Analysis of the impact of EEA stapler size on risk of anastomotic complications in colorectal anastomosis: does size matter?

BACKGROUND: Colorectal anastomotic complications are dreaded and dramatically affect outcomes. Causes are multifactorial, with the size of the end-to-end anastomosis (EEA) stapler a modifiable factor and potential target for risk reduction. Our goal was to examine the impact of the EEA stapler size on the risk of anastomotic complications in left-sided colorectal resections. METHODS: A prospective divisional database was reviewed for consecutive elective left-sided resections with a colorectal anastomosis using an EEA stapler from January 2013 May 2018 inclusive. Patients were stratified into 25-29 mm or 30-33 mm cohorts. Patient and disease demographics, operative variables, and postoperative outcomes were evaluated. The main outcome measures were the rate and factors associated with anastomotic complications. RESULTS: Four hundred seventy-three cases were evaluated, 185 ( 39.1%) were in the 25-29 mm group and 288 (60.9%) in the 30-33 mm group. Patients were comparable in demographics and operative variables. More males were anastomosed with the 30-33 mm than with the 25-29 mm stapler (57.6% vs 28.6%, p < 0.01). Significantly more patients developed an anastomotic stricture with the 25-29 mm than with the 30-33 mm staplers (7.1% vs. 2.1%; p = 0.007). There was no significant difference in leak rates or reoperation/interventions between groups. On logistic regression, neither gender, operative indication nor approach were associated with anastomotic leak, readmission, or reoperation/intervention. Stapler size remained significantly associated with stricture (p = 0.032). CONCLUSIONS: The 25-29 mm EEA staplers were associated with an increased rate of anastomotic stricture compared to 30-33 mm staplers in left-sided colorectal anastomoses. As stapler size is a simple process measure that is easily modifyable, this is a potential target for improving anastomotic complication rates. Further controlled trials may help assess the impact of stapler size on improving patient and quality outcomes.

A genetic-based algorithm for personalized resistance training.

Association studies have identified dozens of genetic variants linked to training responses and sport-related traits. However, no intervention studies utilizing the idea of personalised training based on athlete's genetic profile have been conducted. Here we propose an algorithm that allows achieving greater results in response to high- or low-intensity resistance training programs by predicting athlete's potential for the development of power and endurance qualities with the panel of 15 performance-associated gene polymorphisms. To develop and validate such an algorithm we performed two studies in independent cohorts of male athletes (study 1: athletes from different sports (n = 28); study 2: soccer players (n = 39)). In both studies athletes completed an eight-week high- or low-intensity resistance training program, which either matched or mismatched their individual genotype. Two variables of explosive power and aerobic fitness, as measured by the countermovement jump (CMJ) and aerobic 3-min cycle test (Aero3) were assessed pre and post 8 weeks of resistance training. In study 1, the athletes from the matched groups (i.e. high-intensity trained with power genotype or low-intensity trained with endurance genotype) significantly increased results in CMJ (P = 0.0005) and Aero3 (P = 0.0004). Whereas, athletes from the mismatched group (i.e. high-intensity trained with endurance genotype or low-intensity trained with power genotype) demonstrated non-significant improvements in CMJ (P = 0.175) and less prominent results in Aero3 (P = 0.0134). In study 2, soccer players from the matched group also demonstrated significantly greater (P < 0.0001) performance changes in both tests compared to the mismatched group. Among non- or low responders of both studies, 82% of athletes (both for CMJ and Aero3) were from the mismatched group (P < 0.0001). Our results indicate that matching the individual's genotype with the appropriate training modality leads to more effective resistance training. The developed algorithm may be used to guide individualised resistance-training interventions.

Microsurgical limb reconstruction in the non-concordant patient.

Substance misuse is common in patients undergoing limb reconstruction secondary to open fractures and fracture related infection. This group risk breaching the social contract with their treating team through reduced engagement with perioperative care. Potential problems include limited social support, intravenous access, analgesia and withdrawal. These factors may negatively influence the range of treatments offered to this group. We aimed to establish the prevalence and outcomes of the problematically non-concordant cohort in our limb reconstruction population, who we aim to treat equitably even where non-concordance is suspected pre-operatively. A retrospective study was performed using our prospectively collected free flap limb reconstruction database from December 2021-October 2023. Patient electronic health records were reviewed for demographics, perioperative details and outcomes. Eighty patients were identified, with 8 identified as problematically non-concordant (10%). All patients had a background of substance abuse; smoking (100%), alcohol (75%), IVDU (63%). Pre-operative non-concordance included absconding (43%), staff abuse (57%) and refusal of care (57%). Post-operative non-concordance included smoking (75%), mobilisation against instructions (75%), absconding (63%). No patients had free flap failure. Inpatient stay varied from 8-83 days, average 28.50% of patients did not attend follow-up. The expanding horizon of microsurgery means complex reconstruction is offered to a greater range of patients. Surgical teams should ensure that this service is offered equitably, individualising treatment plans to achieve the best outcomes. Risk of non-concordance is usually evident pre-operatively. We advise early involvement of substance misuse teams, discharge support and an understanding team to achieve good outcomes.

Setting up a new microsurgical breast service in a non-tertiary hospital: Is it safe, and do outcomes compare to centres of excellence?

AIMS: Access to autologous reconstruction continues to be limited in some areas of the United Kingdom. This is, in part, due to the perceived difficulty offering this service outside of a large tertiary centre. We present our experience setting up a new microsurgical breast reconstruction service in a district hospital and compare our results to the published outcomes of large volume centres. METHODS: Patient data were collected prospectively from the start of the service to date (July 2018- July 2020) with the capture of demographics, management, and outcomes. The BREAST-Q tool was used preoperatively and at a minimum of 3 months. RESULTS: The first 40 patients undergoing DIEP reconstruction were included. Of these, 70% were immediate, mean age was 49 years (27-68) and BMI was 28.1 kg/m2 (22-32.5). In all, 50% had one or more co-morbidities other than breast cancer. Median length of stay was 3 days (2-6) with 75% of patients discharged on day 2 or 3. Ten patients' stay exceeded 3 days - mostly due to social reasons. Flap loss occurred in 1 patient (2.5%). Twenty-one patients developed complications (52%) within 90 days: seven Clavien-Dindo Grade I, two Grade II and ten Grade IIIb. Fat necrosis and mastectomy flap necrosis were the most common complications. Surgical intervention was higher in those needing adjuvant therapy. Patient-reported outcomes showed post-operative improvement across all domains except abdominal physical well-being at median 11.3 months. CONCLUSIONS: We present the shortest published length of stay for unilateral DIEP reconstructions. We are the first paper to publish patient-reported outcomes following a breast microsurgical enhanced recovery protocol. We demonstrate how a new microsurgical service, utilising an enhanced recovery protocol and careful patient selection can immediately achieve outcomes comparable to well-established centres. There is no reason why all patients should not have access to microsurgical breast reconstruction locally.

The modulation of lymphocyte functions by molecules secreted by macrophages. II. Conditions leading to increased secretion.

Cultures of peritoneal exudate cells rich in macrophages were studied for the secretion of lymphostimulatory molecules. Two conditions produced increased secretion: (a) addition to the cultures of various agents that readily interacted with macrophages, such as latex particles, antibody-coated red cells, endotoxin, Listeria organisms, or Be salt; or (b) addition of activated lymphocytes. In the first case the increased activity was found during the first 24 or 48 h after uptake of the stimuli. Increased activity was found in normal or peptone-stimulated macrophages but not in macrophages after injection of endotoxin or thioglycollate. The addition of T lymphocytes from Listeria-infected mice to macrophage cultures increased greatly the activities. This increase was also produced by addition to antigen-primed T cells together with antigen. The lymphocytes by themselves did not secrete active factors. The lymphostimulatory activities were tested on thymocyte DNA synthesis and on antibody formation in vitro. The latter assay was done on spleen cells from immunized mice where one striking effect was the stimulation of differentiation to antibody-secreting cells. Some dissociation of both activities (thymocyte DNA synthesis and B-cell differentiation) was observed with selected culture fluids.

The modulation of lymphocyte functions by molecules secreted by macrophages. I. Description and partial biochemical analysis.

Culture fluids of peritoneal exudate cells rich in macrophages stimulated DNA synthesis of thymocytes and, to lesser extent, of spleen cells. We also investigated the effects of culture fluids from macrophages on the in vitro response to a hapten-carrier protein (fluorescein-menocyanin) using spleen cells from immune mice. Macrophage culture fluids contained an activity that increased the plaque-forming cell response of both IgG and IgM class. This increase was observed in the absence of any added hapten protein to the culture. The helper function of T lymphocytes (as evidenced by challenging with the hapten on the homologous carrier) was also increased by the macrophage culture fluid. However, this enhancement was best observed in conditions of relatively low T-cell activity. Also, the macrophage fluid allowed spleen cells of nude athymic mice to make a plaque-forming cell response to sheep red blood cells of both the IgM and IgG class. The macrophage was the cell source of the stimulatory molecule since it was generated only in cultures of macrophages devoid of significant number of lymphocytes. Stimulatory activity was not found in cultures of lymphocytes, mouse embryo cells, or 3T3 cells. The thymocyte stimulatory molecule did not contain H-2 antigens, was resistant to diisopropylfluorophosphate treatment, eluted from Sephadex with a size ranging from 15,000 to 21,000 daltons, and was sensitive to chymotrypsin and pepsin.

Inhibition of E-selectin gene expression by transforming growth factor beta in endothelial cells involves coactivator integration of Smad and nuclear factor kappaB-mediated signals.

Transforming growth factor (TGF)-beta(1) is a pleiotropic cytokine/growth factor that is thought to play a critical role in the modulation of inflammatory events. We demonstrate that exogenous TGF-beta(1) can inhibit the expression of the proinflammatory adhesion molecule, E-selectin, in vascular endothelium exposed to inflammatory stimuli both in vitro and in vivo. This inhibitory effect occurs at the level of transcription of the E-selectin gene and is dependent on the action of Smad proteins, a class of intracellular signaling proteins involved in mediating the cellular effects of TGF-beta(1). Furthermore, we demonstrate that these Smad-mediated effects in endothelial cells result from a novel competitive interaction between Smad proteins activated by TGF-beta(1) and nuclear factor kappaB (NFkappaB) proteins activated by inflammatory stimuli (such as cytokines or bacterial lipopolysaccharide) that is mediated by the transcriptional coactivator cyclic AMP response element-binding protein (CREB)-binding protein (CBP). Augmentation of the limited amount of CBP present in endothelial cells (via overexpression) or selective disruption of Smad-CBP interactions (via a dominant negative strategy) effectively antagonizes the ability of TGF-beta(1) to block proinflammatory E-selectin expression. These data thus demonstrate a novel mechanism of interaction between TGF-beta(1)-regulated Smad proteins and NFkappaB proteins regulated by inflammatory stimuli in vascular endothelial cells. This type of signaling mechanism may play an important role in the immunomodulatory actions of this cytokine/growth factor in the cardiovascular system.

Poorly differentiated cutaneous squamous cell carcinomas have high incomplete excision rates with UK minimum recommended pre-determined surgical margins.

BACKGROUND: In the UK, the British Association of Dermatology-British Association of Plastic, Reconstructive and Aesthetic Surgery (BAD-BAPRAS) guidelines recommend excision of high-risk cutaneous squamous cell carcinomas (cSCCs), including poorly differentiated cSCCs, with a minimum peripheral margin of 6 mm1. OBJECTIVES: We assess whether the BAD-BAPRAS minimum margin achieves histological clearance in poorly differentiated cSCCs. PATIENTS AND METHODS: Demographics, surgical notes and histological reports from all patients having a primary cSCC excised at the Plastic Surgery Department of Addenbrooke's Hospital, Cambridge, UK, between January 2017 and April 2018 were analysed. Ordinal regression was performed for excision margin status versus histological grade by using size and site as co-variates. RESULTS: Of 296 cSCCs, 38(12.8%) were poorly differentiated. Patients with poorly differentiated cSCCs were older (81.1 years vs. 76.7 years, p = 0.038), had lesions on the face or scalp (89.2% vs. 52.1%, p = 0.0001), and had lymphovascular (10.5% vs. 0%, p = 0.001) or perineural invasion (15.8% vs. 2%, p = 0.002). Well-differentiated cSCCs were excised with an average peripheral margin of 4.72 mm (95% CI 4.25-5.18 mm), while poorly differentiated cSCCs were excised with a margin of 6.42 mm(95% CI 5.58-7.28 mm). Close or involved peripheral margins were seen in 3% of well-differentiated lesions but in 13.2% of poorly differentiated lesions (OR=45.02; p = 0.003). Deep margins were close in 13.1% (none involved) of well-differentiated lesions but close or involved in 50% of poorly differentiated lesions (OR=11.94; p = 0.001). CONCLUSIONS: We demonstrate that poorly differentiated cSCCs are frequently incompletely excised in both peripheral and deep planes, despite adherence to guidelines. The UK BAD-BAPRAS guidelines should be urgently updated in line with international consensus.

A retrospective study of 694 Basal Cell Carcinoma excisions to quantify deep margin documentation and clearance compared to histological type and surgical margin.

AIMS: Basal cell carcinoma (BCC) is the most common malignancy worldwide. Although rarely a risk to life, they are potentially destructive and disfiguring. Current treatment guidelines are predominantly based on low-risk BCC and make no recommendations regarding the deep excision margin. We aim to clarify the prevalence of high-risk BCC and appropriate surgical management of the deep margin. METHODS: Data of 556 patients presenting for primary excision of 694 basal cell carcinoma to CUH Plastic Surgery between January 2017 and April 2018 were collected by capture of demographics, surgical notes and histology. We defined the deep surgical margin as numbered anatomical planes, with subcutaneous fat as 0, the first plane under this as 1 and so forth. This allowed comparison of the surgical excision depth, and resulting deep margin histology, across disparate sites. Histological margin clearance was analysed using ordinal regression of age, site, size, histological type and surgical margin. This allowed identification of factors associated with clear, close or incomplete lesion excision. Subgroup analysis was then performed to make recommendations for surgical margins to achieve adequate lesion clearance. RESULTS: Six hundred ninety-four BCCs were identified, 66% were male and the average age of patients was 74 years. Of the BCCs, 49% were nodular but 39% were mixed. An infiltrative component was seen in 24% (mixed infiltrative), but only 4% were purely infiltrative. Mean size, site and patient age were similar across histological types. Deep margin involvement was very rare in nodular or superficial BCCs but occurred in 7% of pure infiltrative and 5% of mixed infiltrative. Peripheral margins were very rarely involved in nodular BCCs but occurred in 9% of mixed infiltrative and 10% infiltrative despite similar surgical margins. A deep margin of the first underlying anatomical plane resulted uninvolved margins in 95% of infiltrative or mixed infiltrative BCC, but subcutaneous fat was sufficient for clearance in 95% of nodular, superficial and mixed non-infiltrative BCC. CONCLUSIONS: High-risk BCC was a common finding in our patient population. This was based not only on site and size but also on histological type. Infiltrative and mixed infiltrative BCCs have a higher risk of close or involved deep margins than other types. We recommend that they are excised to the first underlying anatomical plane. Nodular, superficial and mixed non-infiltrative BCC can usually be safely excised with a cuff of fat alone.

The magnitude of Yo-Yo test improvements following an aerobic training intervention are associated with total genotype score.

Recent research has demonstrated that there is considerable inter-individual variation in the response to aerobic training, and that this variation is partially mediated by genetic factors. As such, we aimed to investigate if a genetic based algorithm successfully predicted the magnitude of improvements following eight-weeks of aerobic training in youth soccer players. A genetic test was utilised to examine five single nucleotide polymorphisms (VEGF rs2010963, ADRB2 rs1042713 and rs1042714, CRP rs1205 & PPARGC1A rs8192678), whose occurrence is believed to impact aerobic training adaptations. 42 male soccer players (17.0 ± 1y, 176 ± 6 cm, 69 ± 9 kg) were tested and stratified into three different Total Genotype Score groups; "low", "medium"and "high", based on the possession of favourable polymorphisms. Subjects underwent two Yo-Yo tests separated by eight-weeks of sports-specific aerobic training. Overall, there were no significant differences between the genotype groups in pre-training Yo-Yo performance, but evident between-group response differentials emerged in post-training Yo-Yo test performance. Subjects in the "high" group saw much larger improvements (58%) than those in the 'medium" (35%) and "low" (7%) groups. There were significant (p<0.05) differences between the groups in the magnitude of improvement, with athletes in the "high" and medium group having larger improvements than the "low" group (d = 2.59 "high" vs "low"; d = 1.32 "medium" vs "low"). In conclusion, the magnitude of improvements in aerobic fitness following a training intervention were associated with a genetic algorithm comprised of five single nucleotide polymorphisms. This information could lead to the development of more individualised aerobic training designs, targeting optimal fitness adaptations.

Characterization of resident glomerular cells in the rat expressing Ia determinants and manifesting genetically restricted interactions with lymphocytes.

The existence of a subpopulation of rat glomerular cells bearing Ia determinants has been demonstrated with the aid of techniques for the enzymatic isolation and culture of glomerular cells. The Ia-positive cell is normally resident in the uninflamed glomerulus. It resembles a mononuclear phagocyte and consists of a functionally heterogeneous cell population with the capacity of Fc receptor display and phagocytosis, both in vivo and in vitro. A new technique for labeling these cells in situ in intact glomeruli has indicated that Ia-positive cells make up approximately 2% of the total glomerular cell population. The isolated glomerular cells can take up antigen and stimulate immune lymphocytes in an I-region-restricted interaction. They are strongly stimulatory in an allogeneic primary mixed lymphocyte culture. Characterization of this cell type suggests potential new insights into the pathogenesis of renal allograft rejection and immunologically mediated glomerulonephritis.

Functions of fission yeast orp2 in DNA replication and checkpoint control.

orp2 is an essential gene of the fission yeast Schizosaccharomyces pombe with 22% identity to budding yeast ORC2. We isolated temperature-sensitive alleles of orp2 using a novel plasmid shuffle based on selection against thymidine kinase. Cells bearing the temperature-sensitive allele orp2-2 fail to complete DNA replication at a restrictive temperature and undergo cell cycle arrest. Cell cycle arrest depends on the checkpoint genes rad1 and rad3. Even when checkpoint functions are wild type, the orp2-2 mutation causes high rates of chromosome and plasmid loss. These phenotypes support the idea that Orp2 is a replication initiation factor. Selective spore germination allowed analysis of orp2 deletion mutants. These experiments showed that in the absence of orp2 function, cells proceed into mitosis despite a lack of DNA replication. This suggests either that the Orp2 protein is a part of the checkpoint machinery or more likely that DNA replication initiation is required to induce the replication checkpoint signal.

Interleukin-8 induces changes in human neutrophil actin conformation and distribution: relationship to inhibition of adhesion to cytokine-activated endothelium.

Interleukin-8 (IL-8) induces diverse biological responses in neutrophils, including inhibition of adhesion to cytokine-activated endothelium, which we have termed the leukocyte adhesion inhibition (LAI) effect. Pretreatment of neutrophils with cytochalasin B abolished the LAI effect of IL-8, suggesting a microfilament-dependent mechanism. Interleukin-8 induced a rapid increase (less than or equal to 15 s) in the polymerization of actin filaments in human neutrophils that was blocked by pretreatment with cytochalasin B. F-actin depolymerization occurred gradually at a rate inversely proportional to IL-8 concentration. This temporal pattern of actin polymerization-depolymerization was similar to that induced by other chemotactic factors such as C5a and N-formylmethionyl-leucyl-phenylalanine, which also exhibit a marked LAI effect, but the lipid mediators, leukotriene B4 and platelet-activating factor, lack any significant LAI effect. Scanning confocal microscopy demonstrated that neutrophil actin microfilaments undergo a dramatic rearrangement prior to detachment of the neutrophil from a surface. We suggest that the ability of IL-8 and certain other leukocyte agonists to regulate the actin polymer network of neutrophils may play an important role in adhesive interactions with the vascular endothelium.

Changes in outcome following surgery for colorectal cancer: one surgeon's experience.

BACKGROUND: Colorectal cancer (CRC) has the second highest mortality rate of all cancers in Ireland. Developments in imaging, surgical technique, and perioperative care in the last two decades have altered management. AIMS: To determine whether outcome following surgery for CRC in the mid-west has changed over a 22-year period. METHODS: Four hundred and twenty-two patients were divided into two time periods: Group A (1980-1991, n = 203) and Group B (1992-2002, n = 219) and demographic, inpatient, and survival data were reviewed. RESULTS: The mean age was 67 years, 59% were male. Group B patients had less advanced disease at presentation (Dukes' stage D 14% vs 22%, p < 0.05), fewer perioperative complications (13% vs 23%, p < 0.05), and fewer local recurrences (6.8% vs 11.8%, p < 0.05) than Group A. No difference in 30-day mortality rate or survival was detected. CONCLUSIONS: Although perioperative CRC management has improved, methods of earlier diagnosis and improvements in adjuvant therapy should be explored to improve survival.

Isolated musculocutaneous neuropathy caused by a proximal humeral exostosis.

We report an isolated musculocutaneous neuropathy caused by a proximal humeral osteochondroma that became symptomatic after the patient played recreational basketball. Lesion resection resulted in complete deficit resolution. Mass lesions involving the musculocutaneous nerve should be considered in patients with atraumatic, isolated musculocutaneous neuropathies that are recurrent or fail to recover, even in the setting of strenuous exercise.

New "ofloxacin" type antibacterial agents. Incorporation of the spiro cyclopropyl group at N-1.

The first example incorporating a spiro cyclopropyl group into an "ofloxacin" type of quinolone antibacterial agent has been prepared by potassium fluoride mediated ring closure of the hydroxymethyl cyclopropyl intermediate to give 9'-fluoro-7'-oxo-10'-(1-piperazinyl)spiro[cyclopropane-1,3'(2'H)-[7H] pyrido[1,2,3-de][1,4]benzoxazine]-6'-carboxylic acid. Analogues were made by substitution at C-7 by various complex amines. Evaluation of these compounds for antibacterial activity was carried out. All examples prepared and examined showed in vitro minimum inhibitory values and in vivo mouse protection results to be diminished as compared to the parent, ofloxacin.