Abstract
Objective
This review aims to examine the available literature on the epidemiology, pathophysiology, and treatment of burn-induced pain.
Methods
A search was conducted on the epidemiology of ...burn injury and treatment of burn pain utilizing the database Medline, and all relevant articles were systemically reviewed. In addition, a critical review was performed on the pathophysiology of burn pain and animal models of burn pain.
Results
The search on the epidemiology of burn injury yielded a total of 163 publications of interest, 72 of which fit the inclusion/exclusion criteria, with no publications providing epidemiological data on burn injury pain management outcomes. The search on the treatment of burn pain yielded a total of 213 publications, 14 of which fit the inclusion/exclusion criteria, highlighting the limited amount of evidence available on the treatment of burn-induced pain.
Conclusions
The pathophysiology of burn pain is poorly understood, with limited clinical trials available to assess the effectiveness of analgesics in burn patients. Further studies are needed to identify new pharmacological targets and treatments for the effective management of burn injury pain.
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis ...is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression (
) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis,
mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in
tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.
Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and Leishmania infantum, is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to ...treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasite Trypanosoma cruzi. Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevant L. donovani and L. infantum isolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the β5 subunit of the L. donovani proteasome. High-resolution cryo-EM structures of apo and compound 8-bound Leishmania tarentolae 20S proteasome reveal a previously undiscovered inhibitor site that lies between the β4 and β5 proteasome subunits. This induced pocket exploits β4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials.
The aim of this study was to investigate long-term breast reconstruction outcomes at a single institution in order to offer data-driven counseling for patients.
A retrospective review was performed ...of 399 patients who underwent mastectomy with 1-stage implant-based breast reconstruction (IBBR), 2-stage IBBR, or autologous tissue reconstruction (ATR) for invasive breast cancer or ductal carcinoma in situ at our institution from 2010 to 2017. Complications were classified as major for any unplanned return to the operating room (OR).
Overall complication rates were similar among 1-stage IBBR (59%), 2-stage IBBR (60%), and ATR (52%, p = 0.54). Factors independently associated with major complications were diabetes (OR = 25.4 95% CI: 3.2–202.4; p = 0.002), and 1-stage IBBR vs. ATR (1-stage: OR = 2.0 95% CI: 1.0–4.0; p = 0.04). Bilateral procedures were also at increased risk of major complications on univariate analysis (OR = 1.59 95% CI: 1.0–2.5; p = 0.04).
Long-term breast reconstruction complication rates are higher than previously anticipated. Patients should be counseled that IBBR is associated with higher rates of complications, including unplanned return to the OR, compared to ATR.
•No differences in overall or major complications were found among reconstruction techniques.•Diabetes and bilateral procedures increase risk of major complications following breast reconstruction.
Background
Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been associated with increased postoperative complications and a prolonged length of stay (LOS). We ...report on our experience following implementation of an Enhanced Recovery After Surgery (ERAS) program for CRS and HIPEC.
Methods
Patients were divided into pre- and post-ERAS groups. Modifications in the ERAS group included routine use of transversus abdominis plane blocks, intra- and postoperative fluid restriction, and minimizing the use of narcotics, drains, and nasogastric tubes.
Results
Of a total of 130 procedures, 49 (38%) were in the pre-ERAS group and 81 (62%) were in the ERAS group. Mean LOS was reduced from 10.3 ± 8.9 days to 6.9 ± 5.0 days (
p
= 0.007) and the rate of grade III/IV complications was reduced from 24 to 15% (
p
= 0.243) following ERAS implementation. The ERAS group received less intravenous fluid during hospitalization (19.2 ± 18.7 L vs. 32.8 ± 32.5 L,
p
= 0.003) and used less opioids than the pre-ERAS group (median of 159.7 mg of oral morphine equivalents vs. 272.6 mg). There were no significant changes in the rates of 30-day readmission or acute kidney injury between the two groups (
p
= non-significant). On multivariable analyses, ERAS was significantly associated with a reduction in LOS (− 2.89 days, 95% CI − 4.84 to − 0.94) and complication rates (odds ratio 0.22, 95% CI 0.08–0.57).
Conclusions
Implementation of an ERAS program for CRS and HIPEC is associated with a reduction in overall intravenous fluids, postoperative narcotic use, complication rates, and LOS.
ATRX is a chromatin remodelling factor found at a wide range of tandemly repeated sequences including telomeres (TTAGGG)n. ATRX mutations are found in nearly all tumours that maintain their telomeres ...via the alternative lengthening of telomere (ALT) pathway, and ATRX is known to suppress this pathway. Here, we show that recruitment of ATRX to telomeric repeats depends on repeat number, orientation and, critically, on repeat transcription. Importantly, the transcribed telomeric repeats form RNA–DNA hybrids (R‐loops) whose abundance correlates with the recruitment of ATRX. Here, we show loss of ATRX is also associated with increased R‐loop formation. Our data suggest that the presence of ATRX at telomeres may have a central role in suppressing deleterious DNA secondary structures that form at transcribed telomeric repeats, and this may account for the increased DNA damage, stalling of replication and homology‐directed repair previously observed upon loss of ATRX function.
Synopsis
This study shows that ATRX recruitment to G‐rich tandem repeats depends on repeat transcription, length and orientation and is associated with R‐loops. ATRX loss increases R‐loops at these sites suggesting that ATRX resolves DNA secondary structures.
Recruitment of ATRX at G‐rich tandem repeats depends on transcription and is associated with the presence of R‐loops.
ATRX recruitment depends on the non‐template strand being G‐rich suggesting the presence of G quadruplex DNA.
R‐loops at these sites increase in the absence of ATRX.
This study shows that ATRX recruitment to G‐rich tandem repeats depends on repeat transcription, length and orientation and is associated with R‐loops. ATRX loss increases R‐loops at these sites suggesting that ATRX resolves DNA secondary structures.
Aims and objectives
To examine the association between subthreshold depression and self‐care behaviours in adults with type 2 diabetes (T2D) attending a tertiary healthcare service.
Background
...Diabetes is a global public health problem. Self‐care behaviours are a fundamental element in managing diabetes as adherence to self‐care activities is associated with improved glycaemic control. Depression in T2D is associated with decreased adherence to self‐care behaviours. Adults with subthreshold depression in diabetes may have difficulties in achieving metabolic control. Further, people with subthreshold depression have an increased risk of developing major depression. Few studies have examined the association between subthreshold depression and self‐care behaviours.
Design
A cross‐sectional study.
Methods
The study will be conducted among 384 adults diagnosed with T2D for at least a year attending their routine outpatient appointment at Tribhuvan University Teaching Hospital in Nepal. Convenience sampling will be used to recruit study participants. Data will be collected via face‐to‐face interviews and a medical record review. Self‐care behaviours will be assessed using the Summary of Diabetes Self‐care activities and subthreshold depression will be determined using the Patient Health Questionnaire‐ 9. Covariates in the study include sociodemographic and clinical factors, diabetes knowledge, perceived social support and self‐efficacy. This paper complies with the STROBE reporting guideline for cross‐sectional studies.
Results
We will use multiple linear regression to examine the association between subthreshold depression and each self‐care behaviours (i.e. diet, physical activity, foot care, blood glucose testing and medication) and total self‐care behaviour.
Conclusions
Effective management of diabetes requires adherence to self‐care behaviours. The findings of the study will help in identifying an effective way to improve diabetes self‐care.
Relevance to clinical practice
Our observations will inform nursing research and practice by providing evidence about how subthreshold depression may influence self‐care behaviours.
Background
The significance of androgen receptor (AR) expression in triple-negative breast cancer (TNBC) is unclear, and published studies so far have been inconclusive.
Methods
A tissue microarray ...was constructed using tissue obtained from 119 patients with primary TNBC and stained for AR expression. Other tissue types obtained included recurrent TNBC, normal breast tissue, adjacent ductal carcinoma-in situ (DCIS), lymph node (LN) and distant metastases. Positive AR expression was defined as ≥10 % nuclear staining.
Results
Epithelial tissue was present and evaluable in 94 TNBC patients with a total of 177 tissue cores. AR expression in TNBC was 22 of 94 (23 %). AR expression was higher in normal breast tissue (88 %) and adjacent DCIS (73 % overall). All LN metastases from AR-positive TNBC patients were also AR positive; in addition, no AR-negative TNBC patient had AR-positive LNs. AR expression was associated with older patient age (63 vs. 57 years, respectively,
p
= 0.051) and LN metastases (
p
= 0.033). Locoregional recurrence and overall/disease-specific survival were similar between AR-positive and AR-negative patients, although AR-positive patients had more advanced disease. On multivariate analysis, the presence of LN metastases was associated with poorer recurrence-free survival in AR-positive patients (hazard ratio, 4.34) (
p
= 0.031).
Conclusions
The AR is expressed in normal breast tissue, and expression decreases with advancement to DCIS and invasive cancer. AR-positive TNBC was more common in older patients and had a higher propensity for LN metastases. AR-positive TNBC may represent a breast cancer subtype with unique features that may be amenable to treatment with alternative targeted therapies.
Introduction
Excisional biopsy is currently recommended for atypical ductal hyperplasia (ADH) diagnosed on core needle breast biopsy (CNB), due to risk of upstaging to invasive or in situ carcinoma ...(DCIS). The study goal was to identify patients who may potentially forego excisional biopsy if the risk of upstaging is low.
Methods
We conducted a retrospective review of patients diagnosed with ADH on CNB who underwent excisional biopsy at one institution (5/2000–5/2011). We evaluated the upstaging rate and clinicopathologic factors associated with increased upstaging risk.
Results
A total of 114 cases of ADH were diagnosed on CNB. The median patient age was 64 years. On mammography, a mass/density/area of distortion was present in 23 % of cases; calcifications were present in 77 %. Most biopsies (79 %) were performed stereotactically. Twenty lesions (18 %) were upstaged to infiltrating carcinoma (5 %) or DCIS (13 %). Residual ADH was present in 43 biopsies (38 %). On univariate analysis, significant variables associated with upstaging included age >50 years, a mass lesion on mammography, and shorter length of biopsy core (
p
< 0.05). No patient ≤50 years of age was upstaged. Three patients who were not upstaged (3 %) developed ipsilateral disease (2 DCIS and 1 infiltrating ductal carcinoma) at a median time of 37 months.
Conclusions
The rate of upstaging when ADH is diagnosed on CNB at our institution is 18 %, and routine excisional biopsy is currently recommended for all patients. However, patients <50 years old with focal atypia only and no residual calcifications postbiopsy may represent a low-risk group who could potentially avoid excisional biopsy.
Background
Although major cancer surgery at a high-volume hospital is associated with lower postoperative mortality, the use of such hospitals may not be equally distributed.
Objective
Our aim was to ...study socioeconomic and racial differences in cancer surgery at Commission on Cancer (CoC)-accredited high-volume hospitals.
Methods
The National Cancer Database (NCDB) was used to identify patients undergoing surgery for colon, esophageal, liver, and pancreatic cancer from 2003 to 2012. Annual hospital volume for each cancer was categorized using quartiles of patient volume. Patient-level predictors of surgery at a high-volume hospital, trends in the use of a high-volume hospital, and adjusted likelihood of surgery at a high-volume hospital in 2012 versus 2003 were analyzed.
Results
African American patients were less likely to undergo surgery at a high-volume hospital for esophageal (odds ratio OR 0.59, 95% confidence interval CI 0.49–0.73) and pancreatic cancer (OR 0.83, 95% CI 0.74–0.92), while uninsured patients and those residing in low educational attainment zip codes were less likely to undergo surgery at a high-volume hospital for esophageal, liver, and pancreatic cancer. In 2012, African Americans, uninsured patients, and those from low educational attainment zip codes were no more likely to undergo surgery at a high-volume hospital than in 2003 for any cancer type. These differences were not seen in colon cancer patients, for whom significant regionalization was not seen.
Conclusions
Differences in the use of CoC-accredited high-volume hospitals for major cancer surgery were seen nationwide and persisted over the duration of the study. Strategies to increase referrals and/or access to high-volume hospitals for African American and socioeconomically disadvantaged patients should be explored.
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