Ncs2* mediates in vivo virulence of pathogenic yeast through sulphur modification of cytoplasmic transfer RNA.

Fungal pathogens threaten ecosystems and human health. Understanding the molecular basis of their virulence is key to develop new treatment strategies. Here, we characterize NCS2*, a point mutation identified in a clinical baker's yeast isolate. Ncs2 is essential for 2-thiolation of tRNA and the NCS2* mutation leads to increased thiolation at body temperature. NCS2* yeast exhibits enhanced fitness when grown at elevated temperatures or when exposed to oxidative stress, inhibition of nutrient signalling, and cell-wall stress. Importantly, Ncs2* alters the interaction and stability of the thiolase complex likely mediated by nucleotide binding. The absence of 2-thiolation abrogates the in vivo virulence of pathogenic baker's yeast in infected mice. Finally, hypomodification triggers changes in colony morphology and hyphae formation in the common commensal pathogen Candida albicans resulting in decreased virulence in a human cell culture model. These findings demonstrate that 2-thiolation of tRNA acts as a key mediator of fungal virulence and reveal new mechanistic insights into the function of the highly conserved tRNA-thiolase complex.

Resource-intensive endoscopy: revenue source or cash drain?

BACKGROUND: Recent research has demonstrated that resource-intensive endoscopic procedures are not financially viable if performed without the need for further clinical care. OBJECTIVE: To determine whether the net income from downstream clinical activities makes resource-intensive endoscopy a financially viable activity. DESIGN: Retrospective database review. SETTING: Tertiary-referral medical center. PATIENTS: Patients whose initial contacts with the medical center were as outpatients who underwent EUS, EMR, or ERCP in 2004. MAIN OUTCOME MEASUREMENTS: Hospital charges, the cost of providing services, revenue, and net income from all services provided through June 2006. RESULTS: A total of 120 patients were reviewed whose initial procedure was EUS (48), ERCP (53), or EMR (19). Although income was lost by performing the endoscopic procedures, revenue was generated by the subsequent clinical care derived from EUS (mean $7093 per patient, standard deviation [SD] $23,686, range $12,316-$117,984 per patient); a loss of revenue was incurred in the clinical care of both patients who underwent ERCP (mean -$5028 per patient, SD $12,565, range -$33,648-$47,481) and patients who underwent EMR (mean -$931 per patient, SD $6515, range -$11,245-$12,196). The most lucrative activity arising from initial endoscopic referral was surgery. Revenue was lost for these procedures in Medicare patients compared with non-Medicare patients. LIMITATION: Indirect costs are institution specific and may not be generalizable to other centers. CONCLUSIONS: EUS is the most remunerative resource-intensive endoscopic procedure. Centralizing these resource-intensive procedures into multispecialty practice sites that provide surgical and oncologic care allows downstream revenue from patient treatment to offset procedural losses. Even taking account of downstream revenues, performing these procedures on Medicare patients is not financially viable. Any future cuts in Medicare physician payment rates will further increase this Medicare/non-Medicare reimbursement imbalance and likely have consequences on the performance of these procedures.

Resource-intensive endoscopic procedures: do the dollars make sense?

BACKGROUND: The rapid development of endoscopic technologies over the past decade has led to an increased utilization of resource-intensive endoscopic procedures in clinical practice. These procedures are technically challenging, time consuming, and typically involve major equipment-related costs. OBJECTIVE: To determine the economics associated with performing resource-intensive endoscopic procedures in a tertiary-referral center DESIGN: A retrospective practice database review. SETTING: A single, North American tertiary-referral medical center. PATIENTS: All the patients whose initial contacts with the medical center were as outpatients for an EUS, EMR, or ERCP between July and November 2004. MAIN OUTCOME MEASUREMENTS: Hospital charges, the cost of providing services, revenue, and net income from all services provided through June 2006. RESULTS: Seventy patients were tracked. During the review period, these 70 patients generated a total of $2.9 million, or $42,126 per patient, in hospital charges. The net profit was $407,263 ($5790 per patient). Endoscopic services alone resulted in a loss of $424 per patient. Surgical services generated just over $300,000 in net profit. CONCLUSIONS: Economics for only resource-intensive endoscopic procedures are not financially viable under the current health care reimbursement system. The first step to removing disincentives to performing these cost-effective procedures would appear to be an insistence that reimbursement be weighted equitably to ensure reasonable profitability.