Outcomes Analysis of Textured Versus Smooth Tissue Expanders in Breast Reconstruction.

INTRODUCTION: Because of concerns related to the correlation of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) and textured implants, the use of smooth devices in breast reconstruction has been increasing. Currently, there is a paucity of literature evaluating the safety of smooth tissue expanders (STEs), which are now being used more frequently in first-stage breast reconstruction. This study sought to compare the safety and outcomes associated with STEs compared with textured tissue expanders in prosthesis-based breast reconstruction. METHODS: A single-institution retrospective review of 394 patients undergoing tissue expander-based breast reconstruction (147 smooth and 247 textured) between 2015 and 2019 was conducted. Patient demographics, comorbidities, treatment characteristics, complications, and surgical outcomes were evaluated. Data analysis was performed using Fisher exact and t tests. RESULTS: No significant difference in demographics or complication rates were identified, including rates of hematoma, seroma, wound dehiscence, delayed wound healing, infection, tissue expander malposition, nipple necrosis, mastectomy flap necrosis, reoperation, readmission, and explantation. Average follow-up was 19 and 22 months for the smooth and textured groups, respectively. No cases of BIA-ALCL were identified in either group. CONCLUSIONS: With equivocal safety profiles and no demonstrated risk in BIA-ALCL associated with STEs, this study supports the safety of using STEs compared with textured tissue expanders in prosthesis-based breast reconstruction with the advantage in preventing BIA-ALCL and concludes that there is no role for textured breast expanders.

Heat shock protein Grp78/BiP/HspA5 binds directly to TDP-43 and mitigates toxicity associated with disease pathology.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure or effective treatment in which TAR DNA Binding Protein of 43 kDa (TDP-43) abnormally accumulates into misfolded protein aggregates in affected neurons. It is widely accepted that protein misfolding and aggregation promotes proteotoxic stress. The molecular chaperones are a primary line of defense against proteotoxic stress, and there has been long-standing interest in understanding the relationship between chaperones and aggregated protein in ALS. Of particular interest are the heat shock protein of 70 kDa (Hsp70) family of chaperones. However, defining which of the 13 human Hsp70 isoforms is critical for ALS has presented many challenges. To gain insight into the specific Hsp70 that modulates TDP-43, we investigated the relationship between TDP-43 and the Hsp70s using proximity-dependent biotin identification (BioID) and discovered several Hsp70 isoforms associated with TDP-43 in the nucleus, raising the possibility of an interaction with native TDP-43. We further found that HspA5 bound specifically to the RNA-binding domain of TDP-43 using recombinantly expressed proteins. Moreover, in a Drosophila strain that mimics ALS upon TDP-43 expression, the mRNA levels of the HspA5 homologue (Hsc70.3) were significantly increased. Similarly we observed upregulation of HspA5 in prefrontal cortex neurons from human ALS patients. Finally, overexpression of HspA5 in Drosophila rescued TDP-43-induced toxicity, suggesting that upregulation of HspA5 may have a compensatory role in ALS pathobiology.

Opioid Prescribing Practices Among Plastic Surgeons: Results of the 2019 American Society of Plastic Surgeons Opioid Survey.

BACKGROUND: Health care providers play an important role in the national opioid crisis with 40% of opioid-related deaths being attributed to prescription medications (Centers for Disease Control and Prevention, U.S. Department of Health and Human Services. 2018) and as many as half of the opioid pills prescribed after outpatient plastic surgery may go unused (Plast Reconstr Surg 2019;143:929-938). The purpose of this study was to provide broad foundational data regarding postoperative analgesic prescribing patterns among members of the American Society of Plastic Surgeons (ASPS) to facilitate inclusion of opioid data fields in the ASPS Tracking Operations and Outcomes for Plastic Surgeons database for longitudinal evaluation. METHODS: A survey regarding opioid prescribing practices was electronically distributed to a representative cohort of 2555 ASPS members. Two hundred seventy-nine responses (11% response rate) were received. RESULTS: The majority of respondents reported prescribing opioids following 1 or more types of cosmetic and reconstructive procedures (90.2% and 81.7%, respectively; p = 0.0057), most commonly oxycodone and hydrocodone. Most (61.9%) reported less than 5% of patients request an opioid refill. Nonopioid medications, most commonly acetaminophen and ibuprofen/naproxen, were also prescribed but less commonly so for cosmetic (80.7-85.8%) than reconstructive (86.3-91.5%) procedures. Local anesthetic was less commonly used for mastopexy (83.7%) than augmentation (91.8%, p = 0.02). CONCLUSIONS: Based on survey responses, potential areas of improvement to reduce opioid prescribing and use include provider education on the use of multimodal pain regimens including nonopioid medication and "as needed" rather than scheduled dosing, use of local anesthetic blocks, as well as patient education on opioid safety and proper disposal of unused medication.

An Allosteric Modulator of RNA Binding Targeting the N-Terminal Domain of TDP-43 Yields Neuroprotective Properties.

In this study, we targeted the N-terminal domain (NTD) of transactive response (TAR) DNA binding protein (TDP-43), which is implicated in several neurodegenerative diseases. In silico docking of 50K compounds to the NTD domain of TDP-43 identified a small molecule (nTRD22) that is bound to the N-terminal domain. Interestingly, nTRD22 caused allosteric modulation of the RNA binding domain (RRM) of TDP-43, resulting in decreased binding to RNA in vitro. Moreover, incubation of primary motor neurons with nTRD22 induced a reduction of TDP-43 protein levels, similar to TDP-43 RNA binding-deficient mutants and supporting a disruption of TDP-43 binding to RNA. Finally, nTRD22 mitigated motor impairment in a Drosophila model of amyotrophic lateral sclerosis. Our findings provide an exciting way of allosteric modulation of the RNA-binding region of TDP-43 through the N-terminal domain.

Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins.

Anti-apoptotic Bcl-2 family proteins are overexpressed in a wide spectrum of cancers and have become well validated therapeutic targets. Cancer cells display survival dependence on individual or subsets of anti-apoptotic proteins that could be effectively targeted by multimodal inhibitors. We designed a 2,5-substituted benzoic acid scaffold that displayed equipotent binding to Mcl-1 and Bfl-1. Structure-based design was guided by several solved cocrystal structures with Mcl-1, leading to the development of compound 24, which binds both Mcl-1 and Bfl-1 with Ki values of 100 nM and shows appreciable selectivity over Bcl-2/Bcl-xL. The selective binding profile of 24 was translated to on-target cellular activity in model lymphoma cell lines. These studies lay a foundation for developing more advanced dual Mcl-1/Bfl-1 inhibitors that have potential to provide greater single agent efficacy and broader coverage to combat resistance in several types of cancer than selective Mcl-1 inhibitors alone.

Electronic Health Record-Based Registries: Clinical Research Using Registries in Colon and Rectal Surgery.

Electronic health records (EHRs) or electronic medical records (EMRs) contain a vast amount of clinical data that can be useful for multiple purposes including research. Disease registries are collections of data in predefined formats for population management, research, and other purposes. There are differences between EHRs and registries in the data structure, data standards, and protocols. Proprietary EHR systems use different coding systems and data standards, which are usually kept secret. For EHR data to flow seamlessly into registries, there is the need for interoperability between EHR systems and between EHRs and registries. The levels of interoperability required include functional, structural, and semantic interoperability. EHR data can be manually mapped to registry data, but that is a tedious, resource-intensive endeavor. The development of data standards that can be used as building blocks for both EHRs and registries will help overcome the problem of interoperability.

Characteristics of Dog Bites in Arkansas.

OBJECTIVE: Dog bite injuries are encountered frequently in emergency departments and can cause significant morbidity. The objective of this study was to explore the associations between the multiple variables at play during these occurrences (eg, the patient's age, the bite location, the bite severity, the dog's relationship with the patient, the breed of dog). METHODS: This two-institution study collected and analyzed dog bite data from Arkansas' only Level I trauma centers. The charts of 740 patients were included in our retrospective chart review. The chart review extracted data, including each individual patient's age, sex, dog bite location, and dog bite severity, as well as the patient's relationship to the dog and the dog's breed. To determine the relation between and among variables, contingency tables were created and analyzed to determine odds ratios (ORs) and confidence intervals (CIs). In addition, standard t tests were used in statistical comparisons of means and proportions. RESULTS: Of the 740 patient charts reviewed, 574 were for patients who presented to Arkansas Children's Hospital and 166 were for patients who presented to the University of Arkansas for Medical Sciences. Of the patients across both institutions, 267 (37.1%) required some form of repair, with 225 (30.4%) receiving closure within the emergency department and 42 (6.7%) requiring an operative intervention. Among children, those younger than age 5 years were >8 times as likely to require an operative repair (OR 8.1, 95% CI 2.77-23.58, P < 0.0001), >4 times as likely to be bitten on the head and neck (OR 4.30, 95% CI 3.00-6.16, P < 0.0001), and ≤3 times as likely to be bitten by a family dog (OR 2.97, 95% CI 2.10-4.20, P < 0.0001). Conversely, children older than age 12 years were >3 times as likely to be bitten on an extremity (OR 3.43, 95% CI 2.08-5.65, P < 0.0001). CONCLUSIONS: The results of this retrospective review are aligned mostly with the general trends found in previous national and global studies, supporting the notion that family dogs represent a more significant threat than often is realized and that, among the breeds identified, pit bulls are proportionally linked with more severe bite injuries. Our data further validate previous studies that note an increased risk of bites and bite severity in children younger than 5 years. In addition, our data show that bites to the head and neck occurred more frequently among children younger than 5 years than among older children, and that boys younger than 5 years were bitten more frequently than girls.

Management of T-cell large granular lymphocyte leukemia and concurrent retroperitoneal liposarcoma.

T-cell large granular leukemia (T-LGL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T lymphocytes. We present a unique case of T-LGL and concurrent retroperitoneal sarcoma occurring in a patient with long-standing rheumatoid arthritis. Pathology revealed a high-grade dedifferentiated liposarcoma. The diagnosis of T-LGL with a synchronous retroperitoneal sarcoma is a case that highlights the surgical management of these two rare conditions.

Phyllodes tumor masquerading as a fungating breast mass.

Phyllodes tumor of the breast is an uncommonly encountered disease. The tumor presenting as fungating breast mass or 'ruptured' breast is an even more rare presentation of an unusual disease. This report documents the case of a 60-year-old female with delayed presentation of a large exophytic mass of the left breast. Biopsy of this lesion was non-diagnostic, so excision via left total mastectomy was performed. The final pathology was consistent with malignant phyllodes tumor. This report highlights the features of a rare breast cancer, the challenges in obtaining a definitive diagnosis, and the treatment of this disease, in an effort to provide clinicians with an example of the management of such a peculiar entity.

Limb salvage and reconstruction following a zebra attack.

Animal bites are fairly rare events but can cause devastating traumatic injuries to the victim. In addition to the soft tissue, vascular, and orthopedic trauma inflicted by these occurrences, bite injuries also have the potential to introduce an inoculum of microbes, which may progress to an infection if not treated properly and expeditiously. We present the case of a healthy male who sustained multiple bite wounds from a domestic zebra to his left upper extremity. This attack caused severe damage, including devascularization of the arm at the brachial artery, disruption of the distal biceps and brachialis, stripping of the forearm nerves, and shearing of the overlying soft tissue. The patient was taken emergently to the operating room for revascularization of the extremity utilizing a vein bypass graft. The soft tissue injuries were addressed with numerous irrigation and debridement procedures, during which coverage of the vein bypass graft was obtained using a variety of techniques, including skin flaps, musculocutaneous advancements, and the application of an acellular dermal matrix (AlloDerm) and a collagen-glycosaminoglycan matrix (Integra). Wound cultures obtained intra-operatively during the irrigation and debridement procedures were notable for the growth of multiple microbes, including Rhodococcus spp., which have been documented to cause infection in immunocompromised patients. The patient in this case was treated with a prolonged course of antibiotics, and wound cultures negative for microbial growth were eventually obtained prior to final closure of his wound. The patient then underwent successful biceps reconstruction with a pedicled latissimus dorsi muscle transfer. This case documents the extraordinary multidisciplinary approach provided in the salvage, management, and eventual reconstruction of a mangled left upper extremity that had sustained devastating traumatic injuries resulting from a rather unusual source.

Rectal gastrointestinal stromal tumor with metastasis to the penis: Case report and review of literature.

We report the case of a 51-year-old gentleman with previously diagnosed gastrointestinal stromal tumor (GIST) of the rectum with metastasis to the penis. The patient underwent abdominoperineal resection of the primary tumor with negative margins and completed a three-year course of imatinib mesylate (Gleevec). Forty months after resection of his rectal tumor, the patient presented to his urologist with worsening testicular pain, mild lower urinary tract obstructive symptoms, and nocturia. A pelvic MRI revealed the presence of an ill-defined mass in the right perineum extending from the base of the penis to the penoscrotal junction. Biopsy of this mass was consistent with metastatic GIST. To our knowledge, this is the first report of metastatic GIST to the penis.

Relationship between renal function and extracorporeal membrane oxygenation use: a single-center experience.

The effects of extracorporeal membrane oxygenation (ECMO) support on renal function in children with critical illness are unknown. The objective of this study was to investigate the impact of ECMO on renal function among children in different age groups. We performed a single-center retrospective observational study in critically ill children ≤ 18 years supported on ECMO for refractory cardiac or pulmonary failure (2006-2012). The patient population was divided into four age groups for the purpose of comparisons. The Acute Kidney Injury Network's (AKIN's) validated, three-tiered staging system for acute kidney injury was used to categorize the degree of worsening renal function. Data on patient demographics, baseline characteristics, renal function parameters, dialysis, ultrafiltration, duration of mechanical cardiac support, and mortality were collected. Comparisons of baseline characteristics, duration of mechanical cardiac support, and renal function were made between the four age groups. During the study period, 311 patients qualified for inclusion, of whom 289 patients (94%) received venoarterial (VA) ECMO, 12 (4%) received venovenous (VV) ECMO, and 8 (3%) received both VV and VA ECMO. A total of 109 patients (36%) received ultrafiltration on ECMO, 58 (19%) received hemodialysis, and 51 (16%) received peritoneal dialysis. There was a steady and sustained improvement in renal function in all age groups during the ECMO run, with the maximum and longest-sustained improvement occurring in the oldest age group. Proportions of patients in different AKIN stages remained similar in the first 7 days after ECMO initiation. We demonstrate that renal dysfunction improves early after ECMO support. Irrespective of the underlying disease process or patient age, renal function improves in children with pulmonary or cardiac failure who are placed on ECMO.

Negative selection and stringency modulation in phage-assisted continuous evolution.

Phage-assisted continuous evolution (PACE) uses a modified filamentous bacteriophage life cycle to substantially accelerate laboratory evolution experiments. In this work, we expand the scope and capabilities of the PACE method with two key advances that enable the evolution of biomolecules with radically altered or highly specific new activities. First, we implemented small molecule-controlled modulation of selection stringency that enables otherwise inaccessible activities to be evolved directly from inactive starting libraries through a period of evolutionary drift. Second, we developed a general negative selection that enables continuous counterselection against undesired activities. We integrated these developments to continuously evolve mutant T7 RNA polymerase enzymes with ∼10,000-fold altered, rather than merely broadened, substrate specificities during a single three-day PACE experiment. The evolved enzymes exhibit specificity for their target substrate that exceeds that of wild-type RNA polymerases for their cognate substrates while maintaining wild type-like levels of activity.

Characterization of the bafilomycin biosynthetic gene cluster from Streptomyces lohii.

New hope for old bones: The plecomacrolide bafilomycin has been explored for decades as an anti-osteoporotic. However, its structural complexity has limited the synthesis of analogues. The cloning of the bafilomycin biosynthetic gene cluster from the environmental isolate Streptomyces lohii opens the door to the production of new analogues through bioengineering.

Tirandamycin biosynthesis is mediated by co-dependent oxidative enzymes.

Elucidation of natural product biosynthetic pathways provides important insights into the assembly of potent bioactive molecules, and expands access to unique enzymes able to selectively modify complex substrates. Here, we show full reconstitution, in vitro, of an unusual multi-step oxidative cascade for post-assembly-line tailoring of tirandamycin antibiotics. This pathway involves a remarkably versatile and iterative cytochrome P450 monooxygenase (TamI) and a flavin adenine dinucleotide-dependent oxidase (TamL), which act co-dependently through the repeated exchange of substrates. TamI hydroxylates tirandamycin C (TirC) to generate tirandamycin E (TirE), a previously unidentified tirandamycin intermediate. TirE is subsequently oxidized by TamL, giving rise to the ketone of tirandamycin D (TirD), after which a unique exchange back to TamI enables successive epoxidation and hydroxylation to afford, respectively, the final products tirandamycin A (TirA) and tirandamycin B (TirB). Ligand-free, substrate- and product-bound crystal structures of bicovalently flavinylated TamL oxidase reveal a likely mechanism for the C10 oxidation of TirE.

A system for the continuous directed evolution of biomolecules.

Laboratory evolution has generated many biomolecules with desired properties, but a single round of mutation, gene expression, screening or selection, and replication typically requires days or longer with frequent human intervention. Because evolutionary success is dependent on the total number of rounds performed, a means of performing laboratory evolution continuously and rapidly could dramatically enhance its effectiveness. Although researchers have accelerated individual steps in the evolutionary cycle, the only previous example of continuous directed evolution was the landmark study of Wright and Joyce, who continuously evolved RNA ligase ribozymes with an in vitro replication cycle that unfortunately cannot be easily adapted to other biomolecules. Here we describe a system that enables the continuous directed evolution of gene-encoded molecules that can be linked to protein production in Escherichia coli. During phage-assisted continuous evolution (PACE), evolving genes are transferred from host cell to host cell through a modified bacteriophage life cycle in a manner that is dependent on the activity of interest. Dozens of rounds of evolution can occur in a single day of PACE without human intervention. Using PACE, we evolved T7 RNA polymerase (RNAP) variants that recognize a distinct promoter, initiate transcripts with ATP instead of GTP, and initiate transcripts with CTP. In one example, PACE executed 200 rounds of protein evolution over the course of 8 days. Starting from undetectable activity levels in two of these cases, enzymes with each of the three target activities emerged in less than 1 week of PACE. In all three cases, PACE-evolved polymerase activities exceeded or were comparable to that of the wild-type T7 RNAP on its wild-type promoter, representing improvements of up to several hundred-fold. By greatly accelerating laboratory evolution, PACE may provide solutions to otherwise intractable directed evolution problems and address novel questions about molecular evolution.

Data sharing, small science and institutional repositories.

Results are presented from the Data Curation Profiles project research, on who is willing to share what data with whom and when. Emerging from scientists' discussions on sharing are several dimensions suggestive of the variation in both what it means 'to share' and how these processes are carried out. This research indicates that data curation services will need to accommodate a wide range of subdisciplinary data characteristics and sharing practices. As part of a larger set of strategies emerging across academic institutions, institutional repositories (IRs) will contribute to the stewardship and mobilization of scientific research data for e-Research and learning. There will be particular types of data that can be managed well in an IR context when characteristics and practices are well understood. Findings from this study elucidate scientists' views on 'sharable' forms of data-the particular representation that they view as most valued for reuse by others within their own research areas-and the anticipated duration for such reuse. Reported sharing incidents that provide insights into barriers to sharing and related concerns on data misuse are included.

Identification of the tirandamycin biosynthetic gene cluster from Streptomyces sp. 307-9.

The structurally intriguing bicyclic ketal moiety of tirandamycin is common to several acyl-tetramic acid antibiotics, and is a key determinant of biological activity. We have identified the tirandamycin biosynthetic gene cluster from the environmental marine isolate Streptomyces sp. 307-9, thus providing the first genetic insight into the biosynthesis of this natural product scaffold. Sequence analysis revealed a hybrid polyketide synthase-nonribosomal peptide synthetase gene cluster with a colinear domain organization, which is entirely consistent with the core structure of the tirandamycins. We also identified genes within the cluster that encode candidate tailoring enzymes for elaboration and modification of the bicyclic ketal system. Disruption of tamI, which encodes a presumed cytochrome P450, led to a mutant strain deficient in production of late stage tirandamycins that instead accumulated tirandamycin C, an intermediate devoid of any post assembly-line oxidative modifications.

Isolation and characterization of tirandamycins from a marine-derived Streptomyces sp.

The novel dienoyl tetramic acids tirandamycin C (1) and tirandamycin D (2) with activity against vancomycin-resistant Enterococcus faecalis were isolated from the marine environmental isolate Streptomyces sp. 307-9, which also produces the previously identified compounds tirandamycins A (3) and B (4). Spectroscopic analysis of 1 and 2 indicated structural similarity to 3 and 4, with differences only in the pattern of pendant oxygenation on the bicyclic ketal system. The isolation of these putative biosynthetic intermediates was enabled by their sequestration on an adsorbent resin during early stationary-phase fermentation.