bluuebunny/crossref_metadata_2025 huggingface dataset:
Derivation of thyroid progenitors from human induced pluripotent stem cells
Authors: Posabella A , Undeutsch H J , Alber A B , Kurmann A , Droeser R , Hollenberg A , Kotton D N
Published: June 2022

Objective

Despite the availability of synthetic thyroid hormone for therapeutic use, a significant number of patients with hypothyroidism do not feel well on replacement doses of thyroid hormones suggesting that better-individualized therapy is needed. For this reason, hypothyroidism resulting from congenital lack of functional thyrocytes, surgical tissue removal, or gland ablation, represents a particularly attractive endocrine disease target that may be conceivably cured by transplantation of long-lived functional thyroid progenitors or mature follicular epithelial cells.

Methods

To generate thyroid follicular progenitors from human induced pluripotent stem cells (hiPSCs), we sought to develop a directed differentiation approach by activating or inhibiting endogenous developmental signaling pathways previously identified in the mouse. To facilitate tracking and purification of candidate human thyroid progenitors, we engineered a hiPSC-line carrying a tdTomato reporter targeted to the PAX8 locus and a GFP reporter targeted to the NKX2-1 locus.

Results

We adapted our published in vitro differentiation protocol previously used to differentiate mouse PSCs into thyroid progenitors and observed tdTomato/GFP co-expressing cells first emerging from our hiPSC line by day 12 of culture and persisting for at least 2 months of further culture in thyroid maturation media, supplemented with TSH. Thus, we profiled all cells deriving from hiPSCs by single-cell RNA sequencing >6,000 cells captured on days 12 and 29 of in vitro differentiation. At day 12, tdTomato/GFP co-expression was observed in 12% of all cells and these cells appeared to be early thyroid follicular progenitors as they uniquely co-expressed the tetrad of thyroid lineage selective transcription factors, NKX2-1, PAX8, FOXE1, and HHEX. By day 29 tdTomato+/GFP+ cells represented 69% of all cells and had upregulated TG, TSHR, NIS and TPO expression in addition to the previously described four thyroid lineage markers, suggesting time-dependent differentiation and maturation of thyroid follicular epithelial cells.

Conclusion

Thus, we have employed a novel hiPSC line to optimize a protocol able to generate human thyroid progenitors and mature follicular epithelial cells, representing a purifiable source of human thyroid lineage cells whose functional and thyroid reconstituting potential can be tested in vivo in animal models of hypothyroidism.
Outer membrane vesicles as carriers for bacterial extracellular ATP modulate local and remote inflammation in peritoneal sepsis
Authors: Spari D , Schmid A , Murugan S , Salm L , Stroka D , Candinas D , Beldi G
Published: June 2022

Objective

Adenosine triphosphate (ATP) may be released to the extracellular space and activate specific purinergic receptors to modulate inflammatory responses. In addition to eukaryotes, ATP is also released by bacteria. This bacterial extracellular ATP (eATP) subsequently may act as an inter-kingdom signaling molecule between bacteria and its host. How ATP is secreted by bacteria and its consequences in systemic infection such as sepsis remains unclear. This study aims to determine how ATP is secreted by bacteria and to elucidate its interaction with the host immune system in a model of peritoneal sepsis.

Methods

Bacteria from septic patients were isolated from peritoneal washes. Peritoneal sepsis in mice was induced by cecal ligation and puncture. Peritoneal fluid was collected, (an)aerobically plated and colonies were identified by 16S-sequencing. EATP was periodically measured from bacteria culture supernatant using a luciferin-luciferase assay. Bacteria in culture were counted by plating and the amount of live/dead bacteria was assessed using flow cytometry. To specifically assess the role of bacterial eATP in vivo, E. coli K-12 BW25113 parental strain from the keio collection was used, transformed with a plasmid coding for an apyrase and i.p. injected. Furthermore, a hypervesiculation mutant of this keio collection was used to collect outer membrane vesicles (OMV). These OMV were then loaded with ATP using electroporation and injected i.p in mice.

Results

All bacteria that were isolated from human or mouse peritoneal washes were able to secrete ATP in a growth-phase dependent manner in vitro. In addition to passive release by dying bacteria, we have identified that the amount of eATP is connected with the formation of outer membrane vesicles (OMV) as shown by the E. coliΔtolB hypervesiculation mutant. Whole bacterial eATP led to a significant worse outcome in mice suffering from peritoneal sepsis. In addition, bacterial eATP specifically delivered via OMV worsened septic outcome as well, critically modulating neutrophil recruitment. At the infection site, ATP-loaded OMV led to an impaired recruitment of neutrophils whereas in the lung they led to an elevated infiltration.

Conclusion

OMV serve as a carrier of bacterial wall LPS on its surface as well as bacterial eATP as its content and specifically alter the outcome during sepsis influencing neutrophils locally as well as at remote sites.
Hyperspectral evaluation of liver oxygenation in a murine model of metabolic associated liver disease and hepatocellular carcinoma
Authors: Peloso A , Lacotte S , Moeckli B , Oldani G , Tihy M , Rubbia-Brandt L , Toso C
Published: June 2022

Objective

Untreated MAFLD is a continuum of disease ranging from hepatic steatosis to cirrhosis and hepatocellular carcinoma (HCC). Throughout the disease progression, a change in hepatic hemodynamics occurs as portal hypertension. Hepatic arterial buffer response is a compensatory mechanism to maintain liver perfusion facing reduction of portal flow. These changes could also impair hepatic oxygenation homeostasis. The aim of this study is to test this hypothesis in mouse models and to shed light on the oxygenation of fatty, portal hypertensive liver and its impact on HCC carcinogenesis.

Methods

C57BL/6 mice were fed a HFD starting from 4 weeks of age, porto-systemic shunts (or sham) were created at 8 weeks, and monitored up to 40 weeks. ND-fed non-shunted mice were used as control group. Hyperspectral imaging (HSI) was utilized to quantify tissue oxygenation (StO2) of ND, HFD and HFD-shunted mice. In a second set of experiment, we explored the role of a common hepatic artery ligation in the studied DEN-induced HFD mouse model.

Results

HFD induced hepatic steatosis and portal pressure compared to ND. Porto-systemic shunt could deviate about 67% of the portal flow through the spleen to the systemic circulation, thus reducing portal pressure close-to-normal levels. Compared to control mice, HFD feeding increased liver oxygenation (p=0.0004), while shunting restored a close to normal level (p<0.001). The oxygenation of small bowel is decreased in a similar manner in both HFD and HFD-shunted mice. In HFD-fed mice, artery ligation led to less carcinogenesis compared to mice without artery ligation (p=0.026). In addition, artery ligation was also associated with smaller HCCs (p=0.027).

Conclusion

Early stages of MAFLD alter hepatic oxygen homeostasis. Fatty liver, when associated to portal hypertension, express higher liver oxygenation levels, compared to control group. This could due to hepatocyte ballooning with a narrowing of portal system, thus bring portal hypertension state with a simultaneous arterial buffer response. Additionally, small bowel of portal hypertensive mice showed lower oxygen levels mirroring an intestinal venous congestion typical of portal hypertension. Oxygen deprivation, through artery ligation, decreases HCC carcinogenesis and reduces HCC nodules volume. Yet further research is needed but oxygen homeostasis seems play a role in MAFLD progression as well in HCC pathophysiology.
Primary infection by E. multilocularis induces distinct patterns of hepatic crosstalk between natural killer T and regulatory T cells in mice
Authors: Yarahmadov T , Wang J , Sanchez-Taltavull D , Brodie T , Büchi I , Stroka D , Keogh A , Alvarez C , Beldi G
Published: June 2022

Objective

The larval stage of the helminthic cestode Echinococcus multilocularis can inflict tumor-like hepatic lesions that cause the parasitic disease alveolar echinococcosis (AE) in humans. Recently, opportunistic properties of the disease have been proposed based on the increased incidence in immunocompromised patients as well as on mouse models, indicating that an appropriate adaptive immune response is required for the control of the disease. However, little is known about how the local hepatic immune responses modulate the infection with E. multilocularis.

Methods

In a mouse model of oral infection that mimics the normal infection route in human patients, the adaptive immune response in the liver was assessed using single cell RNA sequencing of isolated hepatic CD3+ T cells at different infection stages.

Results

Single-cell RNA sequencing revealed specific temporal changes of natural killer T (NKT) cells and regulatory T (Treg) cells, indicating that these two cell types expand in the early phase and are subsequently inhibited in the late phase of infection. Receptor-ligand complex analysis via CellPhoneDB, consistently revealed high number of interactions between Tregs and NKT mainly at day 10 post infection. Relevant interactions between NKT and Treg cells at early phases include regulation of cell adhesion molecules such as integrins and selectins and TNF-dependent signalling. Immune suppressing interactions that include the checkpoint inhibitors (PD-1 and PD-L1), purinergic (ENTPD1, ADORA2A) and TGF-beta signalling are down regulated at early time points. String analysis supported these findings.

Conclusion

The data indicate that early interactions between NKT and Tregs potentially promote the formation of hepatic lesions and later also contribute to immunological suppression of the resolution of parasite-induced pathology. The obtained data provide a fresh insight on the adaptive immune responses and local regulatory pathways at different infection stages of E. multilocularis in mice.
Phase Ib dose-escalation study of the hypoxia-modiﬁer myo-inositol trispyrophosphate in patients with hepatopancreatobiliary tumors
Authors: Schneider M , Linecker M , Fritsch R , Mühlematter U , Stocker D , Pestalozzi B , Samaras P , Jetter A , Kron P , Petrowsky H , Nicolau C , Lehn J-M , Humar B , Graf R , Clavien P-A , Limani P
Published: June 2022

Objective

Hypoxia is present in most solid tumors and acts as a driver of malignancy. Myo-inositol trispyrophosphate (ITPP) is a novel re-oxygenating compound without apparent toxicity. In preclinical models, it potentiates the efficacy of subsequent chemotherapy through vascular normalization. We sought to assess the safety, tolerability, and preliminary efficacy of ITPP.

Methods

In this monocentric, open-label, dose-escalation study following a 3+3 design, eligible patients with advanced primary and secondary hepatopancreatobiliary tumors received nine 8-h infusions of ITPP during 3 weeks across eight dose levels (1866–14,500 mg/m2/dose), followed by standard chemotherapy. Primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetics and estimation of efficacy based on radiological responses and angiogenic serum markers. Registration number: NCT02528526.

Results

From April 2015 to July 2018, a total of 28 enrolled patients were assessed for the primary endpoints. ITPP was safe up to single doses of 12,390 mg/m2, and 32 ITPP-related adverse events occurred: 19 (67.8%) hypercalcemia, 5 (17.8%) hyponatremia, and 4 (14.2%) hypomagnesemia. Following ITPP monotherapy, 52% of patients displayed morphological disease stabilization. Following subsequent chemotherapy, 10% showed a partial response, and 60% had stable disease. Angiogenic markers were decreased in 60% after ITPP and tended to correlate with responses and survival after chemotherapy.

Conclusion

Administration of ITPP is safe up to 12,390 mg/m2 with favorable pharmacokinetics. Preliminary translational efficacy data show decreased angiogenic markers, which might indicate an anti-hypoxic effect and enhancement of chemotherapy through ITPP.
Robotic distal pancreatectomy, a novel standard of care? First benchmark values for surgical outcomes from 14 international expert centers
Authors: Müller P , Breuer E , Tschuor C , Saint-Marc O , Keck T , Coratti A , De Oliveira M , Allen P , Giulianotti P , Oberkofler C , Nickel F , Groot Koerkamp B , Martinie J , Yeo C , Hackert T , Petrowsky H , He J , Boggi U , Borel-Rinkes I H , Clavien P-A
Published: June 2022

Objective

Robotic distal pancreatectomy (DP) is emerging as the preferred treatment for body and tail tumors of the pancreas. To enable conclusive comparisons with the standard open or laparoscopic approaches and robotic surgery among centers, novel benchmark outcome values are urgently needed. Therefore, the aim of this study was to identify benchmark values from expert centers beyond the learning curve.

Methods

This multicenter study analyzed outcomes from consecutive patients undergoing robotic DP for resectable malignant or benign lesions from 14 international expert centers. After the learning curve, defined as the first 10 cases of robotic DP, all consecutive patients were included from the start of the program up to June 2020 with a minimum follow-up of 1 year. Benchmark patients were those without significant comorbidities including obesity (BMI >35 kg/m2) cardiac disease, chronic pulmonary disease.

Benchmark cutoff values were derived from the 75th or the 25th percentile of the median values of all benchmark centers.

Results

After reaching the learning curve, 289 (47%) of a total of 614 consecutive patients qualified as benchmark cases. The proportion of benchmark patients varied between 24%-64% per center. Benchmark cut-offs showed a low 6 month- postoperative mortality (<0.6%), but high overall morbidity (<58.3%). Benchmark cutoffs for operative time (<300 min), conversion rate (<3%), clinically relevant pancreatic fistulas (<26.9%), CCI at 90-days (<14.8), hospital stay (<7 days) and readmission rate (<22.9%). Benchmark cut-offs for complications remained unchanged after 3 months follow-up. For ductal adenocarcinoma benchmark cutoffs for number of lymph nodes were > 19 with an R0 resection rate of > 85%, and an overall survival of >86% and >52% after 1- and 5-years, respectively. Centers with a low cohort of benchmark patients (more difficult cases) had less clinically relevant pancreatic fistula (9% vs. 23%) and less overall complications (32% vs. 48%).

Conclusion

This benchmark analysis sets novel reference values for robotic DP, indicating favorable outcomes as compared to laparoscopic and open DP. These references values may serve for quality control of surgery in centers embarking in robotic DP, and include the procedure in the standard of care.
Compliance to infection-preventing measures in colorectal surgery – a word of caution
Authors: Deslarzes P , Jurt J , Hübner M , Demartines N , Grass F
Published: June 2022

Objective

The success of a colorectal surgical site infection (SSI) preventing bundle is dependent on compliance to individual infection-preventing measures. The present study aimed to assess whether challenging circumstances may affect bundle compliance.

Methods

Retrospective analysis including consecutive patients undergoing colorectal surgery and appendectomy between November 2018 and October 2020, after implementation of an evidence-based SSI-preventing care bundle. Bundle items were antibiotic administration, disinfection, core temperature control, glove change, intra-abdominal lavage and drain placement according to pre-defined standards. Compliance to each item was assessed according to surgical duration, patient age and time of surgery.

Results

Over the study period, 463 patients underwent appendectomy, 458 patients colonic surgery and 98 patients rectal resections. Compliance to intraabdominal lavage standards decreased significantly with surgical duration of colonic resections (88% for surgeries lasting <90 minutes vs. 56% for surgeries lasting > 180 minutes), while similar decreasing compliance patterns were observed regarding intraabdominal drain placement (86% vs. 68%) and core temperature control (64% vs. 57%, all p>0.05) with long lasting procedures. Compliance to antibiotic timing and glove change recommendations was higher in patients undergoing day-time colectomies (08 h and 16 h) compared to patients operated on during night shifts (0h-08 h, 93% vs. 69% and 87% vs. 58%, respectively, both p<0.05). Specific compliance patterns were not observed in patients undergoing appendectomy or rectal surgery. Furthermore, patient age had no impact on bundle compliance.

Conclusion

The present study revealed decreasing compliance to several infection-preventing bundle items with increasing surgical duration and during night shifts. This may contribute to worse outcomes in these challenging settings but may be a point of attention that can be corrected.
A multifactorial intervention to reduce use of antibiotics in acute uncomplicated diverticulitis – a single centre feasibility study
Authors: Galli R , Mitas D , Molteni P , Burri E , Lamm S , Rosenberg R
Published: June 2022

Objective

Standard treatment for uncomplicated diverticulitis in our institution consists of antibiotics. However, current evidence suggests that bacterial infection has a less predominant role than previously thought, and that uncomplicated acute diverticulitis may be a self-limiting condition in which inflammation can be managed without antibiotics. With the support of a multidisciplinary team we developed an intervention in order to reduce the use of antibiotics for patients with uncomplicated diverticular disease.

Methods

Standard practice and knowledge of current evidence were investigated with a structured survey sent to general practitioners and gastroenterologists with private practice in the area. A clinical process model for treatment of uncomplicated left-sided diverticulitis was created and exclusion criteria were selected in order to define patients with a high risk of developing complications. An educational intervention based on current evidence and the new treatment pathway was conducted on hospital staff as well as primary care physicians in the area in order to raise awareness about the possibility of avoiding antibiotics in uncomplicated diverticulitis. Patients were also involved and received an informative sheet about the rationale of the new treatment, the planned follow up and warning signs warranting further investigations and referral in case of outpatient treatment. All patients from May 2021 to December 2021 with a computed tomography-verified left-sided acute uncomplicated diverticulitis were included in the study and evaluated prospectively.

Results

Of 60 patients with acute uncomplicated diverticulitis, 23 (38%) were eligible for treatment without antibiotics. High inflammatory markers on presentation were the main reason (84%) for giving antibiotics. Adherence to the new policy was 74%. None of the 17 patients initially managed without antibiotics failed conservative treatment.

Conclusion

This project confirmed that treatment of uncomplicated diverticulitis without antibiotics can successfully be offered to a selected group of patients without altering the course of the disease. Further efforts are needed in order to overcome existing barriers to rational antimicrobial use such as lack of trust in new guidelines, general uncertainty and risk avoidance, patients’ expectations for antibiotic treatment, and fear of legal consequences.
Swiss pilot low-dose computed tomography lung cancer screening study
Authors: Jungblut L M , Walter J E , Zellweger C , Patella M , Franzen D , Schneiter D , Matter A , Frauenfelder T , Opitz I
Published: June 2022

Objective

Low-dose computed tomography (LDCT) lung cancer screening is endorsed by US guidelines and has recently been shown effective in a large European randomized controlled trial. Nevertheless, actual realization of a lung cancer screening program is challenging and depends on country-specific factors. This pilot study aimed to evaluate implementation, execution, and performance of LDCT lung cancer screening in Switzerland.

Methods

Since October 2018, asymptomatic participants aged 55–74 years with more than 30 pack-years smoking history were enrolled at a tertiary hospital in Switzerland. Participants with history of lung cancer, major (palliative) health problems or those that had a thorax CT scan 18 months prior to enrollment were excluded. First, we evaluated lung cancer risk according to NLST guidelines. Second, we estimated lung cancer risk using the PLCOm2012 model risk calculator with threshold of 5%. Lung nodules were assessed according to Lung-RADS (Version 1.1. 2019). Participants were recruited through flyers, a newspaper article and pulmonary specialists. Screening consisted of one LDCT-scan, follow-up was recommended for suspicious nodules only. LDCT assessment was performed by two radiologists, one of them a board certified chest radiologist. Enrollment and follow-up are currently ongoing.

Results

To date, 75 participants (25 (33%) females) with a median age of 62 years (interquartile range [IQR] 56–67 years) were included. Median number of pack years smoked was 49 (IQR 41–58 pack years). Median PLCOm2012 6-year lung cancer probability was 2.7% (IQR 2.6–2.9%), 19 (26%) participants had stopped smoking before enrollment. 6 participants required follow up imaging of suspect nodules, resulting in a recall rate of 8%. At baseline, lung cancer was found in 2 (2.7%, one squamous cell (stage IIIA) and one adenocarcinoma (stage IV)) participants.

Conclusion

In this Swiss LDCT lung cancer screening pilot study using modified inclusion criteria, 2.7% were diagnosed with lung cancer to date.
Local control and short-term outcomes after VATS segmentectomy vs lobectomy for pT1c pN0 NSCLC (2–3 cm)
Authors: Forster C , Abdelnour-Berchtold E , Bédat B , Perentes J Y , Sauvain M-O , Christodoulou M , Triponez F , Karenovics W , Krueger T , Gonzalez M
Published: June 2022

Objective

Pulmonary segmentectomy has shown comparable oncological results to lobectomy for non-small cell lung cancers (NSCLC) of less than 2 cm. However, controversy remains for tumors of larger size. The aim of this study was to compare short-term outcomes and local control in pT1c pN0 NSCLC that were intentionally treated by VATS segmentectomy or lobectomy.

Methods

Multicenter retrospective study from January 2014 to October 2021 of 162 consecutive patients undergoing complete (R0) anatomical resections for pT1c pN0 NSCLC. Two groups, VATS lobectomy (VL) or VATS segmentectomy (VS) were defined according to the extension of the resection. Patients’ characteristics, postoperative outcomes and survival were compared.

Results

In total, 162 patients underwent VL (n=81) or VS (n=81). Except for age (median of 68 vs 71 years, p=0.034) and past medical history of cancer (32% vs 48%, p=0.038), there was no difference between VL and VS in terms of demographics and comorbidities (table1). Segmentectomies were performed in upper lobes in 68% and single segments represented 46% of all cases. Conversion thoracotomy rate was 5% in both groups. Morbidity were similar in both groups (34% vs 30%, p=0.5). The median time for chest tube removal (3 vs 2 days, p=0.002) and median LOS (6 vs 5 days, p=0.039) were in favor of the VS group. Significantly larger tumor (25 mm vs 23.5 mm p=0.001) and an increased number of lymph nodes removal (median 14 vs 10, p<0.001) were found in the VL group. During the follow-up (median: 31 months), no statistical difference was found for local and distant recurrence in VL groups (12.3%) and VS group (6.2%) (p=0.414). Overall survival was comparable in-between both groups (p=0.166).

Conclusion

Despite a short follow-up, our preliminary data shows that local control is comparable for VATS lobectomy and VATS segmentectomy. Further prospective randomized trials are needed to corroborate these results.
The Prembion® pre-biotic improves the impact of anti-CTLA4 immune checkpoint inhibitor in a murine model of malignant pleural mesothelioma
Authors: Gattlen C , Chriqui L-E , Hao Y , Gonzalez M , Krueger T , Siankevich S , Dyson P , Cavin S , Perentes J-Y
Published: June 2022

Objective

Immune checkpoint inhibition (ICI) therapy has revolutionized the outcome of certain cancers such as malignant pleural mesothelioma (MPM). However, patient responsiveness to this treatment remains unpredictable. Recently, a role for the gut microbiota composition has emerged for patients to generate a robust immune response against their tumors, following immunotherapy. Here, we studied the impact of Prembion®, a pre-biotic and modulator of the gut microbiota, on tumor control and lymphocyte infiltration in a murine MPM model treated by ICI.

Methods

Prembion® (diluted into drinking water) was administrated to BALBc mice for 14 days. These animals were then inoculated orthotopically with a syngeneic MPM cell line (AB12-luc cells injected in the pleura) and followed by bioluminescence imaging. We determined the tumor growth and mouse survival in different groups: untreated control, Prembion®, IgG control, anti-PDL-1, anti-CTLA4, Prembion®+anti-PDL-1 and Prembion®+anti-CTLA4. A correlation between tumor response/animal survival and MPM infiltration with CD8+ lymphocytes was also performed by immunohistochemistry.

Results

Prembion® was well tolerated and did not affect animal weight or activity. Interestingly, Prembion® was as effective as anti-PDL1 and anti-CTLA4 monotherapy on tumor control, prolonging survival by 4.0 ± 1.1 days compared to controls (p<0.05). Moreover Prembion® potentiated anti-CTLA4 efficacy with a significant improvement in mouse survival of the Prembion®+anti-CTLA4 compared to controls (3.6 ± 1.1 days, p<0.05). Additionally, this finding correlated with enhanced MPM infiltration by CD8+ lymphocytes compared to controls (p<0.05).

Conclusion

Prembion® positively regulated the adaptive immune response against MPM and helped to improve the impact of anti-CTLA4 ICI on MPM. Further work focusing on the gut microbiome changes induced by Prembion® are ongoing to better understand the mechanisms involved.
Minimally invasive plate osteosynthesis for clavicle shaft fractures
Authors: Burkhard M D , Michelitsch C , Stillhard P F , Müller T , Sommer C
Published: June 2022

Objective

Whereas open reduction and internal fixation remains the surgical standard for displaced clavicle shaft fractures, the minimally invasive plate osteosynthesis (MIPO) technique has been introduced for multifragmentary, non-antomically reducible fractures, and unstable fractures with significant soft tissue injuries. Its advantages lie in the preservation of the vascular supply of the fracture zone and the preservation of the supraclavicular nerve. The aim of this study was to prove feasibility and share our experiences with this technique.

Methods

In this single center retrospective case series, we analyzed all patients that underwent MIPO for displaced clavicular shaft fractures from 2001–2021. Patient history, fracture morphology and perioperative data were documented. Outcomes were assessed based on clinical and radiographic follow-up reports.

Results

In total, 1128 clavicle osteosyntheses were performed, of which 908 (80.5%) were treated with a plate and 220 (19.5%) with titanium elastic nail (TEN). Of the 908 plate osteosyntheses, 43 (4.7%) were performed with the MIPO approach. Mean age was 44 ± 15 years, 83.3% were males and 79.1% were sports injuries. The fractures were categorized as AO/OTA type C injuries (n=26) in most patients, followed by A (n=9) and B (n=8). Two open (Gustilo I) and 41 closed fractures were noted (Tscherne 0=26; I=13, II=2). In seven patients (16.7%), the clavicle fractures were part of a severe polytrauma. Concomitant serial rib fractures and scapular fractures were found in 19 (45.2%) and 10 patients (23.8%), respectively. Length of surgery was 63 ± 28 min, and hospitalization was 4 ± 3 days (excl. polytraumas). 27 of the 43 fractures (62.8%) were clinically and radiographically followed up in our outpatient clinic, of which 26 (96.3%) healed with noticeable callus formation. In one case, a pseudoarthrosis was found two years after fracture treatment. Otherwise, all patients followed a remarkable postoperative course, were pain-free and able to return to work, most within five weeks.

Conclusion

In this retrospective analysis, 96.3% of the clavicle shaft fractures treated with MIPO healed in a timely manner. The MIPO technique is feasible and plausibly advantageous for distinct fracture and injury patterns (i.e. multifragmentary fractures or unstable fractures with soft tissue injuries). Future comparative studies are warranted to clarify our observations.
Hospital incidence and mortality of patients treated for AAA in Switzerland
Authors: Meuli L , Menges A-L , Steigmiller K , Kuehnl A , Reutersberg B , Held U , Zimmermann A
Published: June 2022

Objective

To analyse hospital incidence and in hospital mortality of patients treated for abdominal aortic aneurysms (AAA) in Switzerland.

Methods

Secondary data analysis of case-related hospital discharge data of the Swiss Federal Statistical Office for the years 2009–2018. Patients who were hospitalized and surgically treated for non-ruptured AAA (nrAAA) or hospitalized and treated for ruptured AAA (rAAA) were included in the analysis. Standardised incidences rates were calculated using the European standard population 2013. In-hospital mortality rates were calculated as raw values and standardized for age, sex, and the Elixhauser comorbidity score.

Results

A total of 10,728 patients were included in this study, of which 87.1% were male. 22.7% of the patients presented with rAAA, 46% of these patients were surgically treated whereas 54% patients received conservative therapy. The age standardized cumulative hospital incidence for treatment of nrAAA was 2.6 (95%-confidence interval: 2.5–2.8) and 19.7 (19.2–20.1) per 100,000 for women and men, respectively; for rAAA 0.4 (0.3–2.4) per 100,000 in women, and 2.7 (2.6–2.9) in men. The incidence rates were stable in the observed decade. The adjusted mortality rates for treatment of nrAAA decreased from 5.5% (2.6–11.2%) in 2009 to 1.4% (0.5–3.6%) in 2018 in women, and from 2.4% (1.3–4.5%) in 2009 to 0.6% (0.2–1.5%) in 2018 in men. The adjusted mortality rates for treatment of rAAA remained high without relevant improvements for both sexes over time; for women 32.4% (24.1–42.1%), for men 19.7% (16.8–22.8%).

Conclusion

The hospital incidence rates for nrAAA and rAAA remained unchanged in the observed decade. The incidence of rAAA is substantially higher than in comparable populations like Germany. Mortality rates in the elective setting are low and decreased in the last decade but remained high in patients treated for rAAA. Efforts to reduce the incidence of rAAA are needed to reduce aneurysm-related mortality in Switzerland.
Wing morphology covaries with migration distance in a highly aerial insectivorous songbird
Authors: Matyjasiak Piotr , López-Calderón Cosme , Ambrosini Roberto , Balbontín Javier , Costanzo Alessandra , Kiat Yosef , Romano Andrea , Rubolini Diego
Published: June 2022

According to classical prediction of aerodynamic theory, birds and other powered fliers that migrate over long distances should have longer and more pointed wings than those that migrate less. However, the association between wing morphology and migratory behavior can be masked by contrasting selective pressures related to foraging behavior, habitat selection and predator avoidance, possibly at the cost of lower flight energetic efficiency. We studied the handwing morphology of Eurasian barn swallows Hirundo rustica from four populations representing a migration distance gradient. This species is an aerial insectivore, so it flies extensively while foraging, and may migrate during the day using a ‘fly-and-forage’ migration strategy. Prolonged foraging flights may reinforce the effects of migration distance on flight morphology. We found that two wings’ aerodynamic properties—isometric handwing length and pointedness, both favoring energetically efficient flight, were more pronounced in barn swallows from populations undertaking longer seasonal migrations compared to less migratory populations. Our result contrast with two recent interspecific comparative studies that either reported no relationship or reported a negative relationship between pointedness and the degree of migratory behavior in hirundines. Our results may thus contribute to confirming the universality of the rule that longer migrations are associated with more pointed wings.
Bend relief fenestration might prevent outflow graft obstruction in patients with left ventricular assist device
Authors: Färber Gloria , Kirov Hristo , Schwan Imke , Gräger Stephanie , Diab Mahmoud , Tkebuchava Sophie , Doenst Torsten
Published: June 2022

OBJECTIVES

Patients with left ventricular assist devices may experience external obstruction of the outflow graft through a gelatinous substance within the bend relief (BR; a stiff tube graft guiding the outflow graft). Preventative strategies have been missing. Having faced this problem, we decided to fenestrate the BR to avoid outflow graft obstruction (OGO).

METHODS

Since December 2010, 167 patients underwent left ventricular assist device implantation using HeartMate II or 3. BR fenestration was introduced on July 2018 (108 patients before, 59 after the introduction of BR fenestration). Follow-up computed tomography scans were obtained from all patients and were screened for OGO by 3 independent investigators. Results were correlated with log file history, echocardiographic and clinical outcomes.

RESULTS

Demographic data were comparable between groups, with mostly male patients. Patients with BR fenestration were older [63 (standard deviation (SD):10.6) vs 58 (SD: 10.7) years] and had shorter support duration [494 (SD: 383) vs 951 (SD: 875) days]. OGO was observed in 5 patients and occurred only in patients without fenestration. Importantly, it occurred late on postoperative Days 412, 462, 1043, 1184 and 1506. Three patients are still asymptomatic. Surgical revision was required in the other 2 patients for pump thrombosis or continuous low flow. One of them died 36 days after revision due to right heart failure.

CONCLUSIONS

Our results suggest that fenestration of the BR may be a preventative strategy to avoid external OGO. OGO occurred late, which suggests a careful long-term follow-up.
Heterotopic lung transplant: a feasible approach to compensate for organ shortages
Authors: Zhao Jin , Ye ShuGao , Liu Feng , Huang Man , Xu Yongshan , Chen Yuan , Chen JingYu
Published: June 2022

Lung transplants are still limited by the shortage of suitable donor lungs, especially during the coronavirus disease 2019 pandemic. A heterotopic lung transplant (HLTx), as a flexible surgical procedure, can maximize the potential of donor lungs in an emergency, but its widespread use is hindered by difficulties in anastomosis and paucity of outcome data. We performed a retrospective review of 4 patients, each of whom received an HLTxs over 1 year, including 1 left-to-right single HLTx, 2 right-to-left single HLTxs and 1 lobar HLTx (right upper lobe-to-left). The median recipient age was 58.5 years (46–68); 3 patients were male. The postoperative hospital stay was 33 days (30–42). One recipient lived for 10 years and died of bronchiolitis obliterans syndrome; the others were alive with no major morbidity at 12 to 31 months after the operation with a 1-year survival of 100%. The follow-up chest images showed that transplanted lungs could be inflated well and adapted morphologically to fill the thoracic cavity in the short and long term. This study demonstrates that an HLTx is a feasible alternative to a conventional lung transplant in emergency cases and could be considered in selected patients at advanced medical centres.
Estimating the swelling potential of non-carbon–based binder (NCBB)-treated clayey soil for sustainable green subgrade using AI (GP, ANN and EPR) techniques
Authors: Onyelowe Kennedy C , Ebid Ahmed M , Onyia Michael E , Amanamba Ezenwa C
Published: June 2022

A zero carbon footprint stabilization approach has been adopted in this research to improve the swelling potential (SP) of clayey soils for a greener construction approach. Construction activities like earthworks during the cement stabilization of unstable soils utilized as reconstituted subgrade materials is responsible for the emission of unhealthy amount of carbon oxides into the atmosphere contributing to ozone layer depletion and eventual global warming. This has been substituted by using eco-friendly cementing materials, quicklime activated rice husk ash (QARHA), formulated in this research work. The SP of clayey soil treated with QARHA has been predicted using the learning abilities of genetic programming (GP), artificial neural network (ANN) and the evolutionary polynomial regression (EPR). This was aimed at reducing the over dependence on repeated laboratory visits and experiments prior to infrastructure (pavement) designs, construction and future monitoring of the performance of the facility. Multiple data were collected from multiple experiments based on the tested emergent material (QARHA) treatment proportions used in this work. The data were subjected to statistical analysis and predictive model exercises. At the end, the predicted models were validated on the basis of performance and accuracy. The performance indices showed that EPR and GP with R2 of 0.997 outclassed ANN with R2 of 0.994, but EPR outclassed the two, GP and ANN with a minimal error of 6.1%. The performances of GP, ANN and EPR were compared with a previously conducted model, which utilized the learning techniques of the adaptive neuro-fuzzy interface system (ANFIS) and it was observed that EPR and GP performed better than ANFIS but ANN performed at par with it. Generally, the predictive models can predict the SP of subgrade soil treated with QARHA, a non-carbon–based binder with accuracy above 90%, which is a very good outcome.
Stochastic optimal control of pre-exposure prophylaxis for HIV infection
Authors: Ðorđević Jasmina , Rognlien Dahl Kristina
Published: June 2022

The aim of the paper is to apply the stochastic optimal control problem in order to optimize the number of individual which will have the pre-exposure prophylaxis (PReP) treatment in the stochastic model for HIV/AIDS with PReP. By using the stochastic maximum principle, we derive the stochastic optimal control of PReP for the unconstrained control problem. Furthermore, by combining the stochastic maximum principle with a version of the Lagrange multiplier method, we solve the PReP problem for two different types of budget constrains with a given constrain for the costs (possible of different kind, transportation, price of the treatment, etc.). Obtained results for the different percentage of the individuals who got the vaccine, as well as results for unconstrained and constrained problems, are illustrated by a numerical example.
The Embodiment of Hegemony: Diplomatic Practices in the Ecuadorian Foreign Ministry
Authors: Aguas Lourdes , Pampinella Stephen
Published: June 2022

In this article, we explain Ecuador's foreign policy shift away from the counter-hegemonic project of the Pink Tide and toward the US-led international order. Current scholarship assumes that small states pursue moral recognition from great powers by reproducing the normative principles of the hegemonic order. However, the dynamics of small-state status seeking remain underexplored. How does domestic elite competition, including their preferred strategic narratives and histories of elite socialization, shape policymakers’ preferences for status within alternative international orders? Bourdieu's practice theory enables us to demonstrate how senior Ecuadorian diplomats embody the principles of the US-led hegemonic order. By analyzing documents, speeches, and the results of semistructured interviews, we show how diplomats’ tacit background knowledge led them to reject former president Rafael Correa's initiatives and replace them with a “professional” diplomacy and “pragmatic” foreign policy. Diplomats pursue moral authority not only for its own sake but also as a means of alleviating stigmas associated with Ecuador's intense subordination. In this way, diplomats legitimated the restoration of the pre-Correa liberal state. Their experience of hysteresis, or a mismatch between their habitus and field position, drove them to assert their taken-for-granted truths as a new orthodoxy once Correa departed.
P01 Urinary tract infections caused by ESBL-producing Escherichia coli in outpatients from Sarajevo, Bosnia and Herzegovina
Authors: Keser Sejla Kotoric , Balihodzic Amina Obradovic
Published: June 2022

Background

Urinary tract infections (UTIs) are common infections acquired in the community. Knowledge of local antibiotic susceptibility profile is important in decision-making of the optimal choice for empirical antimicrobial therapy and its duration. ESBL-producing strains of Enterobacterales are considered to be emerging pathogens. Recurrent UTI is one of the risk factors for infection with ESBL-producing bacteria.

Objectives

To report the prevalence of Escherichia coli uropathogens and the frequency of ESBL-producing E. coli strains isolated from urine of outpatients in Sarajevo Canton in Bosnia and Herzegovina.

Materials and methods

In this retrospective study, we collected antibiotic susceptibility data from urine samples analysed in the Microbiology Laboratory of the Institute for Public Health of Canton Sarajevo from 1 January to 31 December 2021. Urine samples were inoculated on CUA III Liofilchem® medium and incubated at 37°C for 24–48 h. A count of ≥ 100 000 cfu/mL of urine was considered positive after incubation, and these isolates were identified. The antimicrobial susceptibility testing was performed using the disc diffusion method, according to EUCAST guidelines and results interpreted following EUCAST breakpoint tables v.10.

Results

There were 34 087 urine samples from outpatients analysed in 2021. Out of this number, 23.72% (n = 8085) were positive. E. coli was identified in 70.27% (n = 5682) samples. ESBL E. coli was identified in 3.36% (n = 191) of all E. coli positive samples.

Conclusions

Geographic variations in pathogen occurrence and susceptibility profiles require continuous monitoring to provide information to guide the empirical therapeutic options.
P05 The impact of COVID-19 on antifungal stewardship in a UK tertiary teaching hospital: a review of prescribing practices and therapeutic drug monitoring of posaconazole
Authors: Andreani Adam , Tyler Netta , Micallef Christiane , Enoch David , Wong Vanessa
Published: June 2022

Background

Posaconazole is a triazole antifungal licensed for the prevention of invasive fungal infections (IFI) in haemato-oncology patients and treatment of IFI where first-line therapy has failed. In January 2020 COVID-19 hit the UK, with many NHS services reduced to meet the unprecedented challenges of the pandemic. We audited prescriptions and therapeutic drug monitoring (TDM) of posaconazole and compared the results with an audit conducted pre-COVID-19 to assess the impact of the pandemic on antifungal stewardship (AFS).

Methods

Inpatients prescribed posaconazole over two 3 month periods (1 October to 31 December 2019 and 2020) at Addenbrooke's Hospital, Cambridge, were identified using an electronic computer system and their records reviewed for demographic, diagnostic and therapeutic data. Posaconazole levels were performed at the national Mycology Reference Laboratory, Bristol, using guide levels of 0.7–3.75 mg/L (prophylaxis) and 1–3.75 mg/L (treatment). The first pre-dose level for each patient was used in analyses. Audit standards included (i) all inpatients on posaconazole to have an indication in local guidelines; (ii) to have the correct loading dose prescribed; (iii) to have a pre-dose level taken (iv) at the correct time (i.e. between Day 3–8) after commencing therapy or a dose change; (v) to have a turnaround time of ≤5 days; and (vi) to stop posaconazole appropriately.

Results

Forty-two 42 inpatients received posaconazole in 2020 (49, 2019). In total, 39/42 (93%) patients had an appropriate indication [46/49, (94%), 2019]: 38/40 (95%) for prophylaxis [45/45, (100%) 2019]; 1/2 (50%) for treatment [1/1, (100%) 2019]. In 2020, 34/42 (81%) of patients received the correct loading dose [41/46 (89%), 2019). TDM was performed on 33/42 (79%) patients [46/46 (100%), 2019], 18/42 (43%) 3–8 days after starting [25/46 (54%), 2019] and 3/13 (23%) after a dose change [9/10 (90%), 2019]; 32/33 (97%) of TDM results were reported in ≤5 days [32/46 (70%), 2019]. Posaconazole was stopped in 24/26 (92%) patients who were no longer receiving immunosuppression and/or neutropenia had resolved [23/23 (100%), 2019].

Conclusions

Despite the pressures of COVID-19, there were good standards of care with only slight reductions in compliance, with the exception of TDM. This may have reflected the change from face-to-face to virtual meetings with haemato-oncology, as well as representing issues of staff shortages and changes in hospital priorities. Such data have highlighted the usefulness of technology to facilitate AFS, e.g. electronic prescribing order sets, which would provide us with quality assurance in a system that will be facing ongoing pressures from the pandemic for years to come.