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The article discusses the Vatican's new declaration on the blessing of same-sex couples, highlighting its significance for LGBTQ Catholics. It explores the doctrinal implications of the declaration, its departure from previous teachings, and its prioritization of pastoral care over doctrinal enforcement. It also examines the theological reasoning behind the Vatican's stance on blessing same-sex couples, comparing it to previous statements and proposing a broader understanding of blessings.

abstract:The connection between liturgy and ethics has been an explicit subject of interest among Christian theologians since the second half of the twentieth century. However, most calls for a substantive integration of worship and Christian morality have proceeded in a single direction. Liturgy provides the foundations of an ecclesial ethic that is directed primarily outward as a witness to the world. A troubling consequence of this general approach to linking liturgy and ethics is that the church, situated in an iconic or kerygmatic role, rarely turns its ethical attention inward. In this essay, I offer a reading of the relationship between liturgy and ethics that may begin to overcome these limitations. In dialogue with Orthodox theologians Alexander Schmemann and Vigen Guroian, I propose a renewed emphasis on the eschatological dimension of eucharistic liturgy that, when theorized through the lens of virtue ethics, can yield a more dynamic, inward-facing ecclesial ethic.

Supplemental Digital Content is Available in the Text.The Viking press exercise is an upper-body strength and power movement with several potential benefits for athletes. The aim of this article is to describe proper exercise technique and introduce variations for the Viking press.

Cells of Aspergillus oryzaeIPT-301 rich in fructosyltransferase (FTase) were successfully immobilized by crosslinking with glutaraldehyde and used for the transfructosylation reaction of sucrose. The glutaraldehyde concentration and pH used in the immobilization process were optimized for maximizing the transfructosylation activity (AT) and minimizing the hydrolytic activity (AH). Also, the operational stability and the influence of temperature, pH and sucrose concentration on the enzymatic activities of the free and crosslinked cells were evaluated. Both the maximum ATand minimum AHwere obtained for cells immobilized with glutaraldehyde concentration of 2.1% (v/v) and pH 7.9. Crosslinked cells showed considerably higher AT/AHratio than free cells at several temperatures, pH and sucrose concentrations in the reaction media. Kinetics data suggested that crosslinked cells present higher substrate-enzyme affinity and transfructosylation rate than free cells. Furthermore, after 12 batch reaction cycles the FTase present in the immobilized cell kept 88.9% of its initial AT, demonstrating a considerably higher operational stability than the FTase present in the free cell, which showed 50.3% of its initial AT. These results suggest the potential use of crosslinked cells of Aspergillus oryzaeIPT-301 for the large-scale production of fructooligosaccharides (FOS).

Noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) are follicular-patterned thyroid neoplasms defined by nuclear atypia and indolent behavior. They harbor RASmutations, rather than BRAFV600Emutations as is observed in papillary thyroid carcinomas with extensive follicular growth. Reliably identifying NIFTPs aids in safe therapy de-escalation, but has proven to be challenging due to interobserver variability and morphologic heterogeneity. The genomic scoring system BRS (BRAF-RAS score) was developed to quantify the extent to which a tumor’s expression profile resembles a BRAFV600Eor RAS-mutant neoplasm. We proposed that deep learning prediction of BRS could differentiate NIFTP from other follicular-patterned neoplasms. A deep learning model was trained on slides from a dataset of 115 thyroid neoplasms to predict tumor subtype (NIFTP, PTC-EFG, or classic PTC), and was used to generate predictions for 497 thyroid neoplasms within The Cancer Genome Atlas (TCGA). Within follicular-patterned neoplasms, tumors with positive BRS (RAS-like) were 8.5 times as likely to carry an NIFTP prediction than tumors with negative BRS (89.7% vs 10.5%, P< 0.0001). To test the hypothesis that BRS may serve as a surrogate for biological processes that determine tumor subtype, a separate model was trained on TCGA slides to predict BRS as a linear outcome. This model performed well in cross-validation on the training set (R2= 0.67, dichotomized AUC = 0.94). In our internal cohort, NIFTPs were near universally predicted to have RAS-like BRS; as a sole discriminator of NIFTP status, predicted BRS performed with an AUC of 0.99 globally and 0.97 when restricted to follicular-patterned neoplasms. BRAFV600E-mutant PTC-EFG had BRAFV600E-like predicted BRS (mean −0.49), nonmutant PTC-EFG had more intermediate predicted BRS (mean −0.17), and NIFTP had RAS-like BRS (mean 0.35; P< 0.0001). In summary, histologic features associated with the BRAF-RAS gene expression spectrum are detectable by deep learning and can aid in distinguishing indolent NIFTP from PTCs.

Noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) are follicular-patterned thyroid neoplasms defined by nuclear atypia and indolent behavior. They harbor RASmutations, rather than BRAFV600Emutations as is observed in papillary thyroid carcinomas with extensive follicular growth. Reliably identifying NIFTPs aids in safe therapy de-escalation, but has proven to be challenging due to interobserver variability and morphologic heterogeneity. The genomic scoring system BRS (BRAF-RAS score) was developed to quantify the extent to which a tumor's expression profile resembles a BRAFV600Eor RAS-mutant neoplasm. We proposed that deep learning prediction of BRS could differentiate NIFTP from other follicular-patterned neoplasms. A deep learning model was trained on slides from a dataset of 115 thyroid neoplasms to predict tumor subtype (NIFTP, PTC-EFG, or classic PTC), and was used to generate predictions for 497 thyroid neoplasms within The Cancer Genome Atlas (TCGA). Within follicular-patterned neoplasms, tumors with positive BRS (RAS-like) were 8.5 times as likely to carry an NIFTP prediction than tumors with negative BRS (89.7% vs 10.5%, P< 0.0001). To test the hypothesis that BRS may serve as a surrogate for biological processes that determine tumor subtype, a separate model was trained on TCGA slides to predict BRS as a linear outcome. This model performed well in cross-validation on the training set (R2= 0.67, dichotomized AUC = 0.94). In our internal cohort, NIFTPs were near universally predicted to have RAS-like BRS; as a sole discriminator of NIFTP status, predicted BRS performed with an AUC of 0.99 globally and 0.97 when restricted to follicular-patterned neoplasms. BRAFV600E-mutant PTC-EFG had BRAFV600E-like predicted BRS (mean −0.49), nonmutant PTC-EFG had more intermediate predicted BRS (mean −0.17), and NIFTP had RAS-like BRS (mean 0.35; P< 0.0001). In summary, histologic features associated with the BRAF-RAS gene expression spectrum are detectable by deep learning and can aid in distinguishing indolent NIFTP from PTCs.

Adeno-associated virus (AAV) vectors are a leading platform for gene-based therapies for both monogenic and complex acquired disorders. The success of AAV gene transfer highlights the need to answer outstanding clinical questions of safety, durability, and the nature of the human immune response to AAV vectors. Here, we present longitudinal follow-up data of subjects who participated in the first trial of a systemically delivered AAV vector. Adult males (n = 7) with severe hemophilia B received an AAV2 vector at doses ranging from 8 × 1010to 2 × 1012vg/kg to target hepatocyte-specific expression of coagulation factor IX; a subset (n = 4) was followed for 12–15 years post-vector administration. No major safety concerns were observed. There was no evidence of sustained hepatic toxicity or development of hepatocellular carcinoma as assessed by liver transaminase values, serum α-fetoprotein, and liver ultrasound. Subjects demonstrated persistent, increased AAV neutralizing antibodies (NAbs) to the infused AAV serotype 2 (AAV2) as well as all other AAV serotypes tested (AAV5 and AAV8) for the duration of follow-up. These data represent the longest available longitudinal follow-up data of subjects who received intravascular AAV and support the preliminary safety of intravascular AAV administration at the doses tested in adults. Data demonstrate, for the first time, the persistence of high-titer, multi-serotype cross-reactive AAV NAbs for up to 15 years post- AAV vector administration. Our observations are broadly applicable to the development of AAV-mediated gene therapy.

Neutralizing antibodies to adeno-associated virus (AAV) vectors are highly prevalent in humans1,2, and block liver transduction3–5and vector readministration6; thus, they represent a major limitation to in vivo gene therapy. Strategies aimed at overcoming anti-AAV antibodies are being studied7, which often involve immunosuppression and are not efficient in removing pre-existing antibodies. Imlifidase (IdeS) is an endopeptidase able to degrade circulating IgG that is currently being tested in transplant patients8. Here, we studied if IdeS could eliminate anti-AAV antibodies in the context of gene therapy. We showed efficient cleavage of pooled human IgG (intravenous Ig) in vitro upon endopeptidase treatment. In mice passively immunized with intravenous Ig, IdeS administration decreased anti-AAV antibodies and enabled efficient liver gene transfer. The approach was scaled up to nonhuman primates, a natural host for wild-type AAV. IdeS treatment before AAV vector infusion was safe and resulted in enhanced liver transduction, even in the setting of vector readministration. Finally, IdeS reduced anti-AAV antibody levels from human plasma samples in vitro, including plasma from prospective gene therapy trial participants. These results provide a potential solution to overcome pre-existing antibodies to AAV-based gene therapy.

Surgical management of pancreatic neuroendocrine tumors (PNETS) is steadily evolving and is influenced by multiple factors. Sporadic PNETs are generally managed more aggressively than those occurring in the background of hereditary syndromes, and functioning PNETs are almost always resected if they are not metastatic. Localized nonfunctioning PNETs less than 2 cm can often be observed. Surgical resection for localized PNET greater than 2 cm comprises parenchymal sparing pancreas resections, such as enucleations, or formal anatomic resection, such as distal pancreatectomy or pancreaticoduodenectomy. PNETs commonly metastasize to the liver, and several systemic and liver-directed options to treat hepatic metastases are available.

This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the surgical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The group reviewed a series of questions of specific interest to surgeons taking care of patients with pancreatic neuroendocrine tumors, and for each, the available literature was reviewed. What follows are these reviews for each question followed by recommendations of the panel.

Pancreatic neuroendocrine tumors originate from hormone-producing islet cells and have a propensity to metastasize to the liver once they reach 2 cm in size. Their diagnosis relies upon a combination of computed tomography, MRI, DOTATATE PET, and endoscopic ultrasound with or without tissue biopsy. Biochemical work-up is driven by patient symptoms of hormone excess.

The FDA’s authorization of Hemgenix® is a significant milestone, constituting not only the first FDA approval of a gene therapy for hemophilia but also the first approval of a liver-targeted AAV gene therapy. This review summarizes the non-clinical studies and clinical development that supported regulatory clearance. Similar to other gene therapies for single gene disorders, both the short-term safety and the phenotypic improvement were unequivocal, justifying the modest-sized safety and efficacy database, which included fifty-seven participants across the Phase 2b (3 participants) and Phase 3 (54 participants) studies. The most common adverse reactions included liver enzyme elevation, headache, flu-like symptoms, infusion-related reactions, creatine kinase elevation, malaise and fatigue; these were mostly transient. One participant was found to have hepatocellular carcinoma on a study-mandated liver ultrasound conducted one year post-vector infusion; molecular analysis of the resected tumor showed no evidence of vector-related insertional mutagenesis as the etiology. A remarkable 96% of participants in the Phase 3 trial were able to stop FIX prophylaxis, with the study demonstrating both non-inferiority and superiority to factor IX prophylaxis in terms of the primary endpoint, annualized bleeding rate. Key secondary endpoints such as the annualized infusion rate —which declined by 97%— and the plasma factor IX activity level at 18 months post-infusion —least squares mean increase of 34.3 percentage points compared to baseline— were both clinically and statistically significant. The FDA's landmark approval of Hemgenix® as a pioneering treatment for hemophilia stands on the shoulders of over 20 years of gene therapy clinical research and heralds a promising future for genomic medicines.

Over 50% of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have stage IV disease at presentation and the most likely organ to be affected by metastases is the liver. Hepatic involvement and hepatic tumor burden is a key prognostic factor affecting survival of these patients and 80% eventually die of liver failure due to tumor dissemination within the liver. This commentary explores the efficacy and limitations of systemic treatments in patients with GEP-NETs and liver metastases. Landmark randomized trials using systemic therapies including sandostatin (PROMID), lanreotide (CLARINET), everolimus (RADIANT 3 and 4), sunitinib and Peptide Receptor Radionuclide Therapy (NETTER-1) have not shown efficacy in reducing liver tumor burden in patients with stage IV GEP-NETs with liver metastases as outlined in this review. Although often overlooked, surgical debulking has been associated with a significant survival advantage in large retrospective studies and in our opinion should remain an important therapeutic option for patients with stage IV GEP-NETs and liver metastases.

Patients with von Hippel-Lindau (vHL) disease caused by a missense VHL mutation have a more severe phenotype compared with other VHL mutation types.

Pancreatic lesions occur in two-thirds of patients with von Hippel–Lindau (VHL) diseaseCystic pancreatic lesions or serous cystadenomas, which occur in almost 50% of all patients with VHL disease, are not malignant and rarely require interventionPancreatic neuroendocrine tumours (pNETs) associated with VHL disease have a variable natural history, which necessitates lifelong follow-up monitoring using imaging, but are less aggressive than sporadic pNETsSurgical removal of VHL-associated pNETs with diameters ≥3 cm and ≥2 cm in the pancreatic body and head, respectively, or that are growing rapidly (doubling time <500 days) should be consideredAdditional criteria for consideration of surgical removal of VHL-associated pNETs include obvious signs of malignancy, such as locoregional invasion and/or regional or distant metastasesA multidisciplinary-team approach is of paramount importance in the management of patients with VHL-disease-associated pancreatic lesions.

Pancreatic neuroendocrine tumors (pNETs) are rare tumors that have a better prognosis than their exocrine counterpart, but frequently present with advanced disease. Management of pNETs has evolved considerably over the past decade. Surgical resection remains the only potentially curative option for patients with pNETs. Patients who have locoregionally advanced and/or metastatic pNETs require additional treatments. These include liver-directed (transarterial (chemo)-embolization, selective intraarterial radio therapy) and systemic therapies (somatostatin analogs, targeted therapy such as tyrosine-kinase inhibitors and mammalian target of rapamycin inhibitor, peptide receptor radionuclide therapy and cytotoxic chemotherapy). The aim of this article is to review the current treatment options as well as potential future therapeutic perspectives for patients with pNETs.

AbstractPancreatic neuroendocrine tumors (pNETs) are rare tumors that have a better prognosis than their exocrine counterpart, but frequently present with advanced disease. Management of pNETs has evolved considerably over the past decade. Surgical resection remains the only potentially curative option for patients with pNETs. Patients who have locoregionally advanced and/or metastatic pNETs require additional treatments. These include liver-directed (transarterial (chemo)-embolization, selective intraarterial radio therapy) and systemic therapies (somatostatin analogs, targeted therapy such as tyrosine-kinase inhibitors and mammalian target of rapamycin inhibitor, peptide receptor radionuclide therapy and cytotoxic chemotherapy). The aim of this article is to review the current treatment options as well as potential future therapeutic perspectives for patients with pNETs.

For patients with newly diagnosed rheumatoid arthritis, treatment aim is early, rapid, and sustained remission. We compared the efficacy and safety of strategies initiating the interleukin-6 receptor-blocking monoclonal antibody tocilizumab with or without methotrexate (a conventional synthetic disease-modifying antirheumatic drug [DMARD]), versus initiation of methotrexate monotherapy in line with international guidelines.

Vacuum-assist venous drainage (VAVD) can increase venous blood return during cardiopulmonary bypass (CPB) procedures. However, the negative pressure created in the closed cardiotomy reservoir can be transmitted to the oxygenator if a nonocclusive or centrifugal arterial pump is used, resulting in bubble transgression (BT) from the gas to blood compartment of the oxygenator. We analyzed the vacuum pressure required to produce BT using an in vitrocircuit including successively a closed reservoir, a pump (centrifugal or roller), and an oxygenator. A constant hydrostatic pressure was maintained onto the oxygenator. Vacuum was applied on the cardiotomy reservoir, progressively increasing negative pressure from 0 to −80 mmHg and monitoring BT with a bubble detector. Six different oxygenators were compared. A partially occlusive roller pump and a centrifugal pump were compared to a control, which was without any pump. A mean negative pressure of −53 ± 7 mmHg was necessary to produce BT in all the oxygenators in the absence of a pump. The presence of a centrifugal pump between the reservoir and the oxygenator significantly increased the negative pressure required to produce BT compared to the control (−67 ± 7 mmHg, p< .05). No bubbles were detected using the roller pump (>−80 mmHg needed for BT), thus statistically significant when compared to the centrifugal pump (p< .05). The centrifugal pump offers significant resistance to BT but not as much compared to the roller pump, though BT cannot be prevented if the pump is turned off while the vacuum remains on the reservoir. Therefore, VAVD is a safe technique as long as the perfusionist stops the vacuum when the arterial pump is no longer in use.

This study compares the gas transfer capacity, the blood trauma, and the blood path resistance of the hollow-fiber membrane oxygenator Dideco D 903 with a surface area of 1.7 m2(oxygenator 1.7) versus a prototype built on the same principles but with a surface area of 2 m2(oxygenator 2).

Site-specific genome editing provides a promising approach for achieving long-term, stable therapeutic gene expression. Genome editing has been successfully applied in a variety of preclinical models, generally focused on targeting the diseased locus itself; however, limited targeting efficiency or insufficient expression from the endogenous promoter may impede the translation of these approaches, particularly if the desired editing event does not confer a selective growth advantage. Here we report a general strategy for liver-directed protein replacement therapies that addresses these issues: zinc finger nuclease (ZFN) –mediated site-specific integration of therapeutic transgenes within the albumin gene. By using adeno-associated viral (AAV) vector delivery in vivo, we achieved long-term expression of human factors VIII and IX (hFVIII and hFIX) in mouse models of hemophilia A and B at therapeutic levels. By using the same targeting reagents in wild-type mice, lysosomal enzymes were expressed that are deficient in Fabry and Gaucher diseases and in Hurler and Hunter syndromes. The establishment of a universal nuclease-based platform for secreted protein production would represent a critical advance in the development of safe, permanent, and functional cures for diverse genetic and nongenetic diseases.

Site-specific genome editing provides a promising approach for achieving long-term, stable therapeutic gene expression. Genome editing has been successfully applied in a variety of preclinical models, generally focused on targeting the diseased locus itself; however, limited targeting efficiency or insufficient expression from the endogenous promoter may impede the translation of these approaches, particularly if the desired editing event does not confer a selective growth advantage. Here we report a general strategy for liver-directed protein replacement therapies that addresses these issues: zinc finger nuclease (ZFN) –mediated site-specific integration of therapeutic transgenes within the albumin gene. By using adeno-associated viral (AAV) vector delivery in vivo, we achieved long-term expression of human factors VIII and IX (hFVIII and hFIX) in mouse models of hemophilia A and B at therapeutic levels. By using the same targeting reagents in wild-type mice, lysosomal enzymes were expressed that are deficient in Fabry and Gaucher diseases and in Hurler and Hunter syndromes. The establishment of a universal nuclease-based platform for secreted protein production would represent a critical advance in the development of safe, permanent, and functional cures for diverse genetic and nongenetic diseases.

Background.To examine cross-national patterns and correlates of lifetime and 12-month comorbid DSM-IV anxiety disorders among people with lifetime and 12-month DSM-IV major depressive disorder (MDD).Method.Nationally or regionally representative epidemiological interviews were administered to 74 045 adults in 27 surveys across 24 countries in the WHO World Mental Health (WMH) Surveys. DSM-IV MDD, a wide range of comorbid DSM-IV anxiety disorders, and a number of correlates were assessed with the WHO Composite International Diagnostic Interview (CIDI).Results.45.7% of respondents with lifetime MDD (32.0–46.5% inter-quartile range (IQR) across surveys) had one of more lifetime anxiety disorders. A slightly higher proportion of respondents with 12-month MDD had lifetime anxiety disorders (51.7%, 37.8–54.0% IQR) and only slightly lower proportions of respondents with 12-month MDD had 12-month anxiety disorders (41.6%, 29.9–47.2% IQR). Two-thirds (68%) of respondents with lifetime comorbid anxiety disorders and MDD reported an earlier age-of-onset (AOO) of their first anxiety disorder than their MDD, while 13.5% reported an earlier AOO of MDD and the remaining 18.5% reported the same AOO of both disorders. Women and previously married people had consistently elevated rates of lifetime and 12-month MDD as well as comorbid anxiety disorders. Consistently higher proportions of respondents with 12-month anxious than non-anxious MDD reported severe role impairment (64.4 v.46.0%; χ21= 187.0, p< 0.001) and suicide ideation (19.5 v.8.9%; χ21= 71.6, p< 0.001). Significantly more respondents with 12-month anxious than non-anxious MDD received treatment for their depression in the 12 months before interview, but this difference was more pronounced in high-income countries (68.8 v.45.4%; χ21= 108.8, p< 0.001) than low/middle-income countries (30.3 v.20.6%; χ21= 11.7, p< 0.001).Conclusions.Patterns and correlates of comorbid DSM-IV anxiety disorders among people with DSM-IV MDD are similar across WMH countries. The narrow IQR of the proportion of respondents with temporally prior AOO of anxiety disorders than comorbid MDD (69.6–74.7%) is especially noteworthy. However, the fact that these proportions are not higher among respondents with 12-month than lifetime comorbidity means that temporal priority between lifetime anxiety disorders and MDD is not related to MDD persistence among people with anxious MDD. This, in turn, raises complex questions about the relative importance of temporally primary anxiety disorders as risk markers v.causal risk factors for subsequent MDD onset and persistence, including the possibility that anxiety disorders might primarily be risk markers for MDD onset and causal risk factors for MDD persistence.