Lunapark deficiency leads to an autosomal recessive neurodevelopmental phenotype with a degenerative course, epilepsy and distinct brain anomalies.

LNPK encodes a conserved membrane protein that stabilizes the junctions of the tubular endoplasmic reticulum network playing crucial roles in diverse biological functions. Recently, homozygous variants in LNPK were shown to cause a neurodevelopmental disorder (OMIM#618090) in four patients displaying developmental delay, epilepsy and nonspecific brain malformations including corpus callosum hypoplasia and variable impairment of cerebellum. We sought to delineate the molecular and phenotypic spectrum of LNPK-related disorder. Exome or genome sequencing was carried out in 11 families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals, including review of previously reported patients. We identified 12 distinct homozygous loss-of-function variants in 16 individuals presenting with moderate to profound developmental delay, cognitive impairment, regression, refractory epilepsy and a recognizable neuroimaging pattern consisting of corpus callosum hypoplasia and signal alterations of the forceps minor ('ear-of-the-lynx' sign), variably associated with substantia nigra signal alterations, mild brain atrophy, short midbrain and cerebellar hypoplasia/atrophy. In summary, we define the core phenotype of LNPK-related disorder and expand the list of neurological disorders presenting with the 'ear-of-the-lynx' sign suggesting a possible common underlying mechanism related to endoplasmic reticulum-phagy dysfunction.

Toxicology of diatomaceous earth, phyto oils and their admixed emulsions against adults of Tribolium castaneum (Herbst).

Tribolium castaneum (Herbst), one of the invasive stored pest, is resistant to the most of synthetic insecticides used against this it. Moreover, synthetic insecticides are a major threat to human health, the environment, and the ecosystem. The development of some smart tools is needed to minimize the use of hazardous chemicals. As an alternative, nano-insecticides are on the horizon. Emulsions are expressed as sustain release of insecticidal components to achieve maximum efficacy and low residual toxicity. In this study, some essential oils (Cymbopogon citratus (DC.) Stapf, Ocimum basilicum L., Curcuma longa L., and Trachyspermum ammi L.), diatomaceous earth (DE), and their nano-emulsions are evaluated against T. castaneum. Essential oils and DE were tested at four (60 ppm, 30 ppm, 15 ppm, 7.5 ppm) different concentrations with and without emulsions, and data was recorded after 6, 12, 24, 48, and 72 h of exposure respectively. The mortality observed in essential oils of C. citratus, O. basilicum, and C. longa without emulsion after 72 h of treatment at the highest concentration was 98%, 95%, and 85%, respectively. While, at the highest concentration the lowest mortalities were observed with DE and T. ammi i.e. 65%. Insecticidal activity of emulsion essential oils increased to 100%, 98%, 90%, and 68.3% for C. longa, C. citratus, O. basilicum, and T. ammi, respectively. The results support that these admixed emulsions could be used as an alternative to synthetic insecticides in conventional formulations.

The Effectiveness of CFRP- and Auxetic Fabric-Strengthened Brick Masonry under Axial Compression: A Numerical Investigation.

Bonded brickwork used for loadbearing walls is widely found in heritage structures worldwide. The evaluation of bonded masonry structures and their strengthening strategies against dynamic actions require appropriate understanding under cyclic loading. Subsequently, a simplified 3D microscale numerical model is developed in this paper to analyse bonded brickwork under cyclic compression. A plasticity-based damage constitutive model to represent damage in masonry bricks under cyclic compression loading was employed, and zero-thickness interfaces were considered with non-linear damage properties to simulate the mechanical behaviour of masonry. A threshold strain level was used to enact the element deletion technique for initiating brittle crack opening in the masonry units. The developed model was validated against the experimental results published by the authors in the past. The models were able to accurately predict the experimental results with an error limit of 10% maximum. Mainly, two types of strengthening materials, possessing (1) high energy absorption characteristics (auxetic fabric) and (2) high strength properties (carbon fibre reinforced polymer composites/CFRP) were employed for damage mitigation under cyclic compression. Results show that the CFRP-strengthened masonry failure was mainly attributed to de-bonding of the CFRP and crushing under compression. However, the auxetic strengthening is shown to significantly minimise the de-bonding phenomenon. Enhanced energy dissipation characteristics with relatively higher ductility (up to ~50%) and reduced damages on the bonded brickwork were observed as compared to the CFRP-strengthened brickwork under cyclic compression loading. Additionally, the auxetic fabric application also increased the compressive resistance of brickwork by 38-60% under monotonic loading, which is comparably higher than with the CFRP strengthening technique.

Splenomegaly May Increase the Risk of Rejection in Low-Risk Matched Related Donor Transplant for Thalassemia, This Risk Can Be Partially Overcome by Additional Immunosuppression during Conditioning.

Severe thalassemia syndromes (ST) are highly curable by bone marrow transplant (BMT), but rejection may still occur. We retrospectively analyzed our fully matched related donor transplants to establish if isolated splenomegaly is an independent risk factor for rejection and if this risk can be reduced by modifying the conditioning protocol. In this study, we compared rejection rates between patients with and without splenomegaly in 189 consecutive low-risk ST transplants across 2 sequential conditioning regimens: regimen A (August 2013 to December 2016): busulfan (14 mg/kg oral, not adjusted to serum levels), cyclophosphamide (200 mg/kg), and anti-thymocyte globulin (ATG) (Genzyme (Sanofi, Paris, France) 4 mg/kg or Fresenius (Grafalon, Neovii Biotech GmbH, Gräfelfing Germany) 16 mg/kg on days -12 to -10), and regimen B: same backbone as regimen A except fludarabine total dose of 150 mg was added upfront and ATG dose was increased to 7 mg/kg in case of splenomegaly and/or sex-mismatched transplants (January 2017 to September 2018). Compared with regimen A, in regimen B, both overall rejection rates (RRs) (16% versus 6.5%, P = .023) and treatment-related mortality (TRM) (9.9% versus 2.8%, P = .038) improved significantly. By Cox regression analysis, the improvement in RR between the 2 protocols was particularly significant in patients with splenomegaly (RR 54.5% versus 6.5%, P = .00015; TRM 18.2% versus 6.5%, P = .25) (hazard ratio, 4.13; confidence interval, 1.61 to 10.6; P = .003). The increased risk of rejection related to splenomegaly can be overcome by adding fludarabine to the standard ATG-Busulfan- Cyclophosphamide (ATG-Bu-Cy) protocol without significantly increasing transplant-related morbidity and mortality or resorting to splenectomy pre-BMT.

ATG vs thiotepa with busulfan and cyclophosphamide in matched-related bone marrow transplantation for thalassemia.

Matched-related bone marrow transplantation (BMT) may cure >80% of low-risk children with severe thalassemia (ST). Very long-term follow-up studies have shown how the standard busulfan-cyclophosphamide (BuCy) regimen may be associated with normalization of health-related quality of life, no second malignancies in the absence of chronic graft-versus-host disease, and fertility preservation in many patients. However, because BuCy may be associated with high rejection rates, some centers incorporate thiotepa (Tt) in busulfan- or treosulfan-based regimens, a combination that may increase the risk of permanent infertility. This study retrospectively compares matched-related BMT outcomes in 2 groups of low-risk ST patients conditioned with either Tt or anti-thymocyte globulin (ATG) in addition to BuCy. A total of 81 consecutive first BMTs were performed in 5 collaborating startup BMT centers in the Indian subcontinent between January 2009 and January 2016; 30 patients were transplanted after conditioning with Tt-BuCy between January 2009 and July 2013, whereas between August 2013 and January 2016, 51 patients received ATG-BuCy. All patients were <15 years and had no hepatomegaly (liver ≤2 cm from costal margin). Actuarial overall survival in the Tt-BuCy and ATG-BuCy groups was 87% and 94% and thalassemia-free survival was 80% and 85% at a median follow-up of 37 and 17 months, respectively, with no significant differences by log-rank statistics. Substituting Tt with ATG in the standard BuCy context seems safe and effective and may decrease transplant-related mortality. Higher fertility rates are expected for patients who received ATG-BuCy.

Role-play as a learning modality in Pakistan.

OBJECTIVES: To assess the effectiveness of role-play practised as a part of an integrated modular curriculum at Shifa College of Medicine, Islamabad. METHODS: Each class of 100 students from the first to the final years of studying for a Bachelor of Medicine, Bachelor of Surgery (MBBS), was split into seven or eight groups. Students divided the roles amongst themselves. Students were given one week's notice to prepare for each session, and had a maximum of 7 minutes for performance and 5 minutes for feedback from faculty members. Faculty staff observed the skills performed and content explored at the level of the students' training. The students' responses were recorded by a formulated questionnaire. Descriptive statistics were used to analyse quantitative data. The results obtained were presented as frequencies and percentages. RESULTS: In this study, 351 (70.2%) of eligible students participated. The advantage of role-play in alleviating potential difficulties in communicating with patients was agreed by 63 per cent (n = 223). Two hundred and forty-two students (69%) considered that role-play promoted teamwork and interpersonnel skills. One hundred and ninety-three students (55%) agreed that role-play helped them to integrate knowledge of basic sciences into clinical skills. That these sessions evoked critical thinking among students was reported by 41 per cent (n = 144). The roles created reflected real life scenarios was agreed by 27 per cent (n = 96) students. Students were given one week's notice to prepare for each session CONCLUSION: Role-play was accepted to enhance communication skills, the promotion of teamwork and the provision of a healthy environment to integrate learning processes among students.