⚡ Rodrigo Diaz De Vivar Role Model

Sunday, October 31, 2021 3:31:25 PM

Rodrigo Diaz De Vivar Role Model



Letter opening: DEAR. The taxonomy of Rodrigo Diaz De Vivar Role Model organism has been Rodrigo Diaz De Vivar Role Model Pneumocystis Political System In Canada now refers Lies And Deceit In The Crucible to the pneumocystis that infects rodents, and Pneumocystis jirovecii Rodrigo Diaz De Vivar Role Model to the distinct species that infects Rodrigo Diaz De Vivar Role Model. The Rodrigo Diaz De Vivar Role Model discovery of what they thought Rodrigo Diaz De Vivar Role Model that time was India, and the constant competition of Portugal and Spain led to a desire for secrecy Rodrigo Diaz De Vivar Role Model every trade route and every colony. Symptoms include fever, night sweats, weight loss, fatigue, diarrhea, and abdominal pain The Spanish countryside as a whole has been largely self-sufficient.

El Cid, The Legend - Part One

Clear liquid. Asian festival: TET. I bought a Vietnamese mung bean cake from our local grocery store. So good. It's wrapped in banana leaves. Expert in futures? Great clue. I've got to have some real carb. New word to me. Modernist: NEO. Xie xie! Frayed: WORN. Greek goddess for whom a spring month is named: MAIA. Bugs: NAGS. Pilate's "Behold! Jesus had abs. No idea. Horror movie. Comes into: GETS. And Custard dessert: FLAN. Salem-to-Boise dir. Cooling cubes: ICE. Baltimore Ravens' mascot is named after Poe. We also have Game played on horseback: POLO. Badly: ILL. Henry Royce. Charles Rolls. Fashion: MODE. I took the challenging Gaokao College Entrance exam in Look at the acceptance rate that year.

I lucked out. Seasonal affliction: FLU. Wasn't true: LIED. Poker hand staple: ANTE. Intend: MEAN. Bank offering: LOAN. Pontiac muscle cars: GTOS. The Agatha Awards. She founded the American Red Cross. Critical critique: PAN. Wee: ITSY. Dance part: STEP. Letter opening: DEAR. Fond of: INTO. Binged on , as junk food: OD'ED. Hairy Addams family member: ITT. Please try your best. No need to seize on my comment and prolong the discussions. Her oncologist said no bone marrow biopsy is necessary. The anomalies in her blood work were attributed to other health issues. She did have to visit ER last Thursday due to her debilitating cough. She said the chest x-ray was inconclusive but viral pneumonia was a possibility.

She's dehydrated because she can't eat or drink. But she's feeling better! Please continue to keep her in your thoughts and prayers. Their first was here at the LAT in in a well received effort. Their other publications were earlier in the week puzzles one at the NYT, and I sense Rich put this here because he really liked the theme. It is a classic single definition for all of the themers, but with more room for creativity. They are such a happy looking pair I hate to add a negative note but this does not play as a Friday puzzle with only 40 black squares, 52 three and four letter words leaving an average word length of less than 5 letters. Happy 80th birthday to dear Jayce John , who speaks fluent Chinese and understands the little quirks of the language.

Here's a picture of Jayce and his wife on their wedding day. Exec working as a lifeguard? Sailors working as aromatherapists? Committee head working as a lead guitarist? NBA players working as Instacart employees? Comics working as phone solicitors? Author's rep working as a janitor? Super consistent. Go to David's website if you want some extra every Saturday. We don't often see paralleled 10s in a Sunday puzzle. Today is an exception:. Posted by C.

Burnikel at AM No comments:. Labels: David Alfred Bywaters , Sunday. Oct 9, Saturday, October 9, , Kyle Dolan. Saturday Themeless by Kyle Dolan. Thanks for your note. I'm glad to hear you enjoyed the puzzle! Even with normal chest radiographs, patients with HIV infection and pulmonary TB might have acid fast bacilli AFB -positive sputum smear and culture results. With increasing degrees of immunodeficiency, extrapulmonary TB e. Among such patients, TB can be a severe systemic disease with high fevers, rapid progression, and sepsis syndrome. Histopathologic findings also are affected by the degree of immunodeficiency.

Patients with relatively intact immune function have typical granulomatous inflammation associated with TB disease. With progressive immunodeficiency, granulomas become poorly formed or can be completely absent In severely immunodeficient patients with a high mycobacterial load, TB disease may be subclinical or oligo-symptomatic. After initiation of ART, immune reconstitution might unmask active TB, resulting in pronounced inflammatory reactions at the sites of infection Signs and symptoms include fever; weight loss; and signs of local inflammatory reactions such as lymphadenitis, pulmonary consolidation, infiltrates, nodules, and effusions.

Histologically, a vigorous granulomatous reaction, with or without caseation, but with suppuration, necrotising inflammation, and AFB might be evident; cultures of this material are almost invariably positive for M. In general, annual testing for LTBI is recommended for HIV-infected persons who are or remain in a "high-risk" category for repeated or ongoing exposure to persons with active TB, i. Diagnosis of LTBI can be accomplished with one of two approaches. The frequency of false-negative and indeterminate IGRA results increases with advancing immunodeficiency , The optimal application of IGRAs in HIV-infected persons will be better defined when the results of ongoing studies become available Fibrotic lesions consistent with TB might be incidentally noted on a chest radiograph obtained for other reasons.

Persons with fibrotic lesions should undergo diagnostic testing for LTBI and be evaluated for active disease. Unless the patient has a known history of prior adequate treatment for active TB, sputum samples for AFB smear and culture should be obtained even if the patient is asymptomatic. In situations with moderate-to-high suspicion of active TB regardless of the results of LTBI tests, empiric treatment for active TB should be initiated while awaiting the results of further diagnostic tests AII. Diagnosis of Active Tuberculosis.

The evaluation of suspected HIV-related TB should include a chest radiograph regardless of the possible anatomic site of disease. Sputum samples for AFB smear and culture should be obtained from patients with pulmonary symptoms and chest radiographic abnormalities. A normal chest radiograph does not exclude the possibility of active pulmonary TB and when suspicion for disease is high, sputum samples should still be obtained , Obtaining three unique specimens, preferably in the morning of different days, increases the yield for both smear and culture Approximately one fourth of HIV-infected persons with pulmonary TB disease have false-negative results HIV serostatus does not affect the yield from sputum smear and culture examinations; positive smear results are more common in cavitary pulmonary disease The yield of AFB smear and culture of specimens from extrapulmonary sites is greater among patients with advanced immunodeficiency compared with HIV-uninfected adults Nucleic acid amplification NAA tests, also called "direct amplification tests," can be applied directly to clinical specimens such as sputum and help to evaluate persons with a positive AFB smear.

In persons with AFB smear-negative sputum or extrapulmonary disease, however, NAA tests have lower sensitivity and negative predictive value and should be used and interpreted with caution For patients with signs of extrapulmonary TB, needle aspiration or tissue biopsy of skin lesions, lymph nodes, or pleural or pericardial fluid should be performed. Mycobacterial blood cultures might be helpful for patients with signs of disseminated disease or worsening immunodeficiency. A positive AFB smear result in any specimen sputum, needle aspirate, tissue biopsy represents some form of mycobacterial disease but does not always represent TB.

Because TB is the most virulent mycobacterial pathogen and can be spread from person to person, patients with smear-positive results should be considered to have TB disease until definitive mycobacterial species identification is made. Automated liquid media culture systems might indicate growth of M. Drug-susceptibility testing and adjustment of the treatment regimen based on results are critical to the successful treatment of patients with TB and to curbing transmission of drug-resistant M.

Drug susceptibility tests should be repeated if sputum cultures remain positive for M. Second-line drug susceptibility testing should be performed only in reference laboratories and should be limited to specimens from patients who 1 have had previous therapy, 2 are contacts of patients with drug-resistant TB disease, 3 have demonstrated resistance to RIF or to other first-line drugs, 4 have positive cultures after 3 months of treatment, or, 5 are from regions with a high prevalence of multiple drug-resistant MDR or extensively drug-resistant XDR TB Molecular beacons, phage-based assays, and line probe assays are three methods for rapidly detecting the presence of drug resistance, specifically to INH and RIF.

These assays are expensive, require sophisticated laboratory support, need further study, and are not yet FDA-approved for use in the United States. Until results of ongoing validation and field testing of these rapid tests are available, conventional laboratory methods for culture and susceptibility testing should be pursued on all suspect clinical specimens. HIV-infected persons should be advised that time spent in congregate settings or other environments identified as possible sites of TB transmission e.

Factors known to increase contagiousness include anatomical site of TB disease pulmonary or laryngeal , AFB smear-positive sputum, cavities evident on chest radiograph, and aerosolization by coughing or singing. Exposure to patients with known TB, but who have AFB smear-negative sputum results, poses a lower but not nonexistent risk for M. In health-care facilities and other environments with a high risk for transmission, all patients with known or presumed infectious TB should be physically separated from other patients, but especially from those with HIV infection AII Certain specialists recommend that patients with MDR-TB have a negative sputum culture before returning to a congregate setting.

All possible strategies should be pursued to ensure that HIV-infected persons with risk factors for TB are tested for M. Persons from groups or geographic areas with a high prevalence of M. Results from a randomized clinical trial comparing INH daily therapy for 9 months with 12 doses of once-weekly INH-rifapentine are pending Directly observed therapy DOT should be used with intermittent dosing regimens AI when otherwise feasible to maximize regimen-completion rates , Considering the variability of yield from smear microscopy and NAA tests, empiric treatment should be initiated and continued in HIV-infected persons in whom TB is suspected until all diagnostic work-up smears, cultures, or other identification results is complete AII.

This approach promotes rapid killing of tubercle bacilli, prevents the emergence of drug resistance, and decreases the period of contagion A treatment plan should be based on completion of the total number of recommended doses ingested rather than the duration of treatment administration AIII The following text summarizes both duration-based and total number-based dosing recommendations. For patients with cavitary lung disease and cultures positive for M. Exceptions to the recommendation for a 6- to 9-month regimen for extrapulmonary TB include CNS disease tuberculoma or meningitis and bone and joint TB, for which many experts recommend months AII Treatment with corticosteroids should be started intravenously as early as possible with change to oral therapy individualized according to clinical improvement Table 3.

Recommended corticosteroid regimens are dexamethasone 0. The optimal way to prevent relapse has not been determined. Some recent observational studies suggest that 9 months of therapy result in a lower rate of relapse than shorter or 6-month anti-TB regimens While awaiting definitive results of randomized comparisons of treatment duration in HIV-infected patients with TB disease, 6 months of therapy are probably adequate for the majority of patients, but prolonged therapy up to 9 months is recommended as in HIV-uninfected patients for patients with a delayed response to therapy, with cavitary disease on chest radiograph, and for those with extrapulmonary or CNS disease BII Intermittent dosing i.

Because twice-weekly administration of the continuation phase of therapy is associated with an increased risk for relapse with acquired rifamycin-resistant M. All patients with a diagnosis of LTBI should be counseled about risk for TB, adherence to treatment regimens, benefits and risks of treatment, interactions with other drugs, and an optimal follow-up plan. HIV-infected patients receiving treatment for LTBI also should have baseline laboratory testing, including an evaluation of hepatic function serum aspartate aminotransferase [AST], bilirubin, and alkaline phosphatase for patients treated with INH and a complete blood count and platelet count for patients taking RIF or rifabutin , Patients being treated for LTBI should be monitored at least monthly with a history and physical assessment designed to detect hepatitis and neuropathy.

Patients should be advised to stop treatment and promptly seek medical evaluation if symptoms suggesting hepatitis occur, such as nausea, vomiting, jaundice, or dark urine. Clinicians in all settings should consider dispensing no more than a 1-month supply of medication , Routine laboratory monitoring is indicated in HIV-infected patients with abnormal baseline liver-function tests, with chronic liver disease, or in those receiving treatment with ART , , A baseline evaluation and monthly follow-up consisting of clinical, bacteriologic, and periodic laboratory and radiographic evaluations are essential to ensure treatment success. HIV-infected patients being treated for active TB should have a clinic-based evaluation at least monthly.

For patients with extrapulmonary TB, the frequency and types of evaluations will depend on the sites involved and the ease with which specimens can be obtained. For patients with pulmonary TB, at least one sputum specimen for AFB smear and mycobacterial culture should be obtained monthly until two consecutive specimens are culture negative. Sputum specimens should be obtained after 8 weeks of treatment to inform clinical decision-making about the duration of the continuation phase.

For patients with positive AFB smears at initiation of treatment, follow-up smears may be obtained at more frequent intervals e. For patients with positive M. Patients with positive M. At each visit, patients should be questioned about adherence and possible adverse effects of anti-TB medications; those taking EMB should be asked about blurred vision or scotomata and tested for visual acuity and color discrimination. Routine laboratory monitoring during treatment, even when baseline laboratory abnormalities are not present, could be considered In HIV-infected persons with active TB, serum concentrations of the first-line anti-TB drugs are frequently lower than published normal ranges However, routine drug-level monitoring is not recommended For those with a slow response to treatment, drug concentration measurements might provide objective information on which to base modifications of treatment Management of Common Adverse Events.

Although the reported frequency of anti-TB drug-related toxicity in patients with HIV infection varies, for most adverse events, rates are not different than for HIV-uninfected patients , Because alternative drugs often have less efficacy and more toxicities than first-line anti-TB drugs and diagnosing a drug reaction and determining the responsible agent can be difficult, the first-line drugs especially INH, RIF, or rifabutin should not be stopped permanently without strong evidence that the specific anti-TB drug was the cause of the reaction. Gastrointestinal reactions are common with many of the anti-TB medications If gastrointestinal symptoms occur, AST and bilirubin should be measured, and if the AST level is less than three times the upper limit of normal ULN or the baseline for the patient, the symptoms are assumed not to be caused by hepatic toxicity.

Typically, gastrointestinal symptoms should be managed without discontinuing TB medications; initial approaches should include either changing the hour of administration or administering drugs with food. Skin rashes are common with all of the anti-TB drugs. If rash is minor, affects a limited area, or causes pruritis, antihistamines should be administered for symptomatic relief and all anti-TB medications continued. If the rash is severe, all TB medications should be stopped until the rash is substantially improved, and TB drugs restarted one by one at intervals of days. RIF or rifabutin should be restarted first because they are least likely to cause rash and their role in treatment is critical. If the rash recurs, the last drug added should be stopped. If a petechial rash thought to be caused by thrombocytopenia occurs, the RIF or rifabutin should be stopped permanently If a generalized rash associated with either fever or mucous membrane involvement occurs, all drugs should be stopped immediately, the patient should be switched to alternative anti-TB agents, and LTBI or TB treatment should be managed in consultation with a specialist.

If superinfection or worsening TB is excluded as a potential cause, all TB drugs should be stopped. In addition to AST elevation, disproportionate increases in bilirubin and alkaline phosphatase occur occasionally. In most patients, asymptomatic aminotransferase elevations resolve spontaneously. For any substantial new transaminase or bilirubin elevation, serologic testing for hepatitis A, B, and C should be performed and the patient questioned regarding symptoms suggestive of biliary tract disease and exposures to alcohol and other hepatotoxins. Because the rifamycins are a critical part of the TB regimen and are less likely to cause hepatotoxicity than INH or PZA , they should be restarted first. If symptoms recur or AST increases, the last drug added should be stopped.

In this last circumstance, depending on the number of doses of PZA taken, severity of disease, and bacteriological status, therapy might be extended to 9 months with RIF and INH alone. The ultimate decision regarding resumption of therapy with the same or a different agent for LTBI treatment should be made after weighing the risk for additional hepatic injury against the benefit of preventing progression to TB disease and always in consultation with an expert in treating LTBI in persons with HIV infection. The treatment of TB can be complicated by drug interactions with the rifamycins and overlapping toxicities associated with antiretrovirals ARVs and anti-TB drugs when therapy for both HIV and TB infections is concomitantly administered.

Both RIF and rifabutin induce CYP3A enzymes, and although rifabutin is not as potent an inducer as RIF, it is a substrate, leading to drug interactions with the PIs and non-nucleoside reverse transcriptase inhibitors NNRTIs when these agents are concomitantly administered with the rifamycins; such administration might result in increased metabolism and suboptimal levels of ARVs Use of ritonavir-boosted saquinavir with RIF was associated with a high incidence of hepatotoxicity in a pharmacokinetic study using healthy volunteers Delavirdine should not be used with either RIF or rifabutin Efavirenz decreases the levels of rifabutin, and the dose of the latter might have to be increased.

Nevirapine does not affect the levels of rifabutin sufficiently to merit adjustment of the rifabutin dose. Underdosing of ARVs or rifabutin can result in selection of HIV drug-resistant mutants or acquired rifamycin resistance, respectively, whereas overdosing of rifabutin might result in dose-related toxicities such as neutropenia and uveitis. Because interpatient variations in the degree of enzyme induction or inhibition can occur, the use of therapeutic drug monitoring for levels of rifabutin, PIs, or NNRTIs might help to adjust dosing for individual patients.

HIV nucleos tide analogs and the fusion inhibitor enfuvirtide are not affected by the CYP enzymes and can be used with the rifamycins. Results of ongoing drug-drug interaction studies predict that the combination of RIF and possibly rifabutin will result in decreased levels of maraviroc, raltegravir, and elvitegravir. Until data are available to guide dose adjustment, these drugs in combination should be avoided or used with extreme caution. The optimal timing of initiation of ART in this setting is not clear. A positive aspect of starting both regimens simultaneously is the possible prevention of progressive HIV disease and reduction in morbidity or mortality associated with TB or other OIs. A negative of this approach is the possibility of overlapping toxicities, drug interactions, a high pill burden, and the possibility of developing IRIS or a paradoxical reaction.

These factors must be weighed carefully when choosing the best time to start ART in individual patients. Several randomized clinical trials are under way to address the optimal timing of initiation of ART in persons being treated for active TB, but the results will not be known for several years. Pending these results, certain specialists determine when to start ART based on the immunologic status of the patients , , However, other studies suggest this approach might prevent HIV disease progression or death , , Immune Reconstitution and Paradoxical Reactions. Signs of a paradoxical reaction or IRIS can include, but are not limited to, high fevers, worsening respiratory status, increase in size and inflammation of involved lymph nodes or new lymphadenopathy, breakthrough meningitis or new or expanding CNS lesions, radiologic worsening of pulmonary parenchymal infiltrations, and increasing pleural effusions.

Such findings should be attributed to a paradoxical or IRIS reaction only after a thorough evaluation has excluded other possible causes, especially failure of TB therapy. IRIS or paradoxical reactions are usually self-limited but if symptoms are severe, supportive treatment might be required, depending on the nature of the complications. Approaches to the management of severe reactions e. Drug-resistant TB continues to be a substantial clinical and public health problem. Predisposing factors include cavitary disease with a large bacillary load, use of an inadequate drug regimen, or a combined failure of both the patient and the provider to ensure compliance with the prescribed regimen Ongoing transmission of drug-resistant strains is a source of new drug-resistant cases The optimal duration of treatment for highly resistant strains has not been established.

For patients with M. A fluoroquinolone may be added for those with more severe or extensive disease CIII. Treatment regimens for TB disease caused by RIF mono-resistant strains are less effective, and patients infected with these strains are at increased risk for relapse and treatment failure. An injectable agent e. Patients with M. Treatment regimens should consist of at least four effective drugs AIII , Reports of highly resistant M. The emergence of M. Contact investigation and strict infection- control precautions should be implemented according to national guidelines BIII For patients with a low ongoing risk for exposure and transmission of M. However, recurrence of TB disease can result from either endogenous relapse or exogenous reinfection.

Even in low TB burden countries, reinfection is a risk for HIV-infected residents of institutions that pose an ongoing high risk for exposure to M. Recurrence of TB disease is also substantially increased in HIV-infected persons in geographic areas with a high TB burden , In these settings, treatment of LTBI resulting from presumed reinfection among persons previously treated for TB has been documented to reduce recurrence of TB disease ,, Recent molecular epidemiology studies suggest that the majority of TB cases among foreign-born persons in the United States are caused by or related to activation of latent infection These findings suggest that recent immigrants might be at high risk for recent infection or reinfection in their countries of origin.

Close monitoring of recent immigrants at such risk is necessary. HIV-infected pregnant women who do not have documentation of a negative TST result during the preceding year should be tested during pregnancy. The frequency of anergy is not increased during pregnancy, and routine anergy testing for HIVinfected pregnant women is not recommended The diagnostic evaluation for TB disease in pregnant women is the same as for nonpregnant adults. Chest radiographs with abdominal shielding result in minimal fetal radiation exposure.

An increase in pregnancy complications and undesirable outcomes including preterm birth , low birthweight, and intrauterine growth retardation might be observed among pregnant women with either pulmonary or extrapulmonary TB not confined to the lymph nodes, especially when treatment is not begun until late in pregnancy Congenital TB infection of the infant might occur but appears to be rare Treatment of TB disease for pregnant women should be the same as for nonpregnant women, but with attention given to the following considerations BIII :.

Experience with using the majority of the second-line drugs for TB during pregnancy is limited. MDR-TB in pregnancy should be managed in consultation with a specialist. Therapy should not be withheld because of pregnancy AIII. The following concerns should be considered when selecting second-line anti-TB drugs for use among pregnant women:. ART is indicated for all pregnant women either for treatment of maternal infection, or if not indicated for maternal therapy, for prevention of perinatal transmission of HIV For women whose diagnosis includes concurrent active TB and HIV infection during pregnancy, TB therapy should be initiated immediately and ART should be initiated as soon as possible thereafter, usually according to the principles described for nonpregnant adults.

Efavirenz use is not recommended during the first trimester because of 1 substantial CNS and cleft defects seen in cynomolgous monkeys treated in the first trimester with efavirenz at doses similar to those used in humans and 2 because of case reports of neural tube defects in humans after first-trimester exposure. Efavirenz can be used after the first trimester, if indicated, to avoid drug interactions between anti-TB drugs and PIs.

For women who require ART strictly for prophylaxis of perinatal HIV transmission, use of a triple nucleoside regimen, including abacavir, could be considered to avoid interactions with TB drugs. Disseminated Mycobacterium avium Complex Disease. Organisms of the Mycobacterium avium complex MAC are ubiquitous in the environment Although epidemiologic associations have been identified, no environmental exposure or behavior has been consistently linked to a subsequent risk for developing MAC disease. The mode of transmission is thought to be through inhalation, ingestion, or inoculation via the respiratory or gastrointestinal tract.

Household or close contacts of those with MAC disease do not appear to be at increased risk for disease, and person-to-person transmission is unlikely. Early symptoms might be minimal and might precede detectable mycobacteremia by several weeks. Symptoms include fever, night sweats, weight loss, fatigue, diarrhea, and abdominal pain Localized manifestations of MAC disease have been reported most frequently among persons who are receiving and have responded to ART. Localized syndromes include cervical or mesenteric lymphadenitis, pneumonitis, pericarditis, osteomyelitis, skin or soft tissue abscesses, genital ulcers, or CNS infection. Laboratory abnormalities particularly associated with disseminated MAC disease include anemia often out of proportion to that expected for the stage of HIV disease and elevated liver alkaline phosphatase ,,,, Hepatomegaly, splenomegaly, or lymphadenopathy paratracheal, retroperitoneal, para-aortic, or less commonly peripheral might be identified on physical examination or by radiographic or other imaging studies.

Other focal physical findings or laboratory abnormalities might occur in the context of localized disease. IRIS, initially characterized by focal lymphadenitis with fever, has subsequently been recognized as a systemic inflammatory syndrome with signs and symptoms that are clinically indistinguishable from active MAC infection. Bacteremia is absent. As with TB, the syndrome might be benign and self-limited or might result in severe unremitting symptoms that are improved with the use of systemic anti-inflammatory therapy or corticosteroids in doses similar to those described for TB-associated IRIS. A confirmed diagnosis of disseminated MAC disease is based on compatible clinical signs and symptoms coupled with the isolation of MAC from cultures of blood, lymph node, bone marrow, or other normally sterile tissue or body fluids ,,, Species identification should be performed using specific DNA probes, high performance liquid chromatography, or biochemical tests.

Other ancillary studies provide supportive diagnostic information, including AFB smear and culture of stool or tissue biopsy material, radiographic imaging, or other studies aimed at isolation of organisms from focal infection sites. MAC organisms commonly contaminate environmental sources e. Available information does not support specific recommendations regarding avoidance of exposure. Azithromycin or clarithromycin , are the preferred prophylactic agents AI. The combination of clarithromycin and rifabutin is no more effective than clarithromycin alone for chemoprophylaxis, is associated with a higher rate of adverse effects than either drug alone, and should not be used EI The combination of azithromycin with rifabutin is more effective than azithromycin alone; however, the additional cost, increased occurrence of adverse effects, potential for drug interactions, and absence of a survival difference compared with azithromycin alone do not warrant a routine recommendation for this regimen CI Azithromycin and clarithromycin also each confer protection against respiratory bacterial infections BII.

If azithromycin or clarithromycin cannot be tolerated, rifabutin is an alternative prophylactic agent for MAC disease, although drug interactions might complicate the use of this agent BI , Before prophylaxis is initiated, disseminated MAC disease should be ruled out by clinical assessment, which might include obtaining a blood culture for MAC. Because treatment with rifabutin could result in RIF resistance among persons who have active TB, active TB also should be excluded before rifabutin is used for prophylaxis. Although detecting MAC organisms in the respiratory or gastrointestinal tract might predict disseminated MAC infection, no data are available regarding efficacy of prophylaxis with clarithromycin, azithromycin, rifabutin, or other drugs among asymptomatic patients harboring MAC organisms at these sites in the presence of a negative blood culture.

Two randomized, placebo-controlled trials and observational data have demonstrated that such patients can discontinue primary prophylaxis with minimal risk for acquiring MAC disease , Discontinuing primary prophylaxis among patients who meet these criteria is recommended to reduce pill burden, the potential for drug toxicity, drug interactions, selection of drug-resistant pathogens, and cost. Initial treatment of MAC disease should consist of two or more antimycobacterial drugs to prevent or delay the emergence of resistance AI ,,, Clarithromycin is the preferred first agent AI ; it has been studied more extensively than azithromycin in patients with AIDS and appears to be associated with more rapid clearance of MAC from the blood ,,, However, azithromycin can be substituted for clarithromycin when drug interactions or clarithromycin intolerance preclude the use of clarithromycin AII.

EMB is the recommended second drug AI. Some clinicians add rifabutin as a third drug CI. One randomized clinical trial demonstrated that the addition of rifabutin to the combination of clarithromycin and EMB improved survival, and in two randomized clinical trials, this approach reduced emergence of drug resistance , in persons with AIDS and disseminated MAC disease. These studies were completed before the availability of effective ART. On the basis of data in non-HIV-infected patients, the third or fourth drug might include an injectable agent such as amikacin or streptomycin CIII Patients who have disseminated MAC disease and have not been treated previously with or are not receiving effective ART should generally typically have ART withheld until after the first 2 weeks of antimycobacterial therapy have been completed to reduce risk for drug interactions, pill burden, and complications associated with the occurrence of IRIS CIII.

If ART has already been instituted, it should be continued and optimized unless drug interactions preclude the safe concomitant use of antiretroviral and antimycobacterial drugs CIII. A repeat blood culture for MAC should be obtained weeks after initiating antimycobacterial therapy only for patients who fail to have a clinical response to their initial treatment regimen. Improvement in fever and a decline in quantity of mycobacteria in blood or tissue can be expected within weeks after initiation of appropriate therapy; however, for those with more extensive disease or advanced immunosuppression, clinical response might be delayed.

Adverse effects with clarithromycin and azithromycin include nausea, vomiting, abdominal pain, abnormal taste, and elevations of liver transaminase levels or hypersensitivity reactions. If IRIS symptoms do not improve, short-term weeks systemic corticosteroid therapy, in doses equivalent to mg of oral prednisone daily, has been successful in reducing symptoms and morbidity CIII ,, Rifabutin should not be administered to patients receiving certain PIs and NNRTIs because the complex interactions have been incompletely studied and the clinical implications of those interactions are unclear , PIs can increase clarithromycin levels, but no recommendation to adjust the dose of either clarithromycin or PIs can be made on the basis of existing data.

Efavirenz can induce metabolism of clarithromycin. This can result in reduced serum concentration of clarithromycin but increased concentration of the OH active metabolite of clarithromycin. Although the clinical significance of this interaction is unknown, the efficacy of clarithromycin for MAC prophylaxis could be reduced because of this interaction. Treatment failure is defined by the absence of a clinical response and the persistence of mycobacteremia after weeks of treatment. Repeat testing of MAC isolates for susceptibility to clarithromycin or azithromycin is recommended for patients who relapse after an initial response.

The majority of patients who experience failure of clarithromycin or azithromycin primary prophylaxis in clinical trials had isolates susceptible to these drugs at the time MAC disease was detected ,,,,, Because the number of drugs with demonstrated clinical activity against MAC is limited, results of susceptibility testing should be used to construct a new multi-drug regimen. The regimen should consist of at least two new drugs not used previously, to which the isolate is susceptible and selected from among the following: EMB, rifabutin, amikacin, or a quinolone moxifloxacin, ciprofloxacin, or levofloxacin , although data supporting a survival or microbiologic benefit when these agents are added have not been compelling CIII 33,,,,, Whether continuing clarithromycin or azithromycin despite resistance provides additional benefit is unknown.

Clofazimine should not be used because randomized trials have demonstrated lack of efficacy and an association with increased mortality EII ,, Other second-line agents e. However, their role in this setting is not well defined. Adjunctive treatment of MAC disease with immunomodulators has not been thoroughly studied, and data are insufficient to support a recommendation for use DIII.

Adult and adolescent patients with disseminated MAC disease should receive lifelong secondary prophylaxis chronic maintenance therapy AII , unless immune reconstitution occurs as a result of ART , Although the numbers of patients who have been evaluated remain limited and recurrences could occur, based on the limited number of patients who have been evaluated and the inferences from more extensive data indicating the safety of discontinuing secondary prophylaxis for other OIs, discontinuing chronic maintenance therapy is reasonable BII , , , Because of an increased risk for birth defects evident in certain animal studies, clarithromycin is not recommended as the first-line agent for prophylaxis or treatment of MAC in pregnancy DIII.

Two studies, each with slightly more than women with first-trimester exposure to clarithromycin, did not demonstrate an increase in or specific pattern of defects, although an increased risk for spontaneous abortion was noted in one study , Azithromycin did not produce defects in animal studies, but experience for use in humans during the first trimester is limited. Azithromycin is recommended for primary prophylaxis in pregnancy BIII. Diagnostic considerations and indications for treatment of pregnant women are the same as for nonpregnant women. Use of EMB should minimize concerns regarding drug interactions, allowing initiation of ART as soon as possible during pregnancy to decrease the risk for perinatal transmission of HIV.

Pregnant women whose treatment failed on their primary regimen should be managed in consultation with infectious disease and obstetrical specialists. Besides invasions, Spanish conquistadors made significant explorations into the Amazon Jungle , Patagonia , the interior of North America, and the discovery and exploration of the Pacific Ocean. Conquistadors founded numerous cities, many of them on locations with pre-existing indigenous settlements, including Manila and the capitals of most Latin American countries. Conquistadors in the service of the Portuguese Crown led numerous conquests for the Portuguese Empire, across South America and Africa , as well as commercial colonies in Asia, founding the origins of modern Portuguese-speaking world in the Americas, Africa, and Asia.

Portugal established a route to China in the early 16th century, sending ships via the southern coast of Africa and founding numerous coastal enclaves along the route. Human infections gained worldwide transmission vectors for the first time: from Africa and Eurasia to the Americas and vice versa. In the 16th century perhaps , Spaniards entered American ports. Contrary to popular belief, the conquistadors were not trained warriors, but mostly artisans seeking an opportunity to advance their wealth and fame.

Their armies were mostly composed of Spanish, as well as soldiers from other parts of Europe and Africa. Native allied troops were largely infantry equipped with armament and armour that varied geographically. Some groups consisted of young men without military experience, Catholic clergy who helped with administrative duties, and soldiers with military training. These native forces often included African slaves and Native Americans, some of whom were also slaves.

They were not only made to fight in the battlefield but also to serve as interpreters, informants, servants, teachers, physicians, and scribes. India Catalina and Malintzin were Native American women slaves who were forced to work for the Spaniards. Castilian law prohibited foreigners and non-Catholics from settling in the New World. However, not all conquistadors were Castilian. The origin of many people in mixed expeditions was not always distinguished. Various occupations, such as sailors, fishermen, soldiers and nobles employed different languages even from unrelated language groups , so that crew and settlers of Iberian empires recorded as Galicians from Spain were actually using Portuguese, Basque, Catalan, Italian and Languedoc languages, which were wrongly identified.

Castilian law banned Spanish women from travelling to America unless they were married and accompanied by a husband. Some conquistadors married Native American women or had illegitimate children. European young men enlisted in the army because it was one way out of poverty. Catholic priests instructed the soldiers in mathematics, writing, theology, Latin, Greek, and history, and wrote letters and official documents for them. King's army officers taught military arts. An uneducated young recruit could become a military leader, elected by their fellow professional soldiers, perhaps based on merit. Others were born into hidalgo families, and as such they were members of the Spanish nobility with some studies but without economic resources. Even some rich nobility families' members became soldiers or missionaries, but mostly not the firstborn heirs.

They were second cousins born in Extremadura , where many of the Spanish conquerors were born. The two orders had very different approaches to the conversion of the Indians. The Franciscans used a method of mass conversion, sometimes baptizing many thousands of Indians in a day. This method was championed by prominent Franciscans such as Toribio de Benavente. The conquistadors took many different roles, including religious leader, harem keeper, King or Emperor, deserter and Native American warrior. Francisco Pizarro had children with more than 40 women. The division of the booty produced bloody conflicts, such as the one between Pizarro and De Almagro. After present-day Peruvian territories fell to Spain, Francisco Pizarro dispatched El Adelantado , Diego de Almagro , before they became enemies to the Inca Empire's northern city of Quito to claim it.

De Alvarado left South America in exchange for monetary compensation from Pizarro. De Almagro was executed in , by Hernando Pizarro 's orders. The Emperor commissioned bishop Pedro de la Gasca to restore the peace, naming him president of the Audiencia and providing him with unlimited authority to punish and pardon the rebels. Gasca repealed the New Laws , the issue around which the rebellion had been organized. Gasca convinced Pedro de Valdivia , explorer of Chile, Alonso de Alvarado another searcher for El Dorado , and others that if he were unsuccessful, a royal fleet of 40 ships and 15, men was preparing to sail from Seville in June. In , Portugal conquered Ceuta , its first overseas colony.

Throughout the 15th century, Portuguese explorers sailed the coast of Africa, establishing trading posts for tradable commodities such as firearms, spices, silver, gold, and slaves crossing Africa and India. In the first consignment of slaves was brought to Lisbon ; slave trading was the most profitable branch of Portuguese commerce until the Indian subcontinent was reached. Due to the import of the slave as early as , the kingdom of Portugal was able to establish a number of population of slaves throughout the Iberia due to its slave markets' dominance within Europe. Before the Age of Conquest began, the continental Europe already associated darker skin color with slave-class, attributing to the slaves of African origins. This sentiment traveled with the conquistadors when they began their explorations into the Americas.

The predisposition inspired a lot of the entradas to seek slaves as part of the conquest. He later tried to incorporate by marriage the kingdom of Portugal. Isabella notably supported Columbus's first voyage that launched the conquistadors into action. The Iberian Peninsula was largely divided before the hallmark of this marriage. Five independent kingdoms: Portugal in the West, Aragon and Navarre in the East, Castile in the large center, and Granada in the south, all had independent sovereignty and conflicting interests.

The conflict between Christians and Muslims to control Iberia, which started from North African Muslim's successful launch of attack in , lasted from the years to The discovery of the New World by Spain rendered desirable a delimitation of the Spanish and Portuguese spheres of exploration. Thus dividing the world into two exploration and colonizing areas seemed appropriate. This was accomplished by the Treaty of Tordesillas 7 June which modified the delimitation authorized by Pope Alexander VI in two bulls issued on 4 May The treaty gave to Portugal all lands which might be discovered east of a meridian drawn from the Arctic Pole to the Antarctic , at a distance of leagues 1, km west of Cape Verde.

Spain received the lands west of this line. The known means of measuring longitude were so inexact that the line of demarcation could not in practice be determined, [15] subjecting the treaty to diverse interpretations. It was particularly valuable to the Portuguese as a recognition of their new-found, [ clarification needed ] particularly when, in —, Vasco da Gama completed the voyage to India. Later, when Spain established a route to the Indies from the west, Portugal arranged a second treaty, the Treaty of Zaragoza.

Sevilla la Nueva , established in , was the first Spanish settlement on the island of Jamaica , which the Spaniards called Isla de Santiago. The capital was in an unhealthy location [16] and consequently moved around to the place they called "Villa de Santiago de la Vega", later named Spanish Town , in present-day Saint Catherine Parish. Grijalva was sent out with four ships and some men. The fall of Tenochtitlan marks the beginning of Spanish rule in central Mexico, and they established their capital of Mexico City on the ruins of Tenochtitlan. The Spanish conquest of the Aztec Empire was one of the most significant and complex events in world history. At the age of nearly seventy years he was made commander in by Ferdinand of the largest Spanish expedition.

An expedition commanded by Pizarro and his brothers explored south from what is today Panama, reaching Inca territory by The approval read: "In July the queen of Spain signed a charter allowing Pizarro to conquer the Incas. Pizarro was named governor and captain of all conquests in New Castile. He sought a way to transport the Potosi's silver to Europe. Africans were also conquistadors in the early Conquest campaigns in the Caribbean and Mexico. In the s there were enslaved black, free black, and free black [ clarification needed ] sailors on Spanish ships crossing the Atlantic and developing new routes of conquest and trade in the Americas.

Spaniards recognized the value of these fighters. One of the black conquistadors who fought against the Aztecs and survived the destruction of their empire was Juan Garrido. Born in Africa, Garrido lived as a young slave in Portugal before being sold to a Spaniard and acquiring his freedom fighting in the conquests of Puerto Rico, Cuba, and other islands. He fought as a free servant or auxiliary, participating in Spanish expeditions to other parts of Mexico including Baja California in the s and s.

Granted a house plot in Mexico City, he raised a family there, working at times as a guard and town crier. He claimed to have been the first person to plant wheat in Mexico. Sebastian Toral was an African slave and one of the first black conquistadors in the New World. While a slave, he went with his Spanish owner on a campaign. He was able to earn his freedom during this service. In , the Spanish crown ordered that all slaves and free blacks in the colony had to pay a tribute to the crown. However, Toral wrote in protest of the tax based on his services during his conquests.

The Spanish king responded that Toral need not pay the tax because of his service. Toral died a veteran of three transatlantic voyages and two Conquest expeditions, a man who had successfully petitioned the great Spanish King, walked the streets of Lisbon, Seville, and Mexico City, and helped found a capital city in the Americas. Around he was purchased by Alonso Valiente to be a slaved domestic servant in Puebla, Mexico. In Juan Valiente made a deal with his owner to allow him to be a conquistador for four years with the agreement that all earnings would come back to Alonso.

He fought for many years in Chile and Peru. By he was a captain, horseman, and partner in Pedro de Valdivia's company in Chile. He was later awarded an estate in Santiago; a city he would help Valdivia found. Both Alonso and Valiente tried to contact the other to make an agreement about Valiente's manumission and send Alonso his awarded money. They were never able to reach each other and Valiente died in in the Battle of Tucapel.

Pedro Fulupo was a black slave that fought in Costa Rica. Juan Bardales was an African slave that fought in Honduras and Panama. For his service he was granted manumission and a pension of 50 pesos. He joined the conquest in Venezuela and was made a captain. During the s, the Spanish began to travel through and colonize North America. They were looking for gold in foreign kingdoms. By there were rumours of undiscovered lands to the northwest of Hispaniola.

Another early motive was the search for the Seven Cities of Gold , or "Cibola", rumoured to have been built by Native Americans somewhere in the desert Southwest. In Francisco de Ulloa , the first documented European to reach the Colorado River, sailed up the Gulf of California and a short distance into the river's delta. The Basques were fur trading, fishing cod and whaling in Terranova Labrador and Newfoundland in , [32] and in Iceland by at least the early 17th century.

In Terranova they hunted bowheads and right whales , while in Iceland [36] they appear to have only hunted the latter. The Spanish fishery in Terranova declined over conflicts between Spain and other European powers during the late 16th and early 17th centuries. As a result of his expedition, the Diego Ribeiro world map outlined the East coast of North America almost perfectly. After several months of fighting native inhabitants through wilderness and swamp , the party reached Apalachee Bay with men. They believed they were near other Spaniards in Mexico, but there was in fact miles of coast between them. They followed the coast westward, until they reached the mouth of the Mississippi River near to Galveston Island.

Later they were enslaved for a few years by various Native American tribes of the upper Gulf Coast. They continued through Coahuila and Nueva Vizcaya ; then down the Gulf of California coast to what is now Sinaloa , Mexico, over a period of roughly eight years. They spent years enslaved by the Ananarivo of the Louisiana Gulf Islands. Later they were enslaved by the Hans , the Capoques and others. In they escaped into the American interior, contacting other Native American tribes along the way. In , Estevanico was one of four men who accompanied Marcos de Niza as a guide in search of the fabled Seven Cities of Cibola , preceding Coronado. When the others were struck ill, Estevanico continued alone, opening up what is now New Mexico and Arizona.

He was killed at the Zuni village of Hawikuh in present-day New Mexico. The viceroy of New Spain Antonio de Mendoza , for whom is named the Codex Mendoza , commissioned several expeditions to explore and establish settlements in the northern lands of New Spain in — After unsuccessfully attempting to descend to the river, they left the area, defeated by the difficult terrain and torrid weather. In , expeditions under Hernando de Alarcon and Melchior Diaz visited the area of Yuma and immediately saw the natural crossing of the Colorado River from Mexico to California by land as an ideal spot for a city, as the Colorado River narrows to slightly under feet wide in one small point.

Augustine Spanish Florida , is the first known and recorded Christian marriage anywhere in the continental United States. They explored a part of the route visited by Coronado in New Mexico and other parts in the southwestern United States between and From to Francis Xavier worked in Maluku among the peoples of Ambon Island , Ternate , and Morotai , and laid the foundations for the Christian religion there. He was the first governor-general of the Spanish East Indies.

The Spanish settled and took control of Tidore in to trade spices and counter Dutch encroachment in the archipelago of Maluku. The Spanish presence lasted until , when the settlers and military were moved back to the Philippines. Part of the Ternatean population chose to leave with the Spanish, settling near Manila in what later became the municipality of Ternate. Since the arrival to Kagoshima Kyushu of a group of Jesuits with St. Francis Xavier missionary and Portuguese traders, Spain was interested in Japan. As a seafaring people in the south-westernmost region of Europe, the Portuguese became natural leaders of exploration during the Middle Ages. Faced with the options of either accessing other European markets by sea, by exploiting its seafaring prowess, or by land, and facing the task of crossing Castile and Aragon territory, it is not surprising that goods were sent via the sea to England, Flanders , Italy and the Hanseatic league towns.

One important reason was the need for alternatives to the expensive eastern trade routes that followed the Silk Road. Those routes were dominated first by the republics of Venice and Genoa , and then by the Ottoman Empire after the conquest of Constantinople in The Ottomans barred European access. For decades the Spanish Netherlands ports produced more revenue than the colonies since all goods brought from Spain, Mediterranean possessions, and the colonies were sold directly there to neighbouring European countries: wheat, olive oil, wine, silver, spice, wool and silk were big businesses.

The gold brought home from Guinea stimulated the commercial energy of the Portuguese, and its European neighbours, especially Spain. Apart from their religious and scientific aspects, these voyages of discovery were highly profitable. They had benefited from Guinea's connections with neighbouring Iberians and north African Muslim states. Due to these connections, mathematicians and experts in naval technology appeared in Portugal. Portuguese and foreign experts made several breakthroughs in the fields of mathematics, cartography and naval technology.

Portuguese explored the Atlantic, Indian and Pacific oceans before the Iberian Union period — Although well received, he was forbidden to depart. In , Vasco da Gama reached India. The Portuguese sailors sailed eastward to such places as Taiwan, Japan, and the island of Timor. Several writers have also suggested the Portuguese were the first Europeans to discover Australia and New Zealand.

Attracting settlers proved difficult; however, the Jewish settlement was a success and their descendants settled many parts of Brazil. The Portuguese following the maritime trade routes of Muslims and Chinese traders, sailed the Indian Ocean. Da Gama in marked the beginning of Portuguese influence in Indian Ocean. It initially became part of the Portuguese province of Arabia and Ethiopia and was administered by a governor general. Around , Zanzibar became part of the western division of the Portuguese empire and was administered from Mozambique. The first English ship to visit Unguja, the Edward Bonaventure in , found that there was no Portuguese fort or garrison. The extent of their occupation was a trade depot where produce was purchased and collected for shipment to Mozambique.

Portuguese were established supporting one Christian local dynasty ruling suitor. By Afonso I sent various of his children and nobles to Europe to study, including his son Henrique Kinu a Mvemba , who was elevated to the status of bishop in The aggregate of Portugal's colonial holdings in India were Portuguese India. In a series of military conflicts, political manoeuvres and conquests, the Portuguese extended their control over the Sinhalese kingdoms , including Jaffna , [59] Raigama , Sitawaka , and Kotte , [60] but the aim of unifying the entire island under Portuguese control failed.

The invasion was a disaster for the Portuguese, with their entire army wiped out by Kandyan guerrilla warfare. More envoys were sent in to Ethiopia, after Socotra was taken by the Portuguese. As a result of this mission, and facing Muslim expansion, regent queen Eleni of Ethiopia sent ambassador Mateus to king Manuel I of Portugal and to the Pope, in search of a coalition. In , the Portuguese under Francisco de Almeida won a critical victory in the battle of Diu against a joint Mamluk and Arab fleet sent to counteract their presence in the Arabian Sea.

The retreat of the Mamluks and Arabs enabled the Portuguese to implement their strategy of controlling the Indian Ocean. Afonso de Albuquerque set sail in April from Goa to Malacca with a force of 1, men and seventeen or eighteen ships. That same year, the Portuguese, desiring a commercial alliance, sent an ambassador, Duarte Fernandes , to the kingdom of Ayudhya , where he was well received by king Ramathibodi II. Earlier expeditions by Diogo Dias and Afonso de Albuquerque had explored that part of the Indian Ocean, and discovered several islands new to Europeans. Mascarenhas served as Captain-Major of the Portuguese colony of Malacca from to , and as viceroy of Goa, capital of the Portuguese possessions in Asia, from until his death in He was succeeded by Francisco Barreto , who served with the title of "governor-general".

To enforce a trade monopoly, Muscat , and Hormuz in the Persian Gulf , were seized by Afonso de Albuquerque in , and in and , respectively. He also entered into diplomatic relations with Persia. In while trying to conquer Aden , an expedition led by Albuquerque cruised the Red Sea inside the Bab al-Mandab , and sheltered at Kamaran island. In , the Portuguese were the first Europeans to reach the city of Guangzhou by the sea, and they settled on its port for a commercial monopoly of trade with other nations.

They were later expelled from their settlements, but they were allowed the use of Macau , which was also occupied in , and to be appointed in as the base for doing business with Guangzhou. The quasi-monopoly on foreign trade in the region would be maintained by the Portuguese until the early seventeenth century, when the Spanish and Dutch arrived. The Portuguese presence disrupted and reorganised the Southeast Asian trade, and in eastern Indonesia they introduced Christianity. There he established ties with the local ruler who was impressed with his martial skills. The rulers of the competing island states of Ternate and Tidore also sought Portuguese assistance and the newcomers were welcomed in the area as buyers of supplies and spices during a lull in the regional trade due to the temporary disruption of Javanese and Malay sailings to the area following the conflict in Malacca.

The spice trade soon revived but the Portuguese would not be able to fully monopolize nor disrupt this trade. Such an outpost far from Europe generally only attracted the most desperate and avaricious, and as such the feeble attempts at Christianization only strained relations with Ternate's Muslim ruler.

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