Femoroacetabular Impingement: Current Status of Diagnosis and Treatment: Marius Nygaard Smith-Petersen, 1886–1953

This biographical sketch of M. N. Smith-Petersen corresponds to the historic text, The Classic: Treatment of Malum Coxae Senilis, Old Slipped Upper Femoral Epiphysis, Intrapelvic Protrusion of the Acetabulum, and Coxa Plana by Means of Acetabuloplasty, available at DOI 10.1007/s11999-008-0670-0

Designing clinical trials in paediatric inflammatory bowel diseases:a PIBDnet commentary

Introduction: The optimal trial design for assessing novel therapies in paediatric IBD (PIBD) is a subject of intense ongoing global discussions and debate among the different stakeholders. However, there is a consensus that the current situation in which most medications used in children with IBD are prescribed as off-label without sufficient paediatric data is unacceptable. Shortening the time lag between adult and paediatric approval of drugs is of the upmost importance. In this position paper we aimed to provide guidance from the global clinical research network (Pediatric Inflammatory Bowel Disease Network, PIBDnet) for designing clinical trials in PIBD in order to facilitate drug approval for children. Methods: A writing group has been established by PIBDnet and topics were assigned to different members. After an iterative process of revisions among the writing group and one face-to-face meeting, all statements have reached consensus of >80% as defined a priori. Next, all core members of PIBDnet voted on the statements, reaching consensus of >80% on all statements. Comments from the members were incorporated in the text. Results: The commentary includes 18 statements for guiding data extrapolation from adults, eligibility criteria to PIBD trials, use of placebo, dosing, endpoints and recommendations for feasible trials. Controversial issues have been highlighted in the text. Conclusion: The viewpoints expressed in this paper could assist planning clinical trials in PIBD which are both of high quality and ethical, while remaining pragmatic

The Telehealth Enhancement of Adherence to Medication (TEAM) in pediatric IBD trial: Design and methodology

Medication nonadherence is a significant health care issue requiring regular behavioral treatment. Lack of sufficient health care resources and patient/family time commitment for weekly treatment are primary barriers to receiving appropriate self-management support. We describe the methodology of the Telehealth Enhancement of Adherence to Medication (TEAM) trial for medication nonadherence in pediatric inflammatory bowel disease (IBD). For this trial, participants 11–18 years of age will be recruited from seven pediatric hospitals and will complete an initial 4-week run in to assess adherence to a daily medication. Those who take less than 90% of their prescribed medication will be randomized. A total of 194 patients with IBD will be randomized to either a telehealth behavioral treatment (TBT) arm or education only (EO) arm. All treatment will be delivered via telehealth video conferencing. Patients will be assessed at baseline, post-treatment, 3-, 6-, and 12-months. We anticipate that participants in the TBT arm will demonstrate a statistically significant improvement at post-treatment and 3-, 6-, and 12-month follow-up compared to participants in the EO arm for both medication adherence and secondary outcomes (i.e., disease severity, patient quality of life, and health care utilization). If efficacious, the TEAM intervention could be disseminated broadly and reduce health care access barriers so that patients could receive much needed self-management intervention

Fusion of Small Peroxisomal Vesicles in Vitro Reconstructs an Early Step in the in Vivo Multistep Peroxisome Assembly Pathway of Yarrowia lipolytica

We have identified and purified six subforms of peroxisomes, designated P1 to P6, from the yeast, Yarrowia lipolytica. An analysis of trafficking of peroxisomal proteins in vivo suggests the existence of a multistep peroxisome assembly pathway in Y. lipolytica. This pathway operates by conversion of peroxisomal subforms in the direction P1, P2→P3→P4→P5→P6 and involves the import of various peroxisomal proteins into distinct vesicular intermediates. We have also reconstituted in vitro the fusion of the earliest intermediates in the pathway, small peroxisomal vesicles P1 and P2. Their fusion leads to the formation of a larger and more dense peroxisomal vesicle, P3. Fusion of P1 and P2 in vitro requires cytosol and ATP hydrolysis and is inhibited by antibodies to two membrane-associated ATPases of the AAA family, Pex1p and Pex6p. We provide evidence that the fusion in vitro of P1 and P2 peroxisomes reconstructs an actual early step in the peroxisome assembly pathway operating in vivo in Y. lipolytica

Human Rights in the Context of Environmental Conservation on the US-Mexico Border

At Cabeza Priesta National Wildlife Refuge, a wilderness area on the US-Mexico border in Arizona, conflicting policies permit the provision of supplementary water for wildlife but not for undocumented immigrants passing through the area. Federal refuge environmental policy prioritizes active management of endangered and threatened species. Vast systems of water resources have been developed to support wildlife conservation in this extremely hot and dry environment. At the same time, humanitarian groups are not allowed to supply water to undocumented border crossers in the park. Human border-crossers must utilize non-potable wildlife water guzzlers for survival and face risk of illness or death by dehydration. This article analyzes human rights via an ethnographic lens. From this perspective, water policy at the wildlife refuge brings into question the value of human life in a border conservation context, especially for those entering the site illegally

Uncoupled Embryonic and Extra-Embryonic Tissues Compromise Blastocyst Development after Somatic Cell Nuclear Transfer

Somatic cell nuclear transfer (SCNT) is the most efficient cell reprogramming technique available, especially when working with bovine species. Although SCNT blastocysts performed equally well or better than controls in the weeks following embryo transfer at Day 7, elongation and gastrulation defects were observed prior to implantation. To understand the developmental implications of embryonic/extra-embryonic interactions, the morphological and molecular features of elongating and gastrulating tissues were analysed. At Day 18, 30 SCNT conceptuses were compared to 20 controls (AI and IVP: 10 conceptuses each); one-half of the SCNT conceptuses appeared normal while the other half showed signs of atypical elongation and gastrulation. SCNT was also associated with a high incidence of discordance in embryonic and extra-embryonic patterns, as evidenced by morphological and molecular “uncoupling”. Elongation appeared to be secondarily affected; only 3 of 30 conceptuses had abnormally elongated shapes and there were very few differences in gene expression when they were compared to the controls. However, some of these differences could be linked to defects in microvilli formation or extracellular matrix composition and could thus impact extra-embryonic functions. In contrast to elongation, gastrulation stages included embryonic defects that likely affected the hypoblast, the epiblast, or the early stages of their differentiation. When taking into account SCNT conceptus somatic origin, i.e. the reprogramming efficiency of each bovine ear fibroblast (Low: 0029, Med: 7711, High: 5538), we found that embryonic abnormalities or severe embryonic/extra-embryonic uncoupling were more tightly correlated to embryo loss at implantation than were elongation defects. Alternatively, extra-embryonic differences between SCNT and control conceptuses at Day 18 were related to molecular plasticity (high efficiency/high plasticity) and subsequent pregnancy loss. Finally, because it alters re-differentiation processes in vivo, SCNT reprogramming highlights temporally and spatially restricted interactions among cells and tissues in a unique way

A Crucial Role for Infected-Cell/Antibody Immune Complexes in the Enhancement of Endogenous Antiviral Immunity by Short Passive Immunotherapy

Antiviral monoclonal antibodies (mAbs) represent promising therapeutics. However, most mAbs-based immunotherapies conducted so far have only considered the blunting of viral propagation and not other possible therapeutic effects independent of virus neutralization, namely the modulation of the endogenous immune response. As induction of long-term antiviral immunity still remains a paramount challenge for treating chronic infections, we have asked here whether neutralizing mAbs can, in addition to blunting viral propagation, exert immunomodulatory effects with protective outcomes. Supporting this idea, we report here that mice infected with the FrCasE murine retrovirus on day 8 after birth die of leukemia within 4–5 months and mount a non-protective immune response, whereas those rapidly subjected to short immunotherapy with a neutralizing mAb survive healthy and mount a long-lasting protective antiviral immunity with strong humoral and cellular immune responses. Interestingly, the administered mAb mediates lysis of infected cells through an antibody-dependent cell cytotoxicity (ADCC) mechanism. In addition, it forms immune complexes (ICs) with infected cells that enhance antiviral CTL responses through FcγR-mediated binding to dendritic cells (DCs). Importantly, the endogenous antiviral antibodies generated in mAb-treated mice also display the same properties, allowing containment of viral propagation and enhancement of memory cellular responses after disappearance of the administered mAb. Thus, our data demonstrate that neutralizing antiviral mAbs can act as immunomodulatory agents capable of stimulating a protective immunity lasting long after the end of the treatment. They also show an important role of infected-cells/antibody complexes in the induction and the maintenance of protective immunity through enhancement of both primary and memory antiviral T-cell responses. They also indicate that targeting infected cells, and not just viruses, by antibodies can be crucial for elicitation of efficient, long-lasting antiviral T-cell responses. This must be considered when designing antiviral mAb-based immunotherapies

Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study

Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn’s disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown

The SARS-CoV2 envelope differs from host cells, exposes pro-coagulant lipids, and is disrupted in vivo by oral rinses

The lipid envelope of SARS-CoV-2 is an essential component of the virus; however, its molecular composition is undetermined. Addressing this knowledge gap could support the design of anti-viral agents, as well as further our understanding of viral-host protein interactions, infectivity, pathogenicity, and innate immune system clearance. Using lipidomics analyses, we revealed that the virus envelope comprised mainly phospholipids (PL), with little cholesterol or sphingolipids, indicating significant differences from the composition of host membranes. Unlike cellular membranes, procoagulant aminophospholipids were present on the external side of the viral envelope at levels exceeding those on activated platelets. As a result, virions directly promoted blood coagulation. To investigate whether these differences could enable selective targeting of the viral envelope in vivo, we tested whether oral rinses containing lipid-disrupting chemicals could reduce viral infectivity. Products containing PL-disrupting surfactants (such as cetylpyridinium chloride (CPC)) met European virucidal standards in vitro; however, components that altered the critical micelle concentration reduced efficacy, and products containing essential oils, PVP-I, or Chlorhexidine were ineffective. This result was recapitulated in vivo, where a 30-second oral rinse with CPC mouthwash eliminated live virus in the oral cavity of COVID-19 patients for at least one hour, while PVP-Iodine and saline mouthwashes were found ineffective. We conclude the SARS-CoV-2 lipid envelope (i) is distinct from the host plasma membrane, which may enable design of selective anti-viral approaches; (ii) contains exposed PE and PS, which may influence thrombosis, pathogenicity, and inflammation; and (iii) can be selectively targeted in vivo by specific oral rinses