Concordance of Identified Cases of Pediatric HA-VTE with American College of Physicians and Cincinnati Children's Hospital HA-VTE Prophylaxis Guidelines Over a 10-Year Period.

Objective: Our aim is to (1) ascertain the proportion of pediatric patients at a tertiary hospital in Western Massachusetts over a 10-year period with hospital-acquired venous thromboembolism (VTE) of particular characteristics and (2) determine whether ACCP or Cincinnati Children's guidelines would have recommended VTE prophylaxis in these patients. Setting: Urban teaching hospital in the United States. Participants: Data from 98 477 pediatric hospital admissions (roughly 10 000 admission per year) from 2008 to 2017 were reviewed. There were a total of 177 VTE cases identified. Outcome measures: Hospital-acquired venous thromboembolism (including deep venous thrombosis and pulmonary embolism). Result: 177 charts were extracted that carried the diagnosis of VTE based on ICD-9 and ICD-10 codes over a 10-year-period. Among these patients, 34 (19%) met the inclusion criteria for HA-VTE; 5 (16%) would qualify for prophylaxis according to ACCP and 7 (21%) according to Cincinnati Children's guideline. The most common age group to have a VTE was infants under 1 year of age (41%), and the most common characteristic was the presence of a central line (82%). Age outside of the recommended range was the sole reason that excluded patients from prophylaxis qualification per Cincinnati Children's. Conclusion: HA-VTE carries increased morbidity and mortality. Although recognition and prevention of HA-VTE in adult populations are routine, prophylaxis for pediatric HA-VTE is not commonly practiced. This may be due to paucity of strong evidence supporting prophylaxis and the challenge of identifying risk factors for HA-VTE. Our results suggest that published guidelines recommend prophylaxis in only a minority of pediatric patients who would have subsequently developed HA-VTE. Further modification and validation of current guidelines are needed to effectively prevent pediatric HA-VTE.

Distinct binding of BRCA2 BRC repeats to RAD51 generates differential DNA damage sensitivity.

BRCA2 is a multi-faceted protein critical for the proper regulation of homology-directed repair of DNA double-strand breaks. Elucidating the mechanistic features of BRCA2 is crucial for understanding homologous recombination and how patient-derived mutations impact future cancer risk. Eight centrally located BRC repeats in BRCA2 mediate binding and regulation of RAD51 on resected DNA substrates. Herein, we dissect the biochemical and cellular features of the BRC repeats tethered to the DNA binding domain of BRCA2. To understand how the BRC repeats and isolated domains of BRCA2 contribute to RAD51 binding, we analyzed both the biochemical and cellular properties of these proteins. In contrast to the individual BRC repeat units, we find that the BRC5-8 region potentiates RAD51-mediated DNA strand pairing and provides complementation functions exceeding those of BRC repeats 1-4. Furthermore, BRC5-8 can efficiently repair nuclease-induced DNA double-strand breaks and accelerate the assembly of RAD51 repair complexes upon DNA damage. These findings highlight the importance of the BRC5-8 domain in stabilizing the RAD51 filament and promoting homology-directed repair under conditions of cellular DNA damage.

Treatment with bazedoxifene and conjugated estrogens results in regression of endometriosis in a murine model.

Bazedoxifene (BZA), a selective estrogen receptor modulator (SERM), inhibits the action of estrogens on endometrial proliferation. Here, we evaluate the effect of a tissue-selective estrogen complex (TSEC) containing BZA and conjugated estrogens (CE) on ectopic endometrial lesions in a mouse model of endometriosis. Experimental endometriosis was created in 60 female CD-1 mice. The mice were randomly divided into 10 groups that received varying doses of either BZA (1, 2, 3, or 5 mg/kg/day), BZA (1, 2, 3, or 5 mg/kg/day) in combination with CE (3 mg/kg/day), CE treatment alone (3 mg/kg/day), or vehicle control for 8 wk. Treatment with BZA alone or the TSEC containing BZA/CE led to a decrease in endometriotic lesion size compared to controls. The mean surface area of the untreated lesions was 19.6 mm(2). Treatment with BZA or BZA/CE resulted in reduced lesion size (to 8.8 and 7.8 mm(2), respectively). No significant difference was found in lesion size between the BZA and BZA/CE treatment groups or between different doses of either treatment. Ovarian cyst formation was not evident in the treated groups. Treatment with the TSEC containing higher BZA dosages (3 and 5 mg/kg/day) led to significantly lower levels of estrogen receptor (Esr1) mRNA expression compared to the control treatment. No differences were observed in expression of progesterone receptor (Pgr). Immunohistochemical analysis also demonstrated a decrease in ESR protein. The combination of CE and BZA may prove to be a novel treatment option for endometriosis.