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Introduction In response to a high burden of opioid use disorder (OUD), Iran established a network of opioid agonist treatment (OAT) centres beginning in 2002. To increase treatment diversity, particularly for patients who use opium as their drug of choice, opium tincture (OT)-assisted treatment was introduced to the network. This study aimed to explore factors influencing OT-assisted treatment selection for OUD in Tehran, Iran. Methods We conducted 54 in-depth interviews with patients with OUD (n = 33), family members of patients (n = 9) and drug treatment providers (n = 12). Participants were recruited from 12 drug treatment centres across Tehran, between September and November 2019. All interviews were audio-recorded, transcribed and coded in OpenCode 4.02 software and analysed using thematic analysis. Results Study participants more commonly reported individual-level factors as facilitators (e.g. to reduce harms associated with illicit opioid use, achieve recovery through a gradual dose reduction regimen combined with Congress 60 recovery program) and structural level factors (e.g. low adoption by OAT system and lack of familiarity of treatment providers) as barriers for utilisation of OT-assisted treatment regimens. OT was perceived to produce lower levels of physiological dependence than methadone, but the requirement for twice supervised dosing was restrictive. Low familial and community acceptance were also seen as barriers to access. Discussion and Conclusions This research identified a range of perceived benefits for OT-assisted treatment ranging from harm reduction to an intermediate step to achieve recovery. However, several structural-, individual-, familial- and community-level barriers impede its availability and acceptability.

Usher syndrome, the most prevalent cause of combined hereditary vision and hearing impairment, is clinically and genetically heterogeneous. Moreover, several conditions with phenotypes overlapping Usher syndrome have been described. This makes the molecular diagnosis of hereditary deaf–blindness challenging. Here, we performed exome sequencing and analysis on 7 Mexican and 52 Iranian probands with combined retinal degeneration and hearing impairment (without intellectual disability). Clinical assessment involved ophthalmological examination and hearing loss questionnaire. Usher syndrome, most frequently due to biallelic variants in MYO7A (USH1B in 16 probands), USH2A (17 probands), and ADGRV1 (USH2C in 7 probands), was diagnosed in 44 of 59 (75%) unrelated probands. Almost half of the identified variants were novel. Nine of 59 (15%) probands displayed other genetic entities with dual sensory impairment, including Alström syndrome (3 patients), cone-rod dystrophy and hearing loss 1 (2 probands), and Heimler syndrome (1 patient). Unexpected findings included one proband each with Scheie syndrome, coenzyme Q10 deficiency, and pseudoxanthoma elasticum. In four probands, including three Usher cases, dual sensory impairment was either modified/aggravated or caused by variants in distinct genes associated with retinal degeneration and/or hearing loss. The overall diagnostic yield of whole exome analysis in our deaf–blind cohort was 92%. Two (3%) probands were partially solved and only 3 (5%) remained without any molecular diagnosis. In many cases, the molecular diagnosis is important to guide genetic counseling, to support prognostic outcomes and decisions with currently available and evolving treatment modalities.

Gadolinium-based contrast agents (GdCAs) have been the most frequently used T1-weighted magnetic resonance imaging (MRI) contrast agents for decades. However, they have serious disadvantages such as low longitudinal relaxivity value (r1) and high dose associated-nephrotoxicity that restrict their wide applications. These emphasize the need for an ideal stable and biocompatible T1-weighted CA with high contrast enhancement performance. Here, we propose a wet-chemical synthesis technique to form a nanocomposite consisting of ultrasmall iron oxide nanoparticles (US-IO) and Gd2O3 hybrid nanoparticles stabilized with dextran (FG-HNPs) for T1-weighted MR imaging. Relaxometry study showed that FG-HNPs have a high r1 value (42.28 mM− 1S− 1) and low relaxivity ratio (r2/r1: 1.416) at 3.0 T. In vivo MRI contrast enhancement factor (ΔSNR) for FG-HNPs (257.025 ± 17.4%) was found to be 1.99-fold higher than US-IO (129.102 ± 15%) and 3.35-fold higher than Dotarem (76.71 ± 14.2%) as routinely-used T1-weighted CA. The cytotoxicity assay and histological examination confirmed the biocompatibility of FG-HNPs. The biodistribution study, transmission electron microscopy (TEM) and Prussian blue (PB) staining of tumor tissue proved the effective tumor localization of FG-HNPs. Therefore, FG-HNPs can be suggested as a promising CA for T1-weighted MRI of tumors by virtue of their remarkable relaxivities and high biocompatibility.

The aim of this study is to compare balloon-retention percutaneous radiologic gastrostomy (PRG) tube insertion performed with and without gastropexy, primarily focusing on pain and patient-reported outcomes. Research ethics board approved a dual-arm, single-centre, randomized trial of 60 patients undergoing primary 14-French PRG tube insertion (NCT04107974). Patients were randomized to receive either PRG with gastropexy or without gastropexy. Data were collected for technical outcomes, patient-reported outcomes pre-procedure, post-procedure and at 1-month, as well as quality of life parameters at 1-month post-procedure (EQ5D-5L, Visual Analogue Scale and Functional Assessment of Cancer Therapy-Enteral Feeding questionnaires). Complications occurring up to 6-months post-procedure were recorded. Sixty patients were randomized to the gastropexy group (n = 30) or non-gastropexy (n = 30) group. One non-gastropexy patient was withdrawn from the study due to failed insertion. PRG procedural time was significantly longer when using gastropexy (mean 11.4 ± 7.19 min) compared with non-gastropexy (mean 6.79 ± 4.63 min; p

Background: Coronavirus disease 2019 (COVID-19) affects the pediatric population. Objectives: Due to limited data, this study aimed to evaluate the safety and efficacy of favipiravir in the hospitalized pediatric population diagnosed with COVID-19. Methods: The present retrospective cohort study was conducted on pediatric patients aged 1 - 18 years with a diagnosis of COVID-19 admitted to Mofid Children’s Hospital, Tehran, Iran. Favipiravir was administrated at a dose of 60 mg/kg/day (max: 3200 mg/day) on the first day and then 23 mg/kg/day (max: 1200 mg/day) for 7 to 14 days. The patients were evaluated regarding the need for invasive mechanical ventilation, intensive care unit admission, duration of hospital stay, and mortality. Safety was measured by the occurrence of related adverse drug reactions (ADRs). Results: A total of 95 patients were included in the study. Favipiravir was administered to 25 patients. The need for invasive mechanical ventilation was reported in 4 (16.00%) and 11 (15.71%) patients in the favipiravir and control groups, respectively (P = 1.000). The median duration of hospital stays was significantly higher in patients who received favipiravir than in the controls (P = 0.002). No difference was observed in the mortality rate (P = 0.695). The ADRs, including decreased appetite, hypotension, and chest pain, were more prevalent in patients who received favipiravir than in the controls (P < 0.05). Conclusions: The administration of favipiravir in the pediatric population is associated with higher ADR occurrence with no positive effect on the need for invasive mechanical ventilation, hospital stay, and mortality. Further randomized controlled trials are necessary for better judgment.

Background: Octreotide has been used to control bleeding episodes with variceal origin in the pediatric population. To date, there is no clear evidence of octreotide use for non-variceal bleeding in clinical trials. Objectives: We aimed to assess the octreotide efficacy as an add-on therapy to the conventional regimen of proton pump inhibitors for controlling upper non-variceal gastrointestinal (GI) bleeding in the pediatric population. Methods: This prospective randomized controlled clinical trial was performed on pediatric patients aged 1 - 15 years and diagnosed with acute non-variceal upper GI bleeding. The participants were allocated to receive octreotide or placebo and pantoprazole concomitantly. The study was conducted in Mofid Children’s Hospital, Tehran, Iran, during February 2019 - December 2019. Patients with hepatic failure, liver stigma, and coagulopathy due to thrombocytopenia were excluded. Demographic, clinical, and preclinical data were recorded in prepared sheets. All the patients were followed until therapy discontinuation. P-value < 0.05 was considered significant. Results: Forty-three patients with a mean age of 4.98 ± 3.79 years and confirmed non-variceal upper GI bleeding were included in the present study. Most patients had no specific etiology for their bleeding episodes. Patients in the intervention and control groups received pantoprazole in comparable doses. No differences were observed between the two groups in terms of baseline hemoglobin values (P = 0.08), while final hemoglobin values were significantly higher in the intervention group (P = 0.014). The bleeding duration was not significantly different between the two groups (P = 0.99). Moreover, none of the cases showed adverse drug reactions due to octreotide infusion. Conclusions: Our study demonstrated that octreotide did not alter bleeding duration or need for blood transfusion. However, positive results were observed for hemoglobin, affecting blood loss volume.

Summary Background Perhaps, as never before, we need innovators. With our growing population numbers, and with increasing pressures on our education systems, are we in danger of becoming more rigid and formulaic and increasingly inhibiting innovation? When young can we predict who will become the great innovators? For example, in medicine, who will change clinical practice? Aims We therefore determined to assess whether the current academic excellence approach to medical school entrance would have captured previous great innovators in medicine, assuming that they should all have well fulfilled current entrance requirements. Methods The authors assembled a list of 100 great medical innovators which was then approved, rejected or added to by a jury of 12 MD fellows of the Royal Society of Canada. Two reviewers, who had taken both the past and present Medical College Admission Test as part of North American medical school entrance requirements, independently assessed each innovator’s early life educational history in order to predict the innovator’s likely success at medical school entry, assuming excellence in all entrance requirements. Results Thirty-one percent of the great medical innovators possessed no medical degree and 24% would likely be denied entry to medical school by today’s standards (e.g. had a history of poor performance, failure, dropout or expulsion) with only 24% being guaranteed entry. Even if excellence in only one topic was required, the figure would only rise to 41% certain of medical school entry. Conclusion These data show that today’s medical school entry standards would have barred many great innovators and raise questions about whether we are losing medical innovators as a consequence. Our findings have important implications for promoting flexibility and innovation for medical education, and for promoting an environment for innovation in general.

We investigate the super-linear spreading in a reaction-diffusion model analogous to the Fisher-KPP equation, but in which the population is heterogeneous with respect to the dispersal ability of individuals, and the saturation factor is non-local with respect to one variable. We prove that the rate of acceleration is slower than the rate of acceleration predicted by the linear problem, that is, without saturation. This hindering phenomenon is the consequence of a subtle interplay between the non-local saturation and the non-trivial dynamics of some particular curves that carry the mass at the front. A careful analysis of these trajectories allows us to identify the value of the rate of acceleration. The article is complemented with numerical simulations that illustrate some behavior of the model that is beyond our analysis., Comment: 55 pages, 11 figures, Numerical appendix by Thierry Dumont

HOX genes are a group of evolutionarily conserved genes that encode a family of transcription factors that regulate early developmental morphogenetic processes and continue to be expressed into adulthood. These highly conserved HOX factors play an unquestioned crucial role as master regulators during embryonic vertebrate development and morphogenesis by controlling the three dimensional body plan organization. HOX genes specify regions of the body plan of an embryo along the head-tail axis. They encode proteins that specify the characteristics of ‘position’, ensuring that the correct structures form in the correct places of the body. Expression of HOX is known to persist in many tissues in the postnatal period suggesting the role of these genes not only during development but also for the functioning of tissues throughout life. The tissue-specific pattern of HOX gene expression is inherent in stromal/stem cells of mesenchymal origin, such as mesenchymal stromal cells, fibroblasts, smooth muscle cells, and preadipocytes, enabling them to memorize their topographic location in the form of their HOX code and to fulfill their location-specific functions. In this chapter, we focus on the expression and potential role of HOX genes in adult tissues. We review evidence that site-specific expression of HOX genes is connected to location-specific disease susceptibility and review studies showing that dysregulated expression of HOX genes can be associated with various diseases. By recognizing the importance of site-specific molecular mechanisms in the organ stroma, we gain new insights into the processes underlying the site-specific manifestation of disease.

Quantum error correction with biased-noise qubits can drastically reduce the hardware overhead for universal and fault-tolerant quantum computation. Cat qubits are a promising realization of biased-noise qubits as they feature an exponential error bias inherited from their non-local encoding in the phase space of a quantum harmonic oscillator. To confine the state of an oscillator to the cat qubit manifold, two main approaches have been considered so far: a Kerr-based Hamiltonian confinement with high gate performances, and a dissipative confinement with robust protection against a broad range of noise mechanisms. We introduce a new combined dissipative and Hamiltonian confinement scheme based on two-photon dissipation together with a Two-Photon Exchange (TPE) Hamiltonian. The TPE Hamiltonian is similar to Kerr nonlinearity, but unlike the Kerr it only induces a bounded distinction between even- and odd-photon eigenstates, a highly beneficial feature for protecting the cat qubits with dissipative mechanisms. Using this combined confinement scheme, we demonstrate fast and bias-preserving gates with drastically improved performance compared to dissipative or Hamiltonian schemes. In addition, this combined scheme can be implemented experimentally with only minor modifications of existing dissipative cat qubit experiments., 24 pages, 18 figures

A proper understanding of the links between varying gene expression levels and complex trait adaptation is still lacking, despite recent advances in sequencing techniques leading to new insights on their importance in some evolutionary processes. This calls for extensions of the continuum-of-alleles framework first introduced by Kimura (1965 Proc. Natl Acad. Sci. USA 54 731–36) that bypass the classical Gaussian approximation. Here, we propose a novel mathematical framework to study the evolutionary dynamics of quantitative alleles for sexually reproducing populations under natural selection and competition through an integro-differential equation. It involves a new reproduction operator which is nonlinear and nonlocal. This reproduction operator is different from the infinitesimal operator used in other studies with sexual reproduction because of different underlying genetic structures. In an asymptotic regime where initially the population has a small phenotypic variance, we analyse the long-term dynamics of the phenotypic distributions according to the methodology of small variance (Diekmann et al 2005 Theor. Popul. Biol. 67 257–71). In particular, we prove that the reproduction operator strains the limit distribution to be a product measure. Under some assumptions on the limit equation, we show that the population remains monomorphic, that is the phenotypic distribution remains concentrated as a moving Dirac mass. Moreover, in the case of a monomorphic distribution, we derive a canonical equation describing the dynamics of the dominant alleles.

This study aims to report the developmental and histopathological features of ocular tissues from an electively aborted human fetus with mutations inBoth eyes of two 17-week gestational aged fetuses, the first withDelayed development in ocular tissues, decreased expression of cytochrome p4501B1 protein, irregular extracellular matrix structure, and increased oxidative stress biomarker were evident in the ocular tissues of the fetus withTo the best of our knowledge, this is the first report of prenatal diagnosis of primary congenital glaucoma. We also describe histopathological changes in the primary congenital glaucoma-affected globes revealing the effect of

Background: Surgical procedures may be complicated by post-surgical infections. This study investigates the role of administering perioperative narrow-spectrum antibiotic prophylaxis in preventing post-surgical infections as compared to routine broad-spectrum antibiotic usage in the surgical ward. Methods: Narrow-spectrum perioperative antibiotic prophylaxis, in accordance with CDC guidelines, was implemented in our hospital in October 2019. In this quasi-experimental study, all the children (one month to fifteen years old) who underwent surgery from April to September 2019 and had received broad-spectrum antibiotics for various durations, as well as those operated after the implementation of the perioperative narrow-spectrum antibiotic prophylaxis plan (October 2019 to March 2020) were enrolled. Surgical wound type (clean, clean/contaminated, contaminated, and dirty), type and site of the infection, and the patient’s age and sex were recorded. Cases with postoperative infections were followed up in the two groups during hospitalization and for 30 days (or 90 days if a prosthetic material was implanted) after discharge. The rate of post-surgical infections was compared between the two groups by the Mann-Whitney and chi-squared tests. Results: In total, 4308 cases were enrolled in the first six months and 3650 in the second six months of the study. The rate of post-surgical infections in the first group was 31/4380 (23.7%) as compared to 22/3650 (20%) in the second group (P-value = 0.3365) Conclusions: There was no increase in the frequency of post-surgical infections after the implementation of the perioperative narrow-spectrum antibiotic prophylaxis protocol. Reducing the use of antibiotics before surgery shrinks costs and antibiotic resistance without any effect on the post-surgical infection rate.

The combination of multiple therapeutic and diagnostic functions is fast becoming a key feature in the area of clinical oncology. The advent of nanotechnology promises multifunctional nanoplatforms with the potential to deliver multiple therapeutics while providing diagnostic information simultaneously. In this study, novel iron oxide-gold core-shell hybrid nanocomposites (Fe

Allogeneic stem cell transplant recipients are at risk of BK virus-associated hemorrhagic cystitis. This condition causes a significant morbidity and worsens clinical outcomes. The standard cares for BK virus-associated hemorrhagic cystitis are saline irrigation and forced diuresis. Notably, several beneficial roles are proposed for antiviral and anti-inflammatory agents against BK virus-associated hemorrhagic cystitis. However, cases who are at risk of cystectomy remain refractory. Herein, we present a 13-year-old boy with severe hematuria by passing two months from his allogeneic stem cell transplantation. The laboratory work up showed high BK viremia >1.1 × 10 copies/ml in this case's urine sample. The patient was treated with antiviral agents in combination with supportive care. Moreover, intravesical alum was administered, but no clinical benefits were achieved. Finally, intravesical alprostadil was prepared under the supervision of a pediatric clinical pharmacist. In this regard, an alprostadil solution was prepared by constitution of 250 μg alprostadil in 50 mL saline. After administrating the first dose of intravesical alprostadil, an acceptable clinical response was observed, and hematuria stopped. Of note, alprostadil induces platelet aggregation and vasoconstriction. Thus, bleeding can be controlled after the administration of intravesical alprostadil. This strategy may be associated with several side effects including bladder spasm. This study is the first report describing the special role of intravesical alprostadil in refractory cases of BK virus-associated hemorrhagic cystitis. In such refractory cases, clinicians can use intravesical alprostadil rather than invasive therapies in the treatment of BK virus-hemorrhagic cystitis.