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Early diagnosis is essential but challenging in severe sepsis. Quantifying and comparing metabolite concentrations in serum has been suggested as a new diagnostic tool. Here we used proton nuclear magnetic resonance spectroscopy (¹H NMR) based metabolomics to analyze the possible differences in metabolite concentrations between sera taken from septic patients and healthy controls, as well as between sera of surviving and non-surviving sepsis patients. We took serum samples from 44 sepsis patients when the first sepsis induced organ dysfunction was found. Serum samples were also collected from 14 age and gender matched healthy controls. The samples were analyzed by quantitative ¹H NMR spectroscopy for non-lipid metabolites. We found that the serum levels of glucose, glycine, 3-hydroxybutyrate, creatinine and glycoprotein acetyls (mostly alpha-1-acid glycoprotein, AGP) were significantly (p < 0.05) higher in sepsis compared to healthy sera, whereas citrate and histidine were significantly (p < 0.05) lower in sepsis patients compared to healthy controls. We found statistically significantly higher serum lactate and citrate concentrations in non-survivors compared to 30-day survivors. According to our study, 3-hydroxybutyrate, citrate, glycine, histidine, and AGP are candidates for further studies to enable identification of phenotype association in the early stages of sepsis.

Background: Although laparoscopic adhesiolysis for adhesive small bowel obstruction is being done more frequently, it is not widely accepted due to the lack of supporting evidence of its superiority over an open approach and concerns regarding its benefits. We aimed to investigate whether laparoscopic adhesiolysis was a superior treatment for adhesive small bowel obstruction compared with an open approach in terms of length of postoperative hospital stay and morbidity. Methods: In this international, multicentre, parallel, open-label trial, we randomly assigned patients (1:1) aged 18–95 years who had adhesive small bowel obstruction that had not resolved with conservative management to have either open or laparoscopic adhesiolysis. The study was done in five academic university hospitals and three community (central) hospitals in two countries (Finland [n=3 academic university hospitals; n=3 community hospitals] and Italy [n=2 academic university hospitals]). We included only patients with high likelihood of a single adhesive band in the trial; additionally, patients who had an anaesthesiological contraindication, were pregnant, living in institutionalised care, or who had a hospital stay of more than 1 week before the surgical consultation were excluded from the trial. The randomisation sequence was generated using block randomisation, with randomly varied block sizes and stratified according to centre. The primary outcome was postoperative length of hospital stay assessed at time of discharge in the modified intention-to-treat population. Findings: Between July 18, 2013, and April 9, 2018, 566 patients were assessed for eligibility, of whom 104 patients were randomly assigned to the open surgery group (n=51) or to the laparoscopy group (n=53). Of these patients, 100 were included in the modified intention-to-treat analyses (49 in the open surgery group; 51 in the laparoscopy group). The postoperative length of hospital stay for open surgery group was on average 1·3 days longer than that in the laparoscopy group (geometric mean 5·5 days [range 2–19] vs 4·2 days [range 1 −20]; ratio of geometric means 1·31 [95% CI 1·06–1·61]; p=0·013). 21 (43%) patients in the open surgery group and 16 (31%) patients in the laparoscopy group had postoperative complications (Clavien-Dindo any grade) within 30 days (odds ratio 0·61 [95% CI 0·27–1·38]; p=0·23). One patient died in each group within 30 days. Interpretation: Laparoscopic adhesiolysis provides quicker recovery in selected patients with adhesive small bowel obstruction than open adhesiolysis.

Introduction: There is a lack of prospective studies comparing Roux-en-Y gastric bypass (RYGB) and one-anastomosis gastric bypass (OAGB). Also, the effects of bariatric surgery and weight loss need a deeper understanding through metabolic studies. We describe the trial protocol and interim analysis of a prospective randomized controlled study comparing RYGB and OAGB: the RYSA trial. Materials and methods: In total, 120 bariatric patients will be randomized between RYGB and OAGB in two academic centers. All patients will be followed up for 10 years with analysis and measurements of weight, comorbidities, blood tests, body composition and questionnaires. Extensive metabolic analyses (mixed meal tests, energy expenditure, biopsies of muscle and subcutaneous fat, urine, saliva and fecal samples) will be carried out in the Obesity Research Unit, University of Helsinki, for all patients treated at the Helsinki University Hospital (80 patients) at baseline, 6 months and 12 months. Bile reflux will be studied for the OAGB group at the Helsinki University Hospital at 6 months with gastroscopy and scintigraphy. Results: At an interim analysis at 3 months (half-way) through recruitment (30 RYGB and 30 OAGB patients) there have been no deaths and no intensive care unit admittances. One patient in both groups required additional gastroscopy, with anastomosis dilatation in the RYGB group but with no additional intervention in the OAGB group. Conclusion: The trial can be safely carried out. Recruitment is estimated to be complete by the end of 2019. Trial registration: Clinical Trials Identifier NCT02882685. Registered on August 30th 2016.

Purpose: Obesity causes a prothrombotic state and is known as a predisposing factor for thromboembolic events. In this pilot study, we assessed the impact of surgery for obesity and the subsequent weight loss on blood coagulation using traditional coagulation tests and thromboelastography (TEG). Material and Methods: We studied blood samples from 18 patients receiving bariatric surgery. Besides traditional blood coagulation tests and high-sensitivity C-reactive protein (hsCRP) as a marker of inflammation, the TEG parameters reaction time (R), kinetics time (K), angle (α), maximum amplitude (MA), clot strength (G), and lysis percent at 60 min (LY60) were determined preoperatively and on the first postoperative day and 6 months after surgery. Results: Altogether, 54 samples were analyzed. The median MA (71.3 mm), G (12,403.3 d/sc), and hsCRP (3.5 mg/l) were elevated preoperatively. The median hsCRP further increased on the first day postoperatively, but declined to the normal range 6 months after surgery, while MA and G remained elevated. In traditional coagulation tests, there was an increase in median fibrinogen and D-dimer postoperatively. D-dimer normalized (0.4 mg/l) during the study period, while the fibrinogen level (4.1 g/l) remained above the upper limit of normal. Conclusions: Measured by TEG, patients receiving bariatric surgery have hemostatic abnormalities indicating hypercoagulation at the 6-month follow-up visit, suggesting an elevated risk for thromboembolic events for at least 6 months after surgery.

The expression intensities of cytokeratins and tight junction proteins were determined on re-epithelization. Experimental blister wound healing was studied in patients with diabetes mellitus and in patients with obstructive jaundice. Suction blisters were induced on healthy volunteers, and the healing blisters were biopsied at different time points. Cytokeratin expression and the tight junction proteins ZO-1 and occludin were studied immunohistochemically. Blisters were induced on 17 patients with diabetes and 11 control subjects, and the healing process was followed indirectly by measuring water evaporation and blood flow in the wounds. Microvascular reactivity in the diabetic patients was also studied by using non-immunologic contact irritants. Wound healing, skin collagen synthesis and serum levels of procollagen propeptides were studied in 24 patients with obstructive jaundice caused by neoplastic pancreaticobiliary obstruction and in 17 control patients with the corresponding condition without jaundice. Cytokeratin expression was altered in healing epidermis. In the suprabasal layer, K10 was replaced by K14 and, most likely, by K16. K18 keratin, which is not present in normal epidermis, was found in the basal and suprabasal layers. Thus, there was a shift towards lower molecular weight cytokeratins, which is a reflection of immaturity, and probably towards motility. The tight junction proteins ZO-1 and occludin were expressed in the migrating epidermal sheet, where they apparently form an early barrier. Enhanced expression was seen in the hyperproliferative zone of the wound edge. The diabetic patients showed slower restoration of the epidermal barrier and a weaker initial inflammatory response. Obstructive jaundice and its resolution had no effect on healing. Skin collagen synthesis was decreased in jaundiced patients, and it increased slightly after drainage. Serum type III collagen propeptide levels were elevated in patients with biliary obstruction and dropped after drainage. The elevated levels may be related to the increased synthesis due to fibrosis. As a conclusion, diabetes mellitus impairs epidermal wound healing, while obstructive jaundice does not.

The skin is the largest organ of the body. Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The protective function of the skin is compromised in sepsis, and septic patients are prone to problems in tissue repair, which causes increased morbidity. However, there are only a few human studies exploring wound healing in sepsis. In this study we observed skin wound healing and the molecular mechanisms behind it in 44 septic patients and 14 healthy controls. From sepsis and healthy sera, metabolites were analyzed with proton nuclear magnetic spectroscopy, and cytokines using multiplex assay. The effect of sepsis and healthy sera was tested in vitro on keratinocyte proliferation, migration and viability. Suction blister wounds were induced on 15 patients and 10 controls and biopsied for immunohistochemical analyses. Serum levels of glucose, glycine, 3-hydroxybutyrate, creatinine and glycoprotein acetyls were significantly higher in sepsis patients compared to healthy controls, whereas levels of histidine and citrate were significantly lower in sepsis. Keratinocyte viability, proliferation and migration were reduced in sepsis in vitro. Sepsis sera supplemented with epithelial growth factor (EGF) or tumor necrosis factor alpha (TNF-α) improved and EGF receptor inhibition reduced keratinocyte migration in healthy and septic wounds. Extracellular vesicles added to healthy or sepsis serum media inhibited keratinocyte migration. Higher serum concentrations of TNF-α and vascular endothelial growth factor (VEGF) and lower levels of EGF were detected in sepsis sera compared to healthy sera. In skin immunohistochemistry samples, the levels of EGF, VEGF and transforming growth factor beta as well as syndecan-1 were increased in septic patients compared to healthy controls. Extracellular matrix (ECM) components tenascin-C and laminin-332 had lower expression in septic skin compared to healthy skin. The results of this study support the clinical findings concerning impaired wound healing in sepsis and provide new information about the underlying mechanisms: hypermetabolism, catabolism and organ dysfunction as well as altered cell signaling and interplay of cytokines and ECM. Understanding the cell level details of wound healing and skin homeostasis in sepsis provides opportunities to improve surgical treatments and their timing. Tiivistelmä Elimistön väärin mitoitettu vaste tulehdukseen vaurioittaa sen omia kudoksia sepsiksessä. Iho on ihmisen suurin elin ja suoja ulkoisia haittatekijöitä vastaan. Kudosparanemisesta sepsiksessä on vain vähän tietoa. Tutkimuksen tarkoituksena on selvittää ihohaavan paranemista ja taustalla vaikuttavia molekyylitason mekanismeja sepsiksessä. Tutkimusta varten otettiin verinäytteet 44 sepsispotilaalta ja 14 terveeltä verrokilta. Lisäksi 15 potilaalle ja 10 terveelle verrokille tehtiin imurakkulahaavat iholle, ja yksi paraneva haava poistettiin kudosnäytteeksi. Aineenvaihduntatuotteiden määrää veressä tutkittiin ydinmagneettisella resonanssispektroskopialla. Haavan paranemista sepsiksessä tutkittiin mittaamalla keratinosyyttien elinkykyisyyttä, lisääntymistä ja liikkumista soluviljelymenetelmin. Lisäksi mitattiin veren kasvutekijäpitoisuuksia. Imurakkulahaavanäytteille tehtiin immunohistokemialliset tutkimukset. Veren glukoosin, glysiinin, 3-hydroksibutyraatin, kreatiniinin ja glykoproteiiniasetyylien pitoisuudet olivat sepsispotilailla korkeammat ja sitraatin ja histidiinin pitoisuudet matalammat terveisiin verrattuna. Keratinosyyttien elinvoimaisuus, liikkuminen ja lisääntyminen keinotekoisessa haavassa olivat alentuneet sepsiksessä terveisiin verrokkeihin verrattuna. Solunulkoiset vesikkelit estivät ja epiteliaalisen kasvutekijän (EGF) tai tuumorinekroositekijä alfan (TNF-α) lisäys haavoille paransi keratinosyyttien liikkumista. Veren TNF-α:n ja verisuonikasvutekijän (VEGF) pitoisuudet olivat sepsiksessä korkeammat, kun taas EGF:n pitoisuus oli matalampi. Paranevan ihohaavan solunulkoisen väliaineen komponenttien tenaskiini-C:n sekä laminiini-332:n määrä oli sepsiksessä vähäisempi ja solun pintareseptori syndekaani-1:n, transformoivan kasvutekijä beetan (TGF-β), VEGF:n ja EGF:n määrä puolestaan korkeampi. Tässä tutkimuksessa saadut tulokset tukevat aiempia kliinisiä havaintoja heikentyneestä haavan paranemisesta sepsiksessä sekä antavat lisätietoa taustalla vaikuttavista mekanismeista: hypermetabolia, proteiinikatabolia, elinvauriot, muutokset solujen välisessä viestinnässä sekä kasvutekijöiden ja solunulkoisen väliaineen vuorovaikutuksessa. Kudosparanemista olisi mahdollista tehostaa vaikuttamalla näihin solutason rakenteisiin ja prosesseihin. Tämä edesauttaisi sepsispotilaiden hoitoa ja ennustetta sekä vähentäisi yhteiskunnalle aiheutuvia kustannuksia.

It is a generally accepted dogma that sepsis disturbs skin function and wound healing, but surprisingly there is only remote pathophysiological evidence available behind that presumption. As the skin is the largest defensive barrier, the skin dysfunction in severe sepsis deserves more attention. In this study, the suction blister model was used to create experimental wounds. The study population included 44 patients with severe sepsis and 15 controls. The blister fluid was collected to analyse cytokine profile of the skin. The transepidermal water loss and blood flow from the wound were measured. A 4mm biopsy was taken under local anaesthesia on the first and the eighth day of the study from the healthy looking skin. Then 15 healing suction blisters were excised. Serum samples were also collected on the first day of the study. The barrier restoration was diminished, and the inflammation in the wound was more intense in severe sepsis than in the controls. The expression of the basement membrane components Laminin-332 and type IV collagen decreased during the septic disease, but increased over the next 3 months without achieving the level oft he controls. The expression of tight junction proteins remained nearly intact in the healing wound in severe sepsis compared to the controls. The expression of occludin on the leading edge of the migrating keratinocytes was more restricted and late in severe sepsis compared to the controls. The levels of the tumour necrosis factor (TNF), interleukin-10 (IL-10) and IL-6 in skin blister fluid were higher in the sepsis compared to controls. The blister fluid and serum cytokine response in the sepsis differed since the levels of epidermal growth factor, vascular endothelial growth factor, TNF and basic fibroblastic growth factor (bFGF) in the blister fluid did not correlate with the levels of serum. The septic patients with multiple organ failure had higher levels of several cytokines than patients without organ failure. Survivors had lower levels of IL-10 and bFGF in blister fluid than the non-survivors. This study offers novel findings for skin and wound healing in sepsis. Together, all the findings suggest that skin dysfunction in severe sepsis exists even when the most profound structures remain intact. Understanding these mechanisms of impaired wound healing can improve future treatments, such as the timing of surgery. Tiivistelmä Sepsiksen ajatellaan heikentävän haavanparanemista, mutta tieteellistä näyttöä on niukasti. Iholla on keskeinen osa elimistön puolustuksessa ja tasapainon ylläpidossa, joten sen toiminnan häiriintyminen systeemisessä tulehduksessa ansaitsee suuremman huomion. Imurakkulahaavat tehtiin 44 septiselle potilaalle ja 15 kontrollille. Haavoista mitattiin veden haihtumista ja veren virtausta sekä otettiin imurakkulaneste näytteeksi sytokiinimäärityksiä varten. Tutkimuksen ensimmäisenä ja kahdeksantena päivänä otettiin 4mm biopsiat terveeltä iholta ja 15 potilaalta poistettiin näytteeksi paraneva imurakkulahaava. Seeruminäytteet otettiin tutkimuksen ensimmäisenä päivänä. Veden haihtuminen haavalta oli voimakkaampaa eli ihon barrierin palautuminen oli hidastunut septisillä potilailla verrattuna kontrolleihin. Haavassa havaittu tulehdus oli sepsiksessä voimakkaampi. Tyvikalvon komponenttien Laminiini-332:n ja tyypin IV kollageenin ilmentyminen oli vähäisempää sepsiksen aikana ja lisääntyi 3kk kohdalla, mutta ei kuitenkaan saavuttanut kontrollien tasoa. Tiivisliitosproteiinien ilmentyminen oli lähes muuttumatonta sepsiksessä kontrolleihin verrattuna. Okludiinin ilmentyminen sen sijaan paranevassa haavassa vaeltavien keratinosyyttien etureunassa oli rajoittuneempaa ja myöhäisempää sepsiksessä kuin kontrolleilla. Sytokiineistä tuumorinekroositekijä (TNF), interleukiini-10 (IL-10) ja IL-6 olivat koholla imurakkulanesteessä verrattuna kontrolleihin. Epidermaalinen kasvutekijä, verisuonten endoteelikasvutekijä, TNF ja perusfibroplastinen kasvutekijä (bFGF) pitoisuudet rakkulanesteessä erosivat seerumin pitoisuuksista eli ihon sytokiiniprofiili erosi systeemisestä sytokiiniprofiilista. Potilailla, joilla oli monielinvaurio, todettiin korkeampia sytokiinipitoisuuksia. Potilailla, jotka menehtyivät 30 vrk kuluessa, oli korkeammat pitoisuudet IL-10 ja bFGF rakkulanesteessä. Tämä tutkimus tarjoaa uutta tietoa ihosta ja haavanparanemisesta sepiksessä. Tulosten perusteella voidaan todeta, että ihon toimintahäiriö on sepsiksessä todellinen, vaikka kaikkein perustavimmat rakenteet säilyvät muuttumattomina. Toimintahäiriön mekanismien ymmärtäminen voisi auttaa septisen potilaan hoidossa, kuten kirurgisten toimenpiteiden ajoittamisessa paranemisen kannalta mahdollisimman otolliseen aikaan.