Mathematical Modelling of Tuberculosis Infection

Tuberculosis is one of the leading causes of death by infectious disease in the world today. However, the majority of individuals infected with Mycobacterium tuberculosis are able to contain bacterial growth and establish a latent infection. The aim of this thesis is to develop mathematical models to study the progression of disease in individuals infected with Mycobacterium tuberculosis. This work focuses on understanding bacterial and host defence mechanisms that govern the outcome of infection, and on identifying factors that affect the outcome of anti-tuberculosis chemotherapy. A detailed model of human tuberculosis infection in the lung and peripheral draining lymph node is developed that builds on models published in the literature. Analysis of this model suggests a differential role for innate and adaptive immune responses in determining the outcome of infection, and a possible role for an intracellular bacterial population in establishing a persistent infection. For certain parameter values this system has multiple steady states so the outcome of infection may also depend on initial conditions. This model is then modified to incorporate the effect of treatment with the antimycobacterial agent rifampicin. The model is used to investigate different treatment regimens and simulation results suggest that the length of tuberculosis therapy can be reduced by further optimizing the standard rifampicin dosing regimen. Simple predator-prey type models of infection are constructed to gain further insight into the mechanisms that control the establishment and maintenance of latency. These models support observations made from the full disease model regarding the roles of innate and adaptive immunity in fighting infection and the influence of an intracellular bacterial population that is protected from the innate immune system. The addition of a population of non-replicating or slow growing bacteria contributes to the establishment of latent infection and generally makes latency a more robust and stable state

THE DISJUNCTIVE OBLIGATIONS BETWEEN IT’S ECONOMIC EFFICIENCY AND IT’S LEGAL REGULATION NEGLECT

A contract places a legal obligation upon the contracting parties to perform their mutual obligations , and it carries on until discharge on termination of contract. The most mutual and usual mode of discharging a contract is to perform. However, the disjunctive obligations facilitate this performance, and help any party of contract to perform him under the contract, because the pratique of contact law demonstrate a lot of economics roles of these disjunctive obligations.This article demonstrate the important of disjunctives obligations in contract law and there economics roles and how they help the contracting parties to perform their mutual obligations

Prediction of Length of Postoperative Ventilation in CDH Survivors; Preoperative and Operative Variables

Background/Purpose: The period taken for complete weaning from ventilation in cases of repaired congenital diaphragmatic hernia (CDH) varies greatly. We tried to relate the endo-tracheal tube removal time (ETTRT) in these cases with the different variables; both preoperative and operative. Materials & Methods: This is a retrospective study of cases of CDH survivors managed by the authors over the period from January 2003 till February 2010. The preoperative variables included gestational age, gender, birth weight, Apgar score, the time of intubation, the ventilation strategy, the presence of a significant PDA in the ECHO study and the time-lapse till surgery. The operative variables (all by laparotomy approach) included the side of the hernia, the herniated contents, the presence of a sac, the insertion of a chest tube and the degree of abdominal wall stretch required. The successful weaning from ventilation and ETTRT were classified into two groups; ≤7 days and > 7 days postoperatively. Results: During the study period, 26 cases were included (21 Males and 5 females). The ETTRT ranged from 2 to 23 days (mean=7.7 ±7.15). Among the variables studied; the statistically significant ones (P value < 0.05) were Apgar score at 1 minute (preoperatively) and the need for "vigorous" abdominal wall stretch (operatively). Conclusion: Apgar score of less than 8 at 1 minute; preoperatively, and the need for "vigorous" abdominal wall stretch; operatively, were associated with delayed weaning from ventilation in CDH survivors. This could have a predictive value in the management of these cases.Index Word: Congenital diaphragmatic hernia, Mechanical ventilation weaning, Endo-tracheal tube removal

Modified Dismembered Technique of Laparoscopic Transperitoneal Pyeloplasty in Children

Background: Laparoscopic pyeloplasty in children gained more and more popularity over the past two decades. However, it remains technically challenging with the most steps of the procedure are ureteric spatulation, DJ insertion, and intracorporeal anastomosis. Many modifications have been proposed to address these issues. In this article, we present our surgical approach to laparoscopic transperitoneal modified dismembered pyeloplasty highlighting some tips to make it easy. Objectives: This study was conducted to evaluate the outcomes of laparoscopic management of ureteropelvic junction obstruction children. Patients and Methods: This was a prospective study carried out on patients who presented with UPJO to our center from May 2019 to October 2021. All the cases underwent laparoscopic transperitoneal modified dismembered pyeloplasty where complete dismembering is deferred after the ureteropelvic anastomosis to prevent ureteral torsion and to use the redundant pelvis as a handle for ureteric manipulation. We used 3 simple techniques for antegrade insertion of DJ. Results: The study included 25 patients (19 males and 6 females) The mean age at operation was 30.88 ± 27.48 months. The mean time needed for the anastomosis was 80 minutes while the mean total operative time was 155 minutes. No conversion was needed. Apart from 2 cases, all other patients showed significant improvement of the degree of hydronephrosis and renal split function. Conclusion: The described modifications facilitated performing the procedure rendering laparoscopic pyeloplasty to be a less demanding and much easier procedure than the conventional technique

Feasibility of overnight closed-loop therapy in young children with type 1 diabetes aged 3-6 years: comparison between diluted and standard insulin strength.

OBJECTIVE: To assess feasibility of overnight closed-loop therapy in young children with type 1 diabetes and contrast closed loop using diluted versus standard insulin strength. RESEARCH DESIGN AND METHODS: Eleven children (male 6; age range 3.75-6.96 years; glycated hemoglobin 60 (14) mmol/mol; body mass index SD score 1.0 (0.8); diabetes duration 2.2 (1.0) years, mean (SD); total daily dose 12.9 (10.6, 16.5) IU/day, median (IQR)) were studied at a clinical research facility on two occasions. In random order, participants received closed loop with diluted insulin aspart (CL_Dil; 20 IU/mL) or closed loop with standard aspart (CL_Std; 100 IU/mL) from 17:00 until 8:00 the following morning. Children consumed an evening meal at 17:00 (44 (12) gCHO) and an optional bedtime snack (6 (7) gCHO) identical on both occasions. Meal insulin boluses were calculated by standard pump bolus calculators. Basal rates on insulin pump were adjusted every 15 min as directed by a model-predictive-control algorithm informed by a real-time glucose sensor values. RESULTS: Mean plasma glucose was 122 (24) mg/dL during CL_Dil vs 122 (23) mg/dL during CL_Std (p=0.993). The time spent in the target glucose range 70-145 mg/dL was 83 (70, 100)% vs 72 (54, 81)% (p=0.328). Time above 145 mg/dL was 13 (0, 27)% vs 19 (10, 45)% (p=0.477) and time spent below 70 mg/dL was 0.0 (0.0, 1.4)% vs 1.4 (0.0, 11.6)% (p=0.161). One asymptomatic hypoglycemia below 63 mg/dL occurred in one participant during CL_Dil versus six episodes in five participants during CL_Std (p=0.09). Glucose variability measured by CV of plasma glucose tended to be reduced during CL_Dil (20% (13, 31) vs 32% (24, 42), p=0.075). CONCLUSIONS: In this feasibility study, closed-loop therapy maintained good overnight glucose control with tendency towards reduced hypoglycemia and reduced glucose variability using diluted insulin. TRIAL REGISTRATION NUMBER: clinicaltrials.gov Identifier: NCT01557634.This work was funded by the Juvenile Diabetes Research Foundation (JDRF Grant Number: 22-2011-668) and supported by NIHR Cambridge Biomedical Research Centre.This is the final published version. It first appeared at http://drc.bmj.com/content/2/1/e000040.abstract

High alcohol intake in deceased donors has no effect on pancreas graft survival: a registry analysis

Outcomes of pancreas transplantation from donors with high alcohol consumption are poorly described. The UK Transplant Registry was used to determine whether donor alcohol intake influenced pancreas survival in simultaneous pancreas–kidney (SPK) transplants performed between 2006 and 2012 (n = 770). Recipients were stratified by donor alcohol intake: group I (n = 122)—high recent alcohol intake (>21 or >14 units of alcohol/week in males or females, respectively) or previous alcohol abuse and group II (n = 648)—low/unknown current intake and no previous alcohol abuse. Median current alcohol intake was higher in group I than group II: 36.3 vs. 10 units/week; P 50 units/week (P = 0.41). Pancreas donors with past alcohol abuse or current high intake are common, and graft outcomes appear to be acceptable. This analysis suggests that high donor alcohol intake, by itself, should not exclude consideration of pancreas transplantation

Pendampingan kewirausahaan melalui branding sandal jepit di Panti Asuhan Muhammadiyah Pamekasan

Branding is urgent in a business because it is through branding that consumers know our commodities. However, business actors often do not pay much attention to branding and marketing their products. This is the reason for holding this mentoring program. Panti Asuhan Muhammadiyah Pamekasan already has produced results in the form of flip-flops but only for the internal needs of the orphanage and has not been able to market it to outside parties because it does not have branding. This empowerment method uses Asset-Based Community-driven Development (ABCD) with a target of 25 children from Panti Asuhan Muhammadiyah Pamekasan. From this mentoring program Panti, Asuhan Muhammadiyah Pamekasan has been able to make flip-flops branding by doing screen printing on the sandals produced so that they can market their products to shops around the orphanage, the results of which are used to support the independence of the orphanage.(Branding menjadi hal yang sangat urgen dalam sebuah usaha karena melalui brandinglah komoditas kita dikenal oleh konsumen. Namun, seringkali para pelaku usaha tidak begitu memperhatikan branding dalam memasarkan hasil peroduksinya. Hal ini menjadi alasan diadakannya program pendampingan ini. Panti Asuhan Muhammadiyah Pamekasan telah memiliki hasil produksi berupa sandal jepit namun hanya untuk kebutuhan internal panti dan belum mampu memasarkan ke pihak luar karena belum memiliki branding. Metode pemberdayaan ini menggunakan Asset Based Community-driven Development (ABCD) dengan target 25 anak Panti Asuhan Pamekasan Muhammadiyah. Dari program pendampingan ini Panti Asuhan Muhammadiyah Pamekasan telah mampu membuat branding sandal jepit dengan melakukan sablon pada sandal yang dihasilkan sehingga mampu memasarkan hasil produksinya  ke took-toko sekitar panti asuhan yang hasilnya digunakan untuk mendukung kemandirian panti asuhan)

Role of DAX-1 (NROB1) and Steroidogenic Factor-1 (NR5A1) in Human Adrenal Function

The nuclear receptor transcription factors DAX-1 (NROB1) and SF-1 (NR5A1) regulate many aspects of adrenal and reproductive development and function. Disruption of the genes encoding these factors can be associated with pediatric adrenal disease. DAX-1 mutations are classically associated with X-linked adrenal hypoplasia congenita, hypogonadotropic hypogonadism and impaired spermatogenesis. However, other phenotypes are also being reported, such as isolated mineralocorticoid insufficiency, premature sexual development, primary adrenal insufficiency in a 46,XX patient and late-onset X-linked adrenal hypoplasia congenita and/or hypogonadotropic hypogonadism. SF-1 mutations have also been associated with primary adrenal insufficiency, together with 46,XY disorders of sex development. However it is emerging that SF-1 changes are a relatively rare cause of primary adrenal failure in humans, and most individuals with SF-1 mutations have a spectrum of 46,XY disorders of sex development phenotypes. These conditions range from 46,XY females with streak gonads and miillerian structures, through children with ambiguous genitalia and inguinal testes, to severe penoscrotal hypospadias with undescended testes. Therefore, the human gonad appears to be more sensitive than the adrenal gland to loss of SF-1 function. This review will focus on the expanding range of phenotypes associated with DAX-1 and SF-1 mutations

New directions for the treatment of adrenal insufficiency

The following funding bodies supported this work: Biotechnology and Biological Sciences Research Council (BBSRC BB/L00267/1, to LG), Rosetrees Trust (to LG), Barts and The London Charity (417/2235, to LG), EU COFUND (PCOFUND-GA-2013-608765, to LG and GRB). IH is supported by a Medical Research Council (MRC, G0802796) PhD studentship