ABSTRACTBackground:The focused assessment with sonography for HIV-associated tuberculosis (TB) (FASH) ultrasound protocol has been increasingly used to help clinicians diagnose TB. We sought to quantify the diagnostic utility of FASH for TB among individuals with HIV in Malawi.Methods:Between March 2016 and August 2017, 210 adults with HIV who had 2 or more signs and symptoms that were concerning for TB (fever, cough, night sweats, weight loss) were enrolled from a public HIV clinic in Lilongwe, Malawi. The treating clinicians conducted a history, physical exam, FASH protocol, and additional TB evaluation (laboratory diagnostics and chest radiography) on all participants. The clinician made a final treatment decision based on all available information. At the 6-month follow-up visit, we categorized participants based on clinical outcomes and diagnostic tests as having probable/confirmed TB or unlikely TB; association of FASH with probable/confirmed TB was calculated using Fisher's exact tests. The impact of FASH on empiric TB treatment was determined by asking the clinicians prospectively about whether they would start treatment at 2 time points in the baseline visit: (1) after the initial history and physical exam; and (2) after history, physical exam, and FASH protocol.Results:A total of 181 participants underwent final analysis, of whom 56 were categorized as probable/confirmed TB and 125 were categorized as unlikely TB. The FASH protocol was positive in 71% (40/56) of participants with probable/confirmed TB compared to 24% (30/125) of participants with unlikely TB (odds ratio=7.9, 95% confidence interval=3.9,16.1; P<.001). Among those classified as confirmed/probable TB, FASH increased the likelihood of empiric TB treatment before obtaining any other diagnostic studies from 9% (5/56) to 46% (26/56) at the point-of-care. For those classified as unlikely TB, FASH increased the likelihood of empiric treatment from 2% to 4%.Conclusion:In the setting of HIV coinfection in Malawi, FASH can be a helpful tool that augments the clinician's ability to make a timely diagnosis of TB.

Caseum, the central necrotic material of tuberculous lesions, is a reservoir of drug-recalcitrant persisting mycobacteria. Caseum is found in closed nodules and in open cavities connecting with an airway. Several commonly accepted characteristics of caseum were established during the preantibiotic era, when autopsies of deceased tuberculosis (TB) patients were common but methodologies were limited. These pioneering studies generated concepts such as acidic pH, low oxygen tension, and paucity of nutrients being the drivers of nonreplication and persistence in caseum. Here we review widely accepted beliefs about the caseum-specific stress factors thought to trigger the shift of Mycobacterium tuberculosis to drug tolerance. Our current state of knowledge reveals that M. tuberculosis is faced with a lipid-rich diet rather than nutrient deprivation in caseum. Variable caseum pH is seen across lesions, possibly transiently acidic in young lesions but overall near neutral in most mature lesions. Oxygen tension is low in the avascular caseum of closed nodules and high at the cavity surface, and a gradient of decreasing oxygen tension likely forms toward the cavity wall. Since caseum is largely made of infected and necrotized macrophages filled with lipid droplets, the microenvironmental conditions encountered by M. tuberculosis in foamy macrophages and in caseum bear many similarities. While there remain a few knowledge gaps, these findings constitute a solid starting point to develop high-throughput drug discovery assays that combine the right balance of oxygen tension, pH, lipid abundance, and lipid species to model the profound drug tolerance of M. tuberculosis in caseum.

In this retrospective study, whole-genome sequencing (WGS) data generated on an Ion Torrent platform was used to predict phenotypic drug resistance profiles for first- and second-line drugs among Swedish clinical Mycobacterium tuberculosis isolates from 2016 to 2018. The accuracy was ~99% for all first-line drugs and 100% for four second-line drugs. Our analysis supports the introduction of WGS into routine diagnostics, which might, at least in Sweden, replace phenotypic drug susceptibility testing in the future.

Doxycycline, an FDA-approved tetracycline, is used in tuberculosis in vivo models for the temporal control of mycobacterial gene expression. In these models, animals are infected with recombinant Mycobacterium tuberculosis carrying genes of interest under transcriptional control of the doxycycline-responsive TetR-tetO unit. To minimize fluctuations of plasma levels, doxycycline is usually administered in the diet. However, tissue penetration studies to identify the minimum doxycycline content in food achieving complete repression of TetR-controlled genes in tuberculosis (TB)-infected organs and lesions have not been conducted. Here, we first determined the tetracycline concentrations required to achieve silencing of M. tuberculosis target genes in vitro. Next, we measured doxycycline concentrations in plasma, major organs, and lung lesions in TB-infected mice and rabbits and compared these values to silencing concentrations measured in vitro. We found that 2,000 ppm doxycycline supplemented in mouse and rabbit feed is sufficient to reach target concentrations in TB lesions. In rabbit chow, the calcium content had to be reduced 5-fold to minimize chelation of doxycycline and deliver adequate oral bioavailability. Clearance kinetics from major organs and lung lesions revealed that doxycycline levels fall below concentrations that repress tet promoters within 7 to 14 days after doxycycline is removed from the diet. In summary, we have shown that 2,000 ppm doxycycline supplemented in standard mouse diet and in low-calcium rabbit diet delivers concentrations adequate to achieve full repression of tet promoters in infected tissues of mice and rabbits.

This study was conducted in treatment-naive adults with drug-susceptible pulmonary tuberculosis in Port-au-Prince, Haiti, to assess the safety, bactericidal activity, and pharmacokinetics of nitazoxanide (NTZ). This was a prospective phase II clinical trial in 30 adults with pulmonary tuberculosis. Twenty participants received 1 g of NTZ orally twice daily for 14 days. A control group of 10 participants received standard therapy over 14 days. The primary outcome was the change in time to culture positivity (TTP) in an automated liquid culture system. The most common adverse events seen in the NTZ group were gastrointestinal complaints and headache. The mean change in TTP in sputum over 14 days in the NTZ group was 3.2 h ± 22.6 h and was not statistically significant (P = 0.56). The mean change in TTP in the standard therapy group was significantly increased, at 134 h ± 45.2 h (P < 0.0001). The mean NTZ MIC for Mycobacterium tuberculosis isolates was 12.3 μg/ml; the mean NTZ maximum concentration (C_max) in plasma was 10.2 μg/ml. Negligible NTZ levels were measured in sputum. At the doses used, NTZ did not show bactericidal activity against M. tuberculosis. Plasma concentrations of NTZ were below the MIC, and its negligible accumulation in pulmonary sites may explain the lack of bactericidal activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02684240.)

In children requiring lopinavir coformulated with ritonavir in a 4:1 ratio (lopinavir-ritonavir-4:1) and rifampin, adding ritonavir to achieve a 4:4 ratio with lopinavir (LPV/r-4:4) overcomes the drug-drug interaction. Possible drug-drug interactions within this regimen may affect abacavir concentrations, but this has never been studied. Children weighing <15 kg needing rifampin and LPV/r-4:4 were enrolled in a pharmacokinetic study and underwent intensive pharmacokinetic sampling on 3 visits: (i) during the intensive and (ii) continuation phases of antituberculosis treatment with LPV/r-4:4 and (iii) 1 month after antituberculosis treatment completion on LPV/r-4:1. Pharmacometric modeling and simulation were used to compare exposures across weight bands with adult target exposures. Eighty-seven children with a median (interquartile range) age and weight of 19 (4 to 64) months and 8.7 (3.9 to 14.9) kg, respectively, were included in the abacavir analysis. Abacavir pharmacokinetics were best described by a two-compartment model with first-order elimination and transit compartment absorption. After allometric scaling adjusted for the effect of body size, maturation could be identified: clearance was predicted to be fully mature at about 2 years of age and to reach half of this mature value at about 2 months of age. Abacavir bioavailability decreased 36% during treatment with rifampin and LPV/r-4:4 but remained within the median adult recommended exposure, except for children in the 3- to 4.9-kg weight band, in which the exposures were higher. The observed predose morning trough concentrations were higher than the evening values. Though abacavir exposure significantly decreased during concomitant administration of rifampin and LPV/r-4:4, it remained within acceptable ranges. (This study is registered in ClinicalTrials.gov under identifier NCT02348177.)

Up until now mask-wearing had only been an unenforced suggestion by the company.

While Fire Emblem: Three Houses seems to finally be put aside by most folks, a few are still learning the dangerous pitfalls of gift giving. As usual, cats and Robin Williams are discussed. Then someone pre-orders Pantsu Hunter and someone else tries to shove CDs into an iPhone to get monsters.

Ever since Tiger King dropped on Netflix, the world has...

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Read our live updates on coronavirus HERE Coronavirus: The symptoms

Follow our live Covid-19 updates HERE Coronavirus: The symptoms

The state accuses the ride-hailing apps of flouting a labor law by classifying drivers as independent contractors instead of employees.

The ride-hailing company is cutting 3,700 jobs. It's the latest U.S. tech company to turn to layoffs to deal with fallout from the coronavirus crisis.

Uber on Wednesday said it would lay off 3,700 full-time employees, or roughly 17 per cent of its head count.

Uber lost US$2.9 billion in the first quarter as its overseas investments were hammered by the coronavirus pandemic, but the company is looking to its growing food delivery business as well as aggressive cost-cutting to ease the pain.

Residents in Los Angeles have been told to only leave their homes for 'essential' journeys

As cities and states come out of COVID-19 stay-at-home orders, Uber is working on technologies to ensure both drivers and riders have masks in place.

The meal delivery service and dating platform have joined forces to encourage the new era of dating

Drivers being cheated out of wages and not being reimbursed for expenses causes California to lose out on payroll taxes, attorney Shannon Liss-Riordan argues in a new legal challenge to Uber's practices.

Uber's first-ever safety transparency report establishes a baseline from which the ride-hailing giant must improve.

Uber and Postmates called AB 5 an "irrational and unconstitutional statute" that targets gig economy companies and workers.

Responding to a new California labor law, Uber making concessions drivers have long sought. But it may change the service in ways that displease drivers and riders alike.

With little warning, Uber notified about 80 customer support workers in its Downtown L.A. office that it was offshoring their jobs to an office in Manila.

Uber and Lyft bring plenty of drawbacks to cities, but solutions aren't easy to find.

Virginia Sen. Mark Warner called on companies including Uber, Postmates to ease financial burdens felt by gig workers because of the novel coronavirus.

People who make their living through on-demand platforms face the possibility of a recession aggravated by a drop in demand caused by coronavirus fears.

A coalition of more than 50 groups is calling on Congress to resist Uber's call for a new category of work and force on-demand gig companies to fund unemployment benefits.

Thousands of California drivers have filed wage claims against Uber and Lyft since February, hoping to pressure the state of California into enforcing a law preventing worker misclassification.

California's suit against Uber and Lyft says the companies have illegally treated drivers as independent contractors, depriving them of benefits.

Stars like Saffron Barker, Big Narstie and Yammy take part in a four-hour event to raise money.

I authorized this significant step following a careful and thorough review process, and I did so only because I believe there is no way for this case to move forward without jeopardizing ongoing intelligence activities that we rely upon to protect the safety of the American people.

The Justice Department announced today that it has reached a settlement agreement with Huber Nurseries, based in Manheim, Pa., resolving allegations that Huber engaged in citizenship status discrimination by preferring to hire temporary visa holders over recent lawful permanent residents from Nepal.

Pham's departure is coming at a crucial time for Uber as stay-at-home orders around the world severely curtail demand for its services.

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The US-based company is said to have an employee base of over 2,000 people in India.

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As a part of the investment, Lime acquired electric bicycle service JUMP Bikes.

The post Uber leads $170m investment round for bike-sharing startup Lime appeared first on DealStreetAsia.

Sauber team boss hailed Kamui Kobayashi as 'absolutely amazing' after the Japanese driver finished seventh from a starting place of 18th at the European Grand Prix

Peter Sauber believes his decision to take on Kamui Kobayashi this year has been justified by his recent performance at the European Grand Prix

Peter Sauber said his team's first point of the season is proof that it has made significant steps forward since updating the car in Spain

Despite Sauber suffering yet another engine failure in China on Sunday, the fingers of blame did not immediately point in supplier Ferrari's direction

The emergence of ride-hailing companies like Uber and Lyft seems to pose a direct challenge to the nation’s overburdened and underfunded transit agencies, potentially siphoning off patrons most able to pay full fare. Yet, amid competition, there exists a real opportunity for collaboration in providing mobility to the agencies’ neediest customers. American public transit needs…

Whether they are are autonomous, self-driving or "shared" like Uber and Lyft, they are still congestion.

Another tool that makes life easier to live without a car.

People are being killed every day and the problem is the design of our streets as much as the cars and drivers.

Uber founder Travis Kalanick's new company runs "CloudKitchens" for cooks without restaurants. This will be big.

New York Times article asks a lot of questions, and doesn't deliver a lot of answers.

A hilarious remix of a classic image demonstrates that the new high-tech alternatives are not solving every problem.

I can't wait for this exciting new world of urban mobility.