Inhaled treprostinil and pulmonary arterial hypertension

Multiple conditions result in development of pulmonary hypertension. Pulmonary arterial hypertension (PAH) is the subclassification of pulmonary hypertension, in which known or unknown underlying conditions lead to similar intrinsic alterations in the pulmonary vasculature. PAH is a progressive condition characterized by restricted blood flow through the pulmonary circulation leading to poor survival in the absence of effective therapy. Over the last two decades, new therapeutic agents have substantially improved the course and prognosis for PAH patients. Three available classes of drugs, ie, prostacyclins, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors provide multiple options for treatment of PAH. Endothelin receptor antagonists and phosphodiesterase-5 inhibitors are administered orally, whereas prostacyclin therapies are delivered by continuous intravenous or subcutaneous infusion, or as aerosols by nebulization. Because of the risks and inconveniences associated with administration, prostacyclins are typically reserved for patients with more advanced disease or progression despite oral therapy. Inhaled administration may be a safer and easier route for prostacyclin administration. Treprostinil is a prostacyclin analog that has been demonstrated to be effective when administered by continuous subcutaneous or intravenous infusion, and more recently by nebulization

Psychological Sequelae of the Station Nightclub Fire: Comparing Survivors with and without Physical Injuries Using a Mixed-Methods Analysis

Background: Surveying survivors from a large fire provides an opportunity to explore the impact of emotional trauma on psychological outcomes. Methods: This is a cross-sectional survey of survivors of The Station Fire. Primary outcomes were post-traumatic stress (Impact of Event Scale – Revised) and depressive (Beck Depression Inventory) symptoms. Linear regression was used to examine differences in symptom profiles between those with and without physical injuries. The free-response section of the survey was analyzed qualitatively to compare psychological sequelae of survivors with and without physical injuries. Results: 104 participants completed the study survey; 47% experienced a burn injury. There was a 42% to 72% response rate range. The mean age of respondents was 32 years, 62% were male, and 47% experienced a physical injury. No significant relationships were found between physical injury and depressive or post-traumatic stress symptom profiles. In the qualitative analysis, the emotional trauma that survivors experienced was a major, common theme regardless of physical injury. Survivors without physical injuries were more likely to experience survivor guilt, helplessness, self-blame, and bitterness. Despite the post-fire challenges described, most survivors wrote about themes of recovery and renewal. Conclusions: All survivors of this large fire experienced significant psychological sequelae. These findings reinforce the importance of mental health care for all survivors and suggest a need to understand factors influencing positive outcomes

The Surgical Infection Society revised guidelines on the management of intra-abdominal infection

Background: Previous evidence-based guidelines on the management of intra-abdominal infection (IAI) were published by the Surgical Infection Society (SIS) in 1992, 2002, and 2010. At the time the most recent guideline was released, the plan was to update the guideline every five years to ensure the timeliness and appropriateness of the recommendations. Methods: Based on the previous guidelines, the task force outlined a number of topics related to the treatment of patients with IAI and then developed key questions on these various topics. All questions were approached using general and specific literature searches, focusing on articles and other information published since 2008. These publications and additional materials published before 2008 were reviewed by the task force as a whole or by individual subgroups as to relevance to individual questions. Recommendations were developed by a process of iterative consensus, with all task force members voting to accept or reject each recommendation. Grading was based on the GRADE (Grades of Recommendation Assessment, Development, and Evaluation) system; the quality of the evidence was graded as high, moderate, or weak, and the strength of the recommendation was graded as strong or weak. Review of the document was performed by members of the SIS who were not on the task force. After responses were made to all critiques, the document was approved as an official guideline of the SIS by the Executive Council. Results: This guideline summarizes the current recommendations developed by the task force on the treatment of patients who have IAI. Evidence-based recommendations have been made regarding risk assessment in individual patients; source control; the timing, selection, and duration of antimicrobial therapy; and suggested approaches to patients who fail initial therapy. Additional recommendations related to the treatment of pediatric patients with IAI have been included. Summary: The current recommendations of the SIS regarding the treatment of patients with IAI are provided in this guideline

Twice-daily amprenavir 1200 mg versus amprenavir 600 mg/ritonavir 100 mg, in combination with at least 2 other antiretroviral drugs, in HIV-1-infected patients

BACKGROUND: Low-dose ritonavir (RTV) boosts plasma amprenavir (APV) exposure. Little has been published on the efficacy, tolerability, and safety of APV 600 mg/RTV 100 mg (APV600/RTV) twice daily (BID) compared to APV 1200 mg BID (APV1200). METHODS: ESS40011 was a 24-week, multicenter, open-label, clinical trial in which antiretroviral therapy-naïve and -experienced HIV-1-infected adults were randomized 3:1 to receive either APV600/RTV BID or APV1200 BID, in combination with ≥ 2 non-protease inhibitor antiretroviral drugs. Non-inferiority of the APV600/RTV regimen to the APV1200 regimen was established if the 95% lower confidence limit for the difference in proportion of patients achieving HIV-1 RNA <200 copies/mL at week 24 with APV 600/RTV minus APV1200 was ≥-0.12. Late in the conduct of the trial, patients not yet completing 24 weeks of therapy were given the option of continuing treatment for an additional 24-week period. RESULTS: 211 patients were randomized, 158 to APV600/RTV and 53 to APV1200. At week 24, APV600/RTV was similar to or better than APV1200 (HIV-1 RNA <200 copies/mL in 62% [73/118] vs 53% [20/38] of patients; intent-to-treat: observed analysis). In the APV600/RTV arm, significantly more patients achieved HIV-1 RNA <50 copies/mL (48% [57/118] vs 29% [11/38] with APV1200, P = 0.04), and greater mean reduction from baseline in HIV-1 RNA was observed (-2.21 vs -1.59 log(10 )copies/mL, P = 0.028). The two treatment arms were similar with respect to mean overall change from baseline in CD4+ count, frequency of drug-related grade 1–4 adverse events, and frequency of discontinuing treatment due to adverse events (most commonly nausea, diarrhea, vomiting or fatigue; 7% vs 8%), although a lower proportion of patients in the APV600/RTV arm experienced drug-related oral/perioral paresthesia (2% vs 8%). Eleven (73%) of 15 patients who had HIV-1 RNA <200 copies/mL at week 24 and chose to continue study treatment maintained this level of virologic suppression at follow-up 24 weeks later. CONCLUSIONS: APV600 RTV BID was similar to or better than APV1200 BID in virologic response. Virologic results in a small number of patients who continued treatment for 24 weeks post-study suggest that virologic suppression with APV600 RTV BID is durable

Concepts in Animal Parasitology, Part 3: Endoparasitic Platyhelminths

Part III: Endoparasitic Platyhelminths, chapters 15-47, pages 231-532, in Concepts in Animal Parasitology. 2024. Scott L. Gardner and Sue Ann Gardner, editors. Zea Books, Lincoln, Nebraska, United States; part III doi: 10.32873/unl.dc.ciap073 Platyhelminthes Chapter 15: Introduction to Endoparasitic Platyhelminths (Phylum Platyhelminthes) by Larry S. Roberts, John J. Janovy, Jr., Steve Nadler, and Scott L. Gardner, pages 231-240 Cestoda Chapter 16: Introduction to Cestodes (Class Cestoda) by Scott L. Gardner, pages 241-246 Eucestoda Chapter 17: Introduction to Cyclophyllidea Beneden in Braun, 1900 (Order) by Scott L. Gardner, pages 247-250 Chapter 18: Taenia (Genus) by Sumiya Ganzorig and Scott. L. Gardner, pages 251-261 Chapter 19: Echinococcus (Genus) by Akira Ito and Scott. L. Gardner, pages 262-275 Chapter 20: Proteocephalidae La Rue, 1911 (Family) by Tomáš Scholz and Roman Kuchta, pages 276-282 Chapter 21: Bothriocephalidea Kuchta et al., 2008 (Order) by Jorge Falcón-Ordaz and Luis García-Prieto, pages 283-288 Chapter 22: Diphyllobothriidea Kuchta et al., 2008 (Order): The Broad Tapeworms by Tomáš Scholz and Roman Kuchta, pages 289-296 Chapter 23: Trypanorhyncha Diesing, 1863 (Order) by Francisco Zaragoza-Tapia and Scott Monks, pages 297-305 Chapter 24: Cathetocephalidea Schmidt and Beveridge, 1990 (Order) by Luis García-Prieto, Omar Lagunas-Calvo, Brenda Atziri García-García, and Berenice Adán-Torres, pages 306-309 Chapter 25: Diphyllidea van Beneden in Carus, 1863 (Order) by Luis García-Prieto, Brenda Atziri García-García, Omar Lagunas-Calvo, and Berenice Adán-Torres, pages 310-315 Chapter 26: Lecanicephalidea Hyman, 1951 (Order) by Luis García-Prieto, Berenice Adán-Torres, Omar Lagunas-Calvo, and Brenda Atziri García- García, pages 316-320 Chapter 27: Litobothriidea Dailey, 1969 (Order) by Luis García-Prieto, Berenice Adán-Torres, Brenda Atziri García-García, and Omar Lagunas-Calvo, pages 321-325 Chapter 28: Phyllobothriidea Caira et al., 2014 (Order) by Brenda Atziri García-García, Omar Lagunas-Calvo, Berenice Adán-Torres, and Luis García-Prieto, pages 326-331 Chapter 29: Rhinebothriidea Healy et al., 2009 (Order) by Omar Lagunas-Calvo, Brenda Atziri García-García, Berenice Adán-Torres, and Luis García-Prieto, pages 332-339 Chapter 30: Relics of “Tetraphyllidea” van Beneden, 1850 (Order) by Berenice Adán-Torres, Omar Lagunas-Calvo, Brenda Atziri García-García, and Luis García-Prieto, pages 340-346 Amphilinidea Chapter 31: Amphilinidea Poche 1922 (Order) by Klaus Rohde, pages 347-353 Gyrocotylidea Chapter 32: Gyrocotylidea (Order): The Most Primitive Group of Tapeworms by Willi E. R. Xylander and Klaus Rohde, pages 354-360 Trematoda Aspidogastrea Chapter 33: Aspidogastrea (Subclass) by Klaus Rohde, pages 361-377 Digenea: Diplostomida Chapter 34: Introduction to Diplostomida Olson et al., 2003 (Order) by Lucrecia Acosta Soto, Bernard Fried, and Rafael Toledo, pages 378-393 Chapter 35: Aporocotylidae (Family): Fish Blood Flukes by Russell Q.-Y. Yong, pages 394-401 Digenea: Plagiorchiida Chapter 36: Introduction to Plagiorchiida La Rue, 1957 (Order) by Rafael Toledo, Bernard Fried, and Lucrecia Acosta Soto, pages 402-404 Chapter 37: Bivesiculata Olson et al., 2003 (Suborder): Small, Rare, but Important by Thomas H. Cribb and Scott C. Cutmore, pages 405-408 Chapter 38: Echinostomata La Rue, 1926 (Suborder) by Rafael Toledo, Bernard Fried, and Lucrecia Acosta Soto, pages 409-422 Chapter 39: Haplosplanchnata Olson et al., 2003 (Suborder): Two Hosts with Half the Guts by Daniel C. Huston, pages 423-427 Chapter 40: Hemiurata Skrjabin & Guschanskaja, 1954 (Suborder) by Lucrecia Acosta Soto, Bernard Fried, and Rafael Toledo, pages 428-435 Chapter 41: Monorchiata Olson et al., 2003 (Suborder): Two Families Separated by Salinity by Nicholas Q.-X. Wee, pages 436-442 Chapter 42: Opisthorchis (Genus) compiled from material from the United States Centers for Disease Control and Prevention, Division of Parasitic Diseases and Malaria by Sue Ann Gardner, pages 443-445 Xiphidiata Chapter 43: Allocreadiidae Looss, 1902 (Family) by Gerardo Pérez-Ponce de León, David Iván Hernández-Mena, and Brenda Solórzano-García, pages 446-459 Chapter 44: Haematoloechidae Odening, 1964 (Family) by Virginia León-Règagnon, pages 460-469 Chapter 45: Lecithodendriidae Lühe, 1901 (Family) by Jeffrey M. Lotz, pages 470-479 Chapter 46: Opecoelidae Ozaki, 1925 (Family): The Richest Trematode Family by Storm B. Martin, pages 480-489 Digenea Summary Chapter 47: Summary of the Digenea (Subclass): Insights and Lessons from a Prominent Parasitologist by Robin M. Overstreet, pages 490-53

The twilight of the Liberal Social Contract? On the Reception of Rawlsian Political Liberalism

This chapter discusses the Rawlsian project of public reason, or public justification-based 'political' liberalism, and its reception. After a brief philosophical rather than philological reconstruction of the project, the chapter revolves around a distinction between idealist and realist responses to it. Focusing on political liberalism’s critical reception illuminates an overarching question: was Rawls’s revival of a contractualist approach to liberal legitimacy a fruitful move for liberalism and/or the social contract tradition? The last section contains a largely negative answer to that question. Nonetheless the chapter's conclusion shows that the research programme of political liberalism provided and continues to provide illuminating insights into the limitations of liberal contractualism, especially under conditions of persistent and radical diversity. The programme is, however, less receptive to challenges to do with the relative decline of the power of modern states

Constitutivism

A brief explanation and overview of constitutivism

Expression of a malarial Hsp70 improves defects in chaperone-dependent activities in ssa1 mutant yeast

Plasmodium falciparum causes the most virulent form of malaria and encodes a large number of molecular chaperones. Because the parasite encounters radically different environments during its lifecycle, many members of this chaperone ensemble may be essential for P. falciparum survival. Therefore, Plasmodium chaperones represent novel therapeutic targets, but to establish the mechanism of action of any developed therapeutics, it is critical to ascertain the functions of these chaperones. To this end, we report the development of a yeast expression system for PfHsp70-1, a P. falciparum cytoplasmic chaperone. We found that PfHsp70-1 repairs mutant growth phenotypes in yeast strains lacking the two primary cytosolic Hsp70s, SSA1 and SSA2, and in strains harboring a temperature sensitive SSA1 allele. PfHsp70-1 also supported chaperone-dependent processes such as protein translocation and ER associated degradation, and ameliorated the toxic effects of oxidative stress. By introducing engineered forms of PfHsp70-1 into the mutant strains, we discovered that rescue requires PfHsp70-1 ATPase activity. Together, we conclude that yeast can be co-opted to rapidly uncover specific cellular activities mediated by malarial chaperones. © 2011 Bell et al

Identification of constrained sequence elements across 239 primate genomes

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3–9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals