PeterWenaweser, MD

• Attending Physician
• Department of Cardiology
• University Hospital Bern
• Bern, Switzerland

Improving the performance of domaindiscovery of protein domain boundary assignment using inter-domain linker index prostate oncology associates buy penegra 100mg line. Praline: a multiple sequence alignment toolbox that integrates homology-extended and secondary structure information prostate health vitamins order penegra 100mg. Improvement of domain linker prediction by incorporating loop-length-dependent characteristics prostate cancer 40 year old male purchase penegra master card. Domnet: protein domain boundary prediction using enhanced general regression network and new profiles prostate cancer 43 buy generic penegra from india. Prediction of protein-protein interactions using pairwise alignment and inter-domain linker region man health urdu buy penegra 100mg amex. A combination of compositional index and genetic algorithm for predicting transmembrane helical segments prostate bleeding generic penegra 50 mg. Proceedings of the 13th Annual Conference on Genetic and Evolutionary Computation. Domain linker region knowledge contributes to protein-protein interaction prediction. Conotoxin protein classification using free scores of words and support vector machines. These enzymes are involved not only in the catalysis of folding [17] but also in regulatory process [7, 25]. This observation is compatible with the results of other computational biology studies. The proposed model has been developed based on the Random Forest data modeling [4] and evolutionary information. In addition, the sequence identity of each pair of sequences is less than 25%, and the protein chains with sequence length less than 60 residues were excluded from the data set. In total, there are 609,182 residues, and every sequence contains at least one proline residue. We selected the windows size l of 9 and built our models as it produced the best predictive results as reported in Reference [20]. Since our data set is composed of 27,196 trans residues (negative samples) and only 1265 cis residues (positive samples), it is important to reduce this data imbalance. There are two general approaches to reduce such imbalance problem: increasing the number of undersamples by random resampling and decreasing the number of oversamples by random removal. Although the mutations at sequence level can obscure the similarity between homologs, the secondary structure patterns of the sequence remain conserved. However, there is one significant limitation in using predicted secondary structure information. The best secondary structure prediction model still cannot reach the upper boundary of its prediction accuracy. Incorrectly predicted secondary structure information within the training data leads to poor learning and inaccurate prediction. Although predicted secondary information may be useful to some extent, it should not be used if one attempts to reach better than 80% Q2 accuracy. To achieve more than 80% Q2 accuracy, accurate, and correct information encoding presented in input data set is critical. If we take a large collection of weak learners, each performing only better than chance, then by putting them together, it is possible to make an ensemble learner that can perform arbitrarily well. Randomness is introduced by bootstrap resampling [3] to grow each tree in the ensemble learner, and also by finding the best splitter at each node within a randomly selected subset of inputs. The Gini index of node impurity is the most commonly used measure for classification problems. If a data set T contains examples from n classes, Gini index n G(T) is calculated as (Pj)2 (13. If a data set this split into two subsets T1 and T2 with sizes N1 and N2, respectively, the Gini index G(T) of the split data containing examples from n classes will be N N (13. First, a random seed is chosen that randomly pulls out a collection of samples from the training data set while maintaining the class distribution. Second, with this selected data set, a set of attributes from the original data set is randomly chosen based on user-defined values. All the input variables are not considered because of enormous computation and high chances of overfitting. The left-hand side shows the main flow of the Method I ensemble while the right-hand side flowchart is the expansion of the process, to build the next split, of the main flowchart of left-hand side. The process repeats for each of the branches until the termination condition stating that leaves are the nodes that are too small to split. Each one is based on the same input data, but uses a different random number seed. The learned classifier depends on the random numbers because the algorithm may find a different local minimum of the error function. Randomization demands more work than bagging because the learning algorithm must be modified, but it can profitably be applied to a greater variety of learners. The training set is given to the inducer and the induced classifier is tested on the test set. The function approximator is then asked to predict the output values for the data in the testing set. The errors it makes are accumulated as before to give the mean absolute test set error, which is used to evaluate the model. However, the holdout method has a key drawback in that the single random division of a sample into training and testing sets may introduce bias in model selection and evaluation. Since the estimated classification rate can be very different depending on the characteristic of the data, the holdout estimate can be misleading if we get an unfortunate split. Hence, in our experiment, we adopted multiple train-and-test experiments to overcome the limitation of the holdout method. The list of the full parameters that we have used in our experiments is provided in the footnote of Table 13. Sn and Sp can handle imbalanced data situation where data points are not equally distributed among classes [19]. For the optimal learning of the prediction models, the most suitable data fold for each model should be sought. The best Q2 accuracy that we have found in the literature was approximately 73% on the same data set as used in this research. Although nonparametric machine-learning models have been proved to be useful in many different applications, their generalization capacity has often been shown to be unreliable because of the potential of overfitting. The symptom of overfitting is that the model fits the training sample too well, and thus the model output becomes unstable for prediction. On the other hand, a more stable model, such as a linear model, may not learn enough about the underlying relationship, resulting in underfitting the data. It is clear that both underfitting and overfitting will affect the generalization capacity of a model. The underfitting and overfitting problems in many data-modeling procedures can be analyzed through the well-known bias-plus-variance decomposition of the prediction error. This result indicates that the proposed methods could be improved by reducing the errors of experimentally verified cis residues that are incorrectly predicted to be trans residues. Method I clearly outperforms other models in terms of generalization ability and stability. Again, using a different random-number seed does not really make the outcome of classification more stable, which contradicts the findings in Reference [11]. The models are trained using a Random Forest ensemble method, which grows multiple trees and classifies according to the most votes over all the trees in the forest. Prediction of cis/trans isomerization using feature selection and support vector machines. Regulation of peptide bond cis/trans isomerization by enzyme catalysis and its implication in physiological processes. Prediction of prolyl residues in cis-conformation in protein structures on the basis of the amino acid sequence. Combining multiple artificial neural networks using random committee to decide upon electrical disturbance classification. Support vector machines for prediction of peptidyl prolyl cis/trans isomerization. Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism. SiteSeek: post-translational modification analysis using adaptive locality-effective kernel methods and new profiles. DomNet: protein domain boundary prediction using enhanced general regression network and new profiles. Machine learning techniques for protein secondary structure prediction: an overview and evaluation. Depending on the sequence of amino acids, environmental conditions, and a number of other factors, the polypeptide chain folds into very well-defined conformational segments called the secondary structure (-strands, -helices, etc. These segments fold into larger conformations with different arrangements creating a tertiary structure. In order to be functional and stable, many of these polypeptide chains Pattern Recognition in Computational Molecular Biology: Techniques and Approaches, First Edition. Quaternary structures are the spatial arrangements including multiple copies of one or multiple types of polypeptide chains, assembling through noncovalent interactions to enable a biological function, which depending on the conditions can be very specific or multipurpose. Knowledge of the protein quaternary structure is important because it enables to discover the biological function of the protein and, hence, it enables to target this function during drug development [18]. The sodium channel is a monomer [11], whereas the p7 hepatitis C virus is a hexamer [52]. In addition, recent findings have revealed that the novel molecular wedge allosteric drug-inhibited mechanism [56] for the M2 proton channel can be understood [39] through a unique left-handed twisting packing [23] arrangement of four transmembrane helices from four identical protein chains [69]. There are three categories of rotational symmetry for oligomeric proteins, including (i) cyclic symmetry Cn, which has an n-fold symmetry by 360 /n rotations (n = 2, 3, 4. Determination of the protein structure and understanding its function is essential for any relevant medical, engineering, or pharmaceutical applications. Therefore, the study of quaternary structure of proteins, despite all the obstacles in acquiring data from large macromolecular assemblies, is one of the major goals in biomolecular sciences. Although the structure of a large number of proteins is experimentally solved, there exist many proteins with unknown fold and without any obvious homology. However, regarding the considerably higher speed and lower cost of computing, the development of computational methods for protein structure prediction is very promising for prediction of unsolved protein structures [65]. Accurate prediction of protein structure is a difficult task due to (i) limited knowledge about stability of protein structure, (ii) the role of chaperons in the folding process of proteins from different families, (iii) multiple folding pathways to attain the native state being evidenced for a single protein, and (iv) an enormous quantity of possible conformations that can be suggested for each protein. Nevertheless, the goal of protein structure prediction projects is to reduce this gap. During its early stage, the problem was simplified by mimicking one possible mechanism of protein folding, which includes the two folding steps: (i) formation of local secondary structures and (ii) arrangement of secondary structures to achieve the folded conformation. Later, before trying to tackle tertiary structure prediction, for decades, many secondary structure prediction methods were developed. Here, we briefly introduce the three generations of secondary structure prediction methods and continue with popular methods for prediction of tertiary structure. Here, we introduce three different generations of these methods in separate sections. In the first generation, a few popular methods were developed by simple analysis of amino acids distribution in -helices and -strands. This method was developed in 1974 on the basis of statistical analysis of preference and avoidance of all 20 amino acids in -helices and -strands. They simply calculated the propensity of all 20 amino acids for -helices and -strands in a small database of solved protein structures. For example, if the property in a window of six amino acids (for a helix) or five amino acids (for a strand) is above a predefined threshold value, this segment is the nucleation point of a possible secondary structure. Secondary structure prediction was primarily based on a sliding window of 17 residues and assigning a value to each residue that expresses the likelihood of it being in a particular secondary structure. The second generation of secondary structure prediction methods covers a combination of methodology development and feature generation. Different predictor methods including statistical learning and machine learning are applied for prediction of secondary structures [62, 63, 72]. Furthermore, a class of features including physicochemical properties and sequence patterns was defined to fit into the predictor models [34]. These methods outperformed developed methods in the earlier generations in terms of accuracy [10, 64]. The main cause for improvement in accuracy was adding evolutionary information to the list of features generated from multiple sequence alignments. In addition to prediction of secondary structure, many other methods are developed for prediction of local attributes of proteins, such as disordered regions, membrane-spanning beta-barrels, and transmembrane helices. In this section, we briefly introduce more popular methodologies for tertiary structure prediction. The homology modeling method needs to have the homologous protein structure as template and threading methods are a new approach in fold recognition, in which the tool attempts to fit the sequence in the known structures. This type of method has five stages, including (i) finding a proper template, (ii) multiple sequence alignment of the query protein to the templates, (iii) modeling the target structure including main chain modeling, loop modeling, and side chain modeling, (iv) energy refinement, and (v) model evaluation.

Membrane sweeping Membrane sweeping appears to result in increased local production of prostaglandins man health over 50 cheap penegra 100mg on line. Systematic review shows that membrane sweeping is associated with an increased rate of spontaneous labour and a reduction in need for formal induction prostate cancer gleason score 6 buy discount penegra 50mg online, particularly in multiparous women prostate cancer grading buy discount penegra on line. However androgen hormone yeast buy discount penegra 50 mg on line, in women with an unfavourable cervix the use of controlled-release pessaries may be preferable because the induction time may be longer and repeated doses of tablet or gel would be required prostate oncology specialists marina del rey discount penegra 100 mg free shipping. For triplets there is an increased risk of spontaneous preterm labour and a significantly higher risk of fetal death after 34 weeks 6 days prostate cancer freezing treatment discount penegra 100 mg without a prescription. It is recommended that women with triplet pregnancies should be offered birth at 35 weeks. Systematic review has compared mechanical methods with placebo, vaginal or cervical prostaglandin, and with misoprostol and intravenous oxytocin; unfortunately the studies are small, with many different comparisons. Cohort studies found that woman being induced in the morning were less likely to require intravenous oxytocin and had lower rates of operative vaginal birth and greater maternal satisfaction. Cord prolapse Cord prolapse is a potential risk when the membranes rupture, especially when the membranes are ruptured artificially. The authors concluded that this effect may arise from non-treatment effects, and that additional trials are needed. Multiple pregnancy: the management of twin and triplet pregnancies in the antenatal period. Outpatient versus inpatient induction of labour for improving birth outcomes Cochrane Database Syst Rev. This also has an unknown impact on the emotional and psychological wellbeing of the mother and her family. A clear clinical indication is needed to interrupt a pregnancy, with careful consideration of the benefits and risks, together with a full explanation to the woman and her family prior to the decision being made. In all of the other cases there were compelling maternal or fetal indications for the procedure. Three women died following uterine rupture, though one of these women had a placenta praevia accreta. It is therefore vital that when discussing management with a patient, the individual risks and benefits must be considered. The aim of this chapter is to attempt to quantify these risks in order that, for each individual, appropriate counselling can be undertaken in planning the next delivery. It is important to realise that women make decisions for a variety of reasons and that their choices may not always be those that we would make ourselves. Consequently, the problem of management of women with a scarred uterus in subsequent pregnancies is one of the most common reasons for hospital referral in multigravida. It is a vital part of antenatal care that women are given a clear understanding of the plan of management from early in pregnancy, with the caveat that this may need to be adapted if the pregnancy presents unexpected problems. It may be that obesity is the factor that increases the risk, rather than caesarean section [C]. A uterine dehiscence is defined as disruption of the uterine muscle with intact uterine serosa. The uterine rupture rate was higher in women induced using prostaglandins, but not in women induced by other methods. The rupture rate was higher in women who had not previously also delivered vaginally. For women who had previously delivered vaginally the risks were 1 in 514 and 1 in 175 respectively. Good antenatal planning should individualise the risks and benefits for each woman for each type of delivery, allowing the woman to make the best choice for herself. Research suggests that most women do not have clear ideas about the best choice for delivery and want accurate information and advice individualised for their own set of circumstances. Given the extremely high rates of uterine rupture with vertical upper-segment incisions, it is best to err on the side of caution whenever there is doubt. J-shaped and inverted-T-shaped incisions are associated with similar rupture rates to low vertical incisions of 1. The evidence on whether a single-layer closure is associated with higher rates of subsequent rupture is conflicting. Because the only studies of rupture are either small or observational the real risks are difficult to quantify. One relatively large observational study showed the risk of uterine rupture was increased 2-fold compared with women with only one uterine scar (rupture risk 1. Because of small numbers the real risk for rupture in women with three or more sections is difficult to quantify. Small observational studies suggest that the rupture risk may be increased by a factor of 2 or 3. It is not surprising therefore that a study has suggested a link between uterine rupture and maternal age. These include fetal macrosomia, delivery after 41 weeks, cervical dilatation of <4 cm at admission, non-white ethnicity, male infant and short maternal stature. Decision making may therefore vary depending on the circumstances at the time, as some of these factors are dynamic. It is especially important to review records where there is any doubt about the type of uterine scar used. Counselling the patient with regard to the likelihood of success is also important, and review of the previous labour is a necessary part of this counselling. Women should be provided with as accurate information as possible pertinent to their particular set of circumstances. Women should be advised that the safest place to labour, should she wish to labour, is in hospital. It is better to support a woman to labour in hospital, even if the clinician feels this is injudicious, than for her to feel unsupported and to choose to labour at home. If a woman is able to make her choice early in the pregnancy her antenatal care can be tailored around this. Women can be offered an open appointment to return should they have further questions, but the provision of antenatal care can rest with the community midwife. Interdelivery interval the interdelivery interval has been the subject of three studies. All of the studies are retrospective and in all the analysis was limited to women with singleton pregnancies, at term, who had one prior caesarean birth and no prior vaginal births. This will therefore skew the data towards slightly higher rupture rates, as women with a previous vaginal birth form the lowest risk group for rupture. It is noted from these studies that high rupture rates are reported, varying from 0. Findings suggestive, but not diagnostic, of a placenta accreta on antenatal ultrasound include: Planning the delivery Value of pelvimetry Pelvimetry performed either clinically or radiographically does not provide any useful information [A]. Four trials of more than 1000 women were included in the most recent Cochrane Review. Value of ultrasound for scar thickness Ultrasound evaluation of the scar antenatally has been investigated as a method of determining women at higher risk of scar rupture during labour. Unfortunately, results do not give a high enough sensitivity for this modality to be used in everyday clinical practice. If an accreta is suspected then it is prudent to take precautions for major haemorrhage. Management of placenta accreta is discussed in Chapter 46, Antepartum haemorrhage. It is important when discussing delivery in the antenatal period to agree a clear plan of management with the patient and for this to be carefully documented and easily available to carers in labour. This can be made with the proviso that if circumstances change, it can be amended, but it does allow women to plan in advance and minimises requests for early delivery later in pregnancy that can compromise neonatal wellbeing. It is possible to apply a little common sense where women have persistently laboured at 38 weeks before, but it must be remembered that if women have a tendency to go well past their dates, even 39 weeks may be early for some babies. Signs of uterine rupture are: fetal bradycardia; upward displacement of the presenting part; sudden loss of contractions; maternal hypotension; heavy vaginal bleeding; abdominal or shoulder pain. Assessment of the risk of placenta accreta this is particularly pertinent in the management of women undergoing delivery after repeated caesarean sections. If the fetus or placenta is extruded into the abdomen, there is very little time to salvage the fetus. Clearly the sign most commonly associated with uterine rupture is a fetal bradycardia. This is however, unhelpful to the clinician on the labour ward as our aim is to intervene before the uterus ruptures. Comparing cases with uterine rupture in the 4 hours preceding the second stage and during the second stage there were no differences in the appearance of any type of deceleration. One study attempted to control for dose and duration of oxytocin use and found a doubling in the rate of rupture which was most marked at doses of greater than 20 mu/min. With the advent of small fetal monitors and more mobility with epidural analgesia, it should be possible to allow women the opportunity to mobilise without compromising fetal surveillance. Forty per cent of women will respond to simple measures such as rehydration (see Chapter 50). A more flexible approach should be adopted in women with a uterine scar, and consideration should be given for lower rates of progress before resorting to syntocinon. When syntocinon is thought to be necessary, the decision should be made at consultant level and the risks and benefits should be discussed with the mother [E]. Assessment of progress in labour should ideally be made by the same person and the frequency of vaginal examination may need to be increased as there is some evidence that early intervention for static progress over 2 hours after augmentation can be used to prevent uterine rupture. Conduct of the labour General management Some general steps can be taken on admission in labour to minimise the risks to the mother and fetus. Only four small randomised trials assessing the method of induction have been performed. Several observational studies have been performed, but all of these have limitations. Because bradycardia is seen in uterine rupture, the consensus opinion of the Expert Committee recommends continuous fetal monitoring in labour for women with a uterine scar [E]. There are no randomised studies to help and only observational data are available [D]. This was almost exactly the same as the risk for women augmented in labour (87/10,000). These methods are associated with a lower risk for induction than prostaglandins (0. Therefore, a low threshold for very active management of the third stage should be implemented. Clearly, when deciding on the best strategy the reason for induction must be considered and weighed against the risks of the procedure. Induction at 41 weeks is recommended to prevent the risk of stillbirth after this time. Documentation: oxytocics at delivery of the shoulders; prompt delivery of the placenta after separation; consideration of continued syntocinon infusion for 4 hours after delivery or a long-acting syntocinon analogue. If the placenta is retained, the possibility of a placenta accreta must be borne in mind. If at the time of manual removal a clear plane of cleavage cannot be defined, placenta accreta is likely. Different treatment options for morbidly adherent placenta have been tried with variable success. Involve a consultant obstetrician in decisions regarding mode of delivery, the need for induction and any decision to augment labour. There should be adequate education of all staff, ensuring awareness of signs and symptoms of uterine rupture. Vaginal delivery is a valid option after almost any prior lowersegment caesarean section. Repeated caesarean sections carry exponentially increasing risks of placenta praevia and accreta, with significant maternal morbidity. Induction of labour may lead to at least a doubling in risk of scar problems but it is possible that the magnitude of increase is higher if prostaglandins are needed. Planned elective repeat caesarean section versus planned vaginal birth for women with a previous caesarean birth. The risk of unexplained antepartum stillbirth in second pregnancies following caesarean section in the first pregnancy. Risk of perinatal death associated with labor after previous cesarean delivery in uncomplicated term pregnancies. Maternal and perinatal outcomes associated with a trial of labor after prior cesarean delivery. Obstetric outcomes in women with two prior cesarean deliveries: is vaginal birth after cesarean delivery a viable option Uterine rupture during a trial of labour after a one-versus-two-layer closure of a low transverse caesarean. Vaginal birth after Caesarean section for arrest of labour: is success determined by maximum cervical dilatation during the prior labour Mode of delivery for the morbidly obese with prior Caesarean delivery: vaginal versus repeat Caesarean. There is a general consensus that the latent phase carries no inherent risk of harm if it fails to progress. As will become apparent in considering this subject these are generally descriptive terms based on observational studies.

Maternal pushing should be discouraged as this may lead to further impaction of the shoulders prostate cancer home remedies discount penegra 50 mg fast delivery. An episiotomy or extension of an episiotomy serves to create increased vaginal access to perform internal manoeuvres but may cause considerable maternal trauma mens health muscle in a bottle buy generic penegra 100 mg. Manoeuvres for shoulder dystocia are aimed at addressing one or a combination of the following: Suprapubic pressure is often used simultaneously man health news za exit buy generic penegra 50 mg online. The aim is to move the shoulders into the wider oblique diameter of the pelvis and force the anterior shoulder under the symphysis pubis man health warehouse buy penegra 100 mg. These may involve considerable discomfort to the mother (and distress to her partner) and warning should be given prostate cancer 4 3 penegra 50mg online. The aim of these manoeuvres is to rotate the fetal trunk into an oblique position to allow delivery of the shoulders prostate oncology san diego cheap penegra 100 mg free shipping. The most spacious part for access is the sacral hollow and the hand should be introduced into the posterior vagina. By approaching the anterior shoulder from behind attempts should be made to rotate the shoulders into the oblique diameter of the pelvis, using a finger hooked into one axilla. Ideally, one should attempt to move the fetus in a direction that allows the shoulder to move inwards towards the chest, which will decrease the dimensions of the shoulders. By simultaneously combining this with a degree of downward traction, the rotated shoulder remains within the pelvis and appears under the symphysis. The first step should always be the McRoberts manoeuvre which is successful in up to 90 per cent of cases. Remember to maintain the head in a neutral position (axial and in line with the fetal spine), avoiding excessive lateral traction. Delivery of the posterior arm By advancing a hand into the uterus posteriorly and finding the fetal hand, delivery of the posterior fetal arm can be achieved by sweeping it across the fetal chest. The McRoberts manoeuvre involves hyperflexion of the maternal thighs onto the maternal abdomen, either by the mother herself or by a pair of assistants. It has been shown radiographically to flatten the lumbosacral curve and lessen any obstruction from the sacral promontory. If delivery still has not been achieved then repeating the above stepwise approach of manoeuvres is recommended. Furthermore, publication bias means that clinicians often only report their successes. It is likely that heroic measures have, on many occasions, been followed by stillbirth, neonatal death or profound disability, at a cost of considerable maternal morbidity. Not only should the individual document their part in the management of the shoulder dystocia with care and detail, but the medical records should be reviewed contemporaneously, checking for completeness and consistency between healthcare professionals. Good documentation is also useful for helping form a plan in any subsequent pregnancy. It is important to record the following: Cleidotomy or deliberately fracturing the fetal clavicle(s) can be used to shorten the biacromial diameter. However, this can be difficult to perform and can lead to injury of underlying vascular and pulmonary structures. This may require additional uterine relaxation, using either bolus tocolytics or general anaesthesia. Abdominal rescue describes intrauterine manipulation through a transabdominal hysterotomy to facilitate vaginal delivery. The presence of known risk factors, particularly two or more, should trigger advance preparations to deal with or avoid the situation, before it actually arises. Since shoulder dystocia will often occur without warning, obstetricians must have well-rehearsed strategies to overcome it. Postpartum haemorrhage and significant maternal trauma are associated with shoulder dystocia. Mothers must understand what went wrong, both to minimise inappropriate blame of themselves or others and so that they may alert their caregivers in the next pregnancy. Mathematic modeling of forces associated with shoulder dystocia: a comparison of endogenous and exogenous sources. Maternal and neonatal outcomes after induction of labor without an identified indication. Effects of treatment in women with gestational diabetes mellitus; systemic review and meta-analysis. Prevention of brachial plexus injury - 12 years of shoulder dystocia training: an interrupted time-series study. Clinical efficiency in a simulated emergency and relationship to team behaviours; a multisite cross-sectional study. It has been established for some time that one-to-one care in labour reduces intervention and improves maternal satisfaction, especially when the continuous carer is not a member of staff [A]. Second-stage caesarean section (see Chapter 53) is associated with increased maternal and neonatal morbidity,1 and therefore should be avoided if safely possible. Chapter 54 covers fetal compromise in the second stage and will therefore not be discussed further here. With appropriate fetal monitoring and intervention if indicated, prolonged second stage does not appear to be associated with significantly increased neonatal morbidity. The onset of the active second stage of labour is defined by the baby being visible, expulsive contractions with a finding of full dilatation of the cervix or other signs of full dilatation of the cervix, or active maternal effort following confirmation of full dilatation of the cervix in the absence of expulsive contractions. With regard to the normal length of the active second stage, it varies depending on parity and whether the woman has an epidural. The range and upper limit of normal for the active second stage in women giving birth to their first baby is about 0. Delay should be diagnosed in nulliparous women when the active second stage has lasted 2 hours and birth is not imminent, and when the active second stage has lasted 1 hour and birth is not imminent in multiparous women. Other maternal indications With respect to maternal fatigue and poor maternal effort, supportive measures should be employed including appropriate analgesia, but if these measures are not successful, operative intervention can be offered. Maternal medical disorders which merit shortening of the active second stage should usually be identified in the antenatal period and appropriate discussion and planning put in place. Vacuum is also contraindicated in face presentation, although forceps can be used if mento-anterior. Careful assessment and a skilled operator are required in these cases, as is appropriate instrument selection taking into account that forceps reduce the haemorrhagic risk compared to vacuum and vacuum reduces the risk of fracture compared to forceps. Before embarking on an instrumental delivery, specific prerequisites must be fulfilled. An operator with the required skills and a willingness to abandon the procedure if indicated. The presenting part should be the vertex, although forceps can be used in mento-anterior face presentations, and in brow presentations where the pelvis is adequate and the fetus small. In these circumstances, the operator must have the appropriate level of expertise to conduct these more complicated instrumental vaginal deliveries. Cervix fully dilated with ruptured membranes (again, skilled operators may perform vacuum extraction prior to full dilatation in specific circumstances. Position of the presenting part must be known to ensure correct application of both forceps and vacuum. In cases of trial of instrumental birth, written consent for the trial and possible caesarean section should be obtained. For forceps, the easiest way to categorise them is secondary to their physical characteristics. Forceps are either curved or straight, depending on whether they have a pelvic curve or not, and either have a long or a short shank. The only straight forceps available are long straight forceps, or Kielland forceps, which are used for rotational deliveries (see later). The most commonly used forceps are long curved forceps of which there are around 700 varieties, with very little to choose between them. There are also different types of vacuum extractors and cups, again with different pros and cons. Large, soft silastic cups gained popularity for their ease of application and lower incidence of scalp trauma, but have been shown to have a higher failure rate when compared to rigid cups [A]. If the cup is placed correctly over the flexion point (a flexing median application), the failure rate for vacuum extraction should be in the region of 4 per cent. A flexing paramedian application increases the failure rate to around 17 per cent, a deflexing median application with the cup placed too far anteriorly is associated with a failure rate of 29 per cent and a deflexing paramedian application has a failure rate of up to 35 per cent. Unless the flexion point is clearly identified and the cup placed correctly, any attempt at vacuum delivery should not proceed. When using vacuum, there is no evidence of benefit in a slow, incremental increase in pressure compared to a rapid increase. For non-rotational deliveries, the options are either non-rotational forceps or vacuum, and there are pros and cons to both [A] (Table 56. Operators should be skilled in the use of both instruments, and fully understand the impact of different clinical situations on likely outcome. In cases of outlet deliveries, there may be little to choose between the two in terms of success rates, but overall forceps are associated with a significantly increased success rate compared to vacuum [A], and achieve delivery more quickly,9 which is an important feature to consider in cases where delivery needs to be achieved quickly. Factors which should warn the operator of an increased risk of failure with vacuum include: excessive caput or moulding (may be an indicator of relative cephalopelvic disproportion, less likely to achieve adequate seal), malposition, and poor maternal effort (particularly following epidural top-up or spinal for a trial in theatre). Most trainees become comfortable with vacuum before forceps, but when looking at the pros and cons listed in Table 56. Many such deliveries are conducted as trials in theatre with regional anaesthesia, which limits maternal effort, and clinicians must be skilled in at least one of the above techniques. Rotational vacuum is most commonly used, but the higher failure rates must be taken into account. The fetal head is flexed and then rotated into the occipito-anterior position, and held there until either the mother pushes and the head descends, or either vacuum or forceps are applied to achieve delivery. The most effective instrument in achieving rotational delivery is Kielland forceps, but in many units the skill in using them has disappeared, mainly because of concerns over increased maternal and perinatal morbidity. There are reports in the literature regarding poor outcomes with Kielland forceps, but many of these are old and from uncontrolled observational studies and in many cases the fault lies with poor case selection and an unwillingness to abandon the procedure at the appropriate time. In cases where the head is in the low cavity or on the perineum, forceps may be the safer option, but caution must be exercised and this should be a senior decision. Any injuries should be explained to the parents and documented, and if there are concerns the baby should be seen by an appropriately qualified practitioner. It is good practice for the operator to note any marks on the neonate to confirm where the instrument used was placed. This gives immediate feedback regarding appropriate application and placement, and will inform skill development. Maternal aftercare should include appropriate analgesia (paracetamol and diclofenac if no contraindications), a venous thromboembolism risk assessment and thromboprophylaxis if indicated [D]23 and good bladder care. The timing and volume of the first void should be monitored and documented [C], and assessment of post-void residual carried out if retention is suspected, to avoid over-distension injury. If regional anaesthesia has been used, an indwelling catheter should be left in situ for 12 hours after delivery. She should also be informed of the high chance of a successful vaginal birth in future pregnancies [B]. Both maternal and neonatal morbidity are increased with prolonged, repeated or excessive traction in the absence of progress. If there is no descent after the first pull, the situation should be reassessed and requesting senior help should be considered, as this may be indicative of an increased risk of failure. As the success rate with forceps is higher than with vacuum, there is a temptation to try forceps if vacuum fails. Successful delivery is more likely to be achieved with forceps, and more quickly, than with vacuum. Correct case selection, correct instrument selection and appropriate skills are all essential to optimise success rates. The effect of sequential use of vacuum and forceps for assisted vaginal delivery on neonatal and maternal outcomes. Effect of low-dose mobile versus traditional epidural techniques on mode of delivery: a randomised controlled trial. Oxytocin infusion during second stage of labour in primiparous women using epidural analgesia: a randomised double-blind placebo-controlled trial. Delayed versus early pushing in women with epidural analgesia: a systematic review and meta-analysis. Cohort study of the decision to delivery interval and neonatal outcome for emergency operative vaginal delivery. A prospective randomized controlled trial of the Kiwi Omnicup versus conventional ventouse cups for vacuum-assisted vaginal delivery. A prospective observational study of 1000 vacuum assisted deliveries with the Omnicup device. Rapid versus stepwise negative pressure application for vacuum extraction assisted vaginal delivery. Cohort study of operative delivery in the second stage of labour and standard of obstetric care. Tragic outcomes for breech are well recognised, yet they happen even after caesarean sections as well as technically flawless vaginal breech births. Every experienced midwife and obstetrician recalls happy memories of mothers who birth their breech so smoothly and naturally, that we worry wakefully that our modern tilt towards caesarean section may be costly and invasive, introducing morbid and mortal risk whilst taxing young mothers with prolonged recovery times.

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Syndromes

• No urine output
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If an eclamptic fit occurs prostate examination proven penegra 100mg, magnesium sulphate is the prophylaxis of choice prostate cancer youtube cheap 100 mg penegra with mastercard, as demonstrated by the Eclampsia Trial [B] mens health testosterone discount penegra 50mg with amex. Magnesium sulphate acts as a membrane stabiliser and vasodilator and reduces intracerebral ischaemia prostate cancer ribbon generic penegra 50 mg without a prescription. In cases of oliguria prostate cancer end stage generic penegra 50mg otc, care must be taken prostate oncology on canvas penegra 100 mg amex, as magnesium sulphate is renally excreted. Toxicity is detected by the absence of patellar reflexes, but ultimately respiratory arrest and muscle paralysis or cardiac arrest will occur. However, the Magpie Trial evaluated magnesium sulphate versus placebo in women with pre-eclampsia and demonstrated a clear benefit of prophylactic therapy [A]. Magnesium sulphate halved the risk of eclampsia and probably reduced the risk of maternal death. There did not appear to be any substantive harmful short-term effects to either the mother or baby. The postnatal visit is also an excellent opportunity to discuss complications of the pregnancy and the planned management of any future pregnancy. It is plausible that active assessment of cardiovascular risk up to 6 months postpartum may lead to earlier identification of cardiovascular risk and the potential for lifestyle modification. Regional blockade is the preferred method of analgesia for labour and of anaesthesia for operative deliveries [E], but a coagulopathy must be excluded. Care must be taken to avoid arterial hypotension (particularly following postpartum haemorrhage) in view of the vasoconstriction and reduced intravascular volume. A low threshold for central invasive monitoring is necessary in women who require a caesarean section [E]. Postpartum care As a third of eclamptic fits occur postpartum, intensive monitoring is required, usually for 48 hours after delivery. Although eclampsia has been reported beyond this time, it is unlikely to be associated with serious morbidity. Both maternal and fetal morbidity and mortality are more likely to occur with early onset disease. Despite the many tests being investigated, pre-eclampsia cannot be accurately predicted. An abnormal uterine artery Doppler at 20 weeks will increase risk approximately six-fold in both high- and low-risk women. Cerebral haemorrhage and adult respiratory distress are common causes of death in pre-eclampsia; therefore acute management focuses on controlling blood pressure and restricting fluid intake. The use of anti hypertensive therapy in moderately hypertensive women demonstrates a significant reduction in severe hypertension only; there are no other proven additional benefits. Low-dose aspirin in pregnancy results in a small (10 per cent) but significant reduction in pre-eclampsia; there is an associated reduction in preterm delivery. Magnesium sulphate is the anticonvulsant of choice following an eclamptic fit, resulting in fewer fits and less maternal morbidity compared with diazepam and phenytoin. Can 24-hour ambulatory blood pressure measurement predict the development of hypertension in primigravidae Angiogenic factors combined with clinical risk factors to predict preterm pre-eclampsia in nulliparous women: a predictive test accuracy study. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Diagnostic accuracy of placental growth factor in women with suspected pre-eclampsia: a prospective multicenter study. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. A good understanding of prescribing principles is necessary as this has relevance to the large majority of core modules. It is reported that approximately 50 per cent of women will take medication during pregnancy. Therefore, a broad understanding of the impact of pregnancy on drug pharmacokinetics (drug handling) and pharmacodynamics (drug actions) is required. Furthermore, the large majority of drugs cross the placenta, and some drugs have significant fetal effects. For this reason, most drugs are not licensed for use in pregnancy, thus prescribing in pregnancy often lies outside licensed indications. A detailed discussion of prescribing for particular disorders during pregnancy can be found in the relevant sections of this book. There is also the opportunity to discuss particular risks and concerns, of both the medical problem itself and the medications that will be prescribed during pregnancy. Thus, women may suddenly stop drugs in early pregnancy that may have a significant impact on their own health. Discussions in the pre-conception period will prevent such non-compliance in early pregnancy of important medications, such as antiepileptics or immunosuppressants. For acidic drugs, such as warfarin, which are highly protein bound, the volume of distribution is relatively low, but the plasma concentration high. Therefore, volume of distribution is dependent upon plasma volume, tissue volume, and the amount of binding of a drug in the tissues and in plasma proteins. It is beneficial for many of these women to be seen pre-conceptually for several reasons. First, it allows optimisation of therapy such that pregnancy can be commenced with the lowest achievable risks. Typical examples of this include optimisation of glycaemic control in diabetic women and the prescription of high-dose (5 mg) folic acid to women at particular risk, such as those with epilepsy. Therefore, pregnancy results in an increase in volume of distribution (due to increased plasma volume) and an increase in the fraction of a drug that is unbound, or active, in the plasma (due to a fall in plasma proteins). Thus, measurements of total drug concentration, which are used for medications such as phenytoin and sodium valproate, underestimate the corresponding unbound or active concentrations. This may result in prescribing higher doses than necessary, which is particularly important as the teratogenicity of both these drugs is reported in registries to be dose dependent [D]. The overall effect is further compounded by genetic variation and the effect of plasma volume and plasma proteins described above. This should be considered when prescribing in pregnancy and, since there are so many unknown factors, clinicians must be guided by the overall clinical affect of a drug. Renal clearance Pregnancy causes an increase in renal blood flow and glomerular filtration rate of more than 50 per cent, which can have a significant effect on drugs that are predominantly excreted by the kidneys. Thus, the clearance of b-lactam antibiotics such as penicillins and cephalosporins is increased during pregnancy [C]. Although the liver smooth endoplasmic reticulum is the main site of enzymatic metabolism, virtually all cells have the ability to metabolise drugs to some degree, with other main sites being the epithelial cells of the gut, kidney, lung and skin. Not only does pregnancy alter the activity of these enzymes, but it also varies with gestation, drug interactions. Enzymes demonstrating increased activity will result in reduced plasma levels of a drug, requiring an increase in dose, and vice versa. Thus, variation of drug metabolism with pregnancy is complex and, although the Table 27. Examples of modification of enzyme activity with pregnancy4 Drug transfer across the placenta the majority of drugs are able to cross the placenta to the fetus to some degree, and there are very few that demonstrate no placental transfer. Transfer of drugs across the placenta can occur by passive transfer, active transport, facilitated diffusion, phagocytosis and pinocytosis. Therefore, small, unionised lipid-soluble drugs are able to cross at the fastest rate. This can be influenced by the degree of plasma protein binding, and by placental metabolism. Whilst it is generally considered that facilitated diffusion, phagocytosis and pinocytosis play little significant role in drug transfer, there is growing interest in placental active transport, utilising energy-requiring drug transporters. All these transporters work against a concentration gradient, and several have now been described within the placenta. Unfortunately, the teratogenicity of most drugs is established only after initial drug licensing, as pregnant women are excluded from human trials of new drugs. The classic and most famous example of this is thalidomide, which was introduced as an antiemetic in the 1950s and was subsequently withdrawn when it was found to cause phocomelia. However, it is known that for some enzymes it varies with gestation, and the activity of many is altered by alcohol and cigarette smoking. Drugs that undergo metabolism in the placenta include steroids, such as dexamethasone, and alcohol. For example, transplacental passage of anti-arrhythmic drugs has been used to treat fetal supraventricular tachycardias since the first report in 1980. Co-administration of other antiarrhythmic drugs has been suggested to improve success by modifying P-glycoprotein transport of digoxin. The amount of drug that the infant is exposed to will be dependent upon volume of milk ingested, maternal plasma levels and infant excretion (which probably varies with age, and is less with increasing immaturity). Plasma protein binding has been shown to have a significant impact on levels in breast milk. Drugs that are highly protein bound result in less infant exposure via breast milk. Measurable infant levels were found only for drugs with less than 70 per cent plasma protein binding. Teratogenicity A teratogen is an agent that is able to permanently alter the development, growth, structure or function of a developing embryo or fetus. Within this period, each structure has a period of maximal vulnerability and, usually, the earlier the insult the more severe the resulting malformation. Some structures that have initially formed during embryogenesis are still vulnerable to effects in the fetal period of development (9 weeks to term). For example, Specific drug considerations in pregnancy Prescribing during pregnancy requires careful consideration of the risks and benefits, in discussion with the woman herself. In general, use of the lowest number of drugs (monotherapy where possible) and the lowest effective dose are recommended, remembering the effects of pregnancy on plasma levels of a drug [E]. For obvious reasons, this is in no way exhaustive and more detailed discussions can be found in the literature referenced at the end of this chapter, or in the relevant sections of this book. Pregnancy is associated with increased plasma volume and reduced levels of plasma-binding proteins, which results in an increased unbound, or active, drug concentration. Effects vary with enzyme, gestation, genotype and other prescribed drugs, and thus are often difficult to predict. Renal clearance of drugs increases during pregnancy, resulting in lower plasma levels of drugs that are predominantly excreted via this route. Drugs cross the placenta predominantly by passive diffusion and there is growing interest in the active transporters. Transfer of drugs into breast milk is determined by lipophilic properties of a drug, molecular size and polarity. In general, drugs in pregnancy and breastfeeding should be used at the lowest effective dose, using the lowest number of drugs (monotherapy where possible). Pharmacokinetics of low molecular weight heparin and unfractionated heparin in pregnancy. Placental transporters relevant to drug distribution across the maternal-fetal interface. Transplacental cardioversion of intrauterine supraventricular tachycardia with digitalis. Transplacental treatment of fetal tachycardia: implications of drug transporting proteins in the placenta. Prescribing in pregnancy and during breastfeeding: using principles in clinical practice. Candidates should be aware of previous findings but should not rely on out-of-date reports. Candidates should be aware of the leading causes of maternal death worldwide and the strategies for tackling them. In Chad, for example, a girl has a 1 in 15 chance of dying as a result of pregnancy or delivery, and in Afghanistan the chance is 1 in 30. Cases are anonymised, so that those involved can comment frankly and make their own suggestions for improvements, and no blame is attached to individuals. Direct death: death resulting from obstetric complications of the pregnant state (pregnancy, labour and puerperium), from interventions, omissions, incorrect treatment or a chain of events resulting from any of the above. Coincidental death: death from an unrelated cause which happens to occur in pregnancy or the puerperium. In 1990 only 55 per cent of deliveries in developing regions were attended by skilled health personnel, but in 2009 this proportion had risen to 65 per cent.