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Introduction: Aesthetic surgery tourism is a flourishing trend, and challenges often arise when patients return home with post-operative complications, necessitating follow-up care., Methods: Between July 2021 and June 2023, we conducted a retrospective analysis of patients who presented with complications from aesthetic surgery tourism in two major teaching hospitals in Ireland., Results: Thirty-three patients with a mean age of 41 years were identified. Procedures were predominantly performed in Turkey (67%), followed by Lithuania (24%). Complications included wound dehiscence (n = 22), infections (n = 9), seroma (n = 9), haematoma (n = 2) and skin necrosis (n = 1). A total of 27 operations were performed, with an average hospital stay of four days and a per-patient cost of €5 486., Conclusion: Complications from aesthetic surgery abroad not only have a psychological and financial impact on the individuals involved but also strain our public healthcare system. Therefore, it is important for us, as medical professionals to advocate for our patients in order for them to make informed and safe decisions before seeking healthcare abroad., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

The inclusion of recovery animals in nonclinical safety studies that support clinical trials is undertaken with a wide diversity of approaches even while operating under harmonized regulatory guidance. While empirical evaluation of reversibility may enhance the overall nonclinical risk assessment, there are often overlooked opportunities to reduce recovery animal use by leveraging robust scientific and regulatory information. In the past, there were several attempts to benchmark recovery practices; however, recommendations have not been consistently applied across the pharmaceutical industry. A working group (WG) sponsored by the 3Rs Translational and Predictive Sciences Leadership Group of the IQ Consortium conducted a survey of current industry practice related to the evaluation of reversibility/recovery in repeat dose toxicity studies. Discussion among the WG representatives included member company strategies and case studies that highlight challenges and opportunities for continuous refinements in the use of recovery animals. The case studies presented in this paper demonstrate increasing alignment with the Society of Toxicologic Pathology recommendations (2013) towards (1) excluding recovery phase cohorts by default (include only when scientifically justified), (2) minimizing the number of recovery groups (e.g., control and one dose level), and (3) excluding controls in the recovery cohort by leveraging external and/or dosing phase data. Recovery group exclusion and decisions regarding the timing of reversibility evaluation may be driven by indication, modality, and/or other scientific or strategic factors using a weight of evidence approach. The results and recommendations discussed present opportunities to further decrease animal use without impacting the quality of human risk assessment., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: This publication was developed with the support of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org/). IQ is a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators and the broader research and development community.

Competing Interests: Conflict of interest None.

Inhibition of sodium-glucose cotransporter-2 (SGLT2) has been shown to be a safe and efficacious approach to support managing Type 2 diabetes. In the 2-year carcinogenicity study with the SGLT2 inhibitor empagliflozin in CD-1 mice, an increased incidence of renal tubular adenomas and carcinomas was identified in the male high-dose group but was not observed in female mice. An integrated review of available nonclinical data was conducted to establish a mode-of-action hypothesis for male mouse-specific tumorigenesis. Five key events were identified through systematic analysis to form the proposed mode-of-action: (1) Background kidney pathology in CD-1 mice sensitizes the strain to (2) pharmacology-related diuretic effects associated with SGLT2 inhib ition. (3) In male mice, metabolic demand increases with the formation of a sex- and species-specific empagliflozin metabolite. These features converge to (4) deplete oxidative stress handling reserve, driving (5) constitutive cellular proliferation in male CD-1 mice. The proposed mode of action requires all five key events for empagliflozin to present a carcinogenicity risk in the CD-1 mouse. Considering that empagliflozin is not genotoxic in the standard battery of genotoxicity tests, and not all five key events are present in the context of female mice, rats, or humans, nor for other osmotic diuretics or other SGLT2 inhibitors, the observed male mouse renal tumors are not considered relevant to humans., (© 2022 John Wiley & Sons, Ltd.)

Pancreatic ductal adenocarcinoma (PDAC) is a disease that remains refractory to existing treatments including the nucleoside analogue gemcitabine. In the current study we demonstrate that an organometallic nucleoside analogue, the ferronucleoside 1-(S,Rp), is cytotoxic in a panel of PDAC cell lines including gemcitabine-resistant MIAPaCa2, with IC50 values comparable to cisplatin. Biochemical studies show that the mechanism of action is inhibition of DNA replication, S-phase cell cycle arrest and stalling of DNA-replication forks, which were directly observed at single molecule resolution by DNA-fibre fluorography. In agreement with this, transcriptional changes following treatment with 1-(S,Rp) include activation of three of the four genes (HUS1, RAD1, RAD17) of the 9-1-1 check point complex clamp and two of the three genes (MRE11, NBN) that form the MRN complex as well as activation of multiple downstream targets. Furthermore, there was evidence of phosphorylation of checkpoint kinases 1 and 2 as well as RPA1 and gamma H2AX, all of which are considered biochemical markers of replication stress. Studies in p53-deficient cell lines showed activation of CDKN1A (p21) and GADD45A by 1-(S,Rp) was at least partially independent of p53. In conclusion, because of its potency and activity in gemcitabine-resistant cells, 1-(S,Rp) is a promising candidate molecule for development of new treatments for PDAC., (© The Author(s) 2022. Published by Oxford University Press.)

Size, shape, and chemical properties of nanoparticles are powerful tools to modulate the optical and physicochemical properties of a particle suspension. Despite having many methods to synthesize anisotropic nanoparticles, often there are challenges in terms of controlling the polydispersity, shape, size, or composition of anisotropic nanoparticles. This work has been inspired by the potential for developing a unique pathway to make different shaped monodispersed anisotropic nano- and microparticles with large flexibility in material choice. Compared to existing methods, this state-of-the-art nanolithographic method is fast, easy to prototype, and much simple in terms of its mechanical requirement. We show that this technique has been efficiently used to make a variety of anisotropic nano- and microparticles of different shapes, such as triangular prisms, ovals, disks, flowers, and stairs following the same pathway, at the same time showing the potential of being flexible with respect to the composition of the particles. The thermal scanning probe lithographic method in combination with dry reactive ion etching was used to make two-dimensional and three-dimensional templates for the fabrication of anisotropic nano- and microparticles. Deposition of different metal/metal oxides by the electron-beam evaporation method onto these templates allowed us to fabricate a range of nanomaterials according to the required functionality in potential applications. The particles were characterized by atomic force microscopy, He-ion microscopy, scanning electron microscopy, and dynamic light scattering to ensure that the developed method is reproducible, flexible, and robust in choosing the shapes for making monodispersed anisotropic nanoparticles with great control over shape and size.

Objective: We describe a structured approach to developing a standardized curriculum for surgical trainees in East, Central, and Southern Africa (ECSA)., Summary Background Data: Surgical education is essential to closing the surgical access gap in ECSA. Given its importance for surgical education, the development of a standardized curriculum was deemed necessary., Methods: We utilized Kern's 6-step approach to curriculum development to design an online, modular, flipped-classroom surgical curriculum. Steps included global and targeted needs assessments, determination of goals and objectives, the establishment of educational strategies, implementation, and evaluation., Results: Global needs assessment identified the development of a standardized curriculum as an essential next step in the growth of surgical education programs in ECSA. Targeted needs assessment of stakeholders found medical knowledge challenges, regulatory requirements, language variance, content gaps, expense and availability of resources, faculty numbers, and content delivery method to be factors to inform curriculum design. Goals emerged to increase uniformity and consistency in training, create contextually relevant material, incorporate best educational practices, reduce faculty burden, and ease content delivery and updates. Educational strategies centered on developing an online, flipped-classroom, modular curriculum emphasizing textual simplicity, multimedia components, and incorporation of active learning strategies. The implementation process involved establishing thematic topics and subtopics, the content of which was authored by regional surgeon educators and edited by content experts. Evaluation was performed by recording participation, soliciting user feedback, and evaluating scores on a certification examination., Conclusions: We present the systematic design of a large-scale, context-relevant, data-driven surgical curriculum for the ECSA region., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Family medicine covers all ages and specializes in chronic disease management as well as acute care medicine. As the health of the population continues to grow in complexity, treating patients appropriately and efficiently is imperative to improving health outcomes and managing health care costs. Family medicine physicians are uniquely poised to provide this type of care. A patient story plus a look at the patients seen over the course of a day within a family medicine residency clinic explores the complexity of care and the ability of family medicine physicians to provide the necessary care. Taking a close look at who comes through our door on a particular day highlights 3 points: primary care physicians are seeing patients with an increasing complexity of needs, our society is witnessing an extreme increase in patients suffering with mental health problems and substance use disorders, and addressing social determinants of health must be part of the solution., (© 2021 Annals of Family Medicine, Inc.)

Background: Retinal microvascular disease reflects, in part, poor blood pressure control and systemic microvascular disease contributes to renal failure progression. This study examined the retinal microvasculature in Alport syndrome., Materials and Methods: Retinal images from 28 males and 28 females with X-linked Alport syndrome, and 13 individuals with autosomal recessive disease were reviewed retrospectively for microvascular/ hypertensive retinopathy (Wong and Mitchell classification), and small vessel calibre (using a computerised semiautomated method and revised Knudtson formula). Data were compared with age and gender-matched individuals with normal blood pressure and renal function., Results: Microvascular/hypertensive retinopathy was more common in males and females with X-linked Alport syndrome than age- and gender-matched controls (23, 82% and 10, 36%, p < 0.01; and 21, 75% and 13, 48%, p = 0.05, respectively), and in individuals with autosomal recessive disease compared with controls (12, 92% and 16, 43%, p < 0.01). Moderate microvascular/hypertensive changes were present in males and females with X-linked or autosomal recessive disease but not controls. Arteriolar calibre was reduced in males with X-linked disease (142.5 ± 18.7 µm, and 150.7 ± 10.1 µm, p = 0.046) and in autosomal recessive disease (133.5 ± 11.10 µm and 149.1 ± 10.6 µm, p < 0.0001). Microvascular/hypertensive retinopathy and arteriolar narrowing in males with X-linked disease were not different after renal transplantation and before (p NS)., Conclusions: Microvascular/hypertensive retinopathy was more common and more severe in Alport syndrome than normotensive controls. Improved BP levels may further slow the rate of renal functional decline in Alport syndrome.

The Asia-Pacific region has 60% of the world's population. There is a huge variability in ethnic groups, geography, diseases, and income. The otolaryngology workforce depends on the number of medical graduates, training programs, scope of practice, and available employment. Training has been influenced by the British, Russian, and US training systems, and by local influences and experience. Otolaryngologic diseases are similar to those seen in the United States but with ethnic and regional differences. There are opportunities for humanitarian service but the most sustainable projects will include repetitive visits with transfer of knowledge., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In a previously reported CD-1 mouse 2-year carcinogenicity study with the sodium glucose cotransporter-2 inhibitor empagliflozin, an increased incidence of renal tubular adenomas and carcinomas was identified only in the male high-dose group. Follow-up investigative studies have shown that the renal tumors in male high-dose mice were preceded by a number of renal degenerative/regenerative findings. Prior cross-species in vitro metabolism studies using microsomes identified an oxidative metabolite (M466/2) predominantly formed in the male mouse kidney and which spontaneously degrades to a metabolite (M380/1) and reactive 4-OH crotonaldehyde (CTA). In order to further evaluate potential modes of action for empagliflozin-associated male mouse renal tumors, we report here a series of in vitro investigative toxicology studies conducted to evaluate the cytotoxic and genotoxic potential of empagliflozin and M466/2. To assess the cytotoxic potential of empagliflozin and M466/2, a primary mouse renal tubular epithelial (mRTE) cell model was used. In mRTE cells, M466/2-derived in vitro 4-OH CTA exposure was cytotoxic, while empagliflozin was not cytotoxic or mitogenic. Empagliflozin and M466/2 were not genotoxic, supporting an indirect mode of action for empagliflozin-associated male mouse renal tumorigenesis. In conclusion, these in vitro data show that M466/2-derived 4-OH CTA exposure is associated with cytotoxicity in renal tubule cells and may be involved in promoting compound-related in vivo renal metabolic stress and chronic low-level renal injury, in turn supporting a nongenotoxic mode of tumor pathogenesis specific to the male mouse.

Hard palate closure with a vomer flap at the time of lip repair has been widely adopted. A recent study by Deshpande et al. showed a high rate of failure of the vomer flap and led the authors to abandon the technique. We conducted a retrospective study of vomer flap healing in a consecutive series of cases performed by the senior author (D.O.). The case records of 71 patients who underwent repair of unilateral cleft lip and palate with a vomer flap at the time of lip repair were studied. Vomer flap healing was assessed and documented by the senior author at the time of definitive palate closure, and this was recorded. Adequate records were available for 66 cases. Twelve patients (18%) had associated syndromes and were included in the analysis. The median age at the time of lip and vomer flap repair was 3.5 months, and that at the time of palate repair was 8 months. At definitive palatoplasty, the vomer flap was intact in 62 patients (94%). Four patients (6%) had partial or complete failure of the vomer flap. All failures occurred in cases where the vomer flap was sutured directly to the nasal mucosa, a technique since abandoned in favour of double-breasting the flap to the raw surface of the oral mucosa. Five patients had incomplete healing of the palate following definitive palatoplasty, two of whom had a previous vomer flap failure. Contrary to Deshpande et al., we found the vomer flap to be highly reliable in closing the hard palate at the time of primary lip repair., (Copyright © 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: An increasing proportion of patients are presenting with colorectal cancer at an early age. A proportion of these occur with genetic syndromes; however the majority present as sporadic. The purpose of this study is to investigate the prognosis and treatment of young patients with sporadic metastatic colorectal cancer., Methods: Following IRB approval, patients with sporadic metastatic colorectal cancer at 40 years or under were identified. Patient charts and pathology reports were analyzed retrospectively for clinical and pathological factors., Results: Three hundred and two patients were identified; 148 with liver metastases only, and 154 with extra-hepatic disease. Five-year overall survival was 19%, 28% for liver only disease, and 12% for extrahepatic disease. For patients with liver metastases only, factors associated with survival on univariable analysis included diagnosis in the 2000's, unilobular hepatic disease, smaller volume liver metastases, intrahepatic pump chemotherapy, resection of the primary, and resection of liver metastases. On multivariable analysis factors associated with survival included resection of the primary, resection of liver metastases, and diagnosis in the 2000's., Conclusion: Sporadic metastatic colorectal cancer in young patients appears to have a similar prognosis to that in older patients. The most significant prognostic factor was the ability to resect all sites of disease. J. Surg. Oncol. 2016;113:473-476. © 2016 Wiley Periodicals, Inc., Competing Interests: None, (© 2016 Wiley Periodicals, Inc.)

Neuroendocrine neoplasias (NENs) consist of a spectrum of tumors which can originate throughout the body, behave in a variety of different ways but are characterized by a similar histological appearance. This article reviews the classification, staging, diagnosis and treatment of Hindgut Neuroendocrine Neoplasias.

Background: Previous reports on the surgical management of appendix cancer show high recurrence rates among patients initially presenting with localized disease. This study sought to characterize predictors of outcome among patients treated for stages 1-3 appendix cancer at the authors' institution., Methods: Patients with nonmetastatic appendix cancer undergoing definitive surgery at a single cancer center from 1994 to 2013 were retrospectively reviewed. Patients with appendiceal adenomas, cystadenomas, or classical carcinoids were excluded from the study. The median follow-up period was 5.2 years (interquartile range 2.9-6.7 years)., Results: The study identified 70 patients, 49 % of whom were women. The median age was 52 years (range 20-84 years). All were explored by an expert surgeon who had treated at least 20 appendiceal cancers. The procedures were appendectomy (n = 2), right hemicolectomy (n = 66), and diagnostic laparoscopy and placement of an intraperitoneal port (n = 2). The final pathology showed that transmural (30 T4, 32 T3, 4 T2, 4 T1) and node-negative disease (80 %) were common. Goblet cell carcinoid (GCC) features were identified in 54 % of the tumors. These were smaller and more likely to present as acute appendicitis than appendiceal adenocarcinoma (AA), but were otherwise similar in clinical presentation and outcome. The presence of lymph node (LN) metastasis was associated with a higher risk of recurrence than of stage 2 appendix cancer (78 vs. 4 % at 5 years; p < 0.0001). A total of 12 patients experienced recurrence (5 GCC, 7 AA): 9 in the peritoneum, 2 in mesenteric LNs, and 1 in the surgical incision., Conclusion: Stages 1-3 invasive AA and GCC behave similarly in terms of clinical presentation and outcome. Perforated appendix and T4 tumor stage were common but not associated with recurrence. Although uncommon, LN metastasis strongly predicted recurrence.

Background: High-grade neuroendocrine carcinomas (HGNECs) of the colon and rectum are rare, constituting less than 1 % of colorectal cancers. The purpose of this study was to identify the natural history and oncologic outcomes of this disease, describe the use of surgery, and determine the clinical and pathological factors associated with outcomes., Methods: Following Institutional Review Board approval, patients with HGNEC were identified from our institutional database. Patient charts and pathology reports were analyzed retrospectively for clinical and pathological factors., Results: A total of 126 patients with a median follow-up of 9 months were identified. Median survival was 13.2 months, and 85 (67 %) patients had metastatic disease at diagnosis. Three-year overall survival (OS) was 5 and 18 % for patients with and without metastatic disease, respectively. Factors associated with improved OS on multivariable analysis were absence of metastatic disease and presence of an adenocarcinoma component within the tumor. In patients with metastatic disease, response to chemotherapy was the only factor associated with survival. In patients with localized disease, an adenocarcinoma component within the tumor was the only factor associated with survival. Resection of tumor was not associated with survival in either localized or metastatic disease., Conclusion: High-grade colorectal NECs are extremely aggressive tumors with poor prognosis. Patients appear to have a marginally better prognosis if they present without metastatic disease, have an adenocarcinoma component within their tumor, or respond to chemotherapy. Surgery, particularly in the presence of metastatic disease, may not offer a survival benefit for the majority of patients.

Background: Anastomotic leak is a serious complication of low anterior resection (LAR). The risk of leak in stage IV rectal cancer patients treated with synchronous or staged resection of the primary tumour and metastatic sites has not been reported. We measured the incidence of anastomotic leak and its association with clinical outcome., Methods: With institutional review board approval, patients undergoing LAR and resection of metastatic disease were analyzed from a prospectively collected colorectal database between 1992 and 2010. Data for use of ileostomy, clinical anastomotic leak, and clinical risk score (for liver metastases, n = 86) were collected. Categorical variables were compared with the χ(2) test. Estimated overall survival was compared using log-rank method and Cox regression analysis., Results: A total of 184 patients with LAR and stage IV disease were identified. Of those, 123 had curative resection for disease at distant sites. 72 % underwent simultaneous resection, 28 % staged resection. Median follow-up was 2.9 years for survivors. Anastomotic leak occurred in 6.5 %. There was one perioperative death (not attributable to leak). Overall 3-year survival following a leak was significantly worse compared with patients without a leak (35 vs. 73 %, P = 0.01). Clinical leak was associated with worse survival when controlled for use of diverting stoma, operative year, clinical risk score, and timing of resection of metastatic disease., Conclusions: In this series of patients with stage IV rectal cancer, anastomotic leak was uncommon. However, patients who developed a clinical leak following surgery had worse survival. This finding was independent of use of diverting stoma or staged resection.

Idiopathic normal pressure hydrocephalus (iNPH) is a poorly understood condition, which typically presents with the triad of balance impairment, urinary incontinence and subacute cognitive decline, while brain imaging shows a marked enlargement of the cerebral ventricles. Few patients with iNPH have come to post-mortem. We identified four patients from the Queen Square Brain Bank archival collection, who had received a diagnosis of iNPH during life, and reviewed their clinical, radiological and pathological characteristics. At post mortem examination, one patient had Parkinson's disease (PD) while the other three had progressive supranuclear palsy (PSP). All four had presented with pure akinesia with gait freezing, accompanied by unsteadiness and falls. An awareness that PSP or PD can mimic the clinical symptoms of iNPH may help to avoid invasive and futile cerebrospinal fluid shunting procedures.

Current theories of the pathophysiology of normal pressure hydrocephalus suggest the classical symptoms are a consequence of disruption of normal frontal function. We present the case of a 70-year-old patient with an isolated, frontal dilatation of his lateral ventricles in the presence of a complete triad as supportive of these theories.

Alpha-T-Catenin (CTNNA3) is a key protein of the adherens junctional complex in epithelial cells playing a crucial role in cellular adherence. What makes this gene particularly interesting is that it is located within a common fragile site, is epigenetically regulated, is transcribed through multiple promoters, and generates a variety of alternate transcripts. Finally, CTNNA3 has a nested gene (LRTMM3) embedded within its genomic context transcribed in the opposite direction. Apart from the complexity of its regulation, alterations in both CTNNA3 and LRTMM3 are implicated in human disease.

Although progress in the treatment of patients with colorectal cancer (CRC) has resulted in improved median survival, most patients with metastatic CRC still die of their disease, and essentially all patients with early-stage disease must undergo surgical resection and subsequently face the possibility of adjuvant chemotherapy. As effective screening and prevention strategies for CRC have been developed, identification of individuals with a hereditary predisposition to developing CRC is especially important and provides the opportunity to reduce disease burden in this high-risk population. Increased awareness and improved diagnostic techniques for hereditary CRC syndromes have facilitated more frequent diagnosis and management of a small number of highly penetrant syndromes within families. However, known high-penetrance genetic predisposition syndromes account for a minority of all familial CRC, leaving much of the genetic basis of CRC unexplained. Recent advances in high-throughput genotyping have made possible genome-wide association studies, which have identified novel genetic variants associated with modest increases in CRC risk. While these associations have helped to identify potentially important pathways in CRC carcinogenesis, at the current time, the clinical use of such genetic risk variants in colon cancer risk stratification remains limited.

An innovative technique has been demonstrated to achieve crank-angle-resolved planar laser-induced fluorescence (PLIF) of fuel followed by OH* chemiluminescence imaging in a firing direct-injected spark-ignition engine. This study used two standard KrF excimer lasers to excite toluene for tracking fuel distribution. The intensified camera system was operated at single crank-angle resolution at 2000 revolutions per minute (RPM) for 500 consecutive cycles. Through this work, it has been demonstrated that toluene and OH* can be imaged through the same optical setup while similar signal levels are obtained from both species, even at these high rates. The technique is useful for studying correlations between fuel distribution and subsequent ignition and flame propagation without the limitations of phase-averaging imaging approaches. This technique is illustrated for the effect of exhaust gas recirculation on combustion and will be useful for studies of misfire causes. Finally, a few general observations are presented as to the effect of preignition fuel distribution on subsequent combustion.