HE ROLE OF ZIC1 IN CRANIAL SUTURE FORMATION

The zic1 gene plays an important role in embryonic development, in part by regulating the expression of many other genes including the engrailed gene. Previous investigators have reported that abnormal engrailed expression shifts the location of cranial suture formation and affects gene expression in the developing sutures (Deckelbaum et al. 2012). Such defects may cause a premature fusion of cranial sutures, leading to a serious birth defect known as craniosynostosis. Dr. Andrew Wilkie (Oxford University) has found that mutations in the human ZIC1 gene cause craniosynostosis.  He hypothesizes that the engrailed gene is abnormally regulated in patients with these ZIC1 mutations. In collaboration with the Wilkie lab, we are testing this hypothesis by injecting RNA derived from the human ZIC1 mutants into Xenopus frog embryos. The goal of our experiments is to observe whether the mutated human ZIC1 genes affect the expression of the engrailed gene in frog embryos, which we were able to show by in situ hybridization.  The degree of abnormality of engrailed expression caused by the various human ZIC1 mutations corresponds to the severity of the patients’ phenotypes. These findings provide a better understanding of the molecular mechanisms underlying craniosynostosis and suggest possible gene regulatory pathways

Responding to AIDS, Tuberculosis, Malaria, and Emerging Infectious Diseases in Burma: Dilemmas of Policy and Practice

Beyrer and colleagues discuss infectious disease threats in Burma and suggest policy options for responding to them

Should human papillomavirus vaccination target women over age 26, heterosexual men and men who have sex with men? A targeted literature review of cost-effectiveness.

BACKGROUND: Human papillomavirus (HPV) vaccination for young women up to age 26 is highly cost-effective and has been implemented in 65 countries globally. We investigate the cost-effectiveness for HPV vaccination program in older women (age > 26 years), heterosexual men and men who have sex with men (MSM). METHOD: A targeted literature review was conducted on PubMed for publications between January 2000 and January 2017 according to the PRISMA guidelines. We included English-language articles that reported the incremental cost-effectiveness ratio (ICER) of HPV vaccination programs for women over age 26, heterosexual men, and MSM and identified the underlying factors for its cost-effectiveness. RESULTS: We included 36 relevant articles (six, 26 and four in older women, heterosexual men and MSM, respectively) from 17 countries (12 high-income (HICs) and five low- and middle-income (LMICs) countries). Most (4/6) studies in women over age 26 did not show cost-effectiveness ($65,000-192,000/QALY gained). Two showed cost-effectiveness, but only when the vaccine cost was largely subsidised and protection to non-naïve women was also considered. Sixteen of 26 studies in heterosexual men were cost-effective (ICER =$19,600-52,800/QALY gained in HICs; $49-5,860/QALY gained in LMICs). Nonavalent vaccines, a low vaccine price, fewer required doses, and a long vaccine protection period were key drivers for cost-effectiveness. In contrast, all four studies on MSM consistently reported cost-effectiveness (ICER =$15,000-$43,000/QALY gained), particularly in MSM age < 40 years and those who were HIV-positive. Countries' vaccination coverage did not significantly correlate with its per-capita Gross National Income. CONCLUSION: Targeted HPV vaccination for MSM should be next priority in HPV prevention after having established a solid girls vaccination programme. Vaccination for heterosexual men should be considered when 2-dose 4vHPV/9vHPV vaccines become available with a reduced price, whereas targeted vaccination for women over age 26 is unlikely to be cost-effective

Mapping of Mycobacterium tuberculosis Complex Genetic Diversity Profiles in Tanzania and Other African Countries

The aim of this study was to assess and characterize Mycobacterium tuberculosis complex (MTBC) genotypic diversity in Tanzania, as well as in neighbouring East and other several African countries. We used spoligotyping to identify a total of 293 M. tuberculosis clinical isolates (one isolate per patient) collected in the Bunda, Dar es Salaam, Ngorongoro and Serengeti areas in Tanzania. The results were compared with results in the SITVIT2 international database of the Pasteur Institute of Guadeloupe. Genotyping and phylogeographical analyses highlighted the predominance of the CAS, T, EAI, and LAM MTBC lineages in Tanzania. The three most frequent Spoligotype International Types (SITs) were: SIT21/CAS1-Kili (n = 76; 25.94%), SIT59/LAM11-ZWE (n = 22; 7.51%), and SIT126/EAI5 tentatively reclassified as EAI3-TZA (n = 18; 6.14%). Furthermore, three SITs were newly created in this study (SIT4056/EAI5 n = 2, SIT4057/T1 n = 1, and SIT4058/EAI5 n = 1). We noted that the East-African-Indian (EAI) lineage was more predominant in Bunda, the Manu lineage was more common among strains isolated in Ngorongoro, and the Central-Asian (CAS) lineage was more predominant in Dar es Salaam (p-value<0.0001). No statistically significant differences were noted when comparing HIV status of patients vs. major lineages (p-value = 0.103). However, when grouping lineages as Principal Genetic Groups (PGG), we noticed that PGG2/3 group (Haarlem, LAM, S, T, and X) was more associated with HIV-positive patients as compared to PGG1 group (Beijing, CAS, EAI, and Manu) (p-value = 0.03). This study provided mapping of MTBC genetic diversity in Tanzania (containing information on isolates from different cities) and neighbouring East African and other several African countries highlighting differences as regards to MTBC genotypic distribution between Tanzania and other African countries. This work also allowed underlining of spoligotyping patterns tentatively grouped within the newly designated EAI3-TZA lineage (remarkable by absence of spacers 2 and 3, and represented by SIT126) which seems to be specific to Tanzania. However, further genotyping information would be needed to confirm this specificity

A first assessment of the genetic diversity of Mycobacterium tuberculosis complex in Cambodia

<p>Abstract</p> <p>Background</p> <p>Cambodia is among the 22 high-burden TB countries, and has one of the highest rates of TB in South-East Asia. This study aimed to describe the genetic diversity among clinical <it>Mycobacterium tuberculosis </it>complex (MTC) isolates collected in Cambodia and to relate these findings to genetic diversity data from neighboring countries.</p> <p>Methods</p> <p>We characterized by 24 VNTR loci genotyping and spoligotyping 105 <it>Mycobacterium tuberculosis </it>clinical isolates collected between 2007 and 2008 in the region of Phnom-Penh, Cambodia, enriched in multidrug-resistant (MDR) isolates (n = 33).</p> <p>Results</p> <p>Classical spoligotyping confirmed that the East-African Indian (EAI) lineage is highly prevalent in this area (60%-68% respectively in whole sample and among non-MDR isolates). Beijing lineage is also largely represented (30% in whole sample, 21% among non-MDR isolates, OR = 4.51, CI_95%[1.77, 11.51]) whereas CAS lineage was absent. The 24 loci MIRU-VNTR typing scheme distinguished 90 patterns with only 13 multi-isolates clusters covering 28 isolates. The clustering of EAI strains could be achieved with only 8 VNTR combined with spoligotyping, which could serve as a performing, easy and cheap genotyping standard for this family. Extended spoligotyping suggested relatedness of some unclassified "T1 ancestors" or "Manu" isolates with modern strains and provided finer resolution.</p> <p>Conclusions</p> <p>The genetic diversity of MTC in Cambodia is driven by the EAI and the Beijing families. We validate the usefulness of the extended spoligotyping format in combination with 8 VNTR for EAI isolates in this region.</p

The role of resuscitation promoting factors in pathogenesis and reactivation of Mycobacterium tuberculosis during intra-peritoneal infection in mice

<p>Abstract</p> <p>Background</p> <p><it>Mycobacterium tuberculosis </it>can enter into a dormant state which has resulted in one third of the world's population being infected with latent tuberculosis making the study of latency and reactivation of utmost importance. <it>M. tuberculosis </it>encodes five resuscitation promoting factors (Rpfs) that bear strong similarity to a lysozyme-like enzyme previously implicated in reactivation of dormant bacteria <it>in vitro</it>.</p> <p>We have developed an intraperitoneal infection model in mice, with immune modulation, that models chronic infection with similar properties in mouse lungs as those observed in the murine aerosol infection model. We have assessed the behavior of mutants that lack two or three <it>rpf </it>genes in different combinations in our intraperitoneal model.</p> <p>Methods</p> <p>C57Bl/6 mice were intraperitonealy infected with H37Rv wild type <it>M. tuberculosis </it>or mutant strains that lacked two or three <it>rpf </it>genes in different combinations. After 90 days of infection aminoguanidine (AG) or anti-TNFα antibodies were administrated. Organ bacillary loads were determined at various intervals post infection by plating serial dilutions of organ homogenates and enumerating bacteria.</p> <p>Results</p> <p>We found that the <it>rpf </it>triple and double mutants tested were attenuated in their ability to disseminate to mouse lungs after intraperitoneal administration and were defective in their ability to re-grow after immunosuppression induced by administration of aminoguanidine and anti-TNFα antibodies.</p> <p>Conclusion</p> <p>Rpf proteins may have a significant physiological role for development of chronic TB infection and its reactivation <it>in vivo</it>.</p

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown