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II.

Keloids are tumor-like skin scars that grow as a result of the aberrant healing of skin injuries, with no effective treatment. We provide new evidence that both overexpression of plasminogen activator inhibitor-1 (PAI-1) and elevated collagen accumulation are intrinsic features of keloid fibroblasts and that these characteristics are causally linked. Using seven strains each of early passage normal and keloid fibroblasts, the keloid strains exhibited inherently elevated collagen accumulation and PAI-1 expression in serumfree, 0.1% ITS؉ culture; larger increases in these parameters occurred when cells were cultured in 3% serum. To demonstrate a causal relationship between PAI-1 overexpression and collagen accumulation, normal fibroblasts were infected with PAI-1-expressing adenovirus. Such cells exhibited a two-to fourfold increase in the accumulation of newly synthesized collagen in a viral dose-dependent fashion in both monolayers and fibrin gel, provisional matrix-like cultures. Three different PAI-1-targeted small interfering RNAs, alone or in combination, produced greater than an 80% PAI-1 knockdown and reduced collagen accumulation in PAI-1-overexpressing normal or keloid fibroblasts. A vitronectin-binding mutant of PAI-1 was equipotent with wild-type PAI-1 in inducing collagen accumulation, whereas a complete protease inhibitor mutant retained approximately 50% activity. Thus, PAI-1 may use more than its protease inhibitory activity to control keloid collagen accumulation. PAI-1-targeted interventions , such as small interfering RNA and lentiviral short hairpin RNA-containing microRNA sequence suppression reported here , may have therapeutic utility in the prevention of keloid scarring.

Differences in cellular competence offer explanation of differences in the healing capacity of tissues of various ages and conditions. The homeobox family of genes plays key roles in governing cellular competence. Of these, we hypothesize that Msx2 is a strong candidate regulator of competence in skin wound healing because it is expressed in the skin during fetal development at stage of scarless healing, affects postnatal digit regeneration, and is re-expressed transiently during postnatal skin wound repair. To address if Msx2 affects cellular competence in injury repair, three millimeter full thickness excisional wounds were created on the back of C.Cg-Msx2tm1Rilm/Mmcd (Msx2 null) mice and the healing pattern was compared with that of the WT mice. Results show that Msx2 null mice exhibited faster wound closure with accelerated re-epithelialization plus earlier appearance of keratin markers for differentiation and increased level of smooth muscle actin and tenascin in the granulation tissue. In vitro, keratinocytes of Msx2 null mice exhibit increased cell migration and the fibroblasts stronger collagen gel contraction. Thus, our results suggest that Msx2 regulates cellular competence of keratinocytes and fibroblasts in skin injury repair.

Objective To determine the association of age at index birth with postpartum contraceptive use and optimal interpregnancy interval (IPI, defined as delivery to next pregnancy >18 months), controlling for provider type and client demographics among adolescent mothers who have repeat pregnancies. Methods California's 2008 birth records were linked to California's Medi-Cal and Family PACT claims data to identify 26,393 women with repeat births between 2002 and 2008, whose index birth occurred as an adolescent, and who received publicly-funded services within 18 months after the index birth. Multivariable regression analyses were conducted to examine the relationship between timing of contraception provision and interpregnancy intervals, adjusting for socio-demographic factors. Results Seventy-eight percent of adolescent women did not receive contraception at their first postpartum visit, and twenty-eight percent of adolescent women never received contraception from a Family PACT or Medi-Cal provider. Adolescents who were older at their index birth had lower rates of optimal IPIs. Native American, Asian-Pacific Islander and Latina women had lower rates of optimal IPIs compared to white women. Compared to those using only barrier methods, adolescent women receiving highly effective contraceptive methods had a 4.25 times higher odds of having an optimal IPI than those receiving hormonal methods (OR 2.10), or using no method (OR 0.70). Conclusion Effective postpartum contraceptive use and being a Family PACT provider were associated with optimal birth spacing among adolescent mothers, yet racial and ethnic disparities persisted. A missed opportunity was the provision of contraception at the first postpartum visit. Providers should aim to remove barriers to initiation of contraception at this visit.

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Background: Prior reports of the DePuy Synthes Trochanteric Fixation Nail Advanced (TFNA) revealed a potential mode of fatigue failure at the proximal screw aperture following fixation of extracapsular hip fractures. We sought to compare the revision risk between the TFNA and its prior-generation forebear, the Trochanteric Fixation Nail (TFN).Methods: A retrospective cohort study was performed using data from a U.S. integrated health-care system's hip fracture registry. The study sample comprised patients who underwent cephalomedullary nail fixation for hip fracture with a TFN (n = 4,007) or TFNA (n = 3,972) from 2014 to 2019. We evaluated the charts and radiographs for patients who underwent any revision. Multivariable Cox regression was used to evaluate the risk of revision related to the index fracture.Results: At the 3-year follow-up, the cumulative probability of revision related to the index fracture was 1.8% for the TFN and 1.9% for the TFNA. After adjustment for covariates, no difference was observed in revision risk (hazard ratio [HR], 1.18 [95% confidence interval (CI), 0.80 to 1.75]; p = 0.40) for the TFNA compared with the TFN. The TFNA was associated with a higher risk of revision for nonunion than the TFN (HR, 1.86 [95% CI, 1.11 to 3.12]; p = 0.018). At the 3-year followup, implant breakage was 0.06% for the TFN and 0.2% for the TFNA; with regard to aperture failures related to the index fracture, there were 1 failure for the TFN group and 3 failures for the TFNA group.Conclusions: In a large cohort from a U.S. hip fracture registry, the TFNA had an overall revision rate that was similar to that of the earlier TFN, with implant breakage being a rare revision reason for both groups. Chart and radiographic review found that the TFNA was associated with a higher risk of revision for nonunion.Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. Implant breakage remains a risk after operative fixation of extracapsular proximal femoral fractures using cephalomedullary nails and is estimated to occur in 2% to 3% of cases despite contemporary implant designs 1-3 . Although earlier modes of failure may be less common, the continued evolution and introduction of new cephalomedullary nails have the potential to yield unexpected unique failure patterns. Furthermore, in spite of advances in design, a revision surgical procedure for lateral implant prominence, implant cut-out, or nonunion remains a risk 4-6 .As with other cephalomedullary designs, the DePuy Synthes Trochanteric Fixation Nail (TFN) has been associated with revision for blade or screw cut-out in the head, although these observations were only described in single-center series [4][5][6][7][8] . With multiple design changes to better accommodate the osseous anatomy of the proximal part of the femur, the Synthes Trochanteric Fixation Nail Advanced (TFNA) was introduced in 2014 as a successor to the TFN 9 . The specific modifications to the TFNA included a reduction of the proximal dia...

Background Yellow fever (YF) is a rare viral disease that can be prevented through receipt of a live attenuated vaccine. In the US military, service members must receive the YF vaccine before assignment to endemic areas, putting active duty service women at heightened risk for inadvertent exposure during preconception or pregnancy. Few studies have investigated the safety of YF vaccination in pregnancy to date, and none in a military population. Methods Department of Defense Birth and Infant Health Research program data were used to identify pregnancies and infants among active duty US military women, 2003–2014. Multivariable regression models estimated associations with YF vaccine exposure during preconception/pregnancy and adverse outcomes (e.g. spontaneous abortion, birth defects). Sensitivity analyses were performed that excluded pregnancies exposed to other live vaccines. For analyses of birth defects only, a secondary sensitivity analysis was performed that excluded infants diagnosed with chromosomal anomalies. Results Of the 196 802 pregnancies and 160 706 singleton infants identified, 1347 (0.7%) and 1132 (0.7%), respectively, were exposed to the YF vaccine. No increased risks for adverse pregnancy or infant outcomes were observed in the main analysis. In sensitivity analyses that excluded pregnancies exposed to other live vaccines, preconception YF vaccine exposure was associated with birth defects (aRR = 1.71, 95% CI = 1.08–2.73); this association was attenuated when further excluding infants with chromosomal anomalies (aRR = 1.59, 95% CI = 0.97–2.62). Conclusions Overall, YF vaccine exposure did not appear to be associated with most adverse outcomes among this population of pregnant military women. A tenuous association between preconception YF vaccine exposure and birth defects was observed in sensitivity analyses, which may warrant further investigation.