PSQ-18 questionnaire. Patients experiencing complications or living in more deprived areas were more satisfied with care. Properative factors independently associated with patient satisfaction were the efficacy in decision-making and age.We showed that efficacy in treatment decision-making and age was the sole predictor of patient satisfaction with their care after radical treatment for early-stage NSCLC. Patients from more deprived areas and patients who suffered complications reported greater subsequent satisfaction. Involving patients in their care may improve satisfaction after treatment for early-stage NSCLC. Lung cancer is associated with high morbidity and mortality. In addition, significant comorbidities often markedly reduce the patient’s baseline performance status. The high prevalence and significant symptomatic burden of lung cancer on patients is befitting to patient satisfaction as a surgical outcome measure.UK National Institute for Clinical Excellence (NICE) guidelines recommend that early-stage non-small cell lung cancer is treated using video-assisted thoracoscopic surgery (VATS) for fit patients, and stereotactic ablation radiotherapy (SABR) for patients for whom VATS is not appropriate NICE .Patient-reported outcome measures (PROMS) provide information additional to long-term survival, risk–benefit decision-making and surgical outcomes in lung cancer surgery. Patient satisfaction is one of many important PROMS and is vital to assess the quality of treatment  non-small-cell lung cancer (NSCLC). The study cohort comprised consecutive patients undergoing VATS anatomical lung resection or SABR for early-stage NSCLC at a single UK centre during a period of 12 months. All participants signed a written consent form and the study received ethical approval from The National Research Ethics Service Yorkshire and the Humber-Leeds East Committee (REC Ref: 16/YH/0407). This study has been registered in the Clinical Trial database .The study population were patients with early-stage lung cancer treated with either VATS or SABR at Leeds Teaching Hospitals Trust over a period of 12 months. Patient eligibility for the study was assessed using the criteria listed in Table Patients were invited to self-report patient-reported outcomes (PROs) using online secure access via QTool software at home or in clinic before the treatment and at follow-up intervals. Appropriate training for the use of the QTool was offered to both clinicians and patients  was chosen as it is a cross-cultural validated survey for use in different settings (Thayaparan and Mahdi The Decision Self-Efficacy (DSE) scale is an 11-item questionnaire assessing the efficacy of decision-making with a 5-point response scale to generate a score between 0 and 100, with 0 indicating very low decision self-efficacy and 100 indicating very high decision self-efficacy. This instrument was shown to be reliable and valid for use in this population , gender, decision self-efficacy scale score (DSE), Index of multiple deprivation decile (IMD), Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) and Carlson comorbidity index (CCI). Although the VATS and SABR groups were highly heterogeneous, limited numbers in each group meant it was not possible to run separate multivariable regression analyses for each group. One multivariable regression analysis of all 134 patients was carried out and adjusted for treatment type. Variables with a In total, 356 patients were eligible to participate in the study in a 12 months period, with 244 consenting to take part (60%). Of these, nineteen patients were excluded from the analysis: seven did not receive any treatments for oncological reasons, and twelve were deemed ineligible prior to treatment due to their suitability for open operation. Of the remaining 225 patients, 44 did not complete the trial: 23 died (13 in the SABR group and 10 in the VATS group); 9 became ineligible and 12 (eight patients in the SABR group and four in the VATS group) actively withdrew. Of the 12 patients who actively withdrew, five felt they had too many other time commitments to continue participation and the remaining seven did not provide a reason. Of the 225 participants, 91 failed to complete a patient satisfaction questionnaire at 6 weeks and thus were excluded from the analysis.The clinical details and baseline (pre-treatment) demographics of the 225 patients who underwent VATS or SABR are presented in Table Clinical outcomes analysis demonstrated that patients treated with SABR experienced a higher proportion of Grade 1–2 complications, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v3.0  and 74 VATS patients (62.7%). We did not find any significant differences between the two groups in any of the PSQ-18 questionnaire subscales. In all scales, patients reported a moderate level of satisfaction with the care provided Table .Table 3PThe comparison between known groups  in terms of general satisfaction showed that patients living in more deprived areas (higher IMD scores) were more satisfied. Patients experiencing minor and major complications were also more satisfied 6 weeks after treatment Table . The conThe univariate analysis of patient satisfaction was carried out on 134 patients (60 SABR + 74 VATS) who completed the PSQ-18. Results of the regression are shown in Table Patient satisfaction results showed no difference between the two treatments for early-stage NSCLC. However, patients who experienced minor or major complications reported higher scores of patient satisfaction. We also demonstrated in our cohort that patients living in the more deprived areas reported higher satisfaction with care, although this association was no longer present in the regression analysis. Further, patients who felt more able to be involved in their treatment decision-making and patients who were older were more satisfied with care.That patient satisfaction measure offers health services something different to clinical indicators, so is useful in helping services to identify ways to improve patient care. The fact that no association was detected between clinical indicators and patient satisfaction probably does not reflect the effect of the disease and treatment but rather provides information about the service.Our results are discordant to the work by Barlesi et al. who found that the absence of postoperative complications in similar thoracic surgery patients, was the only quality index that showed weak but significant positive correlation with an index rating the satisfaction with the structure  compared to the affluent group (46%).p = 0.1) and could suggest that the association between IMD and satisfaction is no longer significant in the multivariable model because the association with DSE is stronger.Our data suggest that patients reported lower patient satisfaction if they also have low DSE whether they are in the affluent or the deprived group. The difference in DSE may be more conflict from the researched, informed affluent group (borderline sig Decision self-efficacy is not a measure of quality of the decision-making process, but rather measures the involvement of the patient in key decisions relating to treatment. But it has highlighted for the first time, the importance of patient attitudes surrounding treatment choices. Understanding the role of post-treatment patient satisfaction and its association with decision-making factors may provide important information for clinical practice and future research.This cohort study was designed to explore factors associated with satisfaction and illustrate that patient satisfaction measures have an independent part to play in informing service quality apart from indicators of clinical and treatment effectiveness. However, it was not a randomised control trial of an intervention designed to improve care, so although we can say decision self-efficacy and patient satisfaction are associated, we cannot say why. Prior evidence would suggest that interventions designed to enhance patient involvement in care are likely to increase decision self-efficacy and patient satisfaction with care, for example those involving patient decision aid interventions (Stacey et al. Patient satisfaction measures are important in service improvement as independent of the patient perception of the health problem and burden of symptoms and impact of treatment. It seems likely that supporting patient involvement in treatment decision-making is associated with satisfaction, independent of the treatment type. Socio-demographic factors did not affect reported satisfaction but may have influenced the efficacy in making the decision about treatment for early-stage NSCLC. The understanding of the clinical decision-process from patients deserves more investigation to improve patient-reported satisfaction with care for early-stage NSCLC.


The aim of this proof-of-concept study was to understand the effect of daily intake of a 14-strain probiotic on mood, reward learning and emotional and cognitive processing in adults with low mood in the absence of prescribed medication. Salivary cortisol was measured as a marker for physiological stress.In this parallel-group double-blind, placebo-controlled trial, 80 healthy adults with self-identified low mood were randomised to receive either the 14-strain probiotic or placebo for a duration of 4 weeks. Data were collected from participants at baseline (week 0) and post-intervention (week 4).Probiotic intake significantly reduced depression scores (by 50%) compared to baseline, as measured by the Patient Health Questionnaire-9 (PHQ-9) scale (p < 0.05). Analysis of individual items in the PHQ-9 revealed that participants taking probiotics reported improved concentration relative to baseline  and felt less tired compared to placebo .Regarding emotional processing, the probiotic group was more accurate at recognising facial expressions compared to those receiving placebo . Furthermore, the probiotic group performed less well at the reward learning task relative to the placebo group  and was less vigilant to emotional cues compared neutral cues . The probiotic group also showed increased susceptibility to emotional interference during a cognitive learning task, relative to placebo .The study also revealed a downward trend in salivary cortisol in the probiotic group over 4 weeks.Together, these results suggest that probiotics may work via a different psychological mechanism to that of conventional antidepressants. In other words, probiotics may work by reducing emotional salience across all emotions whereas conventional antidepressants are thought to work by increasing bias to positive emotional cues and decreasing bias to negative ones.These data suggest that intake of Bio-Kult® Advanced has an effect on mood and that this is achieved in ways distinct from the effects of pharmacological antidepressants. While more research is needed, these results suggest that certain probiotics could form part of an ‘early intervention’ strategy for people experiencing low mood. A second randomised controlled trial (currently recruiting) will provide data on this intervention in patients with a formal diagnosis of depression undergoing concurrent pharmacological treatment.ClinicalTrials.gov Identifier: NCT03801655


Percutaneous coronary intervention (PCI) in the acute coronary syndrome (ACS) setting is associated with a greater probability of device failure. The currently ongoing development of new scaffold technologies has concentrated an effort on improving the PCI outcomes, including the use of new biodegradable materials. This pilot study evaluates the performance of a magnesium bioresorbable scaffold  in comparison to the sirolimus‐eluting bioresorbable polymer stents (BP-SES)  in the NSTE-ACS setting.  The population of this pilot comprised 362 patients assigned to one of two arms (193-Magmaris vs 169-Ultimaster). The data regarding the primary outcome comprised of death from cardiac causes, myocardial infarction, and stent thrombosis, along with target-lesion failure (TLF) and other clinical events was collected in the 1-yearfollow-up.  There were no statistically significant differences in clinical outcomes in the short term (30 days) or in the 1-yearfollow-up between both groups.  At 12 months, there were no statistically significant differences between the Magmaris and Ultimaster for composed endpoints or the TLF. The clinical outcomes of patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) have remarkably improved following the introduction of second-generationdrug-eluting stents (DES). Nevertheless, PCI in an acute coronary syndrome (ACS) setting remains associated with an increased rate of device failure . These pOne of the concepts assumed replacing of permanent polymer with a biodegradable substitute, which allowed for gradual drug release and leave bare metal scaffold in place facilitating local reendothelialization, reducing thus the inflammatory reaction and in consequence lowering the rate of late stent-related complications .The other strategy is related to the complete resorption of scaffolds (BRS) and allows for anatomical and functional restoration of the vessel without maintaining any material in the treated vessel in the long-term outcome.The first generation of BRS (Absorb) was built from biodegradable poly-L-lactide (PLLA) and had initial encouraging outcomes . HoweverDespite the initial setback of the BRS technology, a new generation of bioresorbable scaffolds has recently appeared. The Magmaris is a novel scaffold with a backbone made of absorbable magnesium alloy—fully coated with biodegradable PLLA polymer BIOlute. The initial data suggested a reasonable safety profile of this device. Nevertheless, the data regarding the head-to-head comparison between Magmaris and the novel generations of DES is still sparse .Hence, this pilot study was designed to investigate the performance of a magnesium bioresorbable scaffold (Magmaris) in comparison to the sirolimus‐eluting bioresorbable polymer stents (BP-SES) Ultimaster in subjects with the non-ST elevation acute coronary syndrome (NSTE-ACS).The study was based on a retrospective two-center analysis of two NSTE-ACS-Registries conducted at the Clinical Departments of Cardiology. The study population comprised 362 patients who were assigned to one out of two study arms. The first one consisted of 193 patients treated with Magmaris implantation. The second arm was composed of 169 subjects treated with Ultimaster implantation. All participants were diagnosed with acute coronary syndrome according to current guidelines  cases) and had a clinical indication for PCI. All the inclusion and exclusion criteria are pooled in Out of all NSTE-ACS-Ultimaster cases (541) performed between January 2015 and December 2018 at our Cardiac departments, we carefully selected 169 patients meeting the inclusion and exclusion criteria. The BRS group was formed by the 193 NSTE-ACS subjects.All the PCI procedures were initiated with a predilation (using a noncompliant (NC) balloon, sized with a 1 : 1 balloon to artery ratio) and followed by mandatory postdilatation with an NC balloon (at least 16 atm) sized 1 : 1 balloon/scaffold ratio or higher. A decision regarding the use of IVUS/OCT support during the PCI was left to the discretion of the operators. An example of the BRS implantation procedure with subsequent follow-up with additional evaluation in intravascular imaging is presented in The Magmaris, initially known as a DREAMS 2G, is a metallic magnesium sirolimus-eluting scaffold covered with a biodegradable polymer (BIOlute) Poly-L-Lactide (PLLA) and is available in two diameter sizes (3.0 mm and 3.5 mm). The approximate scaffold bioresorption time is 12 months.The second device used in this study was Ultimaster–an ultrathin cobalt-chromiumsirolimus-eluting stent, coated with a biodegradable poly- copolymer (PDLLA-PCL) with an average degradation time of 3-4 months.death from cardiac causesmyocardial infarctionin-stent thrombosisThe primary outcomes includedtarget-lesion failure (TLF) including deathtarget vessel-related myocardial infarction (TV-MI)target lesion revascularization (TLR)The secondary outcomes were device-orientated and defined as follows:Other clinical variables were collected, including scaffold restenosis, death from any reason, cerebrovascular episodes, need for any revascularization procedure, or myocardial infarction.All the clinical data were obtained by trained staff (physicians or/and nurses) during personal visits or telephone contact during the 30-day and 1-yearfollow-up period. The definition of myocardial infarction was based on the Fourth Universal Definition of Myocardial Infarction .T-Test as an appropriate test for continuous variables and Fisher's Exact Test for categorical variables. The Bonferroni correction was applied to adjust for the multiple comparisons. The power calculation was performed using the power.fisher.test from a statmod R package. p value <0.05 was considered statistically significant.The R language was used for analyses. Continuous variables were characterized by their mean and standard deviation, or median and interquartile range, dependent on their distribution, whereas the frequencies were used for categorical variables. The study subjects were compared between groups using a two-sample Mann–Whitney's or p < 0.001) Among all comorbidities atrial fibrillation was less frequently observed in the Magmaris group . Similarly, lower total cholesterol  and LDL cholesterol levels were observed in the Magmaris group . Additionally, subjects from the Magmaris arm were characterized by higher left ventricular ejection fraction at discharge time . The average duration of hospitalization was shorter in the Magmaris group All the data regarding patients' clinical characteristics are presented in p < 0.001). Noteworthy, there were no differences in the size of the balloon catheter used for predilatation in both arms. Similar differences were observed regarding the postdilatation parameters size , as well as regarding the mean pressure used during postdilatation . On the other hand, significantly lower radiation was used during the Magmaris implantation . All data regarding procedural characteristics were collected in Subjects from the Magmaris arm maintained slightly more aggressive lesion preparation  there were no differences in clinical outcomes in the 30 days follow-up between both study arms. At 1-yearfollow-up, no significant differences among primary and secondary endpoints between both study groups were noticed. However, in the Magmaris cohort, a slightly lower rate of the primary endpoint  which however did not reach statistical significance in this pilot study. A similar trend was observed for the principal secondary outcomes . Moreover, in the Magmaris arm, we reported a lower rate of other coronary revascularization  again without statistical significance. The power calculations revealed that for comparing 3 outcomes out of 193 vs. 9 outcomes of 169, the power of the Fisher test at 0.05 significance level was 0.467.All the data regarding clinical outcomes are summarized in This is the first report comparing the 1-year clinical outcome of two sirolimus‐eluting magnesium bioresorbable scaffolds (Magmaris), and ultrathin cobalt-chromium stent coated with a bioresorbable polymer (Ultimaster) in NSTE-ACS conditions.Since publishing the data from the first-in-man trial  and receIn our relatively small, retrospective, nonrandomized study cohort Magmaris and Ultimaster showed no differences in clinical outcomes for the Primary Endpoint  as well as regarding the TLF in the 30-day and 1-year-follow-up periodMagmaris did not present any definite scaffold-related thrombosis after a 12-month observation periodThe main findings of this study are as follows:vs 7.9%), we might assume that the Magmaris might demonstrate the outcomes compared to the ones observed in the new-generation DES devices.In recently conducted studies Ultimaster has demonstrated good overall device performance, in the ACS cohort . These fvs 6.4% in Orsiro group). On the other hand, a small study by Toušek et al. [A similar suggestion was made by Hideo–Kajita et al. , whereink et al.  suggestsk et al. , particuvs 5.3%), despite the use of a dedicated implantation technique [These results were partially confirmed in MAGSTEMI randomized control trial  which evechnique . Howeverechnique , 26, 27.echnique .The selection process for our study was based on the inclusion and exclusion criteria of the Magmaris registry. We qualified patients with rather “unchallenging” anatomy of the lesions without complex calcified cases, requiring implantation of multiple scaffolds (including two stent techniques for bifurcation lesions). This could constitute some limitations of our study, however, what needs to be emphasized, the aim of this pilot study was focused on the clinical evaluation of Magmaris—a novel BRS that has not been widely used in clinical practice (implanted mainly in selected cardiac centers familiar with the magnesium BRS technology). Therefore, we believe that the results of our study despite some limitations may provide valuable information regarding the safety and efficacy of the magnesium BRS in the real-life NSTE-ACS setting.This study has several limitations. First, the data were collected retrospectively in the relatively short-term observation period (1-year follow-up). Second, this is a comparison between the 2 non-randomized observational registries. Third, performed power calculation revealed that in terms of the 30-day and 1-yearfollow-up, the study is underpowered, which might be however justified by its pilot character. Fourth, the study groups were not fully homogenous several differences among clinical features were observed. Finally, even though we can presume that the low rate of image-guided PCI performed in this study could have affected the outcomes, the study population consisted of NSTE-ACS patients, where the use of the OCT/IVUS procedures in an emergency setting is less frequent, which makes this study more relevant to the real-life clinical scenario.In both study arms (BRS and Ultimaster), no definite scaffold-related thrombosis occurred after 12 months of follow-up. We have observed similar outcomes in terms of the two major composed endpoints—primary outcome  and TLF. Nevertheless, the pilot character of this study and relatively low sample size point to the need for a subsequent large multicenter prospective trial in order to address precisely the efficacy and safety concerns of BRS, as well as to draw final conclusions and formulate precise recommendations in this matter.


Hemodialysis is a life-sustaining therapy for millions of people worldwide. However, despite considerable technical and scientific improvements, results are still not fully satisfactory in terms of morbidity and mortality. The membrane contained in the hemodialyzer is undoubtedly the main determinant of the success and quality of hemodialysis therapy. Membrane properties influence solute removal and the interactions with blood components that define the membrane’s biocompatibility. Bioincompatibility is considered a potential contributor to several uremic complications. Thus, the development of more biocompatible polymers used as hemodialyzer membrane is of utmost importance for improving results and clinical patient outcomes. Many different surface-modified membranes for hemodialysis have been manufactured over recent years by varying approaches in the attempt to minimize blood incompatibility. Their main characteristics and clinical results in hemodialysis patients were reviewed in the present article. End-stage renal disease (ESRD) requiring chronic renal replacement treatment represents a growing health problem all over the world. Natural replacement of renal function by kidney transplant is the best treatment option but is limited by the shortage of donor organs. Thus, most ESRD patients are treated via dialysis, i.e., hemodialysis (HD) or peritoneal dialysis, targeting patient survival and quality of life. Dialysis is a life-sustaining therapy for approximately 3.4 million people worldwide , a numbeHD is a renal replacement technique that uses a semipermeable polymeric membrane in an extracorporeal system to filter blood. Artificial membrane packed in the hemodialyzer represents the centerpiece of the entire HD therapy. It allows removal by diffusion and convection of retained low molecular weight (MW) toxic substances and excess water—which accumulate in blood because of kidney failure—providing life support for patients to live with variable degrees of rehabilitation. Removal of high MW substances may also occur by adsorption on the surface of certain membranes. In addition, blood–membrane interactions occurring during the HD procedure, which can lead to activation of various biochemical pathways and cells and which characterize the membrane’s bio(in)compatibility, have had increasingly focused clinical interest ,4,5. BioThe material of the dialysis membrane is the primary determinant of intradialytic biological reactions. Several new membrane materials aiming to improve the interactions with blood components have been developed over the years. This article reviewed the most recent technological advancements to improve the biocompatibility profile of HD membranes, focusing on results obtained by clinical use in vivo. Studies on materials under experimental development were not covered here and were reported in a recent extensive review . The aimThe exposure of blood to a foreign surface in a medical device such as the membrane packed in the hemodialyzer results in almost instantaneous adsorption of plasma proteins . This inProtein adsorption is dependent on various physiochemical characteristics of the blood-contacting surface including the intrinsic properties of the material as well as the concentration, relative affinity, and diffusion coefficient of plasma proteins . It has The phenomenon of plasma protein adsorption markedly influences the performance characteristics of the HD membrane . BesidesThus, it appears that any biomaterial for HD treatment should be carefully examined for its adsorptive properties, possibly by evaluating the amount, composition, and conformational change of the surface-adsorbed protein layer. One suitable approach for examining protein adsorption during HD is the application of proteomic techniques. Several studies have shown that proteomics allow one to investigate in an unbiased manner the full adsorption potential of dialysis membranes ,19,20,21All blood-contacting medical devices can trigger either coagulation, resulting in clot formation, or immune reactions . HD membA brief description of these processes is provided in the next sections. The problem of biomaterial-associated thrombogenicity has been fully discussed in a series of four recent reviews ,23,24,25Adsorption of contact system components onto HD membrane material facilitates activation of the intrinsic coagulation pathway . AutoactGiven the tendency of blood–membrane interactions to activate a coagulation cascade, one resorts to anticoagulation in order to avoid the risk of premature clotting or premature termination of the HD session. Systemic anticoagulation with unfractionated heparin or low MW heparin is routinely employed and effective . HoweverPlatelet activation also causes thrombogenicity of HD membranes following blood–membrane interaction. Platelet activation occurs through adhesion to proteins (mainly fibrinogen) adsorbed onto the membrane and indirectly via biomaterial-induced activation of the coagulation system and others . PlateleSurface modifications designed to suppress platelet activation and subsequent biological responses are a current trend in membrane development. Activation of the complement system in HD has long been known . MechaniActivation by biomaterial of the complement cascade leads to C3 cleavage, forming C3a and C3b. Increased levels of this last generate C5-convertase which cleaves C5 into C5a (a powerful anaphylatoxin like C3a) and C5b. Finally, the binding of C5b to the surface and interaction by it with C6-C9 results in formation of the membrane attack complex (MAC/C5b-9) . Note thActivation of the complement system leads to the generation of effector molecules triggering several biological responses . Short-tLong-term complications of HD such as cardiovascular events and infection have been linked to complement activation. Particularly, by causing inflammation and coagulation, complement may contribute to HD patients’ susceptibility to cardiovascular disease . Thus, iDuring HD, myeloid leukocytes such as neutrophils and monocytes may adhere or be activated on a biomaterial surface. The main triggers for leukocyte activation are adsorbed proteins  and adherent platelets . AdsorbeBesides the actual blood composition, adsorption of plasma proteins onto dialysis membranes is related to the physicochemical properties of the polymer that constitutes the membrane ,40. The The evidence available indicates that each single dialysis membrane material has multiple and different characteristics that may contribute to interactions with blood components, including the adsorption of proteins . To imprIn the following sections, we report the effects of recently developed surface-modified membranes on biocompatibility during clinical HD.Physicochemical methods affect protein–cell–material interactions by modulation of surface charge, topography, and hydrophobic or hydrophilic interactions . SeveralCellulose triacetate (CTA) is a polymer characterized by replacement of the hydroxyl group of cellulose with an acetate group. CTA membrane has high diffusion efficiency and better antithrombotic properties than other synthetic membranes, which is related to its lower protein adsorption capacity . To imprThis last characteristic of ATA membrane  is expected to affect the protein adsorption process during HD. Preliminary studies in vitro have demonstrated lower protein adsorption onto ATA membrane than onto CTA membrane  or a polThe ATA membrane’s low tendency to activate the coagulation cascade was confirmed in subsequent clinical investigations. Vanommeslaeghe et al.  comparedThat the ATA membrane outperformed a high-flux polysulfone membrane in avoiding clotting (as expressed by the relative number of open fibers at the end of a post-dilution hemodiafiltration session) was confirmed in a randomized cross-over study where patients received either a regular or half dose of anticoagulation . Two furOverall, the evidence available indicates that the ATA membrane has excellent biocompatibility in terms of its low tendency to activate the coagulation cascade. Use of ATA appears to be a promising, safe, and efficacious strategy in patient conditions which need reduced or even zero systemic anticoagulation ,49.Polymethylmethacrylate (PMMA)-based HD membranes have been developed by controlling the stereocomplex structures that are formed from a mixture of syndiotactic PMMA and isotactic PMMA polymers. PMMA membrane has a homogeneous pore structure that provides a high specific surface area and a high protein adsorption property allowing removal of high MW proteins that are not efficiently removed by HD or hemodiafiltration . HoweverOne major factor in the structural changes to adsorbed protein consists in the structure of the water adsorbed onto the membrane surface (adsorbed water). Since changes in the structure of adsorbed water may disturb the hydration structure of proteins adsorbed (which preserves their structure and activity), it is important to counteract any factors that trouble the adsorbed water . Comparen = 18) or a polysulfone membrane (n = 19) for one year [Two clinical investigations have been performed with the PMMA NF membrane . Masakane et al. compared in vitro and in vivo the new PMMA NF membrane to conventional (BG series) PMMA . Studiesone year . While tone year . By contone year .Polysufone is one of the most widely used materials for HD membranes due to its properties including excellent performance in solute removal, thermodynamic stability, chemical inertness, and mechanical strength. However, use of polysulfone is restricted by poor hydrophilicity and blood compatibility .TM NV) onto the inner surface of the polysulfone material [To improve the biocompatibility of polysulfone material, a new polysulfone-modified membrane was developed though application of a new hydrophilic polymer  was specifically designed aiming at antifouling and antithrombogenic effects during HD . Yamaka Other studies examined the effect of the NV membrane-containing dialyzer on some complications frequently encountered in patients on maintenance HD.Hypotension during the HD session is a common side effect . It is caused by a failure to compensate reduced circulating blood volume and is associated with increased mortality. It is also defined by a fall in systolic blood pressure (SBP) > 20 mmHg from baseline or by the appearance of symptoms along with hypotension calling for medical intervention . TsuchidAnemia is a common complication in HD patients and is associated with many adverse clinical consequences . Adminisn = 122) or conventional polysulfone (n = 129). While both ESA dose and ERI were unchanged with the NV dialyzer, ERI increased with conventional polysulfone. In addition, a significant decrease in ESA dose and ERI was found in highly ESA-resistant patients of the NV group [Management of inflammation anemia in patients suffering from renal failure remains quite challenging . Kakuta NV group . The difNV group . The autNV group . While tNV group ,73 hampeTM  family are fluoro-oligomeric additives that are able to migrate to the surface, thus providing passive surface modification which suppresses adsorption-induced conformational changes to procoagulant proteins and reduces platelet adhesion and activation [A more recent approach to reducing blood-contacting surface interactions and hence the need for anticoagulation during dialysis uses a novel polysulfone membrane obtained by mixing basic polymeric material with surface-modifying molecules ,75. Surftivation . Currenttivation ,77. A netivation . Surfacetivation .n = 664 treatments over 13 weeks). There was good tolerance to the device and no related serious adverse events. No overt evidence of complement activation  was found during dialysis with either dialyzer. Performance of the SMMA-modified dialyzer proved generally similar to that of unmodified standard polysulfone, though the removal rate of beta2-microglobulin achieved with the modified dialyzer was higher  [The first clinical experience of the novel dialyzer containing an SMM1 fluorinated polyurethane was a prospective, sequential, and open-labeled study , carriedrection) . Interesrection) .Surface biofunctionalization seeks to endow the surface with the capacity to interact actively with cell surface receptors or enzymatic activation . SurfaceHeparin-coated membranes were realized for patients at high risk of bleeding. One example is heparin coating of AN69 ST membrane, a polyacrylonitrile sodium methallylsulfonate copolymer coated with high-MW polyethyleneimine before heparin grafting to reduce electronegativity of the original AN69 polymer, resulting in the capacity to bind heparin to its surface [Observational and uncontrolled studies showed promising results with heparin-coated membranes, albeit less confirmed by controlled studies. In experimental in vitro and in vivo models, AN69 ST membrane coated with heparin demonstrated a sustained anticoagulation property . Use of A precoated heparin-grafted membrane differing from the previous design was then manufactured ,81,82 sin = 4 with each dialyzer: two with reduced heparin dose and two without anticoagulation) without a clotting event causing premature interruption of the session, was 78% with vitamin E-coated membrane and 81% with heparin-coated membrane. Both dialyzers exposed patients to a failure rate judged unacceptable by the authors [The HepZero study was a controlled randomized study monitoring up to three heparin-free dialysis sessions in 251 maintenance HD patients at increased risk of hemorrhage, randomly allocated to a heparin-coated membrane  or to “standard-of-care” heparin-free dialysis, defined as regular saline flushes or predilution hemodiafiltration . The stu authors .More recently, a randomized cross-over study was carried out in six dialysis patients with thrombocytopenia, each dialyzed at the midweek session without anticoagulation using either a heparin-coated  or a polysulfone membrane . DialyzeOverall, the rate of clotting in anticoagulant-free HD using heparin-coated dialyzer is considered to be too high . Use of n = 25) were treated with a combination of heparin-grafted membrane  plus citrate-containing dialysate or regional citrate anticoagulation (RCA). Citrate-containing dialysate, besides the advantage of being an acetate-free dialysate, can reduce (though without abolishing) the need for heparinization during HD [A combined anticoagulation strategy might help to decrease the rate of clotting observed with heparin-coated membrane. This is suggested by the results of the CiTED  study . In the uring HD . In turnuring HD . By conturing HD .Finally, heparin-coated membrane might unexpectedly reduce the concentration of pro-inflammatory cytokines . NineteeESRD patients on HD have increased levels of oxidative stress resulting from the reduced antioxidant defense given their uremic status and intradialytic generation of ROS . OxidatiOxidative stress in HD patients has been associated with CV disease progression . MoreoveVitamin E supplementation may provide antioxidant and anti-inflammatory effects in patients on HD. Vitamin E is a lipid-soluble antioxidant composed of eight compounds with high anti-inflammatory properties . Two recVitamin E-modified membranes were designed to reduce oxidative stress in HD patients and improve biocompatibility . The firBioactive vitamin E  present on the blood surface of the modified membrane acts as an ROS scavenger and seems to control oxidative stress and lipid peroxidation . Many stThe effects of ViE-m on oxidative stress were characterized by a significant improvement in sensitive clinical biomarkers of oxidative stress: plasma and erythrocyte malondialdehyde (MDA), thiobarbituric acid reactive substances, and plasma and blood erythrocyte vitamin E levels. These findings may hold clinical relevance since in HD patients, elevated MDA and other biomarkers of oxidative stress can contribute to morbidity and mortality , while lAs for inflammatory biomarkers, the meta-analysis indicated that use of ViE-m induced a significant decrease in circulating levels of IL-6 but not C-reactive protein .A more recent study investigated the effect of ViE-modified membrane on hemodialysis inflammaging . Inflammp = 0.001). These results indicated that ViE dialyzer can improve ESA response, possibly though a decrease in the IL-6 level [Another major point of interest in the meta-analysis by D’Arrigo et al. pertains to the anemic status . Use of -6 level . However-6 level ,114.A more recent clinical study  was carrIn the aggregate, the available evidence indicates that coating with vitamin E improves the biocompatibility profile of membranes for HD, though the true potential of the modified membrane in the overall clinical management of HD patients remains to be elucidated.A further improvement in the biocompatibility of vitamin E-modified membrane may be represented by enriching the material with alpha-lipoic acid (ALA) . ALA is Hemodialysis is a life support therapy for a growing number of patients suffering from kidney failure. Survival and quality of life have improved compared with the past, but despite the considerable technical and scientific advances, results are still not satisfactory and high mortality and morbidity still characterize HD therapy . The maiThe biocompatibility of the membrane material is undoubtedly a key factor for the therapeutic effect of HD, and modifications to dialysis membrane biomaterials should aim at ameliorating blood compatibility as a top priority . Recogni


Although the feasibility of ultrasound stimulation has been reported in preclinical and clinical settings, its mechanistic understanding remains limited. While optical microscopy has become the “gold standard” tool for investigating population-level neural functions in vivo.We aimed to develop a transparent acoustic transducer based on a glass coverslip called the acousto-optic window (AOW), which simultaneously provides ultrasound neuromodulation and microscopic monitoring of neural responses The AOW was fabricated by the serial deposition of transparent acoustic stacks on a circular glass coverslip, comprising a piezoelectric material, polyvinylidene fluoride-trifluoroethylene, and indium-tin-oxide electrodes. The fabricated AOW was implanted into a transgenic neural-activity reporter mouse after open craniotomy. Two-photon microscopy was used to observe neuronal activity in response to ultrasonic stimulation through the AOW.The AOW allowed microscopic imaging of calcium activity in cortical neurons in response to ultrasound stimulation. The optical transparency was in vivo.The AOW is an implantable ultrasonic transducer that is broadly compatible with optical imaging modalities. The AOW will facilitate our understanding of ultrasound neuromodulation  However, most conventional ultrasound transducers are barely compatible with microscopy systems. First, the form factors of conventional ultrasound transducers are typically large compared to the several millimeter-scale working distances of a typical high numerical aperture objective lens.,,Two-photon microscopic imaging on a cranial window model is a well-established approach to observe spatiotemporal activities of specific neuronal and glial subtypes longitudinally in vivo using two-photon microscopy.Here, we propose a solution to this technical challenge by introducing an optically transparent acoustic transducer, termed the acousto-optic window (AOW). The AOW simultaneously allows ultrasound stimulation over a defined brain area and two-photon fluorescence imaging of neuronal activity through the transducer. We describe the fabrication of an AOW based on a transparent piezoelectric material and its surgical implantation on a mouse brain under anesthesia and demonstrate the feasibility of recording ultrasound-evoked functional activity in a genetically specified neuronal subtype 22.1Surface of glass coverslip was cleansed using a series of solutions of acetone , degenerative alcohol , 1% water dissolved detergent , and deionized water. After masking the glass coverslip with a Kapton masking tape  excluding the central region  with an electrical transmit pulse of 1 ns of The acoustic beam profile of the AOW was measured using a needle hydrophone  in a tank filled with deionized water. The needle hydrophone was installed in a custom-made motorized three-axes stage. The beam profile of the AOW was scanned with a resolution of spatial translation along the axial and lateral directions of 100 and 2.3All mice were housed with littermates in groups of two to five in a reverse day/night cycle and provided ad libitum access to food and water. Male or female C57BL6J wild-type mice aged 8 to 16 weeks (Orient Bio) were used to image the cortical vasculature. Male or female Gad2-GCaMP6-tdTomato mice aged 8 to 16 weeks were obtained by crossing Gad2-IRES-Cre  and CAG-floxed-GCaMP6f-tdTomato . All animal experiments were performed in compliance with institutional guidelines and were approved by the Subcommittee on Research Animal Care of Seoul National University.2.4The AOW was implanted over the somatosensory cortex following the procedures previously described for the cranial window model.l cement . After t2.5The imaging procedure was initiated 2 h after AOW implantation under isoflurane anesthesia. For the vascular imaging, a wild-type mouse received retro-orbital injection of tetramethylrhodamine isothiocyanate-dextran  and high-power LED . Two-photon microscopy images were processed using ImageJ FIJI (NIH) and MATLAB (MathWorks). Image processing included adjustment of brightness and contrast, averaged projection of 2.7Statistical and regression analyses were performed using the Prism software (GraphPad). Data are expressed as mean ± Standard Error of the Mean (SEM), unless otherwise indicated. A one-way ANOVA (Dunnett’s multiple comparison test) is shown in 33.1–in vivo. Considering the small form factor of the glass coverslip, we designed the transducer with an area of To fabricate an AOW capable of being implanted on mouse cranium, we formed transparent acoustic stacks on a circular glass coverslip with a diameter of As shown in  1000 nm . In two-3.2To characterize the acoustic performance of AOW, we first simulated the pulse-echo impulse response [center frequency of 24 MHz with As shown in the impedance curve in Because the use of higher frequencies -dextran [For -dextran . Owing t-dextran , the inp3.4Finally, we tested whether the AOW allows the microscopic observation of ultrasound-mediated neuromodulation. We used a Gad2-GCaMP6-tdTomato mouse line to measure functional calcium activity in a subset of inhibitory interneurons. Two-photon imaging through AOW provided near-artifact-free microscopic imaging of subcellular neuronal structures in Gad2-GCaMP6-tdTomato mice .The relatively bright tdTomato signal helped us to confirm the minimal influence of movement artifacts from ultrasonic waves or physiologic motions. Upon ultrasound stimulation at an operation frequency of 10 MHz, a subset of fluorescent interneurons showed a reliable increase in calcium signal with the 10-s stimulation . To furt4in vivo. However, the simultaneous monitoring of neuronal responses with ultrasound stimulation is hindered by the conventional transducers and the glass coverslip used in a cranial window model, which increases the attenuation of ultrasonic waves. To apply ultrasound stimulation at the same position as the optical field of view, the stimulant transducer needs to be positioned to introduce an acoustic beam between the optical lens and cortical surface. We presently observed that the incidence of lower frequency along the normal direction reduced the postglass intensity by only 27% and that the ultrasound beam intensity introduced at an angle of 45 deg was reduced by 97% in the postglass region . Therefore, a transparent transducer loaded directly on a glass coverslip is necessary for studies that simultaneously combine confocal microscopy monitoring with ultrasound brain stimulation.There is an increasing need for two-photon microscopic imaging in ultrasound neuromodulation investigations of neuronal functions Presently, we describe the AOW, an optically transparent acoustic transducer that can be implanted into the mouse brain under anesthesia for monitoring ultrasound-mediated neuromodulation with microscopic precision. An optical transmittance of Supplemental Material. The opacity of the piezoelectric could be increased with an increase thickness because of the inherent low transparency of the PVDF-TrFE ,For more generalized applications, several technical improvements in AOW remain to be addressed. The current version of AOW provides a limited tuning range for ultrasound parameters, such as the frequency and input voltage range. The operational frequency can be further lowered by changing the thickness of the glass coverslip and PVDF-TrFE.,,Unlike the instantaneous excitatory responses to the short ultrasound stimulations nse peak . The del,Finally, the compatibility of the AOW with optical imaging allows the monitoring of neuronal activity in response to ultrasound stimulation. The fusion of advanced imaging technologies with the AOW would help understand the extensive effect of ultrasound on neuromodulation, as the performance was demonstrated using two-photon microscopy. Although two-photon microscopy allowed the monitoring of neuronal activities from a single in-plane imaging slice, the activities from out-of-focus planes could not be acquired. Robust volumetric imaging techniques, such as the Bessel-beamClick here for additional data file.


Despite the growing availability of multifunctional prosthetic hands, users’ control and overall functional abilities with these hands remain limited. The combination of pattern recognition control and targeted muscle reinnervation (TMR) surgery, an innovative technique where amputated nerves are transferred to reinnervate new muscle targets in the residual limb, has been used to improve prosthesis control of individuals with more proximal upper limb amputations .The goal of this study was to determine if prosthesis hand grasp control improves following transradial TMR surgery.Eight participants were trained to use a multi-articulating hand prosthesis under myoelectric pattern recognition control. All participated in home usage trials pre- and post-TMR surgery. Upper limb outcome measures were collected following each home trial.Three outcome measures  improved 9–12 months post-TMR surgery compared with pre-surgery measures. The Assessment of Capacity for Myoelectric Control and Activities Measure for Upper Limb Amputees outcome measures had no difference pre- and post-surgery. An offline electromyography analysis showed a decrease in grip classification error post-TMR surgery compared to pre-TMR surgery. Additionally, a majority of subjects noted qualitative improvements in their residual limb and phantom limb sensations post-TMR.The potential for TMR surgery to result in more repeatable muscle contractions, possibly due to the reduction in pain levels and/or changes to phantom limb sensations, may increase functional use of many of the clinically available dexterous prosthetic hands. Transradial amputations account for over 40% of major upper limb amputations  and greaThe newest generation of prosthetic hand components addresses one of these factors. More anthropometric, multi-articulating hands with variable design tradeoffs , 4, 5, pTargeted Muscle Reinnervation (TMR) surgery is an additional significant advancement in the control of multifunction prostheses –20. WithFor individuals with a transradial amputation, TMR surgery has the potential to restore data from intrinsic hand muscles. The inclusion of neural information from intrinsic hand muscles has been shown to improve hand grasp and finger movement classification . For indAll intrinsic hand muscles are innervated by the median and ulnar nerves, thus only two nerve transfers are needed to provide more complete neural information for pattern recognition control. Potential target muscle sites in the residual forearm include flexor digitorum superficialis (FDS), flexor digitorum profundus (FDP), or brachioradialis for the median nerve and flexor carpi ulnaris (FCU) or flexor pollicis longus (FPL) for the ulnar nerve –30. ThesThe goal of this study was to evaluate hand grasp control for individuals with a transradial amputation following TMR surgery. Study objectives were to 1) determine if TMR improved functional outcome measures for individuals with transradial amputations, 2) assess improvement in EMG signals during offline analysis, and 3) evaluate user’s subjective representation of their phantom limbs after TMR.Individuals were recruited from across the US from January 2015 through October 2018. All fittings, surgery, and testing were conducted from September 2015 through September 2020 at the Shirley Ryan AbilityLab in Chicago, IL and Walter Reed National Military Medical Center in Bethesda, MD. The method of recruitment was via physician or prosthetist referral  and study advertisements on the Shirley Ryan AbilityLab website and social media accounts. Inclusion criteria were: age 18–95, unilateral amputation below the elbow, and demonstrated the ability to use a myoelectric prosthesis. Exclusion criteria were: inability to use a prosthesis, cognitive impairments that would interfere with their understanding of study requirements, or any significant co-morbidity that would preclude completion of the study. The study  and online recruitment materials were approved by the Institutional Review Boards of Northwestern University (STU00101444) and Walter Reed National Military Medical Center (IRBNet#410731). All subjects provided written informed consent. The authors confirm that all ongoing and related trials for this intervention are registered.Subjects were fitted by a certified and licensed prosthetist with a custom-made myoelectric prosthesis consisting of a multi-articulating hand, the i-limb Ultra Revolution (OSSUR ), a passThe clinically available pattern recognition system , 33, cusIndividuals participated in therapy with a certified and licensed occupational therapist to learn how to control the multi-articulating hand with pattern recognition. Clinical judgment and user feedback were used to determine the maximum number of grips the user could access. This determination included a discussion of the user’s activities of daily living, demonstration of the 8 available i-limb grips , and prIndividuals received a minimum of four training sessions of 2–3 hours in length prior to taking the prosthesis home for at least 8-weeks (Pre-TMR). While at home, users had the ability to use the auto-calibration procedure whenever they desired. During auto-calibration users are prompted to follow along and perform muscle contractions in sync with pre-programmed motions of the prosthesis while EMG data is recorded and auto-labeled for each trained grip. Participants were required to check-in regularly with the occupational therapist, maintain an average usage of at least 2 hours per day with the study device, and log the activities they were performing with their prosthesis. Notably, subjects were allowed to use their own prescribed  prostheses if they desired, so long as they maintained an average usage of at least 2 hours per day with the study device. This decision was made as their non-study device may have had a powered wrist rotator or different terminal device  which may have been more suitable for their occupation and/or some of their activities of daily living. Electronic usage data  was recorded on the pattern recognition controller.At the conclusion of the home trial, participants returned to the lab to perform a series of outcome measures  includinAll participants then underwent TMR surgery in their residual forearm from a board-certified plastic surgeon either at Shirley Ryan AbilityLab or Walter Reed National Military Medical Center. The planned surgery involved transferring the remaining ulnar nerve to the flexor carpi ulnaris muscle and the remaining median nerve to either the flexor digitorum superficialis or brachioradialis muscle –30. TargAfter surgery, participants were allowed to resume prosthesis use of their own prescribed prosthesis as soon as they were comfortable. After at least six months post-surgery, in order to allow the TMR sites to re-innervate and mature, a prosthetist re-checked socket fit of the study prosthesis. Participants received additional occupational therapy to re-assess their selected grips and practice pattern recognition control. They participated in another 8-week home trial (Post-TMR-1) and in-lab outcome measure testing similar to the pre-TMR home trial. Participants then completed one last home trial, this time for 3 months in duration with no minimum usage requirement. They returned to the lab a final time to perform outcome measures (Post-TMR-2). Following fulfillment of all study requirements, participants were allowed to keep the prosthesis used in this study.A sample size of 9 participants was calculated based on preliminary data from transhumeral and shoulder disarticulation TMR patients on the Box and Blocks Test. We hypothesized that the study’s primary outcome measure, Box and Blocks, and secondary outcome measures  will improve following transradial TMR compared to pre-surgery. To compare outcomes measures between pre- and post-TMR surgery, we report values as across-user average changes between pre- and post-TMR surgery time points . From the electronic usage data we calculated average daily wear time as the total number of hours the device was turned on divided by the total number of days the device was turned on. Since the configured grips for each user were selected based on the most functional grips for their own activities of daily living, the time spent in each grip was ranked in order of descending usage and the percentage of time spent in each grip was calculated.To further investigate the potential for advanced prosthetic grasp and digit control, a separate EMG data collection was performed following each 8-week home trial pre- and post-TMR surgery was conducted. An array of 32 surface bipolar pre-gelled silver/silver chloride EMG electrodes were placed on each subjects’ residual forearm. Individuals were asked to perform various hand muscle contractions including hand open, 9 different grasp patterns , 8 different individual finger and thumb movements , and rest. Muscle contractions were held for 2 seconds and repeated 8 times for a total of 16 seconds per movement.An offline analysis was performed on these data using a similar pattern recognition system to what was used during home trial. The data were separated into two separate sets of movements: 1) hand open, 9 different grasp patterns, and rest and 2) 8 different individual finger and thumb movements and rest. For each user and each set of movements, a search was performed to find the optimal 4 channels using classification error  as the optimization metric. In this offline analysis, we chose to optimize our analysis using four channels instead of eight channels  because clinical experience has found that it is sometimes difficult to place the 16 dome electrodes that are necessary for 8 bipolar EMG channels in a transradial socket. Four channels (and therefore eight dome electrodes) represents a more clinically viable transradial system. Using the 4 optimal channels per user per movement set, a search was performed to evaluate reduction in classification error as additional grips were added to the system. This analysis was performed separately on the pre- and post-TMR data sets.Eleven individuals with a unilateral transradial amputation were enrolled in this study , Table 1Two subjects withdrew prior to having TMR surgery  and one subject (TR9) withdrew after TMR surgery prior to the start of the post-TMR 8-week home trial. Seven subjects completed the full study protocol and one subject (TR1) completed all but the final Post-TMR-2 home trial. Of the eight subjects that completed both pre- and post-TMR home trials, one subject (TR5) had his post-TMR home trial during the spring of 2020 which was affected by the COVID-19 pandemic; his post-TMR home usage was severely impacted and his outcomes testing was delayed by 5 weeks. He had not achieved the minimum usage requirement nor used the study prosthesis at all during this 5-week delay. Therefore, his data were excluded from the quantitative analyses.All users successfully used the multi-articulating hand prosthesis both before and after TMR surgery. Only minor fitting adjustments were necessary to the socket post-surgery; the location of all the electrodes remained the same for all subjects. Comparing between the pre-TMR and post-TMR 8 week home trials, there were no significant differences between the number of configured grips, the cumulative hours powered on, nor the number of recalibration sessions  Fig 2)..Fig 2). Offline classification errors from the 32-channel EMG data collection using all 32 channels as well as the 4 optimal channels show a slight reduction in error rate Post-TMR compared to Pre-TMR for the grip movement set as well as the individual thumb and finger movement set . When onFor the participants with a transradial amputation included in this study, our results demonstrate some benefits of TMR surgery. Outcomes data indicate that control improvements were seen following the Post-TMR-2 home trial compared to the Pre-TMR home trial for the SHAP, Jebsen-Taylor and Box and Blocks. The SHAP, a timed outcome measure that evaluates unilateral hand functions required for activities of daily living , improveThe Post-TMR-2 home trial occurred approximately 9–12 months post-TMR surgery. It is likely that the targeted muscles continued to reinnervate and strengthen over the year following the TMR surgery, which is our primary explanation for the improved outcomes; however, there are other potential explanations. Control improvements may have been due to users having more experience with the multi-articulating hand prosthesis. Due to the nature of the study protocol of users serving as their own baseline for TMR surgery, we were unable to randomize the condition order: 8-week Pre-TMR home trial, 8-week Post-TMR-1 home trial, and 3 month Post-TMR-2 home trial. While additional time with the prosthesis may allow users to better predict hand speed and how the hand moves within each grasp pattern it is important to note that the first two home trials constituted an average of 51 and 48 usage days, providing the users with experience using the prosthesis. It is also possible the users simply learned to complete the tests better. However, given the length of time between the tests, we feel this contribution would be small if it existed at all. Individuals with a transradial amputation have shown to improve their pattern recognition-based control of a virtual prosthesis over the course of 10 days of training . AdditioThe 32-channel EMG analysis also showed a decrease in classification error post-TMR surgery compared to pre-TMR surgery, although these differences were more prominent with a more complex system . Additionally, this analysis showed that four optimally placed EMG channels could provide a highly accurate pattern recognition system: under 10% error for 5 grips pre-TMR or 6 grips Post-TMR and under 20% error for 7 grips pre-TMR or 8 grips post-TMR . SimilarThe current study saw a smaller improvement in functional prosthesis control than previous studies investigating TMR surgery following more proximal upper limb amputation. This is likely because TMR surgery subsequent to more proximal level amputation allows for access of hand and wrist information where there was none prior. Conversely, following transradial amputation there already exists hand and wrist neural information due to native innervation of the forearm and extrinsic hand muscles. For the subjects in this study, activation of the newly reinnervated muscles either may not have added considerable neural content or these TMR signals were small and overshadowed by surrounding forearm activation for similar hand movements. It is important to note that denervation of the target muscles used in this study  did not lead to worse prosthetic control nor negatively affect residual limb control.Four subjects described improvements to either the resting position of their phantom hand or the amount of movement they are able to visualize with their phantom. For example, one subject described the resting position of his phantom limb as fingers tightly clenched over one another with a feeling that his fingernails were going through his palm. It had remained that way since his amputation. Post-TMR his phantom hand relaxed such that his hand was more open and in a more relaxed hand position. Additionally, six subjects saw reductions in pain and/or were able to reduce their pain medication levels post-TMR surgery. The one subject who reported no change in pain, however, was no longer taking pain medication that he had been pre-TMR. A recent TMR clinical trial on treatment of neuromas  found siThe results of this study may not be fully generalizable to the full population due to some limitations of the study design. Recruitment for this study was challenging due subject consent and retention for the year-long study testing protocol as well as the surgical component. Additionally, because the intervention was TMR surgery, the order of conditions could not be randomized. Therefore the results may be prone to biases including selection bias and regression to the mean. And since there was no control group  it is not possible to quantify the potential for additional learning, if any, to have occurred during the post-TMR conditions. Ultimately, the number of subjects who enrolled and completed the study was lower than planned for due to unexpected subject dropout and the impact of the COVID-19 pandemic. Due to these potential biases, care should be taken while interpreting our results; as such statistical analyses were not included to avoid over generalizing the results.The current study also had other limitations. Because the specific goal was to investigate potential improvements in control due to TMR surgery and the transferred nerves provided additional hand control information, powered wrist control was not included. It is unclear if the addition of a powered wrist would have impacted control or functional outcomes. All participants continued to wear their own, clinically prescribed prosthesis during the home trials; this was allowed as long as they were able to maintain the minimum average usage of 2 hours per day with the study prosthesis. We cannot say definitively what the total prosthesis wear-time (study and non-study devices) was for users. Subjects chose to use their clinically prescribed devices for a variety of reasons including the addition of a powered wrist rotator or the preference to use a different terminal device.Transradial amputation is the most common arm amputation and although affected individuals can control wrist and hand movements of a powered prosthesis, functional and reliable control still remains a challenge. The goal of this study was to determine if these individuals could benefit from the additional neural information that TMR surgery provides. Our results show that the subjects included in this study showed functional control benefits of using a multi-articulating hand prosthesis 9–12 months post-TMR surgery. Additional qualitative TMR and TSR benefits were observed in some, but not all, enrolled subjects. Future work incorporating both the sensory feedback benefits for individuals with transradial amputation as well as the potential for TMR surgery to result in more repeatable muscle contractions, possibly due to the reduction in pain levels and/or changes to phantom limb sensations, has the potential to increase functional use of many of the clinically available dexterous prosthetic hands.S1 Checklist(PDF)Click here for additional data file.S1 File(PDF)Click here for additional data file.S1 Data(XLSX)Click here for additional data file.S2 Data(XLSX)Click here for additional data file.