Opportunities to create new general surgery residency programs to alleviate the shortage of general surgeons

Purpose To estimate the capacity for supporting new general surgery residency programs among U.S. hospitals that currently do not have such programs. Method The authors compiled 2011 American Hospital Association data regarding the characteristics of hospitals with and without a general surgery residency program and 2012 Accreditation Council for Graduate Medical Education data regarding existing general surgery residencies. They performed an ordinary least squares regression to model the number of residents who could be trained at existing programs on the basis of residency program-level variables. They identified candidate hospitals on the basis of a priori defined criteria for new general surgery residency programs and an out-of-sample prediction of resident capacity among the candidate hospitals. Results The authors found that 153 hospitals in 39 states could support a general surgery residency program. The characteristics of these hospitals closely resembled the characteristics of hospitals with existing programs. They identified 435 new residency positions: 40 hospitals could support 2 residents per year, 99 hospitals could support 3 residents, 12 hospitals could support 4 residents, and 2 hospitals could support 5 residents. Accounting for progressive specialization, new residency programs could add 287 additional general surgeons to the workforce annually (after an initial five- to seven-year lead time). Conclusions By creating new general surgery residency programs, hospitals could increase the number of general surgeons entering the workforce each year by 25%. A challenge to achieving this growth remains finding new funding mechanisms within and outside Medicare. Such changes are needed to mitigate projected workforce shortages

E5 transforming proteins of papillomaviruses do not disturb the activity of the vacuolar H(+)-ATPase

Papillomaviruses contain a gene, E5, that encodes a short hydrophobic polypeptide that has transforming activity. E5 proteins bind to the 16 kDa subunit c (proteolipid) of the eukaryotic vacuolar H(+)-ATPase (V-ATPase) and this binding is thought to disturb the V-ATPase and to be part of transformation. This link has been examined in the yeast Saccharomyces cerevisiae. The E5 proteins from human papillomavirus (HPV) type 16, bovine papillomavirus (BPV) type 1, BPV-4 E5 and various mutants of E5 and the p12' polypeptide from human T-lymphotropic virus (HTLV) type I all bound to the S. cerevisiae subunit c (Vma3p) and could be found in vacuolar membranes. However, none affected the activity of the V-ATPase. In contrast, a dominant-negative mutant of Vma3p (E137G) inactivated the enzyme and gave the characteristic VMA phenotype. A hybrid V-ATPase containing a subunit c from Norway lobster also showed no disruption. Sedimentation showed that HPV-16 E5 was not part of the active V-ATPase. It is concluded that the binding of E5 and E5-related proteins to subunit c does not affect V-ATPase activity or function and it is proposed that the binding may be due to a chaperone function of subunit c

The formation of phosphatidylcholine oxidation products by stimulated phagocytes

Phagocytic cells produce a variety of oxidants as part of the immune defence, which react readily both with proteins and lipids, and could contribute to the oxidation of low density lipoprotein in atherosclerosis. We have investigated the oxidation of phospholipid vesicles by neutrophils and mononuclear cells, to provide a model of lipid oxidation in the absence of competing protein. Phorbol 12-myristate 13-acetate-stimulated neutrophils were incubated with phospholipid vesicles containing dipalmitoyl phosphatidylcholine, palmitoyl-arachidonoyl phosphatidylcholine (PAPC) and stearoyl-oleoyl phosphatidylcholine, before extraction of the lipids for analysis by HPLC coupled to electrospray mass spectrometry. The formation of monohydroperoxides (814 m/z) and bis-hydroperoxides (846 m/z) of PAPC was observed. However, the major oxidized product occurred at 828 m/z, and was identified as 1-palmitoyl-2-(5,6-epoxyisoprostane E-2)-sn-glycero-3-phosphocholine. These products were also formed in incubations where the neutrophils were replaced by mononuclear cells, and the amounts produced per million cells were similar. These results show that following oxidative attack by phagocytes stimulated by PMA, intact phospholipid oxidation products can be detected. The identification of an epoxyisoprostane phospholipid as the major product of phagocyte-induced phospholipid oxidation is novel, and in view of its inflammatory properties has implications for phagocyte involvement in atherogenesis

The lipid-lowering effects of lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia - A post-hoc analysis of a Phase 3, single-arm, open-label trial

Objectives: Lomitapide (a microsomal triglyceride transfer protein inhibitor) is an adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH), a rare genetic condition characterised by elevated low-density lipoprotein-cholesterol (LDL-C), and premature, severe, accelerated atherosclerosis. Standard of care for HoFH includes lipid-lowering drugs and lipoprotein apheresis. We conducted a post-hoc analysis using data from a Phase 3 study to assess whether concomitant apheresis affected the lipid-lowering efficacy of lomitapide. Methods: Existing lipid-lowering therapy, including apheresis, was to remain stable from Week-6 to Week 26. Lomitapide dose was escalated on the basis of individual safety/tolerability from 5mg to 60mg a day (maximum). The primary endpoint was mean percent change in LDL-C from baseline to Week 26 (efficacy phase), after which patients remained on lomitapide through Week 78 for safety assessment and further evaluation of efficacy. During this latter period, apheresis could be adjusted. We analysed the impact of apheresis on LDL-C reductions in patients receiving lomitapide. Results: Of the 29 patients that entered the efficacy phase, 18 (62%) were receiving apheresis at baseline. Twenty-three patients (13 receiving apheresis) completed the Week 26 evaluation. Of the six patients who discontinued in the first 26 weeks, five were receiving apheresis. There were no significant differences in percent change from baseline of LDL-C at Week 26 in patients treated (-48%) and not treated (-55%) with apheresis (p=0.545). Changes in Lp(a) levels were modest and not different between groups (p=0.436). Conclusion: The LDL-C lowering efficacy of lomitapide is unaffected by lipoprotein apheresis