Spontaneous clearance of vertically acquired hepatitis c infection: implications for testing and treatment

Background. Current guidelines recommend that infants born to women with hepatitis C (HCV) viremia are screened for HCV antibody at age 18 months, and if positive, referred for RNA testing at 3 years to confirm chronic infection. This policy is based in part on analyses suggesting 25%-40% of vertically acquired HCV infections clear spontaneously within 4-5 years. Methods. Data on 179 infants with RNA and/or anti-HCV evidence of vertically acquired viraemia (single PCR+) or confirmed infection (2 PCR+ or anti-HCV beyond 18 months) in three prospective European cohorts were investigated. Ages at clearance of viremia and confirmed infection were estimated taking account of interval censoring and delayed entry. We also investigated clearance in infants in whom RNA was not detectable until after 6 weeks. Results. Clearance rates decline rapidly over the first 6 months. An estimated 90.6% (95%CrI: 83.5-95.9) of viremia cleared by 5 years, most within 3 months, and 65.9% (50.1-81.6) of confirmed infection cleared by 5 years, at a median 12.4 (7.1-18.9) months. If treatment began at age 6 months, 18 months or 3 years, at least 59.0% (42.0-76.9), 39.7 (17.9-65.9), and 20.9 (4.6-44.8) of those treated would clear without treatment. In seven (6.6%) confirmed infections, RNA was not detectable until after 6 weeks, and in 2 (1.9%) not until after 6 months. However, all such cases subsequently cleared. Conclusions. Most viraemia clears within 3 months, and most confirmed infection by 3 years. Delaying treatment avoids but does not eliminate over-treatment and should be balanced against loss to follow-up.

Comprehensive Study Identifies a Sensitive, Low-Risk, Closed-System Model for Detection of Fungal Contaminants in Cell and Gene Therapy Products

The United States Food and Drug Administration (FDA) regulates manufacturing and testing of advanced therapeutic medicinal products (ATMPs) to ensure the safety of each product for human use. Gold standard sterility testing (USP<71>) and alternative blood culture systems have major limitations for the detection of fungal contaminants. In this study, we evaluated the performance of i LYM media (designed originally for the food and beverage industry) to assess its potential for use in the biopharmaceutical field for ATMP sterility testing. We conducted a parallel evaluation of four different test systems (USP<71>, BacT/ALERT, BACTEC, and Sabouraud Dextrose Agar [SDA] culture), three different bottle media formulations ( i LYM, i FA + , and Myco/F Lytic), and two incubation temperatures (22.5°C and 32.5-35°C) using a diverse set of fungi ( n =51) isolated from NIH cleanroom environments and previous product contaminants. Additionally, we evaluated the effect of agitation versus “delayed entry” static pre-incubation on test sensitivity and time to detection (TTD). Overall, delayed entry of bottles onto the BacT/ALERT or BACTEC instruments (with agitation) did not improve test performance. USP<71> and SDA culture continued to significantly outperform each automated culture condition alone. However, we show for the first time, that a closed-system, dual-bottle combination of i LYM 22.5°C and i FA + 32.5°C can provide high fungal sensitivity, statistically comparable to USP<71>, when tested against a diverse range of environmental fungi. Our study fills a much-needed gap in biopharmaceutical testing and offers a favorable testing algorithm that maximizes bacterial and fungal test sensitivity whilst minimizing risk of product contamination associated with laboratory handling.

On Waiting Willfully in Urban Uganda: Toward an Anthropology of Pace

Women in Uganda strategically time their entry into married motherhood in relation to others with whom they want to be connected. Although much of the burgeoning literature on “waithood” laments global youth’s delayed entry into social adulthood, I show that women in urban Uganda intentionally pause, slowing down their movement through the life course to cultivate networks of interdependence that will propel them not only forward through the life course but also upward socioeconomically. The logics and practices by which they pace themselves point beyond a neoliberal conception of time and agency, instead highlighting the heightened importance of divine connections and social coordination under increasingly capitalist and urban conditions. The lens of pace helps bring into view the situated, multilayered, relational projects of moving through life with others. EKIHANDIIKO OMUBUGUFU Abakazi omuri Uganda nibetebekanisiza gye obwiire bw’okutaaha omubushweere n’obuzaire waaba n’ogyeragyeranisa naabo abubarikweenda kwegaita/kuba nabo. N’obu ebihaandiiko ebirikweyongyera kukanya ebirikukwaata aha bunyeeto biraabe nibyooreka okutoonzya ahabw’eminyeeto kukyerererwa kukura, ninyoreka ngu abakazi omumyaanya ekurakureine omuri Uganda nibariindaho bakigyendereire, bakyeendeeza ahamigyendere omumituurire yaabo kwenda ngu babaase kwombeka emikago y’okuhweerahweerana etarikubayaamba kwongyera kubutuura emituurire yaabo kwonka kureka na n’okwongyera kubatunguura omubyentaatsya. Enteekateeka hamwe n’emitwaarize eyibarikutwaazamu n’ehingura ahanyetegyereza y’obweire hamwe n’obugabe bw’okwehitsyaho ebyetaago eya abakurakureine, beitu byongyera kumurika ekyetaago kihaango ky’okumanya ebyenyikiriza hamwe n’okutuuragye n’abaantu omumbeera z’obushuubuzi hamwe n’entunguuka ebiriyo nibikanya. Ekitangaazo ky’emitwarize nikiyaamba kureeba omubury’obuhikire, entebekanisa zitarikushushwana z’okubaasa kutuuragye nabaandi.

Exploring the Associations between Delayed School Entry and Achievement in Primary and Secondary School

This research investigated whether delayed school entry was associated with higher achievement in national tests of reading and numeracy in grades 3, 5, 7 and 9 (n=2823). Delayed entry was related to advantages in reading (0.14SD) and numeracy (0.08SD) at grade 3, although little variance was explained (1-2%). This slight advantage persisted for both domains in grades 5 and 7, albeit with smaller effects. In grade 9 there was no association between delayed entry and either reading or numeracy. Exploratory analyses with subsamples in each grade (n=424-667) revealed no associations between delayed entry and achievement after controlling for inattention and hyperactivity, and negative associations between inattention and achievement in all grades in both domains (-0.33, -0.49SD).

Horizontal Shareholdings and Paragraph IV Generic Entry in the U.S. Pharmaceutical Industry

The Federal Trade Commission frequently files complaints against “pay-for-delay” settlements between brand-name pharmaceutical companies and generic-drug manufacturers, the latter of which challenge the monopoly status of patent-protected drugs. I document than when the top 20 generic shareholders have more substantial financial interests in the brand, then the likelihood that the brand enters into a settlement agreement with the first generic to challenge the brand goes up. The result of such a settlement is a payment from brand to generic, in exchange for the generic’s delayed entry. Only after the first generic’s entry, a 180-day period of marketing exclusivity for that particular generic starts. Other generics can only market their drugs after that period expires. As such, the settlement between brand and the first generic extends the brand’s monopoly position. I conclude that horizontal shareholdings facilitate coordination between brand-name patent holders and generic challengers in response to the threat of entry.

Relapse risk following truncation of PEG-asparaginase in childhood acute lymphoblastic leukemia

Truncation of asparaginase treatment due to asparaginase related toxicities or silent inactivation (SI) is common and may increase relapse risk in acute lymphoblastic leukemia (ALL). We investigated relapse risk following suboptimal asparaginase exposure among 1401 children aged 1-17 years, diagnosed with ALL between July 2008 and February 2016, and treated according to the NOPHO ALL2008 protocol including extended asparaginase exposure (1,000 IU/m2 intramuscularly weeks 5 to 33). Patients were included with delayed entry at their last administered asparaginase treatment or detection of SI and followed until relapse, death, secondary malignancy, or end of follow-up (median: 5.71 years, interquartile range: 4.02-7.64). In a multiple Cox model comparing patients with (n=358) and without (n=1043) truncated asparaginase treatment due to clinical toxicity, the adjusted relapse-specific hazard ratio (aHR) was 1.33 (95% confidence interval [CI]: 0.86-2.06, P=0.20). In a substudy including only patients with information on enzyme activity (n=1115), the 7-year cumulative incidence of relapse for the 301 patients with truncation of asparaginase treatment or SI (157 hypersensitivity, 53 pancreatitis, 14 thrombosis, 31 other, 46 SI) was 11.1% (95% CI: 6.9-15.4) versus 6.7% (95% CI: 4.7-8.6) for the 814 remaining patients. The relapse-specific aHR was 1.69 (95% CI: 1.05-2.74, P=0.03). The unadjusted bone-marrow relapse-specific HR was 1.83 (95% CI: 1.07-3.14, P=0.03) and 1.86 (95% CI: 0.90- 3.87, P=0.095) for any CNS relapse. These results emphasize the importance of therapeutic drug monitoring and appropriate adjustment of asparaginase therapy when feasible.

Effect of delayed entry on performance of the BACT/ALERT FAN PLUS bottles in the BACT/ALERT VIRTUO blood culture system

Delayed entry of patient blood culture samples into a microbial detection system is unavoidable at times, due to off-shift staffing or transporting samples to centralized laboratories. Pre-incubation time and temperature of blood culture bottles are the most critical factors impacting recovery and detection of microorganisms. A total of 1377 BACT/ALERT® (BTA) Fastidious Antimicrobial Neutralization (FAN® PLUS) bottles (FA PLUS, FN PLUS, and PF PLUS) were tested after delayed entry times of 24 and 36 h at 20–25 °C (room temperature, RT) prior to loading into the BACT/ALERT® VIRTUO® microbial detection system (VIRTUO). Clinically relevant organisms were inoculated into bottles with 5–84 colony forming units (CFU) per bottle, and human blood (0 to 10 mL), and then loaded into the VIRTUO. When bottles were loaded without delay, a mean time to detection (TTD) of 9.6 h was observed. For delayed bottles, the TTD reported by the VIRTUO was added to the 24-h and 36-h delay times and resulted in average time to results of 32.5 h and 42.5 h, respectively. The FAN PLUS bottles in conjunction with the VIRTUO produced acceptable results when delays up to 24 h at 20–25 °C occur in loading.