Key Points to Consider When Evaluating Andexxa for Formulary Addition

Neurocritical Care -     

Single-Port Laparoscopic Repair of Perforated Duodenal Ulcers

Background

Laparoscopic single-port surgery has widely been introduced for the treatment of various abdominal conditions. But controversies still exist regarding its potential advantages and risks, especially for emergency surgery. The aim of this study was to evaluate the results of a single-port laparoscopic repair using straight laparoscopic instruments for the treatment of perforated duodenal ulcers.

Methods

A prospective consecutive case series was conducted including all patients with a perforated duodenal ulcer who underwent a laparoscopic single-port repair at a single institution from January 2012 to June 2018. The operation was performed through a single port using conventional straight laparoscopic instruments and intra-corporeal knot tying techniques.

Results

Out of 75 patients, simple closure of the perforation without omental patch was accomplished in 96% of cases. Conversion to an open operation was required in one patient (1.3%) due to a posterior duodenal perforation, and additional trocar placement was needed in another patient (1.3%). The mean incision length was 2.0 ± 0.2 cm. The mean operation time was 63.0 ± 26.6 min. Meantime a nasogastric tube remained in place was 2.9 ± 0.8 days. Mean duration of analgesic use was 2.8 ± 0.8 days. The rate of postoperative complications was 2.7%, including two patients with wound infections. There were no instances of intestinal leak or abscess. The postoperative hospital stay was 5.7 ± 1.2 days.

Conclusion

Laparoscopic single-port repair using conventional straight laparoscopic instruments with intra-corporeal knot tying technique was safe and feasible for patients with perforated duodenal ulcers with low risk factors. This method offers results comparable to those expected with the standard multiport laparoscopic approach with the addition of improved cosmetic outcomes.

     

Crystal Structures of KPC-2 and SHV-1 β-Lactamases in Complex with the Boronic Acid Transition State Analog S02030

Resistance to expanded-spectrum cephalosporins and carbapenems has rendered certain strains of Klebsiella pneumoniae the most problematic pathogens infecting patients in the hospital and community. This broad-spectrum resistance to β-lactamases emerges in part via the expression of KPC-2 and SHV-1 β-lactamases and variants thereof. KPC-2 carbapenemase is particularly worrisome, as the genetic determinant encoding this β-lactamase is rapidly spread via plasmids. Moreover, KPC-2, a class A enzyme, is difficult to inhibit with mechanism-based inactivators (e.g., clavulanate). In order to develop new β-lactamase inhibitors (BLIs) to add to the limited available armamentarium that can inhibit KPC-2, we have structurally probed the boronic acid transition state analog {"type":"entrez-protein","attrs":{"text":"S02030","term_id":"83679","term_text":"pir||S02030"}}S02030 for its inhibition of KPC-2 and SHV-1. {"type":"entrez-protein","attrs":{"text":"S02030","term_id":"83679","term_text":"pir||S02030"}}S02030 contains a boronic acid, a thiophene, and a carboxyl triazole moiety. We present here the 1.54- and 1.87-Å resolution crystal structures of {"type":"entrez-protein","attrs":{"text":"S02030","term_id":"83679","term_text":"pir||S02030"}}S02030 bound to SHV-1 and KPC-2 β-lactamases, respectively, as well as a comparative analysis of the {"type":"entrez-protein","attrs":{"text":"S02030","term_id":"83679","term_text":"pir||S02030"}}S02030 binding modes, including a previously determined {"type":"entrez-protein","attrs":{"text":"S02030","term_id":"83679","term_text":"pir||S02030"}}S02030 class C ADC-7 β-lactamase complex. {"type":"entrez-protein","attrs":{"text":"S02030","term_id":"83679","term_text":"pir||S02030"}}S02030 is able to inhibit vastly different serine β-lactamases by interacting with the conserved features of these active sites, which includes (i) forming the bond with catalytic serine via the boron atom, (ii) positioning one of the boronic acid oxygens in the oxyanion hole, and (iii) utilizing its amide moiety to make conserved interactions across the width of the active site. In addition, {"type":"entrez-protein","attrs":{"text":"S02030","term_id":"83679","term_text":"pir||S02030"}}S02030 is able to overcome more distantly located structural differences between the β-lactamases. This unique feature is achieved by repositioning the more polar carboxyl-triazole moiety, generated by click chemistry, to create polar interactions as well as reorient the more hydrophobic thiophene moiety. The former is aided by the unusual polar nature of the triazole ring, allowing it to potentially form a unique C—H…O 2.9-Å hydrogen bond with S130 in KPC-2.     

Distribution of extended-spectrum beta-lactamases in clinical isolates of Enterobacteriaceae in Vietnam

Among 730 Escherichia coli, 438 Klebsiella pneumoniae, and 141 Proteus mirabilis isolates obtained between September 2000 and September 2001 in seven hospitals in Ho Chi Minh City, Vietnam, 26.6% were resistant to ceftazidime, 30% were resistant to cefotaxime, 31.5% were resistant to ceftriaxone, 15.9% were resistant to cefoperazone, and 6% were resistant to cefepime. Resistance to imipenem was found in 5.6% of the isolates. In 55 strains producing extended-spectrum beta-lactamases (32 E. coli isolates, 13 K. pneumoniae isolates, and 10 P. mirabilis isolates), structural genes for VEB-1 (25.5%), CTX-M (25.5%), SHV (38.1%), and TEM (76.3%) enzymes were detected alone or in combination. Sequencing of the PCR products obtained from the K. pneumoniae isolates revealed the presence of bla(VEB-1), bla(CTX-M-14), bla(CTX-M-17), bla(SHV-2), and bla(TEM-1). Molecular typing of the strains with a similar resistance phenotype to broad-spectrum cephalosporins indicated polyclonal spread. ISEcp1 was presumably responsible for dissemination of the bla(CTX-M-like) gene.     

Follicular lymphoma lacking the t(14;18)(q32;q21): identification of two disease subtypes

The clinical and pathological features, including karyotype data and BCL2 protein expression pattern, of follicular lymphoma without a t(14;18)(q32;q21) have not been well defined. We have identified and conducted a detailed analysis of 50 cases with follicular lymphoma who lack the t(14;18). Fluorescent in situ hybridization (FISH) analysis was used to exclude cases with a cryptic IGH/BCL2 rearrangement. BCL2 protein expression level was assessed by immunohistochemistry. The karyotypes were assessed for recurrent sites of structural rearrangement, duplications and deletions on a band-by-band basis, and compared with a large cohort of cases with t(14;18). A distinct pattern of chromosomal alterations was identified in the cases without t(14;18). BCL2 protein overexpression was detected in 33% of 49 tested cases. In this minority, the karyotypes frequently showed increased copies of chromosome 18. The majority of cases (67%) did not show BCL2 overexpression and were characterized prominently by the presence of t(3;14)(q27;q32), implying a role for BCL6. Follicular lymphomas that lack a t(14;18) were segregated into two subgroups with distinct cytogenetic, phenotypic and possibly clinical features: one with BCL2 protein overexpression not related to an IGH/BCL2 rearrangement and a second without BCL2 overexpression. Objective identification of BCL2 expression level as well as BCL2 and BCL6 status by cytogenetic or FISH analysis has potential clinical utility and may yield insights into alternative genetic mechanisms associated with B-cell lymphomas with a follicular growth pattern.     

Structure and hemolytic activity relationships of triterpenoid saponins and sapogenins

We evaluated the hemolytic activity of 41 commercially available triterpenoid saponins and sapogenins derived from three types of structural skeletons. Structure–activity relationships were established by comparing the structural characteristics of both the aglycone and sugar moieties among the tested compounds. The majority of oleanane-type sapogenins had stronger hemolytic effects than those of the ursane and dammarane types. The presence of polar regions on sapogenins, such as a carboxyl (COOH) at position 28, an α-hydroxyl (α-OH) at position 16, and/or a β-hydroxyl (β-OH) at position 2, significantly enhanced hemolysis. Meanwhile, the introduction of an α-OH at position 2 or a methyl hydroxyl (CH₂OH) at positions 23 or 24 was closely associated with reduced activity. Our findings suggest that not only the complexity of sugar moieties but also the types and stereochemical configurations of functional groups at different positions, as well as the skeleton types, are important structural features affecting hemolytic potential. Our results provide a baseline in terms of the toxicity of saponins and sapogenins to erythrocytes, which holds promise for drug development.