Effect of progressive resistance training on persistent pain after axillary dissection in breast cancer: a randomized controlled trial.

PURPOSE: Persistent pain is a known challenge among breast cancer survivors. In secondary analyses of a randomized controlled trial, we examined the effect of progressive resistance training on persistent pain in the post-operative year in women treated for breast cancer with axillary lymph node dissection. METHODS: We randomized 158 women after BC surgery with Axillary Lymph Node Dissection (ALND) (1:1) to usual care or a 1-year, supervised and self-administered, progressive resistance training intervention initiated 3 weeks after surgery. A questionnaire at baseline, 20 weeks and 12 months assessed the intensity and frequency of pain, neuropathic pain and influence of pain on aspects of daily life. We analysed the effect using linear mixed models and multinomial logistic regression models for repeated measures. RESULTS: A high percentage of participants experienced baseline pain (85% and 83% in the control and intervention groups respectively) and by the 12 month assessment these numbers were more than halved. A high proportion of participants also experienced neuropathic pain (88% and 89% in control and intervention group respectively), a finding that was stable throughout the study period. The effect on intensity of pain indicators favoured the exercise group, although most estimates did not reach statistical significance, with differences being small. CONCLUSION: For women who had BC surgery with ALND, our progressive resistance training intervention conferred no benefit over usual care in reducing pain. Importantly, it did not increase the risk of pain both in the short and long term rehabilitative phase.

Deletion of T-type calcium channels Cav3.1 or Cav3.2 attenuates endothelial dysfunction in aging mice.

Impairment of endothelial function with aging is accompanied by reduced nitric oxide (NO) production. T-type Cav3.1 channels augment nitric oxide and co-localize with eNOS. Therefore, the hypothesis was that T-type channels contribute to the endothelial dysfunction of aging. Endothelial function was determined in mesenteric arteries (perfusion) and aortae (isometric contraction) of young and old wild-type (WT), Cav3.1, and Cav3.2 knockout mice. NO production was measured by fluorescence imaging in mesenteric arteries. With age, endothelium-dependent subsequent dilatation (following depolarization with KCl) of mesenteric arteries was diminished in the arteries of WT mice, unchanged in Cav3.2-/- preparations but increased in those of Cav3.1-/- mice. NO synthase inhibition abolished the subsequent dilatation in mesenteric arteries and acetylcholine-induced relaxations in aortae. NO levels were significantly reduced in mesenteric arteries of old compared to young WT mice. In Cav3.1-/- and Cav3.2-/- preparations, NO levels increased significantly with age. Relaxations to acetylcholine were significantly smaller in the aortae of old compared to young WT mice, while such responses were comparable in preparations of young and old Cav3.1-/- and Cav3.2-/- mice. The expression of Cav3.1 was significantly reduced in aortae from aged compared to young WT mice. The level of phosphorylated eNOS was significantly increased in aortae from aged Cav3.1-/- mice. In conclusion, T-type calcium channel-deficient mice develop less age-dependent endothelial dysfunction. Changes in NO levels are involved in this phenomenon in WT and Cav3.1-/- mice. These findings suggest that T-type channels play an important role in age-induced endothelial dysfunction.

Identification of protein phosphatase involvement in the AT2 receptor-induced activation of endothelial nitric oxide synthase.

The Angiotensin II type 2 receptor (AT2R) promotes vasodilation by nitric oxide (NO) release from endothelial cells. However, the mechanisms underlying the AT2R-induced stimulation of endothelial NO synthase (eNOS) is still not completely understood. Therefore, we investigated whether in addition to the known AT2R-mediated phosphorylation of eNOS at Ser1177, activation of phosphatases and dephosphorylation of eNOS at Tyr657 and Thr495 are also involved. Human aortic endothelial cells (HAEC) were stimulated with the AT2R-agonist Compound 21 (C21) (1 µM) in the presence or absence of either PD123319 (10 µM; AT2R antagonist), l-NG-Nitroarginine methyl ester (l-NAME) (10 µM; eNOS inhibitor), MK-2206 (100 nM; protein kinase B (Akt) inhibitor) sodium fluoride (NaF) (1 nM; serine/threonine phosphatase inhibitor) or sodium orthovanadate (Na3VO4) (10 nM; tyrosine phosphatase inhibitor). NO release was estimated by quantifying 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM) fluorescence. The phosphorylation status of activating (eNOS-Ser1177) or inhibitory eNOS residues (eNOS-Tyr657, eNOS-Thr495) was determined by Western blotting. Phosphorylation of Akt at Ser473 was measured to estimate Akt activity. AT2R stimulation significantly increased NO release from HAEC, which was blocked by PD123319, l-NAME and both phosphatase inhibitors. Intracellular calcium transients were not changed by C21. AT2R stimulation resulted in phosphorylation of eNOS-Ser1177 and dephosphorylation of eNOS-Tyr657 and eNOS-Thr495 Phosphorylation at eNOS-Ser1177 was prevented by inhibition of Akt with MK-2206. From these data, we conclude that AT2R stimulation in human endothelial cells increases eNOS activity through phosphorylation of activating eNOS residues (eNOS-Ser1177) by Akt, and through dephosphorylation of inactivating eNOS residues (eNOS-Tyr657, eNOS-Thr495) by serine/threonine and tyrosine phosphatases, thus increasing NO release.

Pain, sensory disturbances and psychological distress are common sequelae after treatment of ductal carcinoma in situ: a cross-sectional study.

Sequelae such as pain, sensory disturbances and psychological distress are well known after treatment for invasive breast cancer (IBC). Patients treated for ductal carcinoma in situ (DCIS) receive a similar treatment as low-risk IBC. The aim of this cross-sectional study was to describe prevalence of postoperative pain, sensory disturbances, psychological distress and rehabilitation needs among Danish women with DCIS. METHODS: A total of 574 women treated for DCIS in Denmark in 2013 and 2014 were enrolled and 473 (82%) completed a detailed questionnaire on demographic factors, pain, sensory disturbances, psychological aspects and rehabilitation needs 1-3 years after surgery. RESULTS: Median age was 60 years. A total of 33% of patients reported any pain and 12% reported moderate to severe pain in the area of surgery. Younger age (<50 years OR 4.7 (95% CI: 1.6-14.0, p = 0.006)), aged 50 to 65 years OR 2.8 (95% CI: 1.1-7.0, p = 0.02) and anxiety and depression (measured by HADStotal >15 OR of 3.1 (95% CI: 1.5-6.3, p = 0.003)) were significantly associated with moderate to severe pain. Approximately one-third of the patients reported sensory disturbances such as pins and needles (32%), numbness (37%) and painful itch (30%) and 94 women (20%) reported anxiety ≥8, 26 (6%) depression and 51 (11%) reported distress. CONCLUSIONS: This cross-sectional study showed that women treated for DCIS suffered from pain, sensory disturbances and psychological impairment and had unmet rehabilitation needs. Further research is warranted, specifically addressing rehabilitation after diagnosis and treatment of DCIS.

The effects of individually tailored nurse navigation for patients with newly diagnosed breast cancer: a randomized pilot study.

AIM: Our aim was to determine the feasibility and effectiveness of an individual, nurse-navigator intervention for relieving distress, anxiety, depression and health-related quality of life in women who have been treated for breast cancer (BC) and are experiencing moderate-to-severe psychological and physical symptoms. METHODS: Fifty women with newly diagnosed BC who reported distress (score ≥7 on distress thermometer) before surgery were included consecutively in a pilot study and randomized 1:1 to the intervention or the control group. The intervention comprised repeated screening with patient reported outcome measures and nurse navigation. A total of 66 women who were not distressed (score <7) were followed longitudinally as an observational group. Participants filled in four questionnaires, at baseline, after 6 months and 12 months. The primary outcome was psychological distress and the secondary outcomes were anxiety, depression, health-related quality of life and feasibility of the intervention. RESULTS: Women in the intervention group reported significantly greater satisfaction with treatment and rehabilitation and lower levels of distress (mean 2.7 vs. 5.1, p<.01), anxiety (mean 5.1 vs. 7.8, p = .02) and depression (mean 2.2 vs. 4.4, p = .04) after 12 months compared to the control group. No significant effects were seen on health-related quality of life. CONCLUSIONS: The study shows promising feasibility of the individually tailored nurse-navigation intervention and while no significant effects were observed after 6 months, we did find statistically significant effects on distress, anxiety and depression 12 months after diagnosis. Our results will assist in developing rehabilitation to the most vulnerable patients.

Pain, Sensory Disturbances, and Psychological Distress among Danish Women Treated for Ductal Carcinoma In Situ: An Exploratory Study.

Ductal carcinoma in situ is a noninvasive precancer condition. The treatment resembles the treatment of invasive breast cancer. The aim of this exploratory study was to gain knowledge on the level of postoperative pain, sensory disturbances, and distress among a small group of Danish women with ductal carcinoma in situ who had sentinel lymph node biopsy in order to plan a population study. A subgroup of patients with ductal carcinoma in situ (n = 20) was compared to patients with invasive breast cancer (n = 455) at time of diagnosis and after 12 months. Six patients were interviewed on the impact of the diagnosis and life after treatment. We found no significant difference in reported sensory disturbances or pain after 12 months between the groups. More than one-third (39%) of ductal carcinoma in situ patients reported moderate to severe distress (≥ 7 on the Distress Thermometer) at time of diagnosis decreasing to 10% after 12 months. Similarly 36% of breast cancer patients reported distress at time of diagnosis and 10% after 12 months. Interviews confirmed that ductal carcinoma in situ patients experienced distress and also uncovered physical problems and rehabilitation needs. The study indicates that women with ductal carcinoma in situ seem to suffer from pain and distress. The study highlights the need for a large study in order to validate the findings. Additional efforts may be needed to improve patients' understanding of diagnosis of ductal carcinoma in situ and alleviate psychological morbidity and physical restraints related to the condition.

Analgesic and Sensory Effects of the Pecs Local Anesthetic Block in Patients with Persistent Pain after Breast Cancer Surgery: A Pilot Study.

BACKGROUND: Persistent pain after breast cancer surgery (PPBCS) develops in 15% to 25% of patients, sometimes years after surgery. Approximately 50% of PPBCS patients have neuropathic pain in the breast, which may be due to dysfunction of the pectoral nerves. The Pecs local anesthetic block proposes to block these nerves and has provided pain relief for patients undergoing breast cancer surgery, but has yet to be evaluated in patients with PPBCS. METHODS: The aim of this pilot study was to examine the effects of the Pecs block on summed pain intensity (SPI) and sensory function (through quantitative sensory testing [QST]) in eight patients with PPBCS. SPI and QST measurements were recorded before and 30 minutes after administration of the Pecs block (20 mL 0.25% bupivacaine). Pain intensity and sleep interference were measured daily before and after the block for 7 days. RESULTS: Patients experienced analgesia (P = 0.008) and reduced hypoesthesia areas to cold (P = 0.004) and warmth (P = 0.01) after 30 minutes. The reported pain relief (P = 0.02) and reduced sleep interference (P = 0.01) persisted for 7 days after the block. CONCLUSIONS: This pilot study suggests that the pectoral nerves play a role in the maintenance of pain in the breast area in PPBCS and begs for further research.

Preoperative Distress Predicts Persistent Pain After Breast Cancer Treatment: A Prospective Cohort Study.

PURPOSE: Persistent pain after breast cancer treatment (PPBCT) affects 25% to 60% of breast cancer survivors and is recognized as a clinical problem, with 10% to 15% reporting moderate to severe pain several years after treatment. Psychological comorbidity is known to influence pain perception, and evidence links signs of depression and anxiety with development of PPBCT. The purpose of this study was to assess preoperative distress as a predictive factor for development of PPBCT. METHODS: Between October 2008 and October 2009, 426 women diagnosed with primary breast cancer, undergoing surgery at the Department of Breast Surgery, Rigshospitalet, Denmark, were invited to participate in the study. Patients filled out a questionnaire preoperatively, and 4 and 8 months after surgery. Preoperative distress was measured with the Distress Thermometer (DT; 11-point scale, 0-10). We examined the association between severe preoperative distress (using DT ≥7) and moderate to severe PPBCT 8 months after diagnosis using a logistic regression model. RESULTS: A total of 357 patients participated in this study and 291 (82%) returned all follow-up questionnaires. Preoperative distress was significantly associated with moderate to severe PPBCT at 8 months, with an adjusted odds ratio (OR) of 2.05 (95% CI, 1.18-3.59; P=.01), and at 4 months, with an OR of 2.23 (95% CI, 1.23-4.05; P=.01). CONCLUSIONS: Preoperative distress was associated with PPCBT, suggesting distress as an independent risk factor for PPBCT. Preoperative identification of patients at risk for PPBCT allows for further research in psychological and pharmacological treatment of this condition.

T-type Ca(2+) channels facilitate NO-formation, vasodilatation and NO-mediated modulation of blood pressure.

Voltage-gated calcium channels are involved in the vascular excitation-contraction mechanism and regulation of arterial blood pressure. It was hypothesized that T-type channels promote formation of nitric oxide from the endothelium. The present experiments determine the involvement of T-type channels in depolarization-dependent dilatation of mesenteric arteries and blood pressure regulation in Cav3.1 knock-out mice. Nitric oxide-dependent vasodilatation following depolarization-mediated vasoconstriction was reduced significantly in mesenteric arteries from Cav3.1(-/-) compared to wild type mice. Four days of systemic infusion of a nitric oxide (NO)-synthase-inhibitor to conscious wild type elicited a significant increase in mean arterial blood pressure that was absent in Cav3.1(-/-) mice. Immunoprecipitation and immunofluorescence labeling showed co-localization of Cav3.1 and endothelial nitric oxide synthase (eNOS) in arteries from wild type mice. Nitric oxide release measured as DAF fluorescence and cGMP levels were significantly lower in depolarized Cav3.1(-/-) compared to wild type arteries. In summary, the absence of T-type Cav3.1 channels attenuates NO-dependent dilatation in mesenteric arteries in vitro, as well as the hypertension after L-NAME infusion in vivo. Furthermore, Cav3.1 channels cluster with eNOS and promote formation of nitric oxide by the endothelium. The present findings suggest that this mechanism is important for the systemic impact of NO on peripheral resistance.

IMWG consensus on maintenance therapy in multiple myeloma.

Maintaining results of successful induction therapy is an important goal in multiple myeloma. Here, members of the International Myeloma Working Group review the relevant data. Thalidomide maintenance therapy after autologous stem cell transplantation improved the quality of response and increased progression-free survival (PFS) significantly in all 6 studies and overall survival (OS) in 3 of them. In elderly patients, 2 trials showed a significant prolongation of PFS, but no improvement in OS. A meta-analysis revealed a significant risk reduction for PFS/event-free survival and death. The role of thalidomide maintenance after melphalan, prednisone, and thalidomide is not well established. Two trials with lenalidomide maintenance treatment after autologous stem cell transplantation and one study after conventional melphalan, prednisone, and lenalidomide induction therapy showed a significant risk reduction for PFS and an increase in OS in one of the transplant trials. Maintenance therapy with single-agent bortezomib or in combination with thalidomide or prednisone has been studied. One trial revealed a significantly increased OS with a bortezomib-based induction and bortezomib maintenance therapy compared with conventional induction and thalidomide maintenance treatment. Maintenance treatment can be associated with significant side effects, and none of the drugs evaluated is approved for maintenance therapy. Treatment decisions for individual patients must balance potential benefits and risks carefully, as a widely agreed-on standard is not established.

Neuropathic pain after surgery - A clinical validation study and assessment of accuracy measures of the 5-item NeuPPS scale.

OBJECTIVE: The aim of this study was to validate the Neuropathic Pain for Post-Surgical Patients (NeuPPS) scale against clinically verified neuropathic pain (NP) by quantitative sensory testing (QST) as well as evaluation of other psychometric properties. The NeuPPS is a validated 5-item scale designed to evaluate NP in surgical populations. METHODS: Data from 537 women aged >18 years scheduled for primary breast cancer surgery enrolled in a previous study for assessing risk factors for persistent pain after breast cancer treatment were used. Exclusion criteria were any other breast surgery or relevant comorbidity. A total of 448 eligible questionnaires were available at 6 months and 455 at 12 months. At 12 months, 290 patients completed a clinical examination and QST. NeuPPS and PainDETECT were analyzed against patients with and without clinically verified NP. NP was assessed using a standardized QST protocol including a clinical assessment. Furthermore, the NeuPPS and PainDETECT scores were psychometrically tested with an item response theory method, the Rasch analysis, to assess construct validity. Primary outcomes were the diagnostic accuracy measures for the NeuPPS, and secondary measures were psychometric analyses of the NeuPPS after 6 and 12 months. PainDETECT was also compared to clinically verified NP as well as NeuPPS comparing the stability of the estimates. RESULTS: Comparing the NeuPPS scores with verified NP using a receiver operating characteristic curve, the NeuPPS had an area under the curve of 0.80. Using a cutoff of 1, the NeuPPS had a sensitivity of 88% and a specificity of 59%, and using a cutoff of 3, the values were 35 and 96%, respectively. Analysis of the PainDETECT indicated that the used cutoffs may be inappropriate in a surgical population. CONCLUSION: The present study supports the validity of the NeuPPS as a screening tool for NP in a surgical population.

Quantitative somatosensory assessments in patients with persistent pain following groin hernia repair: A systematic review with a meta-analytical approach.

OBJECTIVES: Quantitative sensory testing (QST) provides an assessment of cutaneous and deep tissue sensitivity and pain perception under normal and pathological settings. Approximately 2-4% of individuals undergoing groin hernia repair (GHR) develop severe persistent postsurgical pain (PPSP). The aims of this systematic review of PPSP-patients were (1) to retrieve and methodologically characterize the available QST literature and (2) to explore the role of QST in understanding mechanisms underlying PPSP following GHR. METHODS: A systematic literature search was conducted from JAN-1992 to SEP-2022 in PubMed, EMBASE, and Google Scholar. For inclusion, studies had to report at least one QST-modality in patients with PPSP. Risk of bias assessment of the studies was conducted utilizing the Newcastle Ottawa Scale and Cochrane's Risk of Bias assessment tool 2.0. The review provided both a qualitative and quantitative analysis of the results. A random effects model was used for meta-analysis. RESULTS: Twenty-five studies were included (5 randomized controlled trials, 20 non-randomized controlled trials). Overall, risk of bias was low. Compared with the contralateral side or controls, there were significant alterations in somatosensory function of the surgical site in PPSP-patients. Following thresholds were significantly increased: mechanical detection thresholds for punctate stimuli (mean difference (95% CI) 3.3 (1.6, 6.9) mN (P = 0.002)), warmth detection thresholds (3.2 (1.6, 4.7) °C (P = 0.0001)), cool detection thresholds (-3.2 (-4.9, -1.6) °C (P = 0.0001)), and heat pain thresholds (1.9 (1.1, 2.7) °C (P = 0.00001)). However, the pressure pain thresholds were significantly decreased (-76 (-123, -30) kPa (P = 0.001)). CONCLUSION: Our review demonstrates a plethora of methods used regarding outcome assessments, data processing, and data interpretation. From a pathophysiological perspective, the most consistent findings were postsurgical cutaneous deafferentation and development of a pain generator in deeper connective tissues. TRIAL REGISTRATION: CRD42022331750.

Effect of a Nurse Navigation Intervention on Mental Symptoms in Patients With Psychological Vulnerability and Breast Cancer: The REBECCA Randomized Clinical Trial.

Importance: The unmet needs regarding symptom management of psychological distress among patients with breast cancer must be addressed. However, little evidence exists on effective interventions, such as nurse navigation. Objective: To compare the long-term effects of the REBECCA (Rehabilitation After Breast Cancer) nurse navigation intervention vs usual care in patients with breast cancer who were psychologically vulnerable. Design, Setting, and Participants: This parallel randomized clinical trial recruited and evaluated for eligibility adult female patients with newly diagnosed breast cancer and symptoms of psychological distress (distress score of ≥7 points on Distress Thermometer) at Rigshospitalet in Copenhagen, Denmark, from August 2017 to October 2019. This study continued the work of a pilot study, extending the follow-up to 18 months. Patients who met the inclusion criteria were randomized to either standard care or the REBECCA intervention. Intention-to-treat analyses were performed from June 2021 to October 2022. Interventions: Patients who were randomized to the REBECCA intervention received nurse navigation and symptom screening as well as standard care. Standard care included regular treatment, nurse support at chemotherapy and radiotherapy appointments, and municipality-based rehabilitation. Main Outcomes and Measures: The primary outcome was distress, as measured using the Distress Thermometer. The secondary outcomes included symptoms of anxiety, symptoms of depression, breast cancer-specific health-related quality of life, fear of recurrence, sleep, cognitive function, patient activation, pain, health behavior, body mass index, and need for support. Long-term effects at 6, 12, and 18 months were examined using mixed-effect models, adjusting for randomization strata of age and treatment modality. Results: A total of 309 female patients were included in the analysis, with 153 patients randomized to the standard care group and 156 patients randomized to the REBECCA intervention group. Mean (SD) age was 56 (11) years with only small between-group differences. Patients receiving the REBECCA intervention compared with standard care had reduced (although not significant) symptoms of distress, especially at the 12-month follow-up (estimated effect = -0.51 [95% CI, -1.05 to 0.04]; effect size [ES] = -0.49). Significant effects were seen for symptoms of depression at 6 months (estimated effect = -1.39 [95% CI, -2.33 to -0.44]; ES = -0.27), and breast cancer-specific health-related quality of life at 12 months (estimated effect = 4.03 [95% CI, 1.28- 6.77]; ES = 0.31). Nonsignificant reductions were seen for symptoms of anxiety at 6 months (estimated effect = -1.00 [95% CI, -1.95 to -0.06]; ES = -0.21) and 12 months (estimated effect = -1.01 [95% CI, -1.97 to -0.04]; ES = -0.21), and a nonsignificant increase was seen for patient activation at 18 months (estimated effect = 3.52 [95% CI, -0.09 to 7.12]; ES = 0.25). Stronger intervention effects were observed for younger age, low patient activation, less education, and low social support. Conclusions and Relevance: Results of this study indicate that patients with breast cancer who were psychologically vulnerable (ie, having moderate to high psychological distress) did not experience significant reduction in distress with nurse navigation. Further research is needed to develop the intervention's framework and investigate its potential use in clinical practice. Trial Registration: ClinicalTrials.gov Identifier: NCT03254875.

Meta-barcoding of 'dirt' DNA from soil reflects vertebrate biodiversity.

DNA molecules originating from animals and plants can be retrieved directly from sediments and have been used for reconstructing both contemporary and past ecosystems. However, the extent to which such 'dirt' DNA reflects taxonomic richness and structural diversity remains contentious. Here, we couple second generation high-throughput sequencing with 16S mitochondrial DNA (mtDNA) meta-barcoding, to explore the accuracy and sensitivity of 'dirt' DNA as an indicator of vertebrate diversity, from soil sampled at safari parks, zoological gardens and farms with known species compositions. PCR amplification was successful in the full pH range of the investigated soils (6.2 ± 0.2 to 8.3 ± 0.2), but inhibition was detected in extracts from soil of high organic content. DNA movement (leaching) through strata was evident in some sporadic cases and is influenced by soil texture and structure. We find that DNA from the soil surface reflects overall taxonomic richness and relative biomass of individual species. However, one species that was recently introduced was not detected. Furthermore, animal behaviour was shown to influence DNA deposition rates. The approach potentially provides a quick methodological alternative to classical ecological surveys of biodiversity, and most reliable results are obtained with spatial sample replicates, while relative amounts of soil processed per site is of less importance.

Islands in the ice: detecting past vegetation on Greenlandic nunataks using historical records and sedimentary ancient DNA meta-barcoding.

Nunataks are isolated bedrocks protruding through ice sheets. They vary in age, but represent island environments in 'oceans' of ice through which organism dispersals and replacements can be studied over time. The J.A.D. Jensen's Nunataks at the southern Greenland ice sheet are the most isolated nunataks on the northern hemisphere - some 30 km from the nearest biological source. They constitute around 2 km(2) of ice-free land that was established in the early Holocene. We have investigated the changes in plant composition at these nunataks using both the results of surveys of the flora over the last 130 years and through reconstruction of the vegetation from the end of the Holocene Thermal Maximum (5528 ± 75 cal year BP) using meta-barcoding of plant DNA recovered from the nunatak sediments (sedaDNA). Our results show that several of the plant species detected with sedaDNA are described from earlier vegetation surveys on the nunataks (in 1878, 1967 and 2009). In 1967, a much higher biodiversity was detected than from any other of the studied periods. While this may be related to differences in sampling efforts for the oldest period, it is not the case when comparing the 1967 and 2009 levels where the botanical survey was exhaustive. As no animals and humans are found on the nunataks, this change in diversity over a period of just 42 years must relate to environmental changes probably being climate-driven. This suggests that even the flora of fairly small and isolated ice-free areas reacts quickly to a changing climate.

A comparative study of ancient sedimentary DNA, pollen and macrofossils from permafrost sediments of northern Siberia reveals long-term vegetational stability.

Although ancient DNA from sediments (sedaDNA) has been used to investigate past ecosystems, the approach has never been directly compared with the traditional methods of pollen and macrofossil analysis. We conducted a comparative survey of 18 ancient permafrost samples spanning the Late Pleistocene (46-12.5 thousand years ago), from the Taymyr Peninsula in northern Siberia. The results show that pollen, macrofossils and sedaDNA are complementary rather than overlapping and, in combination, reveal more detailed information on plant palaeocommunities than can be achieved by each individual approach. SedaDNA and macrofossils share greater overlap in plant identifications than with pollen, suggesting that sedaDNA is local in origin. These two proxies also permit identification to lower taxonomic levels than pollen, enabling investigation into temporal changes in species composition and the determination of indicator species to describe environmental changes. Combining data from all three proxies reveals an area continually dominated by a mosaic vegetation of tundra-steppe, pioneer and wet-indicator plants. Such vegetational stability is unexpected, given the severe climate changes taking place in the Northern Hemisphere during this time, with changes in average annual temperatures of >22 °C. This may explain the abundance of ice-age mammals such as horse and bison in Taymyr Peninsula during the Pleistocene and why it acted as a refugium for the last mainland woolly mammoth. Our finding reveals the benefits of combining sedaDNA, pollen and macrofossil for palaeovegetational reconstruction and adds to the increasing evidence suggesting large areas of the Northern Hemisphere remained ecologically stable during the Late Pleistocene.

Persistent pain, sensory disturbances and functional impairment after adjuvant chemotherapy for breast cancer: cyclophosphamide, epirubicin and fluorouracil compared with docetaxel + epirubicin and cyclophosphamide.

BACKGROUND: Taxanes used in adjuvant therapy for breast cancer are neurotoxic, and thereby being a potential risk factor for persistent pain after breast cancer treatment (PPBCT) and sensory disturbances. The purpose was to compare patients treated with cyclophosphamide, epirubicin and fluorouracil (CEF) and cyclophosphamide and epirubicin + docetaxel (CE + T) in relation to PPBCT, sensory disturbances, peripheral sensory disturbances and functional impairment. MATERIAL AND METHODS: A comparative nationwide cross-sectional questionnaire study on two cohorts treated with CEF respectively CE + T, based on the Danish Breast Cancer Cooperative Groups database. INCLUSION CRITERIA: women treated with chemotherapy as adjuvant treatment for primary breast cancer, age 18-69 years, without recurrence. RESULTS: One thousand two hundred and forty-one patients allocated to CEF in 2005-2006 and 1652 patients allocated to CE + T in 2007-2008 were included. Six hundred and sixty-four (53%) with CEF and 861 (53%) patients with CE + T reported pain. In the multivariate analysis including available risk factors, CE + T did not confer an increased risk of PPBCT, OR 0.95 (95% CI 0.81-1.11), p = 0.52, compared to CEF. Patients treated with CE + T had a lower risk of sensory disturbances in the area of surgery compared with CEF, OR 0.75 (95% CI 0.62-0.90), p = 0.002. More CE + T patients reported peripheral sensory disturbances in the hands, OR 1.56 (95%CI 1.27-1.92), p < 0.0001, and in the feet, OR 2.0 (95% CI 1.66-2.42) p < 0.0001, compared to CEF. There was no difference in functional impairment (p = 0.62). CONCLUSION: Docetaxcel as adjuvant treatment for breast cancer does not increase the risk of PPBCT, sensory disturbances in the surgical area or functional impairment, but increase risk for peripheral sensory disturbances.

Long-term results of a standardized enhanced recovery protocol in unilateral, secondary autologous breast reconstructions using an abdominal free flap.

BACKGROUND: In 2015, we published one of the first reports using an enhanced recovery protocol (ERP) in microsurgery1, and in 2016, our final ERP setup in autologous breast reconstruction (ABR) using free abdominal flaps2. We showed that by adhering to a few simple, easy to measure, functional discharge criteria, it was possible to safely discharge the patients by the third postoperative day (POD). However, one of the challenges of interpreting studies using ERP in ABR is the often heterogenous patient populations and the need to clearly distinguish between primary and secondary and unilateral and bilateral reconstructions. MATERIALS AND METHODS: In the 5-year period from 2016-2020, the same surgical team, performed 147 unilateral, delayed breast reconstructions (135 DIEP, 9 MS-TRAM-2, and 3 SIEA flaps) according to our previous analgesic protocol and surgical strategy. Data were collected prospectively. RESULTS: Three flaps were lost (2%) and 82% of the patients(n=128) were discharged to home by POD 2 (n=8%) or 3 (74%). The remaining 18% (n=26) were discharged by POD 4 (12.5%) or 5 (5.5%). Ten patients (7%) were reoperated, and 17 patients (12%) had minor complications within POD 30 (infection, seroma, etc.) that did not necessitate hospital admission. CONCLUSION: Using our ERP, unproblematic discharge directly to home is possible on POD 3 in more than 80% of patients after ABR. ERP is no longer a research tool but considered standard of care in microsurgical breast reconstruction.

Use of Medical Supplies at the Roskilde Festival 2016: A Prospective Observational Study.

INTRODUCTION: Music festivals are popular events often including camping at the festival site. A mix of music, alcohol, drugs, and limited hygiene increases health risks. This study aimed to assess the use of medical supplies at a major music festival, thereby aiding planning at similar events in the future. METHOD: The Medical Health Care Organization (MHCO) at Roskilde Festival 2016 (Denmark) collected prospective data on disposable medical supply use and injuries and illnesses presenting to the MHCO. RESULTS: A total of 12,830 patient presentations were registered by the MHCO and a total of 104 different types of disposable medical supplies were used by the MHCO from June 25, 2016 through July 3, 2016. Out of 12,830 cases, 594 individuals (4.6%) had a potential or manifest medical emergency, 6,670 (52.0%) presented with minor injuries, and 5,566 (43.4%) presented with minor illnesses. The overall patient presentation rate (PPR) was 99.0/1,000 attendees and the transport-to-hospital rate (TTHR) was 2.1/1,000 attendees. For medical emergencies, the most frequently used supplies were aluminum rescue blankets (n = 627), non-rebreather masks (n = 121), and suction catheters for an automatic suction unit (ASU) for airway management (n = 83). Most used diagnostic equipment were blood glucose test strips (n = 1,155), electrocardiogram electrodes (n = 960), and urinary test strips (n = 400). The most frequently used personal protection equipment were non-sterile gloves (n = 1,185 pairs) and sterile gloves (n = 189). CONCLUSION: This study demonstrates a substantial use of disposable medical supplies at a major music festival. The results provide aid for planning similar mass-gathering (MG) events.

Inflammation and insulin resistance induced by trans-10, cis-12 conjugated linoleic acid depend on intracellular calcium levels in primary cultures of human adipocytes.

We previously demonstrated that trans-10, cis-12 (10,12) conjugated linoleic acid (CLA) induced inflammation and insulin resistance in primary human adipocytes by activating nuclear factor kappaB (NFkappaB) and extracellular signal-related kinase (ERK) signaling. In this study, we demonstrated that the initial increase in intracellular calcium ([Ca2+]i) mediated by 10,12 CLA was attenuated by TMB-8, an inhibitor of calcium release from the endoplasmic reticulum (ER), by BAPTA, an intracellular calcium chelator, and by D609, a phospholipase C (PLC) inhibitor. Moreover, BAPTA, TMB-8, and D609 attenuated 10,12 CLA-mediated production of reactive oxygen species (ROS), activation of ERK1/2 and cJun-NH2-terminal kinase (JNK), and induction of inflammatory genes. 10,12 CLA-mediated binding of NFkappaB to the promoters of interleukin (IL)-8 and cyclooxygenase (COX)-2 and induction of calcium-calmodulin kinase II (CaMKII) beta were attenuated by TMB-8. KN-62, a CaMKII inhibitor, also suppressed 10,12 CLA-mediated ROS production and ERK1/2 and JNK activation. Additionally, KN-62 attenuated 10,12 CLA induction of inflammatory and integrated stress response genes, increase in prostaglandin F2alpha, and suppression of peroxisome proliferator activated receptor gamma protein levels and insulin-stimulated glucose uptake. These data suggest that 10,12 CLA increases inflammation and insulin resistance in human adipocytes, in part by increasing [Ca2+]i levels, particularly calcium from the ER.