Clinical biological and genetic heterogeneity of the inborn errors of pulmonary surfactant metabolism

Pulmonary surfactant is a multimolecular complex located at the air-water interface within the alveolus to which a range of physical (surface-active properties) and immune functions has been assigned. This complex consists of a surface-active lipid layer (consisting mainly of phospholipids), and of an aqueous subphase. From discrete surfactant sub-fractions one can isolate strongly hydrophobic surf acta nt proteins B (SP-B) and C (SP-C) as well as collectins SP-A and SP-D, which were shown to have specific structural, metabolic, or immune properties. Inborn or acquired abnormalities of the surfactant, qualitative or quantitative in nature, account for a number of human diseases. Beside hyaline membrane disease of the preterm neonate, a cluster of hereditary or acquired lung diseases has been characterized by periodic acid-Schiff-positive material filling the alveoli. From this heterogeneous nosologic group, at least two discrete entities presently emerge. The first is the SP-B deficiency, in which an essentially proteinaceous material is stored within the alveoli, and which represents an autosomal recessive Mendelian entity linked to the SFTPB gene (MIM 1786640). The disease usually generally entails neonatal respiratory distress with rapid fatal outcome, although partial or transient deficiencies have also been observed. The second is alveolar proteinosis, characterized by the storage of a mixed protein and lipid material, which constitutes a relatively heterogeneous clinical and biological syndrome, especially with regard to age at onset (from the neonate through to adulthood) as well as the severity of associated signs. Murine models, with a targeted mutation of the gene encoding granulocyte macrophage colony-stimulating factor (GM-CSF) (Csfgm) or the beta subunit of its receptor (II3rb1) support the hypothesis of an abnormality of surfactant turnover in which the alveolar macrophage is a key player. Apart from SP-B deficiency, in which a near-consensus diagnostic chart can be designed, the ascertainment of other abnormalities of surfactant metabolism is not straightforward. The disentanglement of this disease cluster is however essential to propose specific therapeutic procedures: repeated broncho-alveolar ravages, GM-CSF replacement, bone marrow grafting or lung transplantation

Safety and Efficacy of Ombitasvir, Paritaprevir With Ritonavir ± Dasabuvir With or Without Ribavirin in Patients With Human Immunodeficiency Virus-1 and Hepatitis C Virus Genotype 1 or Genotype 4 Coinfection: TURQUOISE-I Part 2.

BACKGROUND: Ombitasvir, paritaprevir with ritonavir, and dasabuvir (OBV/PTV/r ± DSV) ±ribavirin (RBV) are approved to treat hepatitis C virus (HCV) genotype 1 and 4 infection. Here, we investigate the safety and efficacy of OBV/PTV/r + DSV ±RBV for HCV genotype 1, and OBV/PTV/r + RBV for HCV genotype 4, in human immunodeficiency virus (HIV)-1 coinfected patients with or without compensated cirrhosis. METHODS: TURQUOISE-I, Part 2 is a phase 3 multicenter study. Patients with or without cirrhosis were HCV treatment-naive or -experienced, on an HIV-1 antiretroviral regimen containing atazanavir, raltegravir, dolutegravir, or darunavir (for genotype 4 only), and had plasma HIV-1 ribonucleic acid <40 copies/mL at screening. Patients received OBV/PTV/r ± DSV ±RBV for 12 or 24 weeks. RESULTS: In total, 228 patients were treated according to guidelines. Sustained virologic response at posttreatment week 12 (SVR12) was achieved by 194 of 200 (97%) and 27 of 28 (96%) patients with HCV genotype 1 and genotype 4 infection, respectively. There were 2 virologic failures: 1 breakthrough and 1 relapse in a cirrhotic and a noncirrhotic patient with genotype 1b and 1a infection, respectively. One reinfection occurred at posttreatment week 12 in a genotype 1a-infected patient. Excluding nonvirologic failures, the SVR12 rates were 98% (genotype 1) and 100% (genotype 4). Adverse events were mostly mild in severity and did not lead to discontinuation. Laboratory abnormalities were rare. CONCLUSIONS: The OBV/PTV/r ±DSV was well tolerated and yielded high SVR12 rates in patients with HCV genotype 1 or genotype 4/HIV-1 coinfection. The OBV/PTV/r ± DSV ±RBV is a potent HCV treatment option for patients with HIV-1 coinfection, regardless of treatment experience

Guillain-Barré syndrome: a century of progress

In 1916, Guillain, Barré and Strohl reported on two cases of acute flaccid paralysis with high cerebrospinal fluid protein levels and normal cell counts — novel findings that identified the disease we now know as Guillain–Barré syndrome (GBS). 100 years on, we have made great progress with the clinical and pathological characterization of GBS. Early clinicopathological and animal studies indicated that GBS was an immune-mediated demyelinating disorder, and that severe GBS could result in secondary axonal injury; the current treatments of plasma exchange and intravenous immunoglobulin, which were developed in the 1980s, are based on this premise. Subsequent work has, however, shown that primary axonal injury can be the underlying disease. The association of Campylobacter jejuni strains has led to confirmation that anti-ganglioside antibodies are pathogenic and that axonal GBS involves an antibody and complement-mediated disruption of nodes of Ranvier, neuromuscular junctions and other neuronal and glial membranes. Now, ongoing clinical trials of the complement inhibitor eculizumab are the first targeted immunotherapy in GBS

A low-eccentricity migration pathway for a 13-h-period Earth analogue in a four-planet system

It is commonly accepted that exoplanets with orbital periods shorter than one day, also known as ultra-short-period (USP) planets, formed further out within their natal protoplanetary disks before migrating to their current-day orbits via dynamical interactions. One of the most accepted theories suggests a violent scenario involving high-eccentricity migration followed by tidal circularization. Here we present the discovery of a four-planet system orbiting the bright (V = 10.5) K6 dwarf star TOI-500. The innermost planet is a transiting, Earth-sized USP planet with an orbital period of ~13 hours, a mass of 1.42 ± 0.18 M⊕, a radius of 1.166−0.058+0.061R⊕ and a mean density of 4.89−0.88+1.03gcm−3. Via Doppler spectroscopy, we discovered that the system hosts 3 outer planets on nearly circular orbits with periods of 6.6, 26.2 and 61.3 days and minimum masses of 5.03 ± 0.41 M⊕, 33.12 ± 0.88 M⊕ and 15.05−1.11+1.12M⊕, respectively. The presence of both a USP planet and a low-mass object on a 6.6-day orbit indicates that the architecture of this system can be explained via a scenario in which the planets started on low-eccentricity orbits then moved inwards through a quasi-static secular migration. Our numerical simulations show that this migration channel can bring TOI-500 b to its current location in 2 Gyr, starting from an initial orbit of 0.02 au. TOI-500 is the first four-planet system known to host a USP Earth analogue whose current architecture can be explained via a non-violent migration scenario

Dental skill mix: a cross-sectional analysis of delegation practices between dental and dental hygiene-therapy students involved in team training in the South of England

BACKGROUND: Research suggests that health professionals who have trained together have a better understanding of one another’s scope of practice and are thus equipped for teamwork during their professional careers. Dental hygiene-therapists (DHTs) are mid-level providers that can deliver routine care working alongside dentists. This study examines patterns of delegation (selected tasks and patients) by dental students to DHT students training together in an integrated team. METHODS: A retrospective sample of patient data (n = 2,063) was extracted from a patient management system showing the treatment activities of two student cohorts (dental and DHT) involved in team training in a primary care setting in the South of England over two academic years. The data extracted included key procedures delegated by dental students to DHT students coded by skill-mix of operator (e.g., fissure sealants, restorations, paediatric extractions) and patient demography. χ(2) tests were conducted to investigate the relationship between delegation and patient age group, gender, smoking status, payment-exemption status, and social deprivation. RESULTS: A total of 2,063 patients managed during this period received treatments that could be undertaken by either student type; in total, they received 14,996 treatment procedures. The treatments most commonly delegated were fissure sealants (90%) and restorations (51%); whilst the least delegated were paediatric extractions (2%). Over half of these patients (55%) had at least one instance of delegation from a dental to a DHT student. Associations were found between delegation and patient age group and smoking status (P <0.001). Children under 18 years old had a higher level of delegation (86%) compared with adults of working age (50%) and patients aged 65 years and over (56%). A higher proportion of smokers had been delegated compared with non-smokers (45% cf. 26%; P <0.001). CONCLUSIONS: The findings suggest that delegation of care to DHT students training as a team with dental students, involved significantly greater experience in treating children and adult smokers, and providing preventive rather than invasive care in this integrated educational and primary care setting. The implications for their contribution to dentistry and the dental team are discussed, along with recommendations for primary care data recording

Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas

Screening of REarranged during Transfection (RET) gene mutations has been carried out in different series of sporadic medullary thyroid carcinomas (MTC). RET-positive tumours seem to be associated to a worse clinical outcome. However, the correlation between the type of RET mutation and the patients' clinicopathological data has not been evaluated yet