Double-strand breaks induce inverted duplication chromosome rearrangements by a DNA polymerase δ-dependent mechanism.

Inverted duplications, also known as foldback inversions, are commonly observed in cancers and are the major class of chromosome rearrangement recovered from yeast cells lacking Mre11 nuclease activity. Foldback priming at DNA double-strand breaks (DSBs) is one mechanism proposed for the generation of inverted duplications. However, the other pathway steps have not been fully elucidated. Here, we show that a DSB induced near natural inverted repeats drives high frequency inverted duplication in Sae2 and Mre11-deficient cells. We find that DNA polymerase δ proof-reading activity, but not Rad1 nuclease, trims the heterologous flaps formed after foldback annealing. Additionally, Pol32 is required for the generation of inverted duplications, suggesting that Pol δ catalyzes fill-in synthesis primed from the foldback to create a hairpin-capped chromosome that is subsequently replicated to form a dicentric inversion chromosome. Finally, we show that stabilization of the dicentric chromosome after breakage involves telomere capture by non-reciprocal translocation mediated by repeat sequences or by deletion of one centromere.

To be or not to be an Obstetrician / Gynaecologist.

OBJECTIVES: This qualitative study aimed to explore motivational sources of physicians, at the time of selection and while pursuing ObGyn career. Secondary aim was to explore challenges and strategies adapted by these physicians to overcome these challenges. METHODS: This is qualitative study with constrictive worldview. ObGyn residents and consultants of Aga Khan University, Karachi, were interviewed from July 2017 till Jan 2019, after ethical approval, using purposeful maximum variation sampling. Analysis were conducted by identifying keywords and phrases, these unedited verbatim with no assumptions provided basis for codes, which then clustered as trends. Emerging findings were discussed among authors and themes were finalized with consensus. Conclusion was formulated by linking these themes. RESULTS: Four themes emerged were, 'grounds for selecting ObGyn as career', 'Motivational Factors', 'Demotivating Factors' and 'Strategies to Cope with Challenges'. Results showed that aptitude and passion not only have pivotal role in career selection but also helped in pursuance. Personal fulfilment and hands-on experience satisfy emotional needs, while family and friends supported participants in maintaining work-life balance and in over-coming challenges. CONCLUSIONS: Considering personal preference and aptitude at the time of career selection helps in endurance and keep motivations high, while challenges in pursuance can be overcome by strong support system.

Pregnancy outcomes amongst adolescents/young adults at tertiary-care hospital in a low-middle-income country: Ten-year retrospective record review.

OBJECTIVE: Adolescent pregnancies are known to be associated with adverse outcomes. Our objective was to compare pregnancy outcomes amongst adolescents (young adolescents YA: 15-17 years; older adolescents OA: 18- 19 years) and young adults (20 to 25 years). METHODS: Study was conducted at the Aga Khan University Hospital, Karachi. Ten-year retrospective record review was done through convenience sampling. Data was collected on predesigned proforma. Participants were 396 primiparous adolescents (15-19 years) with singleton low-risk pregnancy. Reference-group included 410 primiparous, low-risk, young adults. Pregnancies complicated with preexisting diabetes mellitus, chronic hypertension, renal disorders or cardiac diseases were excluded. Maternal /neonatal outcomes were compared amongst groups. RESULTS: Out of 806 charts reviewed, 75 (9.3%) were YA, 321 (39.8%) were OA and 410 (50.9%) were 20-25 years old young adults. Most of the un-booked cases were in young adolescents; 17 (22.7% YA), 41 (12.8% OA) and 33 (8.0% reference -group) (p-value 0.001). This group also booked at a later gestational age; YA (19.6±10.4 weeks), OA (17.2±9.3 weeks) and controls (15.5n±8.8 weeks) (p-value 0.002). Gestational age at delivery was not significantly different among the groups. Adolescents had a decreased likelihood of Caesarian section with youngest group having 29% less chance of Caesarian delivery (OR 95% CI 0.41, 0.2) compared to women of 20-25 years of age. Difference in maternal/neonatal outcomes remained insignificant between groups at univariate and multivariate analysis. CONCLUSIONS: Maternal/neonatal outcomes in adolescents were comparable to young adults. Good antenatal care, evidence-based protocols and strong family backing may reduce risks to mothers/babies in adolescent pregnancies.

Antibiotic prophylaxis in the surgical management of miscarriage in low-income countries: a cost-effectiveness analysis of the AIMS trial.

BACKGROUND: There is ongoing debate on the clinical benefits of antibiotic prophylaxis for reducing pelvic infection after miscarriage surgery. We aimed to study the cost-effectiveness of antibiotic prophylaxis in the surgical management of miscarriage in low-income countries. METHODS: We did an incremental cost-effectiveness analysis using data from 3412 women recruited to the AIMS trial, a randomised, double-blind, placebo-controlled trial designed to evaluate the effectiveness of antibiotic prophylaxis in the surgical management of miscarriage in Malawi, Pakistan, Tanzania, and Uganda. Economic evaluation was done from a health-care-provider perspective on the basis of the outcome of cost per pelvic infection avoided within 2 weeks of surgery. Pelvic infection was broadly defined by the presence of clinical features or the clinically identified need to administer antibiotics. We used non-parametric bootstrapping and multilevel random effects models to estimate incremental mean costs and outcomes. Decision uncertainty was shown via cost-effectiveness acceptability frontiers. The AIMS trial is registered with the ISRCTN registry, number ISRCTN97143849. FINDINGS: Between June 2, 2014, and April 26, 2017, 3412 women were assigned to receive either antibiotic prophylaxis (1705 [50%] of 3412) or placebo (1707 [50%] of 3412) in the AIMS trial. 158 (5%) of 3412 women developed pelvic infection within 2 weeks of surgery, of whom 68 (43%) were in the antibiotic prophylaxis group and 90 (57%) in the placebo group. There is 97-98% probability that antibiotic prophylaxis is a cost-effective intervention at expected thresholds of willingness-to-pay per additional pelvic infection avoided. In terms of post-surgery antibiotics, the antibiotic prophylaxis group was US$0·27 (95% CI -0·49 to -0·05) less expensive per woman than the placebo group. A secondary analysis, a sensitivity analysis, and all subgroup analyses supported these findings. Antibiotic prophylaxis, if implemented routinely before miscarriage surgery, could translate to an annual total cost saving of up to $1·4 million across the four participating countries and up to $8·5 million across the two regions of sub-Saharan Africa and south Asia. INTERPRETATION: Antibiotic prophylaxis is more effective and less expensive than no antibiotic prophylaxis. Policy makers in various settings should be confident that antibiotic prophylaxis in miscarriage surgery is cost-effective. FUNDING: UK Medical Research Council, Wellcome Trust, and the UK Department for International Development.

A Randomized Trial of Prophylactic Antibiotics for Miscarriage Surgery.

BACKGROUND: Surgical intervention is needed in some cases of spontaneous abortion to remove retained products of conception. Antibiotic prophylaxis may reduce the risk of pelvic infection, which is an important complication of this surgery, particularly in low-resource countries. METHODS: We conducted a double-blind, placebo-controlled, randomized trial investigating whether antibiotic prophylaxis before surgery to complete a spontaneous abortion would reduce pelvic infection among women and adolescents in low-resource countries. We randomly assigned patients to a single preoperative dose of 400 mg of oral doxycycline and 400 mg of oral metronidazole or identical placebos. The primary outcome was pelvic infection within 14 days after surgery. Pelvic infection was defined by the presence of two or more of four clinical features (purulent vaginal discharge, pyrexia, uterine tenderness, and leukocytosis) or by the presence of one of these features and the clinically identified need to administer antibiotics. The definition of pelvic infection was changed before the unblinding of the data; the original strict definition was two or more of the clinical features, without reference to the administration of antibiotics. RESULTS: We enrolled 3412 patients in Malawi, Pakistan, Tanzania, and Uganda. A total of 1705 patients were assigned to receive antibiotics and 1707 to receive placebo. The risk of pelvic infection was 4.1% (68 of 1676 pregnancies) in the antibiotics group and 5.3% (90 of 1684 pregnancies) in the placebo group (risk ratio, 0.77; 95% confidence interval [CI], 0.56 to 1.04; P = 0.09). Pelvic infection according to original strict criteria was diagnosed in 1.5% (26 of 1700 pregnancies) and 2.6% (44 of 1704 pregnancies), respectively (risk ratio, 0.60; 95% CI, 0.37 to 0.96). There were no significant between-group differences in adverse events. CONCLUSIONS: Antibiotic prophylaxis before miscarriage surgery did not result in a significantly lower risk of pelvic infection, as defined by pragmatic broad criteria, than placebo. (Funded by the Medical Research Council and others; AIMS Current Controlled Trials number, ISRCTN97143849.).

Radiomorphometric Evaluation of the Frontal Sinus in Relation to Age and Gender in Saudi Population.

BACKGROUND: Radiographs have been used for forensic identification purpose. At times when only skull remains are found and other means of identification fail, radiographs of skull may be used for identification purpose. AIM: The objective of this study was morphometric evaluation of the frontal sinus by using digital posteroanterior skull radiograph in relation to age and gender and to establish its forensic importance. MATERIALS AND METHODS: The study was conducted at Alfarabi Private College for Dentistry and Nursing, Jeddah, Kingdom of Saudi Arabia. It included 400 subjects (200 males and 200 females), aged 14-70 years. Radiographs of the individuals were taken by digital radiography, and morphometric evaluation of frontal sinus was carried out by using Adobe Photoshop CS3 Extended. RESULTS: Unilateral absence of sinus was noted in 2.5% males and 1.5% females. Bilateral absence was noticed in 2% males and 0.5% females. Right and left frontal sinus symmetry was seen in 83.20% of the individuals. The left-dominated asymmetry was observed in 6.98% individuals. The right-dominated asymmetry was observed in 9.82% individuals. Simple logistic regression analysis of gender by different variables showed right width and left width, which are most suited regressors for sex determination. The rate of accuracy in classification of males and females varied from 67.70% to 95.90%. Stepwise multiple regression analysis of estimation of age by different variables showed right sinus height is the best predictor of age. CONCLUSION: In this study, the radiographic images of the frontal sinus showed significant morphological difference in relation to age and gender in Saudi population. On the basis of this evidence, it is proposed that the morphologic evaluation of frontal sinus can be used for personal identification.

Hybrid simulation training: An effective teaching and learning modality for intrauterine contraceptive device insertion.

Background: Hybrid simulation training (HST) is a teaching modality that combines patient interaction using simulated patient (SP) with pelvic model. This provides realism to learners, lacking in manikins alone. This study was designed to compare knowledge, procedural, and communication skills of medical students regarding intrauterine contraceptive device (IUCD) insertion before and after introducing HST and to assess learner satisfaction with this methodology. Methods: This quasi-experimental mixed-method study was conducted at Aga Khan University Hospital, Karachi, from October 2016 to September 2017, for third-year medical students (n = 90). IUCD insertion was introduced to students through interactive session and provision of literature/video clip on IUCD insertion. Students were pretested on objectively structured clinical examination -station (IUCD insertion) using SP and manikin simultaneously. This was followed by practice on manikin and subsequent posttest on same OSCE-station. Learner evaluation of activity was through validated pro forma with both, Likert scale and open-ended questions. Results: Out of the 90 students, 73 completed pre/posttest and evaluation survey. There was significant increase in pre- and post-simulation mean scores for all clinical skills; history taking (5.1 pretest, 8.8 posttest, P ≤ 0.0005), counseling (40.11 pretest, 57.85 posttest, P ≤ 0.0005), procedural (15.16 pretest, 49.09 posttest, P ≤ 0.0005) and total scores (60 pretest, 115.6 posttest, P ≤ 0.0005), when compared using two-sided Wilcoxon signed rank sum test. Overall, activity was assessed as "very good" to "excellent" by 83.5% participants. Themes generated from open-ended questions of evaluation forms were "Process-descriptors," "Teaching-utility," "Pedagogic-efficacy" and "Way-forward." Discussion: HST is an effective teaching strategy with potential to improve competency of medical students. Students acknowledged it, as innovative learning strategy that increased their satisfaction and confidence in performing IUCD insertion.

Comparison of neonatal outcomes between category-1 and non-category-1 Primary Emergency Cesarean Section: A retrospective record review in a tertiary care hospital.

OBJECTIVE: To compare neonatal outcomes between Category-1 and Non-Category-1 Primary Emergency Cesarean Section. METHODS: This was a retrospective analysis, conducted at Aga Khan University Hospital Karachi from January 1st 2016 till December 31st 2016. Non-probability purposive sampling technique was used. A sample size of 375 patients who had primary Emergency Caesarean Section (Em-CS) was identified by keeping CS rate of 41.5% and 5% bond on error. Data was collected from labor ward, operating theatre and neonatal ward records by using structured questionnaire. RESULTS: In the current study, out of 375 participants who underwent primary Em-CS; majority (89.3%) were booked cases. Two-hundred-eighty-two (75.2%) were primiparous women. Two hundred and thirty (61.3%) were at term and 145(38.7%) were preterm. The main indication among Category-1 CS was fetal distress (15.7%). For Non-Category-1 CS, non-progress of labour (45.1%) was the leading cause of abdominal delivery. Except for APGAR score at one minute (p value = 0.048), no other variables were statistically significant when neonatal outcomes were compared among Category-1 and Non-Category-1 CS. CONCLUSION: In this study, fetal distress and non-progress of labor were the main indications for Category-1 and Non-Category-1 CS respectively. We did not find statistically significant association between indications of Em CS and neonatal outcomes. However further prospective studies are required to confirm this association.

Caesarean Section rate amongst Obstetricians at a tertiary-care hospital of Karachi.

OBJECTIVE: To analyze the Caesarean Section (CS) rate among different groups of consultants dealing with Nulliparous Term Singleton pregnancy with Vertex (NTSV) presentation delivering at a tertiary care hospital of Karachi over four months. METHODS: This is a secondary analysis of a retrospective data that analyzed factors affecting the CS-rate of NTSV patients. Patients with CS (n=106) were taken as cases and vaginal deliveries (n=106) as controls. This was an unmatched retrospective case-control study. RESULTS: Mean age of patients was 26.6(SD: 4.2) years. Mean gestational-age was 38.6(SD: 1.0) weeks. Likelihood of CS was slightly less in patients who were attended by feto-maternal consultants(OR:0.81 CI:0.38-1.07) and was slightly more in patients managed by non-full-time faculty (OR:1.04 CI:0.59-1.85). Odds of CS was highest amongst consultants having average monthly volumes of 21-30 patients/month (OR:1.069 CI:0.48-2.34). However none of the above findings were statistically significant. A non-significant increase in risk of CS was observed with increase in experience of physicians (p=0.787). CONCLUSION: The results did not show statistically significant difference in CS rate among different groups of Obstetricians. This might indicate that managing labour according to standard guidelines can eliminate physicians' bias. This can be further evaluated with larger multicenter prospective studies.

Prophylactic antibiotics to reduce pelvic infection in women having miscarriage surgery - The AIMS (Antibiotics in Miscarriage Surgery) trial: study protocol for a randomized controlled trial.

BACKGROUND: The estimated annual global burden of miscarriage is 33 million out of 210 million pregnancies. Many women undergoing miscarriage have surgery to remove pregnancy tissues, resulting in miscarriage surgery being one of the most common operations performed in hospitals in low-income countries. Infection is a serious consequence and can result in serious illness and death. In low-income settings, the infection rate following miscarriage surgery has been reported to be high. Good quality evidence on the use of prophylactic antibiotics for surgical miscarriage management is not available. Given that miscarriage surgery is common, and infective complications are frequent and serious, prophylactic antibiotics may offer a simple and affordable intervention to improve outcomes. METHODS: Eligible patients will be approached once the diagnosis of miscarriage has been made according to local practice. Once informed consent has been given, participants will be randomly allocated using a secure internet facility (1:1 ratio) to a single dose of oral doxycycline (400 mg) and metronidazole (400 mg) or placebo. Allocation will be concealed to both the patient and the healthcare providers. A total of 3400 women will be randomised, 1700 in each arm. The medication will be given approximately 2 hours before surgery, which will be provided according to local practice. The primary outcome is pelvic infection 2 weeks after surgery. Women will be invited to the hospital for a clinical assessment at 2 weeks. Secondary outcomes include overall antibiotic use, individual components of the primary outcome, death, hospital admission, unplanned consultations, blood transfusion, vomiting, diarrhoea, adverse events, anaphylaxis and allergy, duration of clinical symptoms, and days before return to usual activities. An economic evaluation will be performed to determine if prophylactic antibiotics are cost-effective. DISCUSSION: This trial will assess whether a single dose of doxycycline (400 mg) and metronidazole (400 mg) taken orally 2 hours before miscarriage surgery can reduce the incidence of pelvic infection in women up to 2 weeks after miscarriage surgery. TRIAL REGISTRATION: Registered with the ISRCTN (international standard randomised controlled trial number) registry: ISRCTN 97143849 . (Registered on April 17, 2013).

Thalassemia review: features, dental considerations and management.

Thalassemia is a genetic disorder that involves abnormal haemoglobin formation. The two main categories of thalassemia are alpha and beta thalassemia that are then divided into further subcategories. While some mild forms of thalassemia might even go unnoticed and only cause mild anaemia and iron deficiency problems in patients, other more severe forms of thalassemia can even result in death. Individuals with thalassemia can get treatment according to the level of severity of their condition. The main oral manifestations of thalassemia are Class II malocclusion, maxillary protrusion, high caries index, severe gingivitis. Any dental surgical procedure for such patients should be done under antibiotic cover and immediately after transfusion. Caution should be exercised in thalassemia patients due to complications related to compromised immunity and cardiovascular issues. Multidisciplinary approach involving dental surgeon, haematologist and orthodontist is the best advised approach.

An in-vitro comparative study for assessment of apical sealing ability of Epiphany/AH Plus sealer with Resilon/gutta-percha root canal filling materials.

AIMS AND OBJECTIVES: Endodontic treatment is directed to eliminate microbial challenges from the root canal system and to create a complete seal. The aim of this study was to assess the apical sealing ability of resin-based Epiphany-Resilon root canal filling system and to compare it with the sealing abilities of different combinations of AH Plus, gutta-percha, Epiphany, and Resilon. MATERIALS AND METHODS: One hundred extracted human maxillary incisor roots were treated endodontically. The samples were divided into groups A, B, C, and D, with each group containing 25 samples. Group A: Canals obturated with gutta-percha and AH Plus sealer; Group B: Canals obturated with Resilon and Epiphany; Group C: Canals obturated with gutta-percha and Epiphany; Group D: Control group canals obturated with gutta-percha without a sealer. The sealing ability of each of the obturation techniques was tested using the dye penetration method followed by the clearing method using alcohol. Stereo microscope was used to measure the extent of dye penetration. Statistical data analysis was performed using analysis of variance and Tukey tests. RESULTS: Microleakage was found in all the four groups. Apical extent of mean microleakage was maximum for gutta-percha, followed by Gutta-percha + AH-plus and Gutta-percha + Epiphany, and the least with Resilon + Epiphany. Statistically significant difference (P < 0.01) was seen in the apical leakage. CONCLUSION: All the samples tested showed microleakage. The "Epiphany soft resin endodontic obturation system" showed a superior result compared to other obturation materials.

Nasopharyngeal polyp causing sensory disturbances: a case report.

Nasopharyngeal polyps are benign abnormal mucosal protrusions associated with nasal and pharyngeal mucosa. They are commonly found in all age groups with various symptoms. This paper presents a case of a 52-year-old male who presented with constant numbness over the dental midline and extending along the right side of the maxilla for the past few weeks. The patient also reported difficulty in breathing, especially lying down. After a comprehensive head and neck examination, including muscle palpation and temporomandibular joint examination, all within normal limits, a CNS lesion was suspected. A cranial nerve screening examination disclosed hyposensitivity in the area of teeth # 7 to 10. A panoramic radiograph demonstrated right sinus abnormality. We determined the need for additional diagnostic testing, including cone beam computed tomography, which showed a thickened sinus membrane with a polypoid structure (extending posterior from the right inferior concha into the oropharynx). The patient was referred to an ear, nose, and throat (ENT) specialist for further evaluation. The ENT diagnosis was a nasal polyp, and the patient was prescribed a steroid spray to be used three times daily. On follow-up, the patient's symptoms were reduced from constant numbness to intermittent "fading sensation" with no breathing difficulties lying down. Ancillary diagnostic testing, such as Cone Beam CT, is useful and may be required for the diagnosis of sensory disturbances in the Orofacial region.

Factors affecting mode of delivery in a nullipara at term with singleton pregnancy and vertex presentation (NTSV).

OBJECTIVE: To analyse the factors associated with Caesarean Section (CS) of Nulliparous, Term and Singleton pregnancies with Vertex presentation (NTSV) at a tertiary care hospital. METHODS: In this unmatched retrospective case-control study, 212 NTSV patients were identified through computerized medical record systems; the data was collected through predesigned Performa by reviewing medical record charts. One hundred six CS and spontaneous vaginal deliveries (SVD) were taken as cases and controls. RESULTS: The mean maternal age of cases (CS) was 26.64 (SD: 3.9) and of controls (SVD) was 26.7(SD: 3.9) years, whereas mean gestational age was 38.66±1.12 and 38.57±0.9 weeks for cases and controls respectively. Ninety per cent of women in the study group were delivered within 10 hours of active labour. Babies that weighed ≤3kg were 45% and >3kg were 55%. The possibility of being high risk was twice more among those delivered by CS. However, it was not statistically significant (p value 0.077). Labour was induced in 38% patients. The Odds of Induction of Labour (IOL) were two times more and delivering at night was three times more amongst CS. The likelihood of labour exceeding 10 hours was four times (81%) if the patient had a CS. Moreover 48% of the babies weighing >3kg were delivered through CS. Maternal age, high risk pregnancies, gender of baby and epidural analgesia were not statistically significant predictors of mode of delivery (MOD) in this study. CONCLUSION: Induction of Labour, night time delivery, prolonged labour and birth weight <3kg were found to be associated with the increased CS rate among NTSV. Therefore further research is required in order to address these factors and to reduce the increasing Caesarean Section.

Effect of different gingival margin restorations of class II cavities on microleakage: an in-vitro study.

INTRODUCTION: Microleakage is one of the important contributing factors in the failure of resin restorations. The aim of this study was to determine the effect of the location of the gingival margin (enamel, dentin, or cementum) on nanohybrid composite resin on the microleakage of Class II posterior restoration. METHODS: This was an in vitro study done at Al-Farabi College of Dentistry and Nursing in Jeddah (Saudi Arabia). Eighty-one previously extracted human molars were taken from clinics at Al-Farabi College and divided into three main groups (27 each) according to the location of the gingival margin. Group 1: the location of the gingival margin was in the enamel. Group 2: at the cemento-enamel junction. Group 3: in the cementum. Each main group was divided into three subgroups (9 each) according to storage time. Subgroup A: storage time was 24 hours. Subgroup B: storage time was one month. Subgroup C: storage time was three months. Class II cavity was prepared in one proximal surface for each molar following the general principles of cavity preparation. All samples were restored by nanohybridresin composite (TetricEvoCeram). The specimens were stored in distilled water at 37°C and a humidity of 100% in an incubator for one day, one month, and three months, respectively, according to the subgroups. After sealing, the samples were stained with 2.5% methylene blue dye. Each sample was examined microscopically by a stereomicroscope using a computerized image analyzing system. Statistical analysis was done by two-way ANOVA test comparing dye penetration mean values (µm). RESULTS: The value of dye penetration increased remarkably from enamel, Cemento-enamel junction [CEJ] to cementum, and this was statistically significant (p < 0.001). CONCLUSION: None of the materials tested was able to completely eliminate marginal microleakage at different gingival margins. The least dye penetration was detected at the enamel gingival margin followed by CEJ and then cementum. The least microleakage was observed at the gingival margin located in the enamel.

Factors associated with failed induction of labour in a secondary care hospital.

OBJECTIVE: To assess the factors associated with failed induction of labour (IOL) in a secondary care hospital. METHOD: This is a retrospective cross sectional study on women admitted for labour induction in Aga Khan Hospital for women Karimabad from 1st Jan, 2009 to 31st Dec, 2009. Induction was considered successful if the patient delivered vaginally and failed if it ended up in Caesarean Section. RESULT: Eighteen percent of our pregnant population who underwent induction of labour failed to deliver vaginally. About 25% of 328 nulliparous women had failed induction. With a Bishop score of <5 in 84.3%. In 28.2% with prolonged latent phase of more than 20 hours in Caesarean section had to be performed. CONCLUSION: Nulliparity, poor Bishop score and prolonged latent phase had strongest association with failed Induction of Labour. Macrosomia, gestation age, bad obstetric history and pre labour rupture of membranes were other significant risk factors for emergency caesarean sections in IOL.