Readiness to provide comprehensive emergency obstetric and neonatal care: a cross-sectional study in 30 health facilities in Tanzania.

BACKGROUND: Despite the global progress in bringing health services closer to the population, mothers and their newborns still receive substandard care leading to morbidity and mortality. Health facilities' capacity to deliver the service is a prerequisite for quality health care. This study aimed to assess health facilities' readiness to provide comprehensive emergency obstetric and newborn care (CEmONC), comprising of blood transfusion, caesarean section and basic services, and hence to inform improvement in the quality of care interventions in Tanzania. METHODS: A cross-sectional assessment of 30 CEmONC health facilities implementing the Safer Births Bundle of Care package in five regions of Tanzania was carried out between December 2020 and January 2021. We adapted the World Health Organization's Service Availability and Readiness Assessment tool to assess amenities, equipment, trained staff, guidelines, medicines, and diagnostic facilities. Composite readiness scores were calculated for each category and results were compared at the health facility level. For categorical variables, we tested for differences by Fisher's exact test; for readiness scores, differences were tested by a linear mixed model analysis, taking into account dependencies within the regions. We used p < 0.05 as our level of significance. RESULTS: The overall readiness to provide CEmONC was 69.0% and significantly higher for regional hospitals followed by district hospitals. Average readiness was 78.9% for basic amenities, 76.7% for medical equipment, 76.0% for diagnosis and treatment commodities, 63.6% for staffing and 50.0% for guidelines. There was a variation in the availability of items at the individual health facility level and across levels of facilities. We found a significant difference in the availability of basic amenities, equipment, staffing, and guidelines between regional, and district hospitals and health centres (p = 0.05). Regional hospitals had significantly higher scores of medical equipment than district hospitals and health centers (p = 0.02). There was no significant difference in the availability of commodities for diagnosis and treatment between different facility levels. CONCLUSION: Facilities' readiness was inadequate and varied across different levels of the facility. There is room to improve the facilities' readiness to deliver quality maternal and newborn care. The responsible authorities should take immediate actions to address the observed deficiencies while carefully choosing the most effective and feasible interventions and monitoring progress in readiness.

High mobility group box 1 and a network of other biomolecules influence fatigue in patients with Crohn's disease.

BACKGROUND: Fatigue is common in patients with chronic inflammatory and autoimmune diseases, often with a severe impact on the patient's daily life. From a biological point of view, fatigue can be regarded as an element of the sickness behavior response, a coordinated set of responses induced by pathogens to enhance survival during an infection and immunological danger. The mechanisms are not fully understood but involve activation of the innate immune system, with pro-inflammatory cytokines, in particular interleukin (IL)-1ß, acting on cerebral neurons. These mechanisms are also active during chronic inflammatory conditions. High mobility group box 1 (HMGB1) protein has interleukin-1 like properties and is a strong inducer of innate immune responses. Its role in generation of fatigue is not clarified. Emerging evidence indicates that also other biomolecules may influence sickness behavior. We aimed to elucidate how HMGB1 influences fatigue in patients with Crohn's disease, and how the protein interacts with other candidate biomarkers of fatigue. METHODS: In 56 patients with newly diagnosed Crohn's disease, fatigue was evaluated using three different fatigue instruments: the fatigue visual analog scale (fVAS), Fatigue Severity Scale (FSS), and the vitality subscale of Medical Outcomes Study Short-Form Health Survey (SF-36vs). The biochemical markers IL-1 receptor antagonist (RA), soluble IL-1 receptor type 2 (sIL-RII), heat shock protein 90 alpha (HSP90α), HMGB1, anti-fully reduced (fr)HMGB1 antibodies (abs), hemopexin (HPX), and pigment epithelium-derived factor (PEDF) were measured in plasma. Multivariable regression and principal component analyses (PCA) were applied. RESULTS: Multivariable regression analyses revealed significant contributions to fatigue severity for HMGB1 in the FSS model, HSP90α in the fVAS model and IL-1RA in the SF-36vs model. Depression and pain scores contributed to all three models. In PCA, two components described 53.3% of the variation. The "inflammation and cellular stress dimension" was dominated by IL-1RA, sIL-1RII, HSP90α, HPX, and PEDF scores, where the "HMGB1 dimension" was dominated by HMGB1, anti-frHMGB1 abs, and fVAS scores. CONCLUSION: This study supports the hypothesis that HMGB1 and a network of other biomolecules influence fatigue severity in chronic inflammatory conditions. The well-known association with depression and pain is also acknowledged.

Importance of endocrine treatment adherence and persistence in breast cancer survivorship: a systematic review.

PURPOSE: Adjuvant endocrine treatment is essential for treating luminal subtypes of breast cancer, which constitute 75% of all breast malignancies. However, the detrimental side effects of treatment make it difficult for many patients to complete the guideline-required treatment. Such non-adherence may jeopardize the lifesaving ability of anti-estrogen therapy. In this systematic review, we aimed to assess the consequences of non-adherence and non-persistence from available studies meeting strict statistical and clinical criteria. METHODS: A systematic literature search was performed using several databases, yielding identification of 2,026 studies. After strict selection, 14 studies were eligible for systematic review. The review included studies that examined endocrine treatment non-adherence (patients not taking treatment as prescribed) or non-persistence (patients stopping treatment prematurely), in terms of the effects on event-free survival or overall survival among women with non-metastatic breast cancer. RESULTS: We identified 10 studies measuring the effects of endocrine treatment non-adherence and non-persistence on event-free survival. Of these studies, seven showed significantly poorer survival for the non-adherent or non-persistent patient groups, with hazard ratios (HRs) ranging from 1.39 (95% CI, 1.07 to 1.53) to 2.44 (95% CI, 1.89 to 3.14). We identified nine studies measuring the effects of endocrine treatment non-adherence and non-persistence on overall survival. Of these studies, seven demonstrated significantly reduced overall survival in the groups with non-adherence and non-persistence, with HRs ranging from 1.26 (95% CI, 1.11 to 1.43) to 2.18 (95% CI, 1.99 to 2.39). CONCLUSION: The present systematic review demonstrates that non-adherence and non-persistence to endocrine treatment negatively affect event-free and overall survival. Improved follow-up, with focus on adherence and persistence, is vital for improving health outcomes among patients with non-metastatic breast cancer.

Laparoscopic rectal cancer resection yields comparable clinical and oncological results with shorter hospital stay compared to open access: a 5-year national cohort.

PURPOSE: Although widely applied, the results following laparoscopic rectal resection (LRR) compared to open rectal resection (ORR) are still debated. The aim of this study was to assess clinical short- and long-term results as well as oncological resection quality following LRR or ORR for cancer in a 5-year national cohort. METHODS: Data from the Norwegian Registry for Gastrointestinal Surgery and the Norwegian Colorectal Cancer Registry were retrieved from January 2014 to December 2018 for patients who underwent elective resection for rectal cancer. Primary end point was 5-year overall survival. Secondary end points were local recurrence rates within 5 years, oncological resection quality, and short-term outcome measures. RESULTS: A total of 1796 patients were included, of whom 1284 had undergone LRR and 512 ORR. There was no difference in 5-year survival rates between the groups after adjusting for relevant covariates with Cox regression analyses. Crude 5-year survival was 77.1% following LRR compared to 74.8% following ORR (p = 0.015). The 5-year local recurrence rates were 3.1% following LRR and 4.1% following ORR (p = 0.249). Length of hospital stay was median 8.0 days (quartiles 7.0-13.0) after ORR compared to 6.0 (quartiles 4.0-8.0) days after LRR. After adjusting for relevant covariates, estimated additional length of stay after ORR was 3.1 days (p < 0.001, 95% CI 2.3-3.9). Rates of positive resection margins and number of harvested lymph nodes were similar. There were no other significant differences in short-term outcomes between the groups. CONCLUSION: LRR was performed with clinical and oncological outcomes similar to ORR, but with shorter hospital stay.

Newborns requiring resuscitation: Two thirds have heart rate ≥100 beats/minute in the first minute after birth.

AIM: The aim was to study the prevalence of bradycardia at birth in newborns requiring positive pressure ventilation (PPV), distribution of first measured heart rate (HR), changes in HR before start of PPV and HR response to PPV. METHODS: A population-based study including newborns ≥30 weeks' gestation receiving PPV at birth. HR was captured immediately after birth and continuously throughout resuscitation using the dry-electrode ECG device NeoBeat. Time of birth was registered in the Liveborn app. Provision of PPV was captured by video. RESULTS: We included 98 newborns receiving PPV at birth. Among newborns with HR measured within 60 s after birth, median (quartiles) first HR was 112 (84, 149) bpm recorded 19 (14, 37) s after birth, of which 33% had first HR <100 and 10% had first HR <60 bpm respectively. First HR was widely distributed. Median HR at start PPV 69 s after birth was 129 bpm. In newborns with an initial low HR, HR typically remained low for 20 s of PPV before increasing rapidly over the next 20-30 s. CONCLUSIONS: First measured HR was ≥100 bpm in two thirds of newborns receiving PPV. In bradycardic infants, HR did not increase until after 20 s of PPV.

Reduction in omission events after implementing a Rapid Response System: a mortality review in a department of gastrointestinal surgery.

BACKGROUND: Hospitals worldwide have implemented Rapid Response Systems (RRS) to facilitate early recognition and prompt response by trained personnel to deteriorating patients. A key concept of this system is that it should prevent 'events of omission', including failure to monitor patients' vital signs, delayed detection, and treatment of deterioration and delayed transfer to an intensive care unit. Time matters when a patient deteriorates, and several in-hospital challenges may prevent the RRS from functioning adequately. Therefore, we must understand and address barriers for timely and adequate responses in cases of patient deterioration. Thus, this study aimed to investigate whether implementing (2012) and developing (2016) an RRS was associated with an overall temporal improvement and to identify needs for further improvement by studying; patient monitoring, omission event occurrences, documentation of limitation of medical treatment, unexpected death, and in-hospital- and 30-day mortality rates. METHODS: We performed an interprofessional mortality review to study the trajectory of the last hospital stay of patients dying in the study wards in three time periods (P1, P2, P3) from 2010 to 2019. We used non-parametric tests to test for differences between the periods. We also studied overall temporal trends in in-hospital- and 30-day mortality rates. RESULTS: Fewer patients experienced omission events (P1: 40%, P2: 20%, P3: 11%, P = 0.01). The number of documented complete vital sign sets, median (Q1,Q3) P1: 0 (0,0), P2: 2 (1,2), P3: 4 (3,5), P = 0.01) and intensive care consultations in the wards ( P1: 12%, P2: 30%, P3: 33%, P = 0.007) increased. Limitations of medical treatment were documented earlier (median days from admission were P1: 8, P2: 8, P3: 3, P = 0.01). In-hospital and 30-day mortality rates decreased during this decade (rate ratios 0.95 (95% CI: 0.92-0.98) and 0.97 (95% CI: 0.95-0.99)). CONCLUSION: The RRS implementation and development during the last decade was associated with reduced omission events, earlier documentation of limitation of medical treatments, and a temporal reduction in the in-hospital- and 30-day mortality rates in the study wards. The mortality review is a suitable method to evaluate an RRS and provide a foundation for further improvement. TRIAL REGISTRATION: Retrospectively registered.

The influence of disease activity on fatigue in patients with ulcerative colitis - a longitudinal study.

OBJECTIVE: The relationship between the disease activity of ulcerative colitis and fatigue is unclear. We investigated how reaching deep remission versus remaining in active disease influenced the severity of fatigue. MATERIALS AND METHODS: We included 149 consecutive patients in a longitudinal study. Patients were re-examined after 3 months of conventional treatment and dichotomized into A: Active disease or B: Deep remission. The Partial Mayo Score (PMS) was recorded in all patients. Fatigue was rated using the fatigue visual analog scale (fVAS), Fatigue Severity Scale (FSS), and Short Form-36 Vitality Subscale (SF-36vs). A control group of 22 age and sex-matched healthy subjects were included as controls for patients reaching deep remission. RESULTS: After 3 months there were no significant differences in fVAS, FSS and SF-36vs scores in patients with active disease compared to patients reaching deep remission, when adjusting for baseline fatigue scores. Patients in remission based on MES-UC scores had no significant reduction in fatigue scores, whereas patients in remission based on PMS had all three fatigue scores reduced. However, patients reaching deep remission still had higher fVAS and lower SF-36vs scores compared to healthy control subjects. CONCLUSIONS: After 3 months of conventional treatment there were no differences in fatigue severity in patients reaching deep remission compared with patients still having active disease. Fatigue was more pronounced in patients in deep remission than in healthy subjects, and was associated with subjective and not objective measures of disease activity. This indicates that other potent factors than inflammation influence fatigue in UC.

Lower conversion rate with robotic assisted rectal resections compared with conventional laparoscopy; a national cohort study.

BACKGROUND: Conversion from laparoscopic to open access colorectal surgery is associated with a poorer postoperative outcome. The aim of this study was to assess conversion rates and outcomes after standard laparoscopic rectal resection (LR) and robotic laparoscopic rectal resection (RR). METHODS: A national 5-year cohort study utilizing prospectively recorded data on patients who underwent elective major laparoscopic resection for rectal cancer. Data were retrieved from the Norwegian Registry for Gastrointestinal Surgery and from the Norwegian Colorectal Cancer Registry. Primary end point was conversion rate. Secondary end points were postoperative complications within 30 days and histopathological results. Chi-square test, two-sided T test, and Mann-Whitney U test were used for univariable analyses. Both univariable and multivariable logistic regression analyses were used to analyze the relations between different predictors and outcomes, and propensity score matching was performed to address potential treatment assignment bias. RESULTS: A total of 1284 patients were included, of whom 375 underwent RR and 909 LR. Conversion rate was 8 out of 375 (2.1%) for RR compared with 87 out of 909 (9.6%) for LR (p < 0.001). RR was associated with reduced risk for conversion compared with LR (aOR 0.22, 95% CI 0.10-0.46). There were no other outcome differences between RR and LR. Factors associated with increased risk for conversion were male gender, severe cardiac disease and BMI > 30. Conversion was associated with higher rates of major complications (20 out of 95 (21.2%) vs 135 out of 1189 (11.4%) p = 0.005), reoperations (13 out of 95 (13.7%) vs 93 out of 1189 (7.1%) p = 0.020), and longer hospital stay (median 8 days vs 6 days, p = 0.001). CONCLUSION: Conversion rate was lower with robotic assisted rectal resections compared with conventional laparoscopy. Conversions were associated with higher rates of postoperative complications.

A Risk Model of Admitting Patients With Silent SARS-CoV-2 Infection to Surgery and Development of Severe Postoperative Outcomes and Death: Projections Over 24 Months for 5 Geographical Regions.

OBJECTIVE: To model the risk of admitting silent COVID-19-infected patients to surgery with subsequent risk of severe pulmonary complications and mortality. SUMMARY BACKGROUND DATA: With millions of operations cancelled during the COVID-19 pandemic, pressure is mounting to reopen and increase surgical activity. The risk of admitting patients who have silent SARS-Cov-2 infection to surgery is not well investigated, but surgery on patients with COVID-19 is associated with poor outcomes. We aimed to model the risk of operating on nonsymptomatic infected individuals and associated risk of perioperative adverse outcomes and death. METHODS: We developed 2 sets of models to evaluate the risk of admitting silent COVID-19-infected patients to surgery. A static model let the underlying infection rate (R rate) and the gross population-rate of surgery vary. In a stochastic model, the dynamics of the COVID-19 prevalence and a fixed population-rate of surgery was considered. We generated uncertainty intervals (UIs) for our estimates by running low and high scenarios using the lower and upper 90% uncertainty limits. The modelling was applied for high-income regions (eg, United Kingdom (UK), USA (US) and European Union without UK (EU27), and for the World (WORLD) based on the WHO standard population. RESULTS: Both models provided concerning rates of perioperative risk over a 24-months period. For the US, the modelled rates were 92,000 (UI 68,000-124,000) pulmonary complications and almost 30,000 deaths (UI 22,000-40·000), respectively; for Europe, some 131,000 patients (UI 97,000-178,000) with pulmonary complications and close to 47,000 deaths (UI 34,000-63,000) were modelled. For the UK, the model suggested a median daily number of operations on silently infected ranging between 25 and 90, accumulating about 18,700 (UI 13,700-25,300) perioperative pulmonary complications and 6400 (UI 4600-8600) deaths. In high-income regions combined, we estimated around 259,000 (UI 191,000-351,000) pulmonary complications and 89,000 deaths (UI 65,000-120,000). For the WORLD, even low surgery rates estimated a global number of 1.2 million pulmonary complications and 350,000 deaths. CONCLUSIONS: The model highlights a considerable risk of admitting patients with silent COVID-19 to surgery with an associated risk for adverse perioperative outcomes and deaths. Strategies to avoid excessive complications and deaths after surgery during the pandemic are needed.

The impact of introducing ambulance and delivery fees in a rural hospital in Tanzania.

BACKGROUND: Access to health care facilities is a key requirement to enhance safety for mothers and newborns during labour and delivery. Haydom Lutheran Hospital (HLH) is a regional hospital in rural Tanzania with a catchment area of about two million inhabitants. Up to June 2013 ambulance transport and delivery at HLH were free of charge, while a user fee for both services was introduced from January 2014. We aimed to explore the impact of introducing user fees on the population of women giving birth at HLH in order to document potentially unwanted consequences in the period after introduction of fees. METHODS: Retrospective analysis of data from a prospective observational study. Data was compared between the period before introduction of fees from February 2010 through June 2013 and the period after from January 2014 through January 2017. Logistic regression modelling was used to construct risk-adjusted variable-life adjusted display (VLAD) and cumulative sum (CUSUM) plots to monitor changes. RESULTS: A total of 28,601 births were observed. The monthly number of births was reduced by 17.3% during the post-introduction period. Spontaneous vaginal deliveries were registered less frequently with a decrease of about 17/1000 births in non-cephalic presentations. Labour complications and caesarean sections increased with about 80/1000 births. There was a reduction in newborns with birth weight less than 2500 g. The observed changes were stable over time. For most variables, a significant change could be detected after a few weeks. CONCLUSION: After the introduction of ambulance and delivery fees, an increase in labour complications and caesarean sections and a decrease in newborns with low birthweight were observed. This might indicate that women delay the decision to seek skilled birth attendance or do not seek help at all, possibly due to financial reasons. Lower rates of births in a safe health care facility like HLH is of great concern, as access to skilled birth attendance is a key requirement in order to further reduce perinatal mortality. Therefore, free delivery care should be a high priority.

Long-Term Outcomes After Open Repair for Ruptured Abdominal Aortic Aneurysm.

BACKGROUND: Early mortality in ruptured abdominal aneurysm (rAAA) is high, but data on long-term outcome are scarce. The aim of this study was to investigate the long-term outcome in survivors after open surgery for rAAA in well-defined population. METHODS: This is a population-based, observational long-term follow-up (beyond 30-day mortality) study of patients surgically treated for rAAA from 2000 through 2014. Long-term survival was analysed using Kaplan-Meier estimates and compared to the general population by analyses of relative survival. RESULTS: Out of 178 patients operated for rAAA, 95 patients (55%) either died in the perioperative period, were referred from other hospitals or were lost to follow-up (two patients). Altogether 83 patients were eligible for long-term outcomes: 72 men and 11 women. Estimated median crude survival time was 6.5 years [95% confidence interval (CI) 4.8-8.2]. Men had a median survival of 7.3 years (95% CI 5.1-9.4) versus 5.4 years in females (95% CI 3.5-7.3) (P = 0.082). Reinterventions during follow-up occurred in 31 (37%). Relative survival demonstrated a slightly higher risk of death in the rAAA population compared to the general age- and gender-matched population. Age, but not comorbidities, had a significant influence on long-term survival. CONCLUSION: For survivors beyond 30 days after surgery for rAAA, long-term survival compares well to that of an age- and sex-matched population. A high frequency of cardiovascular comorbidities did not seem to affect long-term survival.

Thyroidectomy Versus Medical Management for Euthyroid Patients With Hashimoto Disease and Persisting Symptoms: A Randomized Trial.

Background: Hashimoto disease is a chronic autoimmune thyroiditis. Despite adequate hormone substitution, some patients have persistent symptoms that may be the result of immunologic pathophysiology. Objective: To determine whether thyroidectomy improves symptoms in patients with Hashimoto thyroiditis who still have symptoms despite having normal thyroid gland function while receiving medical therapy. Design: Randomized trial. (ClinicalTrials.gov: NCT02319538). Setting: Secondary care hospital in Norway. Patients: 150 patients aged 18 to 79 years with persistent Hashimoto-related symptoms despite euthyroid status while receiving hormone replacement therapy and with serum antithyroid peroxidase (anti-TPO) antibody titers greater than 1000 IU/mL. Intervention: Total thyroidectomy or medical management with hormone substitution to secure euthyroid status in both groups. Measurements: The primary outcome was general health score on the Short Form-36 Health Survey (SF-36) at 18 months. Secondary outcomes were adverse effects of surgery, the other 7 SF-36 subscores, fatigue questionnaire scores, and serum anti-TPO antibody titers at 6, 12, and 18 months. Results: During follow-up, only the surgical group demonstrated improvement: Mean general health score increased from 38 to 64 points, for a between-group difference of 29 points (95% CI, 22 to 35 points) at 18 months. Fatigue score decreased from 23 to 14 points, for a between-group difference of 9.3 points (CI, 7.4 to 11.2 points). Chronic fatigue frequency decreased from 82% to 35%, for a between-group difference of 39 percentage points (CI, 23 to 53 percentage points). Median serum anti-TPO antibody titers decreased from 2232 to 152 IU/mL, for a between-group difference of 1148 IU/mL (CI, 1080 to 1304 IU/mL). In multivariable regression analyses, the adjusted treatment effects remained similar to the unadjusted effects. Limitation: Results are applicable only to a subgroup of patients with Hashimoto disease, and follow-up was limited to 18 months. Conclusion: Total thyroidectomy improved health-related quality of life and fatigue, whereas medical therapy did not. This improvement, along with concomitant elimination of serum anti-TPO antibodies, may elucidate disease mechanisms. Primary Funding Source: Telemark Hospital.

Drug monitoring of tamoxifen metabolites predicts vaginal dryness and verifies a low discontinuation rate from the Norwegian Prescription Database.

PURPOSE: Tamoxifen is an important targeted endocrine therapy in breast cancer. However, side effects and early discontinuation of tamoxifen remains a barrier for obtaining the improved outcome benefits of long-term tamoxifen treatment. Biomarkers predictive of tamoxifen side effects remain unidentified. The objective of this prospective population-based study was to investigate the value of tamoxifen metabolite concentrations as biomarkers for side effects. A second objective was to assess the validity of discontinuation rates obtained through pharmacy records with the use of tamoxifen drug monitoring. METHODS: Longitudinal serum samples, patient-reported outcome measures and pharmacy records from 220 breast cancer patients were obtained over a 6-year period. Serum concentrations of tamoxifen metabolites were measured by LC-MS/MS. Associations between metabolite concentrations and side effects were analyzed by logistic regression and cross table analyses. To determine the validity of pharmacy records we compared longitudinal tamoxifen concentrations to discontinuation rates obtained through the Norwegian Prescription database (NorPD). Multivariable Cox regression models were performed to identify predictors of discontinuation. RESULTS: At the 2nd year of follow-up, a significant association between vaginal dryness and high concentrations of tamoxifen, Z-4'-OHtam and tam-NoX was identified. NorPD showed a tamoxifen-discontinuation rate of 17.9% at 5 years and drug monitoring demonstrated similar rates. Nausea, vaginal dryness and chemotherapy-naive status were significant risk factors for tamoxifen discontinuation. CONCLUSIONS: This real-world data study suggests that measurements of tamoxifen metabolite concentrations may be predictive of vaginal dryness in breast cancer patients and verifies NorPD as a reliable source of adherence data.

Interleukin-1-related activity and hypocretin-1 in cerebrospinal fluid contribute to fatigue in primary Sjögren's syndrome.

BACKGROUND: Fatigue is a common and sometimes debilitating phenomenon in primary Sjögren's syndrome (pSS) and other chronic inflammatory diseases. We aimed to investigate how IL-1 ß-related molecules and the neuropeptide hypocretin-1 (Hcrt1), a regulator of wakefulness, influence fatigue. METHODS: Hcrt1 was measured by radioimmunoassay (RIA) in cerebrospinal fluid (CSF) from 49 patients with pSS. Interleukin-1 receptor antagonist (IL-1Ra), IL-1 receptor type 2 (IL-1RII), IL-6, and S100B protein were measured by enzyme-linked immunosorbent assay (ELISA). Fatigue was rated by the fatigue visual analog scale (fVAS). RESULTS: Simple univariate regression and multiple regression analyses with fatigue as a dependent variable revealed that depression, pain, and the biochemical variable IL-1Ra had a significant association with fatigue. In PCA, two significant components were revealed. The first component (PC1) was dominated by variables related to IL-1ß activity (IL-1Ra, IL-1RII, and S100B). PC2 showed a negative association between IL-6 and Hcrt1. fVAS was then introduced as an additional variable. This new model demonstrated that fatigue had a higher association with the IL-1ß-related PC1 than to PC2. Additionally, a third component (PC3) became significant between low Hcrt1 concentrations and fVAS scores. CONCLUSIONS: The main findings of this study indicate a functional network in which several IL-1ß-related molecules in CSF influence fatigue in addition to the classical clinical factors of depression and pain. The neuropeptide Hcrt1 seems to participate in fatigue generation, but likely not through the IL-1 pathway.

Influence of pre-operative oral carbohydrate loading vs. standard fasting on tumor proliferation and clinical outcome in breast cancer patients ─ a randomized trial.

BACKGROUND: Conflicting results have been reported on the influence of carbohydrates in breast cancer. OBJECTIVE: To determine the influence of pre-operative per-oral carbohydrate load on proliferation in breast tumors. DESIGN: Randomized controlled trial. SETTING: University hospital with primary and secondary care functions in South-West Norway. PATIENTS: Sixty-one patients with operable breast cancer from a population-based cohort. INTERVENTION: Per-oral carbohydrate load (preOp™) 18 and 2-4 h before surgery (n = 26) or standard pre-operative fasting with free consumption of tap water (n = 35). MEASUREMENTS: The primary outcome was post-operative tumor proliferation measured by the mitotic activity index (MAI). The secondary outcomes were changes in the levels of serum insulin, insulin-c-peptide, glucose, IGF-1, and IGFBP3; patients' well-being, and clinical outcome over a median follow-up of 88 months (range 33-97 months). RESULTS: In the estrogen receptor (ER) positive subgroup (n = 50), high proliferation (MAI ≥ 10) occurred more often in the carbohydrate group (CH) than in the fasting group (p = 0.038). The CH group was more frequently progesterone receptor (PR) negative (p = 0.014). The CH group had a significant increase in insulin (+ 24.31 mIE/L, 95% CI 15.34 mIE/L to 33.27 mIE/L) and insulin c-peptide (+ 1.39 nM, 95% CI 1.03 nM to 1.77 nM), but reduced IGFBP3 levels (- 0.26 nM; 95% CI - 0.46 nM to - 0.051 nM) compared to the fasting group. CH-intervention ER-positive patients had poorer relapse-free survival (73%) than the fasting group (100%; p = 0.012; HR = 9.3, 95% CI, 1.1 to 77.7). In the ER-positive patients, only tumor size (p = 0.021; HR = 6.07, 95% CI 1.31 to 28.03) and the CH/fasting subgrouping (p = 0.040; HR = 9.30, 95% CI 1.11 to 77.82) had independent prognostic value. The adverse clinical outcome of carbohydrate loading occurred only in T2 patients with relapse-free survival of 100% in the fasting group vs. 33% in the CH group (p = 0.015; HR = inf). The CH group reported less pain on days 5 and 6 than the control group (p <  0.001) but otherwise exhibited no factors related to well-being. LIMITATION: Only applicable to T2 tumors in patients with ER-positive breast cancer. CONCLUSIONS: Pre-operative carbohydrate load increases proliferation and PR-negativity in ER-positive patients and worsens clinical outcome in ER-positive T2 patients. TRIAL REGISTRATION: CliniTrials.gov; NCT03886389. Retrospectively registered March 22, 2019.

A Population-Based Study of Incidence, Presentation, Management and Outcome of Primary Thromboembolic Ischemia in the Upper Extremity.

OBJECTIVES: To investigate the epidemiology of acute upper limb thromboembolism in a well-defined Norwegian population. METHODS: This study was a retrospective, single-center, observational population-based cohort study of acute upper limb thromboembolism. The study included all patients from the hospital's primary catchment area from January 2000 to December 2015. Age- and gender-adjusted incidence rates were calculated using population demographics from Statistics Norway. RESULTS: A total of 54 patients were identified, of which 49 were included in the analyses: 27 (55%) females (median age 83 years, range 40-96) and 22 (45%) males (median age 70 years, range 42-95) (P = .053). The adjusted incidence rate for the period was 1.6 patients per 100,000 inhabitants per year (95% confidence interval 1.2-2.2) and did not change significantly during the period studied. Atrial fibrillation was detected by electrocardiography in 30 (61%) patients; in this group, 10 patients were on warfarin but only two had an international normalized ratio > 1.9 and the remaining 20 were not anticoagulated. Altogether, 38 (78%) patients underwent surgery, 1 (2%) was treated with thrombolysis, and the remaining patients were treated conservatively; no amputations were performed. Four patients (8%) died within 30 days, and 12 of the surviving 45 patients (27%) had recurrent thromboembolism. CONCLUSION: The incidence rate was stable during the study period. Patients with upper limb thromboembolism due to atrial fibrillation were inadequately anticoagulated. One in four patients experienced a recurrent thromboembolic event. Lifelong anticoagulation should be considered in all patients with upper limb thromboembolism.

Tolerability and safety of long-term rituximab treatment in systemic inflammatory and autoimmune diseases.

Rituximab, an anti-CD20 monoclonal antibody causing selective B-cell depletion, is used for various systemic inflammatory and autoimmune diseases (SIADs). Long-term safety data on rituximab are limited. The objectives of this study were to evaluate the long-term safety and tolerability of rituximab treatment for SIADs. A retrospective, single-center observational study including all patients ≥ 16 years treated with rituximab for SIADs was performed. The electronic medical records were reviewed, and data concerning indication and duration of rituximab treatment, prior and concurrent immunosuppressive therapy, and adverse events such as infections requiring hospitalization, dysgammaglobulinemia and end organ damage, were collected. A total of 70 patients were included, with a median treatment duration of 54 months, ranging 30-138 months. The most common indications for rituximab treatment were granulomatosis with polyangiitis (22.9%), primary Sjögren's syndrome (20.0%) and systemic lupus erythematosus (14.3%). Infections and persistent dysgammaglobulinemia were the most common adverse events, occurring in 34.3% and 25.7%, respectively. A total of 64 infections were observed in 24 (34.3%) patients, including 1 case of fatal infection. Seventeen patients performed B-cell quantitation during the first 2 years following discontinuation, of which only four (19.0%) demonstrated B-cell reconstitution. End organ damage occurred in two patients, presenting as pyoderma gangrenosum and interstitial pneumonitis. No opportunistic infections were observed. Three patients died during the observational period, of which one was due to lethal infection. This study presents observational data with long treatment duration. It demonstrates that long-term rituximab treatment is relatively well tolerated, and that no cumulative side effects were observed.

Heat shock protein 90 and inflammatory activity in newly onset Crohn's disease.

OBJECTIVE: The aim of the study was to investigate whether heat shock protein (HSP)90α plasma concentrations were associated with disease activity in patients with Crohn's disease. MATERIALS AND METHODS: This cross-sectional study included 53 patients who were newly diagnosed with Crohn's disease. Demographic data and disease distribution were recorded, and disease activity was rated using the Simple Endoscopic Score for Crohn's Disease (SES-CD) and the Harvey Bradshaw Index (HBI). Faecal calprotectin and plasma concentrations of CRP and HSP90α were measured. RESULTS: The median SES-CD was 7, and the median HSP90α level was 17.2 ng/mL. The HSP90α level was significantly correlated with SES-CD, CRP, and faecal calprotectin, but not with HBI. Linear regression analysis revealed that HSP90α was significantly associated with SES-CD (r2 = 0.27, p < .001) and with CRP (r2 = 0.18, p = .002). HSP90α concentrations were significantly higher in the 10 patients with the highest SES-CD scores compared to the 10 patients with the lowest SES-CD scores. CONCLUSIONS: Objective measures of disease activity and inflammation in Crohn's disease - SES-CD and CRP - were closely associated with HSP90α concentrations in plasma, suggesting that HSP90α may be a biomarker of Crohn's disease.