Evaluation of efficacy and safety of cryotherapy in benign and premalignant cervical lesion

 Background: Cervical cancer ranks 3rd leading cause of cancer in the world. Cervical erosion is mostly asymptomatic in women but when symptoms like postcoital bleeding and vaginal discharge occur in the presence of cervical erosion, it becomes important to identify whether the erosion is a benign lesion or CIN or cancer by means of PAP smear and Biopsy. Treatment for benign and precancerous lesion can be provided by ablative or excisional methods. Cryotherapy was reliably used to treat cervical lesions.Methods: Women among 18 to 60 years of age attending outpatient department who had history of chronic discharge per vaginum, postcoital bleeding, dyspareunia, chronic pelvic pain. Patients were divided in two by PAP smear in erosion with inflammatory changes and presence of low grade squamous intraepithelial lesion. Cryotherapy was performed using double-freeze single session procedure. Each patient was followed up at 2, 6 and at 12 weeks. Complications and patients’ satisfaction were recorded and compared to calculate cure rate of symptoms, healing of lesion.Results: The healing efficacy of cryotherapy at 6th and 12th week was 87.8% and 91.1% respectively. Cryotherapy had high satisfaction rate. The cure rate was not affected by location of lesion and size of lesion in both inflammation and LSIL.Conclusions: Cryotherapy is an effective method for treatment of cervical erosion and effectively eliminates symptoms. Patients were highly satisfied. Cryotherapy is cheap, easy, and safe treatment. It is suitable for both hospital and office-based practice

Micro-Symposium on Orin Kerr\u27s \u27A Theory of Law\u27

For more than a century, careful readers of the Green Bag have known that “[t]here is nothing sacred in a theory of law...which has outlived its usefulness or which was radically wrong from the beginning...The question is What is the law and what is the true public policy?” Professor Orin Kerr bravely, creatively, and eloquently answered that question in his article, “A Theory of Law,” in the Autumn 2012 issue of the Green Bag. Uniquely among all theories of law that I know of, Kerr’s answer to the fundamental question of law and true public policy enables all scholars to answer that same question in their own ways. The Green Bag is pleased to be featuring his “A Theory of Law” in its first micro-symposium, and just as pleased with the quality, quantity, and diversity of the responses to the call for papers. Blessed with an abundance of good work but cursed by a shortage of space, we were compelled to select a small set – representative and excellent – of those essays to publish in the Green Bag or its sibling publication, the Journal of Law. We regret that we cannot do full justice to the outpouring of first-rate legal-theoretical commentary we received

Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium

Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider. Deciding how to weigh each type of evidence is difficult, and standards have been needed. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases. Nine molecular diagnostic laboratories involved in the Clinical Sequencing Exploratory Research (CSER) consortium piloted these guidelines on 99 variants spanning all categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign). Nine variants were distributed to all laboratories, and the remaining 90 were evaluated by three laboratories. The laboratories classified each variant by using both the laboratory's own method and the ACMG-AMP criteria. The agreement between the two methods used within laboratories was high (K-alpha = 0.91) with 79% concordance. However, there was only 34% concordance for either classification system across laboratories. After consensus discussions and detailed review of the ACMG-AMP criteria, concordance increased to 71%. Causes of initial discordance in ACMG-AMP classifications were identified, and recommendations on clarification and increased specification of the ACMG-AMP criteria were made. In summary, although an initial pilot of the ACMG-AMP guidelines did not lead to increased concordance in variant interpretation, comparing variant interpretations to identify differences and having a common framework to facilitate resolution of those differences were beneficial for improving agreement, allowing iterative movement toward increased reporting consistency for variants in genes associated with monogenic disease

An improved predictive recognition model for Cys2-His2 zinc finger proteins

Cys2-His2 zinc finger proteins (ZFPs) are the largest family of transcription factors in higher metazoans. They also represent the most diverse family with regards to the composition of their recognition sequences. Although there are a number of ZFPs with characterized DNA-binding preferences, the specificity of the vast majority of ZFPs is unknown and cannot be directly inferred by homology due to the diversity of recognition residues present within individual fingers. Given the large number of unique zinc fingers and assemblies present across eukaryotes, a comprehensive predictive recognition model that could accurately estimate the DNA-binding specificity of any ZFP based on its amino acid sequence would have great utility. Toward this goal, we have used the DNA-binding specificities of 678 two-finger modules from both natural and artificial sources to construct a random forest-based predictive model for ZFP recognition. We find that our recognition model outperforms previously described determinant-based recognition models for ZFPs, and can successfully estimate the specificity of naturally occurring ZFPs with previously defined specificities

Determination of specificity influencing residues for key transcription factor families

Transcription factors (TFs) are major modulators of transcription and subsequent cellular processes. The binding of TFs to specific regulatory elements is governed by their specificity. Considering the gap between known TFs sequence and specificity, specificity prediction frameworks are highly desired. Key inputs to such frameworks are protein residues that modulate the specificity of TF under consideration. Simple measures like mutual information (MI) to delineate specificity influencing residues (SIRs) from alignment fail due to structural constraints imposed by the three-dimensional structure of protein. Structural restraints on the evolution of the amino-acid sequence lead to identification of false SIRs. In this manuscript we extended three methods (Direct Information, PSICOV and adjusted mutual information) that have been used to disentangle spurious indirect protein residue-residue contacts from direct contacts, to identify SIRs from joint alignments of amino-acids and specificity. We predicted SIRs forhomeodomain (HD), helix-loop-helix, LacI and GntR families of TFs using these methods and compared to MI. Using various measures, we show that the performance of these three methods is comparable but better than MI. Implication of these methods in specificity prediction framework is discussed. The methods are implemented as an R package and available along with the alignments at stormo.wustl.edu/SpecPred

‘To minimise that risk, there are some costs we incur’: Examining the impact of gender-based violence on the urban poor

Urban environments marked by violence create fear that can have real impacts on the urban poor, particularly women and girls. Any efforts to tackle poverty and promote health must address the impacts to their access to livelihoods and education, healthcare, markets, and social support that underlie wellbeing. This study aimed to elucidate specific impacts that violence and fear have on the very poor in rapidly growing cities and the coping strategies employed. This multi-country qualitative study was conducted in Dhaka, Bangladesh, Port-au-Prince, Haiti; and Addis Ababa, Ethiopia. Participants in all three cities employed similar tactics to avoid violence. People adjusted how, when, and where they travel and how they interact with people who threaten them. These coping strategies led participants to spend more money on goods and to restrict access to livelihood opportunities, education, healthcare, and social activities. Women are impacted more than men in all spheres and city specific differences are highlighted. Residents of urban slums, particularly women, in these three cities cope with urban violence in many ways, suffering consequences in a range of categories – leading to significant impacts to their own health and well-being and their families

Comparative Activities of Telavancin Combined with Nafcillin, Imipenem, and Gentamicin against \u3ci\u3eStaphylococcus aureus\u3c/i\u3e

Beta-lactams enhance the killing activity of vancomycin. Due to structural and mechanistic similarities between vancomycin and telavancin, we investigated the activity of telavancin combined with nafcillin and imipenem compared to the known synergistic combination of telavancin and gentamicin. Thirty strains of Staphylococcus aureus, 10 methicillin susceptible S. aureus (MSSA), 10 methicillin resistant S. aureus (MRSA), and 10 heterogeneously vancomycin intermediate S. aureus (hVISA) were tested for synergy by time-kill methodology. Six strains (2 each of MSSA, MRSA, and hVISA) were further evaluated in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated regimens of telavancin 10 mg/kg once daily alone and combined with nafcillin 2 g every 4 h, imipenem 500 mg every 6 h, or gentamicin 5 mg/kg once daily over 72 h. In the synergy test, 67% of strains displayed synergy with the combination of telavancin and gentamicin, 70% with telavancin + nafcillin, and 63% with telavancin + imipenem. In the PK/PD model against MRSA and hVISA all three combinations were superior to all individual drugs alone (P ≤ 0.002) and were similar to each other (P ≥ 0.187). Against MSSA all three combinations were generally similar to each other except one strain where telavancin + imipenem was superior to all other regimens (P ≤ 0.011). The combination of telavancin and beta-lactam agents was similar in activity compared to telavancin + gentamicin against S. aureus, including resistant strains. Because beta-lactam combinations are less likely to be nephrotoxic than telavancin + gentamicin, these beta-lactam combinations may have clinical utility