Severe osteomyelitis caused by Myceliophthora thermophila after a pitchfork injury

BACKGROUND: Traumatic injuries occurring in agricultural settings are often associated with infections caused by unusual organisms. Such agents may be difficult to isolate, identify, and treat effectively. CASE REPORT: A 4-year-old boy developed an extensive infection of his knee and distal femur following a barnyard pitchfork injury. Ultimately the primary infecting agent was determined to be Myceliophthora thermophila, a thermophilic melanized hyphomycete, rarely associated with human infection, found in animal excreta. Because of resistance to standard antifungal agents including amphotericin B and caspofungin, therapy was instituted with a prolonged course of terbinafine and voriconazole. Voriconazole blood levels demonstrated that the patient required a drug dosage (13.4 mg/kg) several fold greater than that recommended for adults in order to attain therapeutic blood levels. CONCLUSION: Unusual pathogens should be sought following traumatic farm injuries. Pharmacokinetic studies may be of critical importance when utilizing antifungal therapy with agents for which little information exists regarding drug metabolism in children

Modelling the intervention effect of opioid agonist treatment on multiple mortality outcomes in people who inject drugs:a three-setting analysis

BACKGROUND: Opioid agonist treatment (OAT) reduces many of the harms associated with opioid dependence. We use mathematical modelling to comprehensively evaluate the overall health benefits of OAT among people who inject drugs (PWID) in Kentucky (USA), Kyiv (Ukraine), and Tehran (Iran). METHODS: We developed a dynamic model of HIV and HCV transmission, incarceration, and mortality through overdose, injury, suicide, disease-related or other causes. The model was calibrated to site-specific data using Bayesian methods. We evaluated ‘preventable drug-related deaths’ (‘pDRD’: HIV/HCV/overdose/suicide/injury) averted over 2020-2040 for four scenarios, added incrementally, compared to a scenario without OAT: existing OAT coverage (setting dependent; community: 4-11%; prison: 0-40%); scaling-up community OAT to 40% coverage; increasing average OAT duration from 4-14 months to 2 years; and scaling-up prison-based OAT. OUTCOMES: Drug-related harms contribute differentially to mortality across settings: overdose contributes 27-47% (range of median projections) of pDRDs over 2020-2040, suicide 6-17%, injury 3-17%, HIV 0-59% and HCV 2-18%. Existing OAT coverage in Tehran (31%) could have substantial impact, averting 13% pDRDs, but will have negligible impact (<2%) in Kyiv and Kentucky due to low OAT coverage (<4%). Scaling-up community OAT to 40% could avert 12-24% pDRDs, including 13-19% of overdose deaths, with greater impact in settings with significant HIV mortality (Tehran and Kyiv). Improving OAT retention and providing prison-based OAT would have significant additional impact, averting 27-48% pDRDs. INTERPRETATION: OAT can substantially reduce drug-related harms, particularly in settings with HIV epidemics among PWID. Maximising these impacts requires research and investment into achieving higher coverage, longer retention and provision of OAT in prisons and the community. FUNDING: UK NIHR, NID

Inhibition of aminoglycoside 6\u3csup\u3e′\u3c/sup\u3e-n-acetyltransferase type ib (Aac(6\u3csup\u3e′\u3c/sup\u3e )-ib): Structure–activity relationship of substituted pyrrolidine pentamine derivatives as inhibitors

The aminoglycoside 6′-N-acetyltransferase type Ib (AAC(6′ )-Ib) is a common cause of resistance to amikacin and other aminoglycosides in Gram-negatives. Utilization of mixture-based combinatorial libraries and application of the positional scanning strategy identified an inhibitor of AAC(6′ )-Ib. This inhibitor’s chemical structure consists of a pyrrolidine pentamine scaffold substituted at four locations (R1, R3, R4, and R5). The substituents are two S-phenyl groups (R1 and R4), an S-hydroxymethyl group (R3), and a 3-phenylbutyl group (R5). Another location, R2, does not have a substitution, but it is named because its stereochemistry was modified in some compounds utilized in this study. Structure–activity relationship (SAR) analysis using derivatives with different functionalities, modified stereochemistry, and truncations was carried out by assessing the effect of the addition of each compound at 8 µM to 16 µg/mL amikacin-containing media and performing checkerboard assays varying the concentrations of the inhibitor analogs and the antibiotic. The results show that: (1) the aromatic functionalities at R1 and R4 are essential, but the stereochemistry is essential only at R4; (2) the stereochemical conformation at R2 is critical; (3) the hydroxyl moiety at R3 as well as stereoconformation are required for full inhibitory activity; (4) the phenyl functionality at R5 is not essential and can be replaced by aliphatic groups; (5) the location of the phenyl group on the butyl carbon chain at R5 is not essential; (6) the length of the aliphatic chain at R5 is not critical; and (7) all truncations of the scaffold resulted in inactive compounds. Molecular docking revealed that all compounds preferentially bind to the kanamycin C binding cavity, and binding affinity correlates with the experimental data for most of the compounds evaluated. The SAR results in this study will serve as the basis for the design of new analogs in an effort to improve their ability to induce phenotypic conversion to susceptibility in amikacin-resistant pathogens

Incarceration history and risk of HIV and hepatitis C virus acquisition among people who inject drugs: a systematic review and meta-analysis

Background People who inject drugs (PWID) experience a high prevalence of incarceration and might be at high risk of HIV and hepatitis C virus (HCV) infection during or after incarceration. We aimed to assess whether incarceration history elevates HIV or HCV acquisition risk among PWID. Methods In this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO databases for studies in any language published from Jan 1, 2000 until June 13, 2017 assessing HIV or HCV incidence among PWID. We included studies that measured HIV or HCV incidence among community-recruited PWID. We included only studies reporting original results and excluded studies that evaluated incident infections by self-report. We contacted authors of cohort studies that met the inclusion or exclusion criteria, but that did not report on the outcomes of interest, to request data. We extracted and pooled data from the included studies using random-effects meta-analyses to quantify the associations between recent (past 3, 6, or 12 months or since last follow-up) or past incarceration and HIV or HCV acquisition (primary infection or reinfection) risk among PWID. We assessed the risk of bias of included studies using the Newcastle-Ottawa Scale. Between-study heterogeneity was evaluated using the I2 statistic and the P-value for heterogeneity. Findings We included published results from 20 studies and unpublished results from 21 studies. These studies originated from Australasia, western and eastern Europe, North and Latin America, and east and southeast Asia. Recent incarceration was associated with an 81% (relative risk [RR] 1·81, 95% CI 1·40–2·34) increase in HIV acquisition risk, with moderate heterogeneity between studies (I2=63·5%; p=0·001), and a 62% (RR 1·62, 95% CI 1·28–2·05) increase in HCV acquisition risk, also with moderate heterogeneity between studies (I2=57·3%; p=0·002). Past incarceration was associated with a 25% increase in HIV (RR 1·25, 95% CI 0·94–1·65) and a 21% increase in HCV (1·21, 1·02–1·43) acquisition risk. Interpretation Incarceration is associated with substantial short-term increases in HIV and HCV acquisition risk among PWID and could be a significant driver of HCV and HIV transmission among PWID. These findings support the need for developing novel interventions to minimise the risk of HCV and HIV acquisition, including addressing structural risks associated with drug laws and excessive incarceration of PWID

Epidemiologic Observations from Passive and Targeted Surveillance during the First Wave of the 2009 H1N1 Influenza Pandemic in Milwaukee, WI

The first wave of the 2009 influenza H1N1 pandemic (H1N1pdm) in Milwaukee, WI has been recognized as the largest reported regional outbreak in the United States. The epidemiologic and clinical characteristics of this large first wave outbreak from April 28th 2009–July 25th 2009, studied using both passive and targeted surveillance methodologies are presented. A total of 2791 individuals with H1N1pdm infection were identified; 60 % were 5–18 years old. The 5–18 year and 0–4 year age groups had high infection (1131 and 1101 per 100,000) and hospitalization (49 and 12 per 100,000) rates respectively. Non-Hispanic blacks and Hispanics had the highest hospitalization and infection rates. In targeted surveillance, infected patients had fever (78%), cough (80%), sore throat (38%), and vomiting or diarrhea (8%). The “influenza like illness” definition captured only 68 % of infected patients. Modeling estimates that 10.3 % of Milwaukee population was infected in the first wave and 59% were asymptomatic. The distinct epidemiologic profile of H1N1pdm infections observed in the study has direct implications for predicting the burden of infection and hospitalization in the next waves of H1N1pdm. Careful consideration of demographic predictors of infection and hospitalization with H1N1pdm will be important for effective preparedness for subsequent influenza seasons

Rapid and highly variable warming of lake surface waters around the globe

In this first worldwide synthesis of in situ and satellite-derived lake data, we find that lake summer surface water temperatures rose rapidly (global mean = 0.34°C decade-1) between 1985 and 2009. Our analyses show that surface water warming rates are dependent on combinations of climate and local characteristics, rather than just lake location, leading to the counterintuitive result that regional consistency in lake warming is the exception, rather than the rule. The most rapidly warming lakes are widely geographically distributed, and their warming is associated with interactions among different climatic factors - from seasonally ice-covered lakes in areas where temperature and solar radiation are increasing while cloud cover is diminishing (0.72°C decade-1) to ice-free lakes experiencing increases in air temperature and solar radiation (0.53°C decade-1). The pervasive and rapid warming observed here signals the urgent need to incorporate climate impacts into vulnerability assessments and adaptation efforts for lakes

Le savant et son époque à travers sa correspondance Seeger A. Bonebakker (1923-2005) et quelques notes sur Ḫalīl b. Aybak al-Ṣafadī (696-764/1297-1363)

This article proposes a survey of two great scholars’ in Arabic literature correspondences: a European of the 20th century, Seeger Adrianus Bonebakker, who is of special interest for us because he bequeathed all of his great library, personal notes and correspondence to Università Ca’ Foscari, and a subject of study of the former, Ḫalīl b. Aybak al-Ṣafadī, great littérateur and scholar of the first century of the Mamluk period. Letters sent and received are preserved in both cases and are primary sources on their network, but also on their personal life, personality and methodology