It is the drug of choice for invasive amoebiasis of the intestine or the liver, but it is less effective against organisms in the lumen of the gut. It is distributed rapidly throughout the tissues, reaching high concentrations in the body fluids, including the cerebrospinal fluid. The drug has a metallic, bitter taste in the mouth but causes few unwanted effects in therapeutic doses. Tinidazole is similar to metronidazole in its mechanism of action and unwanted effects, but is eliminated more slowly, having a half-life of 12­14 h. In both types of the disease, there is an initial local lesion at the site of entry, which may (in the case of T. This is followed by bouts of parasitaemia and fever as the parasite enters the haemolymphatic system. The parasites and he toxins they release during the second phase of the disease cause organ damage. The initial phases of the infection are similar but parasites damage the heart, muscles and sometimes liver, spleen, bone and intestine. Related trypanosome infections also pose a major risk to livestock and thus have a secondary impact on human health and well-being. In the case of Chagas disease, some 7 million people are believed to harbour the infection. Nifurtimox, eflornithine and benznidazole are used in Chagas disease: however, there is no totally effective treatment for this form of trypanosomiasis. Suramin is relatively toxic, particularly in malnourished patients, the main organ affected being the kidney. Many other slowly developing adverse effects have been reported, including optic atrophy, adrenal insufficiency, skin rashes haemolytic anaemia and agranulocytosis. A small proportion of individuals have an immediate idiosyncratic reaction to suramin injections, which may include nausea, vomiting, shock, seizures and loss of consciousness. The drug is administered intravenously or by deep intramuscular injection, usually daily for 10­15 days. After absorption from the injection site, it binds strongly to tissues (especially in the kidney) and is eliminated slowly, only 50% of a dose being excreted over 5 days. Fairly high concentrations of the drug persist in the kidney, the liver and the spleen for several months, but it does not penetrate the blood­brain barrier. Its usefulness is limited by its unwanted effects ­ an immediate decrease in blood pressure, with tachycardia, breathlessness and vomiting, and later serious toxicity, such as kidney damage, hepatic impairment blood dyscrasias and hypoglycaemia. The amastigotes multiply, and eventually the infected cell releases a new crop of parasites into the haemolymphatic system, where they can infect further macrophages and possibly other cells. Different species of Leishmania exist in different geographical areas and cause distinctive clinical manifestations (see Table 55. This manifestation is encountered mainly in the Indian subcontinent and West Africa. There is some cause for optimism and new agents, as well as new treatment modalities, are under investigation (Barrett, 2010; Brun et al. Side effects are common and may be severe, but are readily reversed when treatment is discontinued. Combined therapy with nifurtimox and eflornithine has yielded promising results in patients with late-stage disease. It is a highly toxic drug that produces many unwanted effects including encephalopathy and, sometimes, immediate fatality. The parasite exists in a flagellated form (promastigote) in the gut of the infected insect, and a eb o Leishmania organisms are flagellate protozoa and leishmaniasis, the infection that they cause, is spread by the sandfly. Virulent strains cause inflammation of the vagina and sometimes of the urethra in males. Miltefosine, an antitumour drug, is also used in some countries (not United Kingdom), as is meglumine antimoniate. Sodium stibogluconate is given intramuscularly or by slow intravenous injection in a 10-day course. The mechanism of action of sodium stibogluconate is not clear, but the drug may increase production of toxic oxygen free radicals in the parasite. Miltefosine (hexadecylphosphocholine) is also effective in the treatment of both cutaneous and visceral leishmaniasis. They may have some action on the parasite in their own right, but their main utility is to control the spread of secondary infections. Resistance to current drugs, particularly the pentavalent antimonials (possibly caused by increased expression of an antimonial efflux pump), is a serious problem and there is no immediate prospect of a vaccine. The pharmacology of current drugs and prospects for new agents have been reviewed by Singh et al. Some useful information and good diagrams, but a bit technical in places) Lanteri, C. It expels the infectious cysts in its faeces; humans can inadvertently become intermediate hosts, harbouring the asexual form of the parasite. Ingested oocysts develop into sporozoites, then to trophozoites, and finally encyst in the tissues. The treatment of choice is pyrimethamine­sulfadiazine (to be avoided in pregnant patients); trimethoprim­ sulfamethoxazole (co-trimoxazole see Ch. But it is not simply a lack of new drugs that is the problem: for economic reasons, the countries and populations most affected often lack an efficient infrastructure for the distribution and safe administration of the drugs that we already possess. Cultural attitudes, civil wars, famine, the circulation of counterfeit or defective drugs, drought and natural disasters also exacerbate this problem. Proteases as antimalarial targets: strategies for genetic, chemical, and therapeutic validation. Infection is then spread by ingestion of food or water contaminated with faecal matter containing the cysts. It is encountered worldwide, and epidemics caused by bad sanitation are not uncommon. Previously considered to be a widely distributed but largely innocuous microorganism, it is now recognised as an important cause of opportunistic infections in immunocompromised patients. High-dose co-trimoxazole (Chs 51 and 52) is the drug of choice in serious cases, with parenteral pentamidine as an alternative Treatment of milder forms of the disease (or prophylaxis) can be effected with atovaquone, trimethoprim­ dapsone or clindamycin­primaquine combinations. Discusses how new agents might be developed using (for example) a systems biology approach) Brun, R. Development of drug resistance in Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. New drugs for the treatment of human African trypanosomiasis: research and development. Less good on drug therapy, but if you are interested in the biology of the insect vector of trypanosomiasis, then this is for you) Barrett, M. Inhabitants of tropical or subtropical low-income countries are most at risk; children often become infected at birth (polyparasitaemia is common) and may remain so throughout their lives. The clinical consequences of helminthiasis vary: for example, threadworm infections mainly cause discomfort but infection with schistosomiasis (bilharzia) or hookworm is associated with serious morbidity. Anaemia, nutritional problems and cognitive impairment are common in helminth-infected children. Helminth infections are an even greater concern in veterinary medicine, affecting both domestic pets and farm animals leading to significant loss of livestock. Because of its prevalence and economic significance, the pharmacological treatment of helminthiasis is therefore of great practical therapeutic importance. The latter group is subdivided into the trematodes (flukes) and the cestodes (tapeworms). The global range and occurrence of helminthiasis has been reviewed by Lustigman et al. Humans are generally the primary (or definitive) host for helminth infections, in the sense that they harbour the sexually mature reproductive form. Direct ingestion is common: eggs or larvae in the faeces of infected humans, enter the soil and subsequently are ingested and infect the secondary (intermediate) host. In some cases, the eggs or larvae may persist in the human host and become encysted, covered with granulation tissue, giving rise to cysticercosis. Encysted larvae may lodge in the muscles and viscera or, more seriously, in the eye or the brain. The adult worms of both sexes live and mate in the veins or venules of the bladder or the gut wall. The female lays eggs that pass into the bladder or gut, triggering inflammation in these organs. This results in haematuria in the former case and, occasionally, loss of blood in the faeces in the latter. The eggs hatch in water after discharge from the body and thus enter the secondary host ­ in this case a particular species of snail. Some 85 million people in Asia, Africa and parts of America harbour one or other of these tapeworm species. Humans become infected by eating raw or incompletely cooked fish containing the larvae. Again, undercooked meat or contaminated food is an important cause of infection by roundworm, threadworm and whipworm, whereas hookworm is generally acquired when their larvae penetrate the skin. Intestinal blood loss is a common cause of anaemia in regions where hookworm is endemic. A skin infestation, termed creeping eruption or cutaneous larva migrans, is caused by the larvae of dog and cat hookworms which often enter through the foot. Visceral larva migrans is caused by larvae of cat and dog roundworms of the Toxocara genus. The adult filariae live in the lymphatics, connective tissues or mesentery of the host and produce live embryos or microfilariae, which find their way into the bloodstream and may be ingested by mosquitoes or other biting insects. After a period of development within this secondary host, the larvae pass into the mouth parts of the insect and thus infect the next victim Major filarial diseases are caused by Wuchereria or Brugia, which cause obstruction of lymphatic vessels, producing elephantiasis ­ hugely swollen legs. Trichinella spiralis causes trichinosis; the larvae from the viviparous female worms in the intestine migrate to skeletal muscle, where they become encysted. The worm may be up to a metre in length and must be removed surgically or by slow mechanical winding of the worm on to a stick over a period of days, to ensure that the worm does not break, because the remains would putrefy. These are cestodes of the Echinococcus species for which dogs are the primary hosts, and sheep the intermediate hosts. The primary, intestinal stage does not occur in humans, but under certain circumstances humans can function as the intermediate host, in which case the larvae develop into hydatid cysts within the tissues, sometimes with fatal consequences. Because the metabolic requirements of these parasites vary greatly from one species to another, drugs that are highly effective against one type of worm may be ineffective against others. To bring about its action, the drug must penetrate the tough exterior cuticle of the worm or gain access to its alimentary tract. A further complication is that many helminths possess active drug efflux pumps that reduce the concentration of the drug in the parasite the route of administration and dose of antihelminthic drugs are therefore important. In a reversal of the normal order of things, several antihelminthic drugs used in human medicine were originally developed for veterinary use. Some individual antihelminthic drugs are described briefly below and indications for their use are given in Table 56. They are thought to act by inhibiting the polymerisation of helminth -tubulin, thus interfering with microtubule dependent functions such as glucose uptake. They have a selective inhibitory action, being 250­400 times more effective in producing this effect in helminth, than in mammalian, tissue. However, the effect takes time to develop and the worms may not be expelled for several days. Only 10% of mebendazole is absorbed after oral administration, but a fatty meal increases absorption. It is rapidly metabolised, the products being excreted in the urine and the bile within 24­48 h. It is generally given as a single dose for threadworm, and twice daily for 3 days for hookworm and roundworm infestations. It may be given twice daily for 3 days for guinea worm and Strongyloides infestations, and for up to 5 days for hookworm and roundworm infestations. Albendazole is also poorly absorbed but, as with mebendazole, absorption is increased by food, especially fats. It is metabolised extensively by presystemic metabolism to sulfoxide and sulfone metabolites. There are no effective drug treatments for guinea worm disease, but clean drinking water or filtering larval-contaminated water through nylon mesh tights have helped reduce global infection from 3. It is the drug of choice for all forms of schistosomiasis and is the agent generally used in large-scale schistosome eradication programmes. The drug affects not only the adult schistosomes but also the immature forms and the cercariae ­ the form of the parasite that infects humans by penetrating the skin. Praziquantel disrupts Ca2+ homeostasis in the parasite by binding to consensus protein kinase C-binding sites in a subunit of schistosome voltage-gated calcium channels (Greenberg, 2005). This induces an influx of Ca2+, a rapid and prolonged contraction of the musculature, and eventual paralysis and death of the worm. Given orally, praziquantel is well absorbed; much of the drug is rapidly metabolised to inactive metabolites on first passage through the liver, and the metabolites are excreted in the urine. The paralysed worms are expelled alive by normal intestinal peristaltic movements. It is partly metabolised, and the remainder is eliminated, unchanged, via the kidney.

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In most cases, the process of puberty occurs normally, although there is a broad variation of "normal" that may lead to anxiety in some patients and families. When the pubertal process does not occur within standards of normal, it may represent underlying health concerns and alert the health-care provider of the need for further evaluation and possible interventions. This article reviews the stages of normal puberty in females and provides guidance on abnormalities that may require investigation. There are multiple factors that influence pubertal timing, including genetic, environmental, neuropeptides, energy balance, intrinsic factors, stress, and sleep; however, the key regulatory step for activation of puberty is unknown. Age of menarche has declined minimally; however, age of thelarche appears to continue to decline. It is plausible that the earlier onset of breast development is related to environmental factors. These factors are called endocrine disruptors and are environmental chemicals, dietary supplements, and/or medications that interfere with the endocrine system. Found in plastic bottles and toys, it has been linked to having an estrogenic effect at low levels and to competing with endogenous estrogen for binding and antiandrogenic properties at higher levels. Some studies suggest leptin, which is related to growth and pubertal development and affects appetite, adiposity, and energy regulation, may be a link associated with this finding. Growth hormone is the primary growth-stimulating factor during prepubertal growth. Sex hormone augmentations of growth hormone secretion, as well as direct growthstimulating effects of sex steroids, cause growth acceleration during puberty. The concerted actions of both growth hormone and thyroid hormone are largely responsible for skeletal growth. When growth is not occurring on a normal trajectory, evaluation for underlying endocrine etiology should be considered. Multiple factors may influence the age at which puberty begins, including family history, environmental factors, underlying health conditions, and nutrition, among others. There are several guidelines to help determine if the child is progressing in a manner that falls within the norm. Growth spurt is typically the first indication of pubertal onset and typically occurs before the onset of secondary sexual characteristics. A longitudinal study reported an increase in both height and foot growth before the onset of secondary sexual characteristics, suggesting change in foot size may be an early marker for puberty. Some growth charts have been developed that allow for the variation in growth pattern of a specific medical condition. These charts represent the standard growth for that condition, thereby allowing a child to be compared against standards in his or her own cohort. Many electronic health records will maintain the growth charts within the electronic system, which is a useful tool and allows multiple providers to see growth patterns over time. The adolescent growth spurt occurs on average 2 years earlier in females compared with males. The final stage when growth velocity decreases, which occurs before epiphyseal fusion It is important to remember, especially when examining patients during this period of rapid growth, that although growth is described in centimeters per year, this represents the average growth for that year, and velocity may change throughout this time period. Body shape changes as the increased body fat is distributed in the lower body to a gynecoid or pear-shaped distribution. The skeleton also undergoes a great amount of growth, not only in length but also in density. Each bone begins with a primary center of ossification and will go through many stages of enlargement and shaping. The adult form is reached when epiphyses ossify and fuse with the main body of the bone. All of these changes are evident on radiographics, as the calcium content of the bone is opaque. The sequence of the changes in bone is the same in all individuals; thus, using radiographs to evaluate skeletal bone age in comparison to chronological age is an excellent clinical tool. The photographic atlas of Greulich and Pyle is the most commonly used resource to compare radiographs of the hand with standards of maturation in a normal population. A longitudinal study demonstrated that during the 4-year adolescent period of peak linear growth, more than 35% of total body bone mineral and 27% of bone mineral at the femoral neck was laid down. Androgens secreted by the adrenal gland contribute to body odor and the growth of pubic and axillary hair. Previous studies focused significantly on differences by ethnic background, but now these ages need to be considered carefully, because the pure lines of racial origin are not as clear as in the past. Thelarche When evaluating the breast, it is important to include palpation of the breast tissue and visual inspection of the areola, papilla, and breast tissue. Palpation is an important tool to differentiate breast tissue from adipose tissue in overweight females. Age of onset of breast development can be influenced by ethnicity, and mean age of onset is 8. Stage 3 represents further enlargement and elevation of breast and areola with no separation of their contours. Projection of the areola and papilla to form a secondary mound above the level of the breast is stage 4. Finally, stage 5 represents the mature stage, which is projection of the areola and papilla due to the recession of the areola to the general contour of the breast. The initial breast tissue in the earlier stage of growth can be unilateral, which may persist for 6­9 months. Knowing this can not only provide reassurance to patients and families, but also may avoid unnecessary diagnostic tests. For example, from the prepubertal stage 1 to stage 2, pubic hair begins to grow along the labia; as maturity continues, growth occurs over the mons pubis; and finally at stage 5, growth has occurred on the medial thigh. However, a gross scale of 1 (no hair) to 3 (adult pattern of hair) is sometimes used. There is an increase in the activity Sleep regulation changes during sexual maturation. During the initial appearance of pubic and axillary hair, the apocrine glands begin to function. Pubarche is considered early or premature when it occurs prior to the age of 8 years in girls. It affects up to 15% of girls and may be considered a normal variant, so the true definition of premature pubarche is not well defined. Under the influence of estrogen, the uterus will grow, and the endometrial lining will become thickened. When ovulation occurs, there is a surge in progesterone, coupled with a fall in estrogen levels. In the absence of pregnancy, this will trigger the shedding of the endometrial lining and menstrual cycle. They encourage asking about last menstrual period and menstrual patterns at each comprehensive or preventive care visit. By including an evaluation of the menstrual cycle as an additional vital sign, clinicians reinforce its importance in assessing overall health status for patients and caregivers. The median age of menarche is 12­13 years across well-nourished populations in developed countries. While the mean age for onset of menarche remains stable, the duration between puberty and menarche varies. This can be made easier with a paper diary or apps that are readily available for this purpose. Adolescent girls may seek medical attention for cycle variations that fall within normal range or be unaware that their bleeding pattern is abnormal and may be attributed to significant underlying medical issues. Menstrual flow requiring a change of sanitary products every 1­2 hours, frequent flooding or soiling, and prolonged bleeding exceeding 7 days are consistent with excessive menstruation (see reference7). Teaching adolescents to evaluate the amount of flow using a visual tool such as the pictorial chart may be beneficial. Abnormal uterine bleeding, its causes, and its management are reviewed in Chapter 14. Growth, pubertal timing and progression, and the onset of menarche can all provide reassurance of overall health when progressing in a normal fashion but can alert the provider to potential underlying health issues when the process is not proceeding normally. In some cases, abnormality in pubertal development and menses can be the first clue to an underlying health problem, so the practitioner must consider a broad differential, including nongynecological conditions, when abnormalities are encountered. Educating patients and caregivers about normal puberty and menstruation can provide anticipatory guidance so they can seek appropriate evaluation if problems arise. Using the menstrual cycle as a vital sign by checking last menstrual period and menstrual pattern at each visit is a quick and effective diagnostic tool in the care of young women. Secondary sex characteristics and menses in young girls seen in office practice: A study from the Pediatric Research in Office Settings network. Evaluation of delayed puberty: What diagnostic tests should be performed in the seemingly otherwise well adolescent National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion. The Saskatchewan Pediatric Bone Mineral Accrual Study: Bone mineral acquisition during the growing years. Development of the adolescent brain: Implications for executive function and social cognition. Cognitive efficiency on match to sample task decreases at the onset of puberty in children. World Health Organization multicentered study on menstrual and ovulatory patterns in the early postmenarcheal period, duration of bleeding episodes and menstrual cycles. Further, a patient who does not understand the management plan is less likely to follow instructions, or return for recommended follow-up. Adolescents have unique expectations, communication styles, and lifestyle practices that warrant specific attention. We review the adolescent developmental stages relevant to social behaviors that impact provider-patient communication. In addition, we provide examples of communication styles that could be particularly effective for interactions with this patient population. Note to Reader: For the purpose of simplification and readability, the authors use she/her pronouns when referring to adolescent gynecology patients. Recommendations regarding care for transgender and gender nonconforming patients can be found in the American College of Obstetricians and Gynecologists 2011 Committee Opinion2 and Chapter 7. At this age, there is a very strong drive to "fit in" with peer groups and an undeniable desire to be "like everyone else. Middle adolescence (age 14­16 years) During this stage, the adolescent has increasing concerns for outward appearance and the frequently changing platonic and romantic relationships that may dominate daily life. This age coincides with the average age of first sexual experience in the United States. This is a time when adolescents engage in high-risk behaviors and are particularly sensitive about their reputation among peers. It is important to communicate openly with your patient about her understanding of romantic relationships, sexuality, and her body. At this age, many adolescents are more focused on instant gratification and living in the moment, which could impact their perception of risk and consequences. Late adolescence (age 17­21 years) Adolescents at this stage begin to think more in the abstract (less concrete) and are able to make long-term plans when prompted. There is an increased awareness of the future, interest in goal setting, and an ability to consider options of delayed gratification. An adolescent at this age may have part-time employment and/or be approaching high school graduation. At the same time, she is considering her options for career choices, higher education, and fulfillment as an adult. Adolescents at this age are fast approaching, or have reached, legal adulthood for financial and medical decision-making purposes. While some are eager to acquire this independence, others may still rely on guardians or parents for scheduling appointments and managing their affairs. This is an excellent time to encourage patients to advocate for themselves and "own" their visit, to help foster their sense of independence. As a general construct for understanding the psychosocial maturation of young adults, adolescence has been divided into three developmental stages. Adolescents may move through these stages at different times; however, understanding this continuum may assist providers working with this population. It is important to note that physical and cognitive development often occur asynchronously. Early adolescence (age 10­13 years) this stage is marked by the early establishment of personal identity, concrete thinking, and self-experimentation. Pertinent to the field of gynecology, this stage usually coincides with menarche and early pubertal changes. Cognitive development Concrete thinking Psychosocial development Desire to fit in Timid around health-care providers Parent/guardian often does most of the talking May prefer same-sex friendships Preoccupied with improving physical appearance Height of conflict with parent/ guardian over independence Average age of first sexual experience Less time with peer groups, more intensive personal relationships Often balancing school, family, and job/extracurricular tasks Effective communication strategies Reassurance and normalization: "Most girls at your age are also going through their first year of periods, and accidents happen to everyone. Having friendly office staff including phone operators is important for creating an environment that is welcoming, and not intimidating. Providing reading materials and resources that are appropriate for teens and young adults in the waiting room is a simple way to cater to adolescents in your office space. Adolescents may have preferred names or nicknames, which should be honored when they provide this information. It can be helpful during intake to ask for preferred pronouns (she/her, he/him, they/them, etc. Many adolescents are accustomed to technology-based communication with peers and may prefer web or textbased communication versus speaking by telephone to arrange medical appointments. When possible, allowing adolescents to schedule appointments and message their providers online can improve their access to health information. Text reminders for appointments are another simple way to communicate easily and increase show rates for appointments. During the visit: Introductions the provider should introduce herself/himself to the adolescent first, even when there is a parent/guardian in the room.

Ampalaya (Bitter Melon). Biltricide.

• Are there any interactions with medications?
• How does Bitter Melon work?
• Diabetes, a skin condition called psoriasis, HIV/AIDS, stomach and intestinal disorders such as ulcers and constipation, kidney stones, liver disease, and skin abscesses and wounds.
• What is Bitter Melon?
• Dosing considerations for Bitter Melon.
• Are there safety concerns?

Source: http://www.rxlist.com/script/main/art.asp?articlekey=96773

Due to the many choices of docking tools, performance comparison of these tools are frequently reported. For example, a comprehensive evaluation of 10 docking tools on sampling power and scoring power was reported [40]. In fact, it is usually observed that comparison studies do not agree with each other on the performance of docking tools. For example, the docking accuracy is specific for a particular protein target family; the target structure preparation and the software parameter settings usually require expert knowledge to conduct a successful docking experiment. According to our experience, there are several considerations for selection docking tools: (1) knowing the docking tool before using it, including theory, parameter settings, and limitations, etc. Advances in structural biology have generated a great number of 3D structures of biological macromolecules, including therapeutic targets, which offer unparalleled opportunities for structure-based virtual screening and drug discovery. To use these structures in virtual screening, it is important to know the structure quality, especially in the binding site area. Because most of the available structures are from X-ray crystallography, atom positions in these models correspond to the interpretation of the electron density maps by the depositors. Thus, validating the reliability of such coordinates before using them in virtual screening is recommended in practice. In general, the higher quality the better for virtual screening; and complex structures with binding ligand are better than those without binding ligand. Moreover, careful consideration should be taken to prepare for the correct protonation and tautomeric states of amino acids. As histidine can serve as both acid and base over physiological pH range, and both as hydrogen bond donor and acceptor in molecular recognition, it needs to be considered on a case-by-case basis based to its immediate environment [44,45]. In addition, water molecules and metal ions in active-site can significantly contribute to a ligand-target interaction and help to place and orient the ligand into a correct pose in the binding site. The neglection of them would inevitably lead to underestimation of the ligand-target interaction [5]. If no target structure is readily available, computational modeling, such comparative/homology modeling, can be used to build a theoretical model of the target structure [46,47]. Comparative modeling is a methodology to predict the 3D structure based on the observation that proteins with similar sequence usually have similar structure. Generally speaking, it is believed that two protein sequences with an identity of 30% or above share a common 3D structure; a sequence identity over 50% is sufficient for prediction of protein-ligand interaction and drug discovery; a sequence identity between 30% and 50% could facilitate druggability prediction and mutagenesis experiment design [47]. The basic assumption is that similar molecules may have similar activity or function, though it is not always true if there is an activity cliff [48]. Each bit (0/1) represents the absence and presence of a certain feature, such as a functional group, a substructure feature, etc. The similarity comparison of the two molecules can be achieved by calculating the similarity between the two fingerprints. In general, there are three types of fingerprints: (1) structural keys-based fingerprints, (2) circular fingerprints, and (3) topological/path-based fingerprints. Some widely used fingerprints and the open-source implementations are listed in Table 4. The fingerprint is used by PubChem [56] for similarity searching and neighboring clustering and is available for download in PubChem system. For example, Molprint2D [58] encodes the atom environments of each atom of molecular connectivity table in strings. It represents molecular structures by circular atom neighborhoods, namely each nonhydrogen atom is encoded into multiple circular layers up to a given diameter. Daylight fingerprint consists of up 2048 bits and encodes all possible connectivity pathways. It has certain variations that can encode linear path and nonlinear connectivity paths. In addition, there are other types of fingerprints, such as pharmacophore fingerprints [61,62]; hybrid fingerprints that combine both structural keys and connectivity path fragments. More details about fingerprint similarity search and comparisons in virtual screening were reviewed [65e67]. With fingerprints, the calculation of similarity between two molecules can be obtained by calculating the fingerprint similarity. Name Tanimoto coefficient Dice coefficient Cosine similarity Equation c aþbÀc 2c aþb pc ffiffiffiffi ab Here, a and b represent two fingerprints respectively; c represents the intersection or common part of the two fingerprints of a and b. An open-source platform has been reported to benchmark fingerprints for ligand-based virtual screening [68]. The study found that the overall performance of all the fingerprints was similar and the intertarget difference was greater than the intratarget difference. Among the 14 tested 2D fingerprints, circular fingerprints were ranked higher and topological torsions fingerprints were always highly ranked regardless of the evaluation methods. In addition, 2D fingerprints have the advantage that they require minimal setup and configuration and less computationally intensive as compared to other virtual screening methods. One of the major disadvantages of 2D fingerprint approaches is the bias toward query molecules [65]. In practice, it is often combined with other virtual screening methods, such as structure-based or shape-based, to avoid such a bias. A high degree of shape complementary has been observed in many crystal structures of protein-ligand and protein-protein complexes. Shape-based virtual screening methods use molecular shape, sometimes with other molecular properties like atom types, to find molecules in a database. Putta and Beroza provided an excellent review on shape-based screening methods [69]. In the review, they divided the representations of a molecular shape into four main categories, (1) moment-based, (2) gnomic-based, (3) volume-based, and (4) surface-based. The moment-based methods represent a shape as a set of multipole moments of inertia and the resulting distribution can be represented by a multiple expansion. Points on the simple shape are encoded as an approximation of the original shape with a set of values [72]. The volume-based representations treat each atom of a molecule as a hard sphere with a radius determined by its van der Waals radius. The surface-based methods focus on the interface between the volume interior and exterior and represent a molecular shape as a set of patches on the surface. Among these four types of molecular shape representations, surface-based methods are considered the most accurate in terms of molecular recognition, whereas the volume-based methods are most commonly used. In this way, the number of overlaps is much reduced, which enable fast and approximate global maxima to be found. Similarly, researchers from Schrodinger implemented Phase Shape in their software. Shape-based methods have been widely used in virtual screening, and they are also compared with the structure-based methods. It should be emphasized that a pharmacophore does not represent a real molecule or a real interaction between functional groups; instead, it is a purely abstract concept that accounts for the common molecular interaction capacities of a group of compounds toward their targets. The core of the pharmacophore concept is the notion that molecular recognition of a group compounds, and their biological target attributes to a small set of common features, such as hydrogen bond donors, hydrogen bond acceptors, positively/negatively charged groups, and hydrophobic regions [8]. The other key component of pharmacophore is the spatial arrangement of these features. Due to the simplicity and versatility of the pharmacophore concept, pharmacophore modeling has been routinely used in combination with other molecular modeling techniques, though it can be potentially used for virtual screening independently. Caporuscio and Tafi reported a review of synergistic combination of pharmacophore modeling with other molecular modeling approaches such as the hot spot analysis of protein binding sites, molecular dynamics, and docking [90]. In general, there are four types of small-molecule libraries used in virtual screenings listed in Table 4. Therefore, the availability and price of real compounds are an important consideration in virtual screening. In-house collections are usually the first choice because they are readily available, but the drawback is limited to the existing compounds that may not be designed for the current project. The second choice is the collection of in-stock compounds from chemical vendors considering the cost and time. The other source of small-molecule are public repositories, which may provide additional information, such as bioactivities and their biological targets. Taking PubChem as an example, it is an open chemistry database containing information about chemical structures, chemical and physical properties, biological 4. At the time of this work, PubChem has over 235 million of chemical substances and 96 millions of unique compounds from more than 600 depositors including 348 chemical vendors [56]. The last type is the virtual compound libraries that not only contain real existing compounds, but also the ones existing theoretically. One of the applications of the virtual libraries is to facilitate the exploration of the chemical space. Chemical space refers to the space spanned by all possible organic compounds that could be synthesized, which is estimated between 1030 and 1060 being routinely cited [96]. It contains millions of isomers of known drugs, including analogues with high shape similarity to the parent drug, and has much richer scaffold types compared to PubChem [94]. When performing a virtual screening of a library containing a large number of compounds, it should be taken into account the potential false-positives issue, which is the largest problem in virtual screening [97]. If considering a virtual screen with a false-positive rate of 1%, as an optimistic estimate even for the best method nowadays, a virtual screen on a library of one million molecules would yield 10000 falsepositive hits. This number of hits may completely swamp out the signal from the true positive hits in experiments [96]. The cleanup is to get rid of unwanted molecules in advance, for example, by removing small fragments of mixture compounds, duplicated compounds, the "frequent hitters" that are interference to biological assays [98], compounds with reactive groups [99], etc. The preparation of a smallmolecule library may be specific to the virtual screening tools. In general, it includes structure normalization, adding charges and hydrogens, converting 2D to 3D structures, as well as enumerating tautomeric states. Any mistakes in the preparation process will be propagated to downstream steps and negatively affect the outcomes of a virtual screening. As an example, tautomerism is one of the most underestimated issues in virtual screening campaigns. A molecule exhibits tautomerism if it is representable by two or more structures that are connected by the movement of a hydrogen from one atom to another; for instance, the proton shift from the enolform to a keto-form of a molecule changes the alcohol group into a carbonyl group. Each tautomer of a single molecule substantially differs from another in electrostatic properties, hydrophobicity, 3D shape, and chemical reactivity. The selection of the wrong tautomer can misguide the assignment of hydrogen bond acceptors and donors, thus leading to false positives and/or false negatives in virtual screening [44]. The concept of druglike and, more stringent, leadlike are introduced to determine the characteristics of a drug or a lead to be successful. The seminal paper by Lipinski and colleagues [101] defined the druglike space to restrict the properties of small molecules for orally active drug candidates in drug discovery. In drug design, the molecular weight is often increased in the optimization process in order to improve the affinity and selectivity. Thus, more stringent rules have been proposed, such as the "rule of three" leadlike filter [102,103], namely, molecular weight is 300, the number of hydrogen bond donors is 3, the number of hydrogen bond acceptors is 3 and ClogP is 3. Compared to druglike, leadlike is more attractive to achieve leads for optimization. Nevertheless, the actual property cut-offs will depend on the objective of the virtual screening. For example, drug discovery aimed at identifying agents for central nervous system that requires passing the blood-brain barrier or different administration routes may need a different profile of these properties. To clean up and prepare small-molecule libraries, most commercial softwares have their own module for such purposes. In other words, the validation is trying to run a mini retrospective virtual screening to check the performance of the workflow before applying to a large-scale screening. To conduct such a validation, one needs to create a collection of active and inactive molecules. Decoy compounds are generally random druglike molecules, which are much more likely to be inactive than active by chance. In practice, decoy compounds are constructed by searching for compounds that have similar physical descriptors, such as molecular weight, number of rotatable bonds, number of hydrogen donors and acceptors, and octanol-water partition coefficient etc. Once the active and inactive/decoy molecules have been defined in validation set, the workflow of virtual screening is applied to classify the molecules based on their rankings. There are also freely available tools reported to calculate and plot the metrics [111]. Because of the imperfection of virtual screening methods, it is still not possible to directly select the best ranking compounds for further experimental testing. Moreover, the typical goal of a screening is to identify a series of molecules with novel structures compared to the known active ones. Therefore, the postscreening process is usually applied to increase the odds of success of a screening. Basically, selecting compounds from a virtual screening for further experimental testing should obtain as much representative as possible and avoid subjective selections. This can be achieved by using unsupervised learning to group hits based on their structure similarities. The structure similarities can use any type of descriptors and methods, but 2D fingerprint similarity is usually employed for such a purpose. One of the widely used machine learning libraries in python programming language, scikit-learn [112] can be used for structure similarity clustering. Consensus scoring is using multiple additional scoring functions to rescore the original poses to increase the overall performance because of the fact that each scoring function has its advantages and disadvantages [113e115].

Usage: p.c.

At 12-month follow-up visit, women presented with lesser improvement of peak exercise oxygen consumption (0. Electrical reconduction between pulmonary veins and left atrium is reported to be lower than in males [33]. The main sources of triggers of extra pulmonary veins are superior vena cava, coronary sinus, and crista terminalis. Repeated ablation targeting even triggers outside pulmonary veins is often indicated; however, very often refused by women due to reluctance to further invasive procedure, satisfactory relief of symptoms, and improvement of the quality of life after first procedure [35]. Atrial fibrosis is more prevalent in women, probably due to older age in the time of ablation [36]. Ablation of atrioventricular node instead of left atrial ablation is more frequently performed in women compared to men [37]. The rate of complications decreases over the time, but some of them can be even life-threatening. It has been repeatedly demonstrated that there are predictors of potential complications both at the patient side (age, comorbiditiesdheart failure, diabetes mellitus, renal failure, anemia, obesity) and at the operator side (education, low-volume center, training). According to worldwide surveys, national databases, and registries, the overall incidence of major complications is about 3%e7%. The risk of cardiac tamponade is generally lower when using intracardiac echocardiography for the transseptal puncture guidance, both for men and women [41]. Similarly, vascular puncture under ultrasound guidance is safer and associated with lower amount of puncture site vascular complications [42]. Prevalence, incidence, prognosis and predisposing conditions for atrial fibrillation: population-based estimates. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Mortality trends in patients diagnosed with first atrial fibrillation: a 21-year community-based study. The impairment of health-related of quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy. Catheter ablation versus antiarrhytmic drugs for atrial fibrillation: the A4 study. Women were more likely to develop vascular complications, tamponade, postprocedural bleeding, acute renal failure, and pneumonia. Higher risk of tamponade was also reported in other multicenter survey, with nearly twofold higher occurrence in women [39]. The left atrial size is smaller, and the left atrial wall is thinner, leading potentially to perforation and cardiac tamponade. The vascular access is more difficult due to higher prevalence of obesity, closer anatomical relationship of femoral artery, and its branches to femoral vein. Female sex is per se risk factor for thromboembolic complications, including cerebrovascular accidents. In contrary, current studies show overall decrease amount of complications, mainly in women. Data from Catheter ablation of atrial fibrillation Chapter 44 507 [13] Bulkova V, Fiala M, Havranek S, Simek J, Sknouril L, Januska J, et al. Improvement in quality of life after catheter ablation for paroxysmal versus long-standing persistent atrial fibrillation: a prospective study with 3-year follow-up. Patients treated with catheter ablation for atrial fibrillation have longterm rates of death, stroke, and dementia similar to patients without atrial fibrillation. A prospective evaluation of haemodynamics, functional status, and quality of life after radiofrequency catheter ablation of longstanding persistent atrial fibrillation. Catheter ablation of asymptomatic lonstanding persistent atrial fibrillation: impact of quality of life, exercise performance, arrhythmia perception, and arrhythmia -free survival. Spontaneous initiation of atrial fibrillation by ectopic betas originating in the pulmonary veins. Small or large isolation areas around the pulmonary veins for the treatment of atrial fibrillation Longterm results of catheter ablation in paroxysmal atrial fibrillation: lessons from a 5-year follow-up. Acute and chronic pulmonary vein reconnection after atrial fibrillation ablation: a prospective characterization of anatomical sites. Use of ablation index-guided ablation results in high rates of durable pulmonary vein isolation and freedom from arrhythmia in persistent atrial fibrillation patients. Atrial tachycardia after circumferential pulmonary vein ablation of atrial fibrillation: mechanistic insights, results of catheter ablation, and risk factors for recurrence. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. Five-year outcome of catheter ablation of persistent atrial fibrillation using termination of atrial fibrillation as procedural endpoint. Functional improvement after successful catheter ablation for longstanding persistent atrial fibrillation. Differences in catheter ablation of paroxysmal atrial fibrillation between males and females. Outcome and complications of catheter ablation for atrial fibrillation in females. Gender differences in atrial fibrillation: a review of epidemiology, management and outcomes. Sex differences in cardiac arrhythmia: consensus document of the European Heart Rhythm Society and Asia Pacific Heart Rhythm Society. Effects of sex on the incidence of cardiac tamponade after catheter ablation of atrial fibrillation. Factors impacting complication rates for catheter ablation of atrial fibrillation from 2003 to 2015. Complications of catheter ablations for atrial fibrillation in a high-volume center with use of intracardiac echocardiography. In particular, in Europe, in subjects older than 55 years, arrhythmia prevalence was 6. Nevertheless, an American study reported an equal absolute number in the two sexes, due to the longer life expectancy in women [4]. Moreover, women were more likely to have atypical presentation, that might contribute to the worse outcomes seen in female, as they might delay diagnosis and care [9]. Potential contributions of sex hormones to electrophysiological properties have been explored in some studies. The effects of progesterone were investigated in isolated guinea pig ventricular myocytes [17]. Focusing on human being and on the specific effects of sex hormones in the atria, Rosano et al. They showed that acute administration of estradiol prolongs right intraatrial and atrioventricular nodal conduction time, as well as right atrial effective refractory period. These observations have been replicated in a female ovariectomy-caused mouse model [20] and confirmed that estradiol has electrophysiologic properties also in vivo and Sex and Cardiac Electrophysiology. Not significant differences between women and men for fatigue, and dizziness in Dagres study and fatigue, chest pain, dizziness, and dyspnea. Sex-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Observational Research Program Pilot survey on Atrial Fibrillation. In the Framingham Heart Study [23], a significant reduction in testosterone level in men aged! An experimental model with gonadectomized male mice confirmed that testosterone deficiency rises atrial arrhythmogenicity, and that its replacement attenuates this effect [24]. Gender Differences in Clinical Outcomes after Catheter Ablation of Atrial Fibrillation. Sex differences in complications of catheter ablation for atrial fibrillation: results on 85,977 patients. It has been argued that the lack of beneficial effect of pharmacological therapy in the overall study may be due to harmful effects of the antiarrhythmic medication used in the rhythm control arm [31]. However, many studies confirmed ablation as more effective than antiarrhythmic drug therapy (when performed by adequately trained teams in experienced centers), and the complication rate, though not negligible, is similar to the complication rate for antiarrhythmic drugs [33]. A significant difference in the targets between women and men was observed by Patel et al. Nevertheless, these foci may have affected the outcome not independently but as an aspect of atrial remodeling. However, in multivariate analysis, the negative impact of these foci appeared to be attenuated, and this factor did not remain as an individual significant predictor. Differences in outcomes and complications of catheter ablation There are conflicting data sex-related difference on safety and efficacy of catheter ablation. Among the patients who did not refuse a second ablation, the efficacy was more than 90% in both sexes. Predictors of nonpulmonary vein ectopic beats initiating paroxysmal atrial fibrillation: implication for catheter ablation. Catheter ablation efficacy was similar in the two groups despite the fact that women were older than their male counterparts. Focusing on the safety of catheter ablation, two recent observational studies [50,51] including a large cohort of patients reported an increased risk of vascular and cardiac complications in women (Table 45. They observed not only more hematomas and pseudoaneurysms but also more pericardial effusions and tamponades in women than in their male counterparts. Hematoma Other vascular (%) complications (%) Men Women Men Women Men Women Men Women Men Women n. Pericardial effusions and tamponades may occur during transseptal puncture, catheter manipulation, or ablation, with a risk of left atrial perforation being the most common. Surgical backup and acute management skills for treating this complication are crucial in centers performing catheter ablation. Women have a twofold higher risk for developing this complication, but the difference decreases significantly in high volume centers [55]. The risk is higher in women probably because of a smaller left atrial volume and a thinner atrial wall compared to men [56,57]. They show alterations in the pharmacokinetics of heparin which could explain a predisposition to bleeding complications. In particular, women have higher activated clotting times during catheter ablation procedures and so tend to require a lower dose of unfractionated heparin, even after adjusting for weight [58]. Analogous considerations can be made on warfarin response as reported by Humphries et al. Meanwhile, no sex-related difference was reported for silent cerebral ischemia lesions detected by magnetic resonance imaging [60]. Atrial fibrillation: current knowledge and future directions in epidemiology and genomics. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Sex-specific increase in the prevalence of atrial fibrillation (The Copenhagen City Heart Study). Prevalence of atrial fibrillation in the general population of Japan: an analysis based on periodic health examination. Prevalence of atrial fibrillation in community-dwelling Japanese aged 40 years or older in Japan: analysis of 41,436 nonemployee residents in Kurashiki-city. New-onset atrial fibrillation: sex differences in presentation, treatment, and outcome. A populationbasedstudy of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Is female sex a risk factor for stroke and thromboembolism in patients with atrial fibrillation Revisiting sex differences in outcomes in non-valvular atrial fibrillation: a population-based cohort study. Association of sex hormones, aging, and atrial fibrillation in men: the Framingham Heart Study. Deficiency of testosterone associates with the substrate of atrial fibrillation in the rat model. Rate control versus electrical cardioversion for persistent atrial fibrillation study group. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Gaita F, Riccardi R, Caponi D, Shah D, Garberoglio L, Vivalda L, Dulio A, Chiecchio A, Manasse E, Gallotti R. Linear cryoablation of the left atrium versus pulmonary vein cryoisolation in patients with permanent atrial fibrillation and valvular heart disease: correlation of electroanatomic mapping and long-term clinical results. Nademanee K, McKenzie J, Kosar E, Schwab M, Sunsaneewitayakul B, Vasavakul T, Khunnawat C, Ngarmukos T. Long-term results of atrial fibrillation ablation: the importance of all initial ablation failures undergoing a repeat ablation. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Catheter ablation of paroxysmal atrial fibrillation initiated by non-pulmonary vein ectopy. Long-term outcome after catheter ablation of paroxysmal atrial fibrillation: impact of different atrial fibrillation foci.