Introduction: Ex-vivo gene therapy has had significant clinical impact over the last couple of years and in-vivo gene therapy products are being approved for clinical use. Gene therapy and gene ...editing approaches have huge potential to treat genetic disease and chronic illness.
Areas covered: This article provides a review of in-vivo approaches for gene therapy in the lung and liver, exploiting non-viral and viral vectors with varying serotypes and pseudotypes to target-specific cells. Antibody responses inhibiting viral vectors continue to constrain effective repeat administration. Lessons learned from ex-vivo gene therapy and genome editing are also discussed.
Expert opinion: The fields of lung and liver in-vivo gene therapy are thriving and a comparison highlights obstacles and opportunities for both. Overcoming immunological issues associated with repeated administration of viral vectors remains a key challenge. The addition of targeted small molecules in combination with viral vectors may offer one solution. A substantial bottleneck to the widespread adoption of in-vivo gene therapy is how to ensure sufficient capacity for clinical-grade vector production. In the future, the exploitation of gene editing approaches for in-vivo disease treatment may facilitate the resurgence of non-viral gene transfer approaches, which tend to be eclipsed by more efficient viral vectors.
Children with neuromuscular disorders with a progressive muscle weakness such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy frequently develop a progressive scoliosis. A severe scoliosis ...compromises respiratory function and makes sitting more difficult. Spinal surgery is considered the primary treatment option for correcting severe scoliosis in neuromuscular disorders. Surgery in this population requires a multidisciplinary approach, careful planning, dedicated surgical procedures, and specialized after care.
The guideline is based on scientific evidence and expert opinions. A multidisciplinary working group representing experts from all relevant specialties performed the research. A literature search was conducted to collect scientific evidence in answer to specific questions posed by the working group. Literature was classified according to the level of evidence.
For most aspects of the treatment scientific evidence is scarce and only low level cohort studies were found. Nevertheless, a high degree of consensus was reached about the management of patients with scoliosis in neuromuscular disorders. This was translated into a set of recommendations, which are now officially accepted as a general guideline in the Netherlands.
In order to optimize the treatment for scoliosis in neuromuscular disorders a Dutch guideline has been composed. This evidence-based, multidisciplinary guideline addresses conservative treatment, the preoperative, perioperative, and postoperative care of scoliosis in neuromuscular disorders.
The regularity of pulsar emissions becomes apparent once we reference the pulses' times of arrivals to the inertial rest frame of the solar system. It follows that errors in the determination of ...Earth's position with respect to the solar-system barycenter can appear as a time-correlated bias in pulsar-timing residual time series, affecting the searches for low-frequency gravitational waves performed with pulsar timing arrays. Indeed, recent array datasets yield different gravitational-wave background upper limits and detection statistics when analyzed with different solar-system ephemerides. Crucially, the ephemerides do not generally provide usable error representations. In this article we describe the motivation, construction, and application of a physical model of solar-system ephemeris uncertainties, which focuses on the degrees of freedom (Jupiter's orbital elements) most relevant to gravitational-wave searches with pulsar timing arrays. This model, BayesEphem, was used to derive ephemeris-robust results in NANOGrav's 11-yr stochastic-background search, and it provides a foundation for future searches by NANOGrav and other consortia. The analysis and simulations reported here suggest that ephemeris modeling reduces the gravitational-wave sensitivity of the 11-yr dataset; and that this degeneracy will vanish with improved ephemerides and with the longer pulsar timing datasets that will become available in the near future.
We have constructed a new timescale, TT(IPTA16), based on observations of radio pulsars presented in the first data release from the International Pulsar Timing Array (IPTA). We used two analysis ...techniques with independent estimates of the noise models for the pulsar observations and different algorithms for obtaining the pulsar timescale. The two analyses agree within the estimated uncertainties and both agree with TT(BIPM17), a post-corrected timescale produced by the Bureau International des Poids et Mesures (BIPM). We show that both methods could detect significant errors in TT(BIPM17) if they were present. We estimate the stability of the atomic clocks from which TT(BIPM17) is derived using observations of four rubidium fountain clocks at the US Naval Observatory. Comparing the power spectrum of TT(IPTA16) with that of these fountain clocks suggests that pulsar-based timescales are unlikely to contribute to the stability of the best timescales over the next decade, but they will remain a valuable independent check on atomic timescales. We also find that the stability of the pulsar-based timescale is likely to be limited by our knowledge of solar-system dynamics, and that errors in TT(BIPM17) will not be a limiting factor for the primary goal of the IPTA, which is to search for the signatures of nano-Hertz gravitational waves.
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