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The use of amniotic membrane in ophthalmic surgery and other surgical procedures in the fields of dermatology, plastic surgery, genitourinary medicine and otolaryngology is on the increase. Furthermore, amniotic membrane and its epithelial and mesenchymal cells have broad use in regenerative medicine and hold great promise in anticancer treatment. Amniotic membrane is a rich source of biologically active factors and as such, promotes healing and acts as an effective material for wound dressing. Amniotic membrane supports epithelialization and exhibits anti-fibrotic, anti-inflammatory, anti-angiogenic and anti-microbial features. Placentas utilised in the preparation of amniotic membrane are retrieved from donors undergoing elective caesarean section. Maternal blood must undergo serological screening at the time of donation and, in the absence of advanced diagnostic testing techniques, 6 months postpartum in order to cover the time window for the potential transmission of communicable diseases. Amniotic membrane is prepared by blunt dissection under strict aseptic conditions, then is typically transferred onto a nitrocellulose paper carrier, usually with the epithelial side up, and cut into multiple pieces of different dimensions. Amniotic membrane can be stored under various conditions, most often cryopreserved in glycerol or dimethyl sulfoxide or their mixture with culture medium or buffers. Other preservation methods include lyophilisation and air-drying. In ophthalmology, amniotic membrane is increasingly used for ocular surface reconstruction, including the treatment of persistent epithelial defects and non-healing corneal ulcers, corneal perforations and descemetoceles, bullous keratopathy, as well as corneal disorders with associated limbal stem cell deficiency, pterygium, conjunctival reconstruction, corneoscleral melts and perforations, and glaucoma surgeries.

Purpose: To evaluate the efficiency of femtosecond laser (FSL) incision of rehydrated human donor corneas after air-drying and its effects on corneal structure. Methods: We compared the rehydrated and fresh-preserved corneas by microscopy following Victus-Tecnolas FSL treatment for straight-edge anterior lamellar keratoplasty (ALK). The corneas were dehydrated at room temperature under a laminar-flow hood. Results: To obtain the horizontal cut in rehydrated corneas, we increased the FSL pulse energy to 1.2 μJ from 0.80 μJ applied for the fresh corneas and obtained a clear-cut separation of the lamellar lenticule cap from the corneal bed. Light microscopy showed regular arrangement of stromal collagen lamellae, with spaces in between the fibers in the corneal stroma in the fresh and the rehydrated corneas, but the uppermost epithelial layers in the rehydrated corneas were lost. Transmission electron microscopy (TEM) revealed no signs of thermal or mechanical damage to the corneal structure. The epithelial basal membrane and Bowman's layer maintained their integrity. The epithelial basal layer and cells were separated by large spaces due to junction alteration in the rehydrated corneas. There were gaps between the lamellar layers in the stroma, especially in the rehydrated corneas. Keratocytes displayed normal structure in the fresh corneas but were devoid of microorganules in the rehydrated corneas. Minor irregularities were observed in the vertical incision and the horizontal stroma appeared smooth on scanning electron microscopy. Conclusion: The corneal stroma of rehydrated corneas maintained morphology and integrity, while corneal cellular components were generally altered. When corneas are intended for FSL-assisted ALK, effective stromal bed incision is best achieved at a laser power higher than that currently adopted for fresh corneas.

IntroductionSince 21 February 2020, the day that the first Italian COVID-19 case was identified, the organizational and regulatory conditions for ocular tissue donation have undergone numerous changes in order to guarantee safety and quality. Herewith we report the key responses of the procurement programme to these challenges.Materials and MethodsA retrospective analysis of the ocular tissue procured between 1 January 2020 and 30 September 2021 is reported.Results9224 ocular tissues were procured during the study period (weekly average: 100 ± 21 tissues, mean ± SD; down to 97 ± 24, if only 2020 is considered). During the first wave, the weekly average reached 80 ± 24 tissues, a significant reduction if compared to the first 8 weeks of the year (124 ± 22 tissues/week, p<0.001), falling to 67 ± 15 tissues/week during the lock-down period. Considering the ocular tissues collected in the Veneto Region alone, the weekly mean was 68 ± 20, a reduction when compared to the first 8 weeks of the year (102 ± 23, p<0.001), arriving at 58 ± 15 tissues/week during the lock-down period. The percentage of healthcare professionals who tested positive during the first wave was on average 12% of the positive cases in the whole country, and equal to 18% in the Veneto Region alone. During the second wave, the mean weekly recovery of ocular tissue was 91 ± 15 and 77 ± 15 in the Veneto Region, compared to positive cases of healthcare professionals of 4% across Italy and in the Veneto Region. During the third wave, the overall weekly mean recovery rate was 107 ± 14, and 87 ± 13 in the Veneto Region, with only 1% of positive cases among healthcare professionals in Italy and in the Veneto Region.ConclusionsThe most dramatic decrease of ocular tissue recovery occurred during the first wave of COVID-19, notwithstanding the lower number of infected people. This phenomenon can be attributed to different factors: a high percentage of positive cases and/or contacts among potential donors; the number of infections among healthcare professionals, favoured by the lack of personal protection equipement and the still partial knowledge of the disease; the exclusion of donors with bilateral pneumonia. Subsequently, the system was better organized with the assimilation of new knowledge about the virus, overcoming the initial fears about transmission and thus guaranteeing the resumption and maintenance of donations.

Magnetic resonance imaging (MRI) of the knee is the preferred method for diagnosing knee injuries. However, interpretation of knee MRI is time-intensive and subject to diagnostic error and variability. An automated system for interpreting knee MRI could prioritize high-risk patients and assist clinicians in making diagnoses. Deep learning methods, in being able to automatically learn layers of features, are well suited for modeling the complex relationships between medical images and their interpretations. In this study we developed a deep learning model for detecting general abnormalities and specific diagnoses (anterior cruciate ligament [ACL] tears and meniscal tears) on knee MRI exams. We then measured the effect of providing the model's predictions to clinical experts during interpretation. Our dataset consisted of 1,370 knee MRI exams performed at Stanford University Medical Center between January 1, 2001, and December 31, 2012 (mean age 38.0 years; 569 [41.5%] female patients). The majority vote of 3 musculoskeletal radiologists established reference standard labels on an internal validation set of 120 exams. We developed MRNet, a convolutional neural network for classifying MRI series and combined predictions from 3 series per exam using logistic regression. In detecting abnormalities, ACL tears, and meniscal tears, this model achieved area under the receiver operating characteristic curve (AUC) values of 0.937 (95% CI 0.895, 0.980), 0.965 (95% CI 0.938, 0.993), and 0.847 (95% CI 0.780, 0.914), respectively, on the internal validation set. We also obtained a public dataset of 917 exams with sagittal T1-weighted series and labels for ACL injury from Clinical Hospital Centre Rijeka, Croatia. On the external validation set of 183 exams, the MRNet trained on Stanford sagittal T2-weighted series achieved an AUC of 0.824 (95% CI 0.757, 0.892) in the detection of ACL injuries with no additional training, while an MRNet trained on the rest of the external data achieved an AUC of 0.911 (95% CI 0.864, 0.958). We additionally measured the specificity, sensitivity, and accuracy of 9 clinical experts (7 board-certified general radiologists and 2 orthopedic surgeons) on the internal validation set both with and without model assistance. Using a 2-sided Pearson's chi-squared test with adjustment for multiple comparisons, we found no significant differences between the performance of the model and that of unassisted general radiologists in detecting abnormalities. General radiologists achieved significantly higher sensitivity in detecting ACL tears (p-value = 0.002; q-value = 0.019) and significantly higher specificity in detecting meniscal tears (p-value = 0.003; q-value = 0.019). Using a 1-tailed t test on the change in performance metrics, we found that providing model predictions significantly increased clinical experts' specificity in identifying ACL tears (p-value < 0.001; q-value = 0.006). The primary limitations of our study include lack of surgical ground truth and the small size of the panel of clinical experts. Our deep learning model can rapidly generate accurate clinical pathology classifications of knee MRI exams from both internal and external datasets. Moreover, our results support the assertion that deep learning models can improve the performance of clinical experts during medical imaging interpretation. Further research is needed to validate the model prospectively and to determine its utility in the clinical setting.

Proficiency testing (PT), or external quality assessment (EQA), is intended to verify on a recurring basis that laboratory results conform to expectations for the quality required for patient care. Key factors for interpreting PT/EQA results are knowledge of the commutability of the samples used and the process used for target value assignment. A commutable PT/EQA sample demonstrates the same numeric relationship between different measurement procedures as that expected for patients' samples. Noncommutable PT/EQA samples frequently have a matrix-related bias of unknown magnitude that limits interpretation of results. PT/EQA results for commutable samples can be used to assess accuracy against a reference measurement procedure or a designated comparison method. In addition, the agreement of the results between different measurement procedures for commutable samples reflects that which would be seen for patients' samples. PT/EQA results for noncommutable samples must be compared to a peer group mean/median of results from participants who use measurement procedures that are expected to have the same or very similar matrix-related bias. Peer group evaluation is used to asses whether a laboratory is using a measurement procedure in conformance to the manufacturer's specifications and/or in conformance to other laboratories using the same technology. A noncommutable PT/EQA sample does not give meaningful information about the relationship of results for patients' samples between different measurement procedures. PT/EQA provides substantial value to the practice of laboratory medicine by assessing the performance of individual laboratories and, when commutable samples are used, the status of standardization or harmonization among different measurement procedures.

Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma and median overall survival for those treated is 12–16 months, but few, if any, novel treatments or chemotherapy combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumour activity in human sarcoma xenografts. We aimed to assess the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma. We did an open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the phase 1b and phase 2 parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and available tumour tissue to determine PDGFRα expression by immunohistochemistry. In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m2) or doxorubicin alone (75 mg/m2) on day 1 of each 21-day cycle for up to eight cycles. Randomisation was dynamic and used the minimisation randomisation technique. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was progression-free survival using a two-sided α level of 0·2 and statistical power of 0·8. This study was registered with ClinicalTrials.gov, number NCT01185964. 15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase 1b study, and 133 patients were randomised (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of whom received at least one dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin). Median progression-free survival in phase 2 was 6·6 months (95% CI 4·1–8·3) with olaratumab plus doxorubicin and 4·1 months (2·8–5·4) with doxorubicin (stratified hazard ratio [HR] 0·67; 0·44–1·02, p=0·0615). Median overall survival was 26·5 months (20·9–31·7) with olaratumab plus doxorubicin and 14·7 months (9·2–17·1) with doxorubicin (stratified HR 0·46, 0·30–0·71, p=0·0003). The objective response rate was 18·2% (9·8–29·6) with olaratumab plus doxorubicin and 11·9% (5·3–22·2) with doxorubicin (p=0·3421). Steady state olaratumab serum concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 μg/mL (geometric coefficient of variation in percentage [CV%] 26·2) to 487 μg/mL (CV% 33·0) and from 123 μg/mL (CV% 31·2) to 156 μg/mL (CV% 38·0), respectively. Adverse events that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhoea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 64 patients vs doxorubicin: nine [14%] of 65 patients). This study of olaratumab with doxorubicin in patients with advanced soft-tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11·8 months in median overall survival, suggesting a potential shift in the treatment of soft-tissue sarcoma. Eli Lilly and Company.

Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics.

This trial involving more than 6000 patients with chronic obstructive pulmonary disease (COPD) compared the effects on all-cause mortality of treatment with an inhaler containing both salmeterol and fluticasone, salmeterol or fluticasone alone, or placebo. After 3 years, the study showed a reduction of 2.6 percentage points in the mortality rate; this fell short of the study's prespecified goals. There were improved clinical outcomes among patients treated with the combination regimen. This trial involving more than 6000 patients with COPD compared the effects on all-cause mortality of treatment with an inhaler containing both salmeterol and fluticasone, salmeterol or fluticasone alone, or placebo. After 3 years, the study showed a reduction of 2.6 percentage points in the mortality rate, which fell short of the prespecified goal. Chronic obstructive pulmonary disease (COPD) is a major cause of illness, death, and the use of health care resources globally. 1 – 3 The disease causes approximately 2.75 million deaths annually, and the number is projected to increase. 2 Treatment for COPD is focused on minimizing risk factors, improving symptoms, and preventing exacerbations. 3 With the exception of smoking-cessation programs for patients with early disease, 4 home oxygen treatment for persistent hypoxemia, 5 , 6 and lung-reduction surgery for selected patients with emphysema, 7 no treatment has been shown to reduce mortality. Pulmonary inflammation is prominent in COPD. 8 Antiinflammatory drugs such as inhaled corticosteroids have little or no . . .

More than 250 patients with uncomplicated, primary spontaneous pneumothorax were treated conservatively or by pleural intervention. In a complete-case analysis, reexpansion within 8 weeks occurred in 98.5% of the patients in the intervention group and in 94.4% of those in the conservative-management group.

Immunoaffinity–mass spectrometry (IA-MS) is an emerging analytical genre with several advantages for profiling and determination of protein biomarkers. Because IA-MS combines affinity capture, analogous to ligand binding assays (LBAs), with mass spectrometry (MS) detection, this platform is often described using the term hybrid methods. The purpose of this report is to provide an overview of the principles of IA-MS and to demonstrate, through application, the unique power and potential of this technology. By combining target immunoaffinity enrichment with the use of stable isotope-labeled internal standards and MS detection, IA-MS achieves high sensitivity while providing unparalleled specificity for the quantification of protein biomarkers in fluids and tissues. In recent years, significant uptake of IA-MS has occurred in the pharmaceutical industry, particularly in the early stages of clinical development, enabling biomarker measurement previously considered unattainable. By comparison, IA-MS adoption by CLIA laboratories has occurred more slowly. Current barriers to IA-MS use and opportunities for expanded adoption are discussed. The path forward involves identifying applications for which IA-MS is the best option compared with LBA or MS technologies alone. IA-MS will continue to benefit from advances in reagent generation, more sensitive and higher throughput MS technologies, and continued growth in use by the broader analytical community. Collectively, the pursuit of these opportunities will secure expanded long-term use of IA-MS for clinical applications.