Primary abandonment of the sac in the management of scrotal hernias: a dual-institution experience of short-term outcomes.

PURPOSE: Management of scrotal hernias presents as a common challenge, with operative interventions to address these hernias associated with higher rates of morbidity compared to those of less-complex pathology. Surgeons have advocated for the use of techniques such as primary abandonment of the distal sac as a potential means to reduce complications for operative intervention, with preliminary findings demonstrating feasibility. We sought to assess outcomes related to primary sac abandonment among patients undergoing minimally invasive (MIS) repair of scrotal hernias. METHODS: A review of prospectively maintained databases among two academic hernia centers was conducted to identify patients who underwent MIS inguinal hernia repairs with primary sac abandonment. Patient demographics, hernia risk factors, intraoperative factors, and postoperative outcomes were evaluated. Short-term outcomes related to patient-reported experiences and surgical-site occurrences requiring procedural intervention were queried. RESULTS: Sixty-seven male patients [median age: 51.6 years; interquartile range (IQR): 45-65 years] underwent inguinal hernia repair with primary sac abandonment. Anatomic polypropylene mesh was used in 98.5% cases. Rates of postoperative complications were low and included postoperative urinary retention (6%), clinically identified or patient-reported seromas/hematomas within a 30-day follow-up period (23.9%), deep venous thrombosis (1.5%), and pelvic hematoma (1.5%). No seromas or hematomas necessitated procedural interventions, with resolution of symptoms within three months of their operation date. CONCLUSION: We report a multi-center experience of patients managed with primary abandonment of the sac technique during repair of inguinoscrotal hernias. Utilization of this technique appears to be safe and reproducible with a low burden of short-term complications.

Patient perspectives on nipple-areola complex micropigmentation during the COVID-19 pandemic.

BACKGROUND: Micropigmentation is a well-recognised option for nipple-areola complex reconstruction, as part of the breast reconstruction pathway for patients following mastectomy. As a part of delayed breast reconstruction, this treatment was put on hold during the COVID-19 pandemic. AIMS: To assess the views of patients regarding micropigmentation in response to the COVID-19 pandemic, and whether their attitudes to seeking out this part of the reconstructive journey had been altered. METHODS: A questionnaire undertaken with 53 patients between August & September 2020 attending the Micropigmentation clinic. FINDINGS: 81.1% of patients reported COVID-19 had not impacted their decision, with a similar proportion happy to proceed with the treatment at the time of questioning. CONCLUSIONS: The results highlight the importance of nipple-areola complex to our patients' reconstructive journey.

Generation of goats by nuclear transfer: a retrospective analysis of a commercial operation (1998-2010).

At LFB USA, Inc., the ultimate use for transgenic cloned goats is for the production of recombinant human protein therapeutics in their milk. This retrospective analysis of the Somatic Cell Nuclear Transfer (SCNT) program, spanning from 1998 to 2010, examined parameters potentially affecting the outcomes and efficiencies in this commercial operation. Over 37,000 + ova were utilized in the SCNT protocol producing a total of 203 cloned goats. Fifty one (51) clones were produced from non-transfected (transgenic and non-transgenic animal donor) cell lines and 152 clones were produced from transfected cell lines. Comparisons and summaries of (a) transfected versus non-transfected cell lines, (b) relationship of SCNT parameters to offspring produced, (c) skin versus fetal cells, (d) fresh versus cryopreserved cells, (e) parameters from all cell lines used versus those producing SCNT offspring, (f) variation among cell sources, (g) methods of SCNT parturition management and effects on live offspring, and lastly (h) SCNT variation by program are reported. Findings indicate that (a) non-transfected cell lines were more efficient versus transfected cell lines in generating viable cloned offspring on a per reconstructed embryo transferred basis, (b) transfected fetal fibroblasts had improved efficiency versus transfected skin fibroblasts, (c) the percentage of non-transfected cell lines that produced offspring was statistically higher than transfected cell lines, (d) and induction of parturition improved the percentage of viable offspring. In summary, this retrospective analysis on the SCNT process has identified certain parameters for improved efficiency in producing viable cloned goats in a commercial setting.

Oral delivery of Hyperimmune bovine serum antibodies against CS6-expressing enterotoxigenic Escherichia coli as a prophylactic against diarrhea.

BACKGROUND: . Oral administration of bovine antibodies active against enterotoxigenic Escherichia coli (ETEC) have demonstrated safety and efficacy against diarrhea in human challenge trials. The efficacy of bovine serum immunoglobulins (BSIgG) against recombinant colonization factor CS6 or whole cell ETEC strain B7A was assessed against challenge with the CS6-expressing B7A. METHODS: . This was a randomized, double-blind, placebo-controlled trial in which healthy adults received oral hyperimmune BSIgG anti-CS6, anti-B7A whole cell killed or non-hyperimmune BSIgG (placebo) in a 1:1:1 ratio then challenged with ETEC B7A. Two days pre-challenge, volunteers began a thrice daily, seven day course of immunoprophylaxis. On day 3, subjects received 1 × 1010 CFUs of B7A. Subjects were observed for safety and the primary endpoint of moderate-severe diarrhea (MSD). RESULTS: . A total of 59 volunteers received product and underwent ETEC challenge. The BSIgG products were well-tolerated across all subjects. Upon challenge, 14/20 (70%) placebo recipients developed MSD, compared to 12/19 (63%; p = .74) receiving anti-CS6 BSIgG and 7/20 (35%; p = .06) receiving anti-B7A BSIgG. Immune responses to the ETEC infection were modest across all groups. CONCLUSIONS: . Bovine-derived serum antibodies appear safe and well tolerated. Antibodies derived from cattle immunized with whole cell B7A provided 50% protection against MSD following B7A challenge; however, no protection was observed in subjects receiving serum antibodies targeting CS6. The lack of observed efficacy in this group may be due to low CS6 surface expression on B7A, the high dose challenge inoculum and/or the use of serum derived antibodies versus colostrum-derived antibodies.

Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.

Cancer and cardiovascular (CV) disease are the most prevalent diseases in the developed world. Evidence increasingly shows that these conditions are interlinked through common risk factors, coincident in an ageing population, and are connected biologically through some deleterious effects of anticancer treatment on CV health. Anticancer therapies can cause a wide spectrum of short- and long-term cardiotoxic effects. An explosion of novel cancer therapies has revolutionised this field and dramatically altered cancer prognosis. Nevertheless, these new therapies have introduced unexpected CV complications beyond heart failure. Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment. This ESMO consensus article proposes to define CV toxicities related to cancer or its therapies and provide guidance regarding prevention, screening, monitoring and treatment of CV toxicity. The majority of anticancer therapies are associated with some CV toxicity, ranging from asymptomatic and transient to more clinically significant and long-lasting cardiac events. It is critical however, that concerns about potential CV damage resulting from anticancer therapies should be weighed against the potential benefits of cancer therapy, including benefits in overall survival. CV disease in patients with cancer is complex and treatment needs to be individualised. The scope of cardio-oncology is wide and includes prevention, detection, monitoring and treatment of CV toxicity related to cancer therapy, and also ensuring the safe development of future novel cancer treatments that minimise the impact on CV health. It is anticipated that the management strategies discussed herein will be suitable for the majority of patients. Nonetheless, the clinical judgment of physicians remains extremely important; hence, when using these best clinical practices to inform treatment options and decisions, practitioners should also consider the individual circumstances of their patients on a case-by-case basis.

Childhood adversity and borderline personality disorder: a meta-analysis.

OBJECTIVE: The aim of this meta-analysis was to better understand the magnitude and consistency of the association between childhood adversity and borderline personality disorder (BPD) across case-control, epidemiological and prospective cohort studies. METHOD: Following the review protocol (reference: CRD42017075179), search terms pertaining to adversity and BPD were entered into three search engines. Random-effects meta-analysis synthesised the size and consistency of the effects. RESULTS: A total of 97 studies compared BPD to non-clinical (k = 40) and clinical (k = 70) controls. Meta-analysis of case-control studies indicated that individuals with BPD are 13.91 (95% CI 11.11-17.43) times more likely to report childhood adversity than non-clinical controls. This effect was smaller when considering retrospective cohort (OR: 2.59; 95% CI 0.93-7.30) and epidemiological (OR: 2.56, 95% CI 1.24-5.30) studies. Findings were significant across adversity subtypes with emotional abuse (OR: 38.11, 95% CI: 25.99-55.88) and neglect (OR: 17.73, 95% CI = 13.01-24.17) demonstrating the largest effects. Individuals with BPD were 3.15 (95% CI 2.62-3.79) times more likely to report childhood adversity than other psychiatric groups. CONCLUSIONS: This meta-analysis corroborates theoretical proposals that exposure to adverse life experiences is associated with BPD. It highlights the importance of considering childhood adversity when treating people diagnosed with BPD.

Do stroke patients screened as lower-nutritional-risk still receive dietitian assessment if indicated? A retrospective evaluation of two dietetic models of care for adult stroke patients.

BACKGROUND: Dietetic models of care at Logan Hospital changed from all patients with a confirmed stroke receiving dietitian assessment (Old pathway) to only those patients screened as high-nutritional-risk (Modified pathway). However, it was unknown whether all low-nutritional-risk patients who were indicated for dietitian assessment for nutrition support actually received assessment. This pre-post retrospective study evaluated whether the Old pathway and the Modified pathway were equally effective in identifying low-nutritional-risk stroke patients who were indicated for dietitian assessment and compared the time spent providing Dietetic care. METHODS: For both pathways, medical charts were reviewed for low-nutritional-risk patients admitted between December 2012 and November 2017 with a confirmed stroke, who were given a standard food and fluid diet code and scored MST < 2 (Malnutrition Screening Tool) on admission. Data collected included demographics, anthropometrics, malnutrition assessment, dietetic intervention and time spent caring for patients. Malnutrition-related clinical indicators were used to classify patients as either Dietitian Assessment for Nutrition Support Indicated or Not Indicated. RESULTS: Low-nutritional-risk patients were similar on the Old (n = 180) and Modified (n = 206) pathways [mean (SD) 66 (13) years, 63% male, 4% malnutrition]. Those classified as Dietitian Assessment for Nutrition Support Indicated (n = 61 of 180) were older, had a longer length of stay (P < 0.05), and were all identified by the Dietitian on both pathways. Ten minutes less dietetic time per patient was required on the Modified pathway (P < 0.001). CONCLUSIONS: The Modified Nutrition Stroke pathway performed more efficiently than the Old pathway and was equally effective at ensuring that stroke patients who were determined as being low-nutritional-risk received dietitian assessment during admission if indicated.

Adipose tissue uncoupling protein 1 levels and function are increased in a mouse model of developmental obesity induced by maternal exposure to high-fat diet.

With brown adipose tissue (BAT) becoming a possible therapeutic target to counteract obesity, the prenatal environment could represent a critical window to modify BAT function and browning of white AT. We investigated if levels of uncoupling protein 1 (UCP1) and UCP1-mediated thermogenesis are altered in offspring exposed to prenatal obesity. Female CD-1 mice were fed a high-fat (HF) or standard-fat (SF) diet for 3 months before breeding. After weaning, all pups were placed on SF. UCP1 mRNA and protein levels were quantified using quantitative real-time PCR and Western blot analysis, respectively, in brown (BAT), subcutaneous (SAT) and visceral (VAT) adipose tissues at 6 months of age. Total and UCP1-dependent mitochondrial respiration were determined by high-resolution respirometry. A Student's t-test and Mann-Whitney test were used (significance: P<0.05). UCP1 mRNA levels were not different between the HF and SF offspring. UCP1 protein levels, total mitochondrial respiration and UCP1-dependent respiration were significantly higher in BAT from HF males (P=0.02, P=0.04, P=0.005, respectively) and females (P=0.01, P=0.04, P=0.02, respectively). In SAT, the UCP1 protein was significantly lower in HF females (P=0.03), and the UCP1-dependent thermogenesis was significantly lower from HF males (P=0.04). In VAT, UCP1 protein levels and UCP1-dependent respiration were significantly lower only in HF females (P=0.03, P=0.04, respectively). There were no differences in total respiration in SAT and VAT. Prenatal exposure to maternal obesity leads to significant increases in UCP1 levels and function in BAT in offspring with little impact on UCP1 levels and function in SAT and VAT.

Generation of transgenic goats by pronuclear microinjection: a retrospective analysis of a commercial operation (1995-2012).

Production of transgenic founder goats involves introducing and stably integrating an engineered piece of DNA into the genome of the animal. At LFB USA, the ultimate use of these transgenic goats is for the production of recombinant human protein therapeutics in the milk of these dairy animals. The transgene or construct typically links a milk protein specific promoter sequence, the coding sequence for the gene of interest, and the necessary downstream regulatory sequences thereby directing expression of the recombinant protein in the milk during the lactation period. Over the time period indicated (1995-2012), pronuclear microinjection was used in a number of programs to insert transgenes into 18,120, 1- or 2- cell stage fertilized embryos. These embryos were transferred into 4180 synchronized recipient females with 1934 (47%) recipients becoming pregnant, 2594 offspring generated, and a 109 (4.2%) of those offspring determined to be transgenic. Even with new and improving genome editing tools now available, pronuclear microinjection is still the predominant and proven technology used in this commercial setting supporting regulatory filings and market authorizations when producing founder transgenic animals with large transgenes (> 10 kb) such as those necessary for directing monoclonal antibody production in milk.

Epidemiology of inflammatory bowel disease among participants of the Millennium Cohort: incidence, deployment-related risk factors, and antecedent episodes of infectious gastroenteritis.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are two pathotypes of inflammatory bowel disease (IBD) with unique pathology, risk factors and significant morbidity. AIM: To estimate incidence and identify IBD risk factors in a US military population, a healthy subset of the US population, using information from the Millennium Cohort Study. METHODS: Incident IBD was identified from medical encounters from 2001 to 2009 or by self-report. Our primary risk factor of interest, infectious gastroenteritis, was identified from medical encounters and self-reported post-deployment health assessments. Other potential risk factors were assessed using self-reported survey responses and military personnel files. Hazard ratios were estimated using Cox proportional hazards analysis. RESULTS: We estimated 23.2 and 21.9 diagnoses per 100 000 person-years, respectively, for CD and UC. For CD, significant risk factors included [adjusted hazard ratio (aHR), 95% confidence interval]: current smoking (aHR: 2.7, 1.4-5.1), two life stressors (aHR: 2.8, 1.4-5.6) and prior irritable bowel syndrome (aHR: 4.7, 1.5-15.2). There was no significant association with prior infectious gastroenteritis. There was an apparent dose-response relationship between UC risk and an increasing number of life stressors. In addition, antecedent infectious gastroenteritis was associated with almost a three-fold increase in UC risk (aHR: 2.9, 1.4-6.0). Moderate alcohol consumption (aHR: 0.4, 0.2-0.6) was associated with lower UC risk. CONCLUSIONS: Stressful conditions and the high risk of infectious gastroenteritis in deployment operations may play a role in the development of IBD in military populations. However, observed differences in risk factors for UC and CD warrant further investigation.

Serologic microbial associated markers can predict Crohn's disease behaviour years before disease diagnosis.

BACKGROUND: Patients with Crohn's disease (CD) have serologic responses to various microbial antigens. Serologic markers are associated with aggressive forms of disease and can be detected before onset of symptoms. Their utility in pre-clinical disease or prediction of complicated disease course before diagnosis is unclear. AIM: To evaluate the pattern of serologic anti-microbial antibodies long prior to diagnosis and the subsequent risk of complicated Crohn's disease at diagnosis. METHODS: Sera from 100 US military personnel with Crohn's disease were obtained from the Department of Defense Serum Repository. For each patient, four samples were obtained at different time points before and around diagnosis, and were tested for 6 microbiota-directed antibodies (ASCA-IgA, ASCA-IgG, anti-OmpC, anti-CBir1, anti-A4-Fla2 and anti-FlaX). Associations between the presence and accumulation of Crohn's disease anti-microbial antibodies before diagnosis and with the later development of complications were evaluated. RESULTS: Overall, 65 patients were positive for at least one Crohn's disease associated anti-microbial antibody in the earliest available sample, at a median of 6 years before Crohn's disease diagnosis (interquartile range, 5.6-8.2). The number of positive anti-microbial antibodies increased up to the time of Crohn's disease diagnosis. Complicated disease developed around the time of diagnosis in 24 patients. The proportion of positive antimicrobial antibodies before diagnosis was higher in patients with complicated vs. noncomplicated Crohn's disease. There was an inverse relationship between the time to first complication and the magnitude of serologic response before diagnosis. CONCLUSION: The presence and accumulation of circulating anti-microbial antibodies years before Crohn's disease diagnosis was associated with complicated Crohn's disease at or shortly after diagnosis.

Understanding breakage in curly hair.

BACKGROUND: In 2005, the L'Oréal Institute for hair and skin research carried out a multiethnic study to investigate hair breakage in women residing in the U.S.A. In this study it was reported that a large percentage (96%) of the African-American respondents experience breakage. A combination of structural differences and grooming-induced stresses seem to contribute to the higher breakage incidence in the African-American group as the chemical composition of African-American hair is not significantly different from other ethnic groups. Some authors have proposed that the repeated elongation, torsion and flexion actions may affect the components of the hair fibre. However, considering the different properties of cuticle and cortex, one would expect a different wearing mechanism of each, leading to the ultimate failure of hair. Knowing in detail how each part of the structure fails can potentially lead to better ways to protect the hair from physical insults. OBJECTIVE: To investigate crack propagation and fracture mechanisms in African-American hair. METHODS: Virgin hair of excellent quality was collected, with informed consent, from a female African-American volunteer. A series of controlled mechanical stresses was applied to 10-mm hair sections using a high-resolution mechanical stage (20 mN) up to the fracture of the fibre. The surface was monitored using scanning electron microscopy imaging during the stress application. X-ray tomographic microscopy images were acquired and quantified to detect changes in energy absorption as a function of applied stress that could be linked to increase in crack density. RESULTS: Analysis of the mechanical response of hair combined with the two imaging techniques led us to propose the following mechanism of hair breakage: cuticle sliding; failure of the cuticle-cortex interface; nucleation of intercellular cracks and growth of cracks at the cuticle-cortex junction; and propagation of intercellular cracks towards the surface of the hair and final breakage when these cracks merge at the cuticular junction. CONCLUSIONS: The combination of scanning electron microscopy and X-ray tomography provided new information about the fracture of hair. Mechanical damage from grooming and some environmental factors accumulate in hair creating internal cracks that eventually result in breakage at unpredictable sites and therefore a continuous care regimen for the hair throughout the life cycle of the fibres is recommended.

A percutaneous needle biopsy technique for sampling the supraclavicular brown adipose tissue depot of humans.

Brown adipose tissue (BAT) has been proposed as a potential target tissue against obesity and its related metabolic complications. Although the molecular and functional characteristics of BAT have been intensively studied in rodents, only a few studies have used human BAT specimens due to the difficulty of sampling human BAT deposits. We established a novel positron emission tomography and computed tomography-guided Bergström needle biopsy technique to acquire human BAT specimens from the supraclavicular area in human subjects. Forty-three biopsies were performed on 23 participants. The procedure was tolerated well by the majority of participants. No major complications were noted. Numbness (9.6%) and hematoma (2.3%) were the two minor complications noted, which fully resolved. Thus, the proposed biopsy technique can be considered safe with only minimal risk of adverse events. Adoption of the proposed method is expected to increase the sampling of the supraclavicular BAT depot for research purposes so as to augment the scientific knowledge of the biology of human BAT.

The Shigella human challenge model.

Shigella is an important bacterial cause of infectious diarrhoea globally. The Shigella human challenge model has been used since 1946 for a variety of objectives including understanding disease pathogenesis, human immune responses and allowing for an early assessment of vaccine efficacy. A systematic review of the literature regarding experimental shigellosis in human subjects was conducted. Summative estimates were calculated by strain and dose. While a total of 19 studies evaluating nine strains at doses ranging from 10 to 1 × 1010 colony-forming units were identified, most studies utilized the S. sonnei strain 53G and the S. flexneri strain 2457T. Inoculum solution and pre-inoculation buffering has varied over time although diarrhoea attack rates do not appear to increase above 75-80%, and dysentery rates remain fairly constant, highlighting the need for additional dose-ranging studies. Expansion of the model to include additional strains from different serotypes will elucidate serotype and strain-specific outcome variability.

Longitudinal assessment of cardiac diastolic function in HIV-infected patients.

Asymptomatic isolated diastolic dysfunction (DD), with normal left ventricular systolic function, may be the first indication of underlying cardiac disease in HIV-negative populations. We previously reported a high prevalence (37%) of DD among asymptomatic HIV-infected patients at low risk for AIDS and cardiovascular disease (CVD). We performed a longitudinal assessment of interval echocardiographic changes in this cohort over a four-year period. Repeat transthoracic echocardiograms (TTEs) utilized standard techniques. Sixty (of the original 91) HIV-infected patients, predominately men, underwent repeat TTE (median follow-up 3.7 years, interquartile range [IQR] 3.5, 4.0). Cohort characteristics (median; IQR) include age 42.0 (36.5, 46.0) years, HIV duration 16.4 years (8.1, 18.9), current CD4 count 572.0 cells/mm(3) (436.5, 839.0), antiretroviral therapy (ART) duration 8.1 years (4.8, 13.4) and Framingham risk score 1.0 (0.0, 2.0). DD was observed in 28/60 patients on re-evaluation (47%, 95% confidence interval [CI] 34%, 60%); 31% (11/36) of patients had new onset DD for an overall incidence of 8.2/100 person-years. On follow-up, subjects with DD were older, had a trend towards higher body mass index, hypertension and longer duration of HIV infection compared with subjects without DD. We confirmed a high prevalence of DD (47%) in asymptomatic HIV-infected patients at low risk for AIDS and CVD.

Integrated genomic analyses identify WEE1 as a critical mediator of cell fate and a novel therapeutic target in acute myeloid leukemia.

Acute myeloid leukemia (AML) remains a therapeutic challenge despite increasing knowledge about the molecular origins of the disease, as the mechanisms of AML cell escape from chemotherapy remain poorly defined. We hypothesized that AML cells are addicted to molecular pathways in the context of chemotherapy and used complementary approaches to identify these addictions. Using novel molecular and computational approaches, we performed genome-wide short-hairpin RNA screens to identify proteins that mediate AML cell fate after cytarabine exposure; gene expression profiling of AML cells exposed to cytarabine to identify genes with induced expression in this context; and examination of existing gene expression data from primary patient samples. Integration of these independent analyses strongly implicates cell-cycle checkpoint proteins, particularly WEE1, as critical mediators of AML cell survival after cytarabine exposure. Knockdown of WEE1 in a secondary screen confirmed its role in AML cell survival. Pharmacologic inhibition of WEE1 in AML cell lines and primary cells is synergistic with cytarabine. Further experiments demonstrate that inhibition of WEE1 prevents S-phase arrest induced by cytarabine, broadening the functions of WEE1 that may be exploited therapeutically. These data highlight the power of integrating functional and descriptive genomics, and identify WEE1 as a potential therapeutic target in AML.

Multilocus sequence typing of human and canine C. upsaliensis isolates.

Risk of Campylobacter infection in humans has been associated with many sources, including dogs. C. upsaliensis is the most common species found in canines, and has been occasionally isolated from symptomatic humans. This study aimed to investigate the genetic diversity of 41 C. upsaliensis isolates carried by dogs and from nine isolates carried by humans using Multilocus sequence typing (MLST). We identified considerable genetic diversity amongst the C. upsaliensis isolates from both dogs and humans, identifying 45 different sequence types (STs). All STs were new, apart from that of the reference strain. Only three STs were found in more than one isolate: ST-72 (2 isolates), ST-98 (2 isolates) and ST-104 (3 isolates). ST-104 was the only ST to be encountered in both dogs and humans. Thirty-one of the 45 STs were assigned to one of 13 clonal complexes (CCs). Four of these CCs contained STs originating from both humans and dogs. None of the CCs contained exclusively human isolates, and two isolates from dogs within the same kennel belonged to the same CC. The large amount of diversity found in both dog and human isolates of C. upsaliensis, combined with the relatively small database, made it difficult to assign strains to sources of infection. This emphasizes the need to increase the size of the database. Dog and human isolates occasionally grouped together, however there were insufficient human-derived isolates to determine whether or not dogs are a common source of infection. Although C. upsaliensis infection is rare in humans, dogs still remain a potential source, and are therefore a possible zoonotic risk. Further work is needed to investigate the epidemiology of C. upsaliensis infection in humans.