Characterization of patients with odontogenic necrotizing soft tissue infections in the head and neck area. A retrospective analysis.

OBJECTIVE: Necrotizing soft-tissue infection (NSTI) in the head and neck area may develop from odontogenic infections. The aim of this study was to characterize patients with NSTI in the head and neck with odontogenic origin in a well-defined prospectively collected cohort. MATERIAL AND METHODS: Patients with NSTI in the head and neck, hospitalized between 2013 and 2017 at Copenhagen University Hospital and registered in the Scandinavian INFECT database were included. Medical records of identified patients and from the INFECT database were screened for a defined set of data including the primary focus of infection, comorbidities, predisposing factors, clinical and radiographic diagnostics, course of treatment, and treatment outcome. RESULTS: Thirty-five patients with NSTI in the head and neck area were included in the study. A total of 54% had odontogenic origin, primarily from mandibular molars, and 94% had radiographic signs of infectious oral conditions. Overall, comorbidities were reported in 51% with cardiovascular disease being the most prevalent. In 20%, no comorbidities or predisposing conditions could be identified. The overall 30-day mortality rate was 9%. CONCLUSIONS: More than half of NSTI cases in the head and neck region had an odontogenic origin, and special attention should be paid to infections related to mandibular molars.

Systemic immune activation profiles in streptococcal necrotizing soft tissue infections: A prospective multicenter study.

OBJECTIVE: Early stages with streptococcal necrotizing soft tissue infections (NSTIs) are often difficult to discern from cellulitis. Increased insight into inflammatory responses in streptococcal disease may guide correct interventions and discovery of novel diagnostic targets. METHODS: Plasma levels of 37 mediators, leucocytes and CRP from 102 patients with ß-hemolytic streptococcal NSTI derived from a prospective Scandinavian multicentre study were compared to those of 23 cases of streptococcal cellulitis. Hierarchical cluster analyses were also performed. RESULTS: Differences in mediator levels between NSTI and cellulitis cases were revealed, in particular for IL-1ß, TNFα and CXCL8 (AUC >0.90). Across streptococcal NSTI etiologies, eight biomarkers separated cases with septic shock from those without, and four mediators predicted a severe outcome. CONCLUSION: Several inflammatory mediators and wider profiles were identified as potential biomarkers of NSTI. Associations of biomarker levels to type of infection and outcomes may be utilized to improve patient care and outcomes.

Neutrophil-derived reactive agents induce a transient SpeB negative phenotype in Streptococcus pyogenes.

BACKGROUND: Streptococcus pyogenes (group A streptococci; GAS) is the main causative pathogen of monomicrobial necrotizing soft tissue infections (NSTIs). To resist immuno-clearance, GAS adapt their genetic information and/or phenotype to the surrounding environment. Hyper-virulent streptococcal pyrogenic exotoxin B (SpeB) negative variants caused by covRS mutations are enriched during infection. A key driving force for this process is the bacterial Sda1 DNase. METHODS: Bacterial infiltration, immune cell influx, tissue necrosis and inflammation in patient´s biopsies were determined using immunohistochemistry. SpeB secretion and activity by GAS post infections or challenges with reactive agents were determined via Western blot or casein agar and proteolytic activity assays, respectively. Proteome of GAS single colonies and neutrophil secretome were profiled, using mass spectrometry. RESULTS: Here, we identify another strategy resulting in SpeB-negative variants, namely reversible abrogation of SpeB secretion triggered by neutrophil effector molecules. Analysis of NSTI patient tissue biopsies revealed that tissue inflammation, neutrophil influx, and degranulation positively correlate with increasing frequency of SpeB-negative GAS clones. Using single colony proteomics, we show that GAS isolated directly from tissue express but do not secrete SpeB. Once the tissue pressure is lifted, GAS regain SpeB secreting function. Neutrophils were identified as the main immune cells responsible for the observed phenotype. Subsequent analyses identified hydrogen peroxide and hypochlorous acid as reactive agents driving this phenotypic GAS adaptation to the tissue environment. SpeB-negative GAS show improved survival within neutrophils and induce increased degranulation. CONCLUSIONS: Our findings provide new information about GAS fitness and heterogeneity in the soft tissue milieu and provide new potential targets for therapeutic intervention in NSTIs.

Effects of an early intervention with Hyperbaric Oxygen Treatment on arm lymphedema and quality of life after breast cancer-an explorative clinical trial.

PURPOSE: Lymphedema (LE) is a common complication after breast cancer treatment, which negatively affects the quality of life (QOL). Hyperbaric Oxygen Treatment (HBOT) is an established treatment for radiation-induced tissue injury, but evidence of effect on breast cancer-related LE is inconclusive. We aimed to explore effects of HBOT on early breast cancer-related LE and the implications for QOL. METHODS: We invited women with breast cancer treated with surgery, axillary dissection and radiotherapy, who had participated in a randomized controlled trial and who presented with LE 1 year after surgery. In a prospective observational study design, change in LE was assessed with perometry, dual-energy X-ray absorptiometry (DXA) and lymphoscintigraphy, and QOL by validated self-report scales. Participants were offered 40 sessions of HBOT on every weekday for 8 weeks and were followed for 6 months. RESULTS: Out of 50 eligible participants, 20 women accepted participation. Nineteen women initiated and completed treatment and follow-up. None of the objective measures of LE severity showed consistent changes during the study period, but participants reported significant improvements in QOL (physical functioning, fatigue, insomnia and breast and arm symptoms), with improvements peaking at 6-month follow-up. CONCLUSION: Participants receiving HBOT experienced improved QOL without consistently significant changes in arm mass, volume or lymphatic drainage. These results call for studies into differential effect in patient sub-groups, and a large-scale, randomized placebo-controlled trial with long-term follow-up to assess the effect of HBOT in patients with soft tissue radiation injuries after breast cancer seems warranted. TRIAL REGISTRATION: Danish Health and Medicines Authority, EUDRACT no. 2015-000,604-25 Ethical committee of the Capitol Region, No. R96-A6604-14-S22.

Analysis of host-pathogen gene association networks reveals patient-specific response to streptococcal and polymicrobial necrotising soft tissue infections.

BACKGROUND: Necrotising soft tissue infections (NSTIs) are rapidly progressing bacterial infections usually caused by either several pathogens in unison (polymicrobial infections) or Streptococcus pyogenes (mono-microbial infection). These infections are rare and are associated with high mortality rates. However, the underlying pathogenic mechanisms in this heterogeneous group remain elusive. METHODS: In this study, we built interactomes at both the population and individual levels consisting of host-pathogen interactions inferred from dual RNA-Seq gene transcriptomic profiles of the biopsies from NSTI patients. RESULTS: NSTI type-specific responses in the host were uncovered. The S. pyogenes mono-microbial subnetwork was enriched with host genes annotated with involved in cytokine production and regulation of response to stress. The polymicrobial network consisted of several significant associations between different species (S. pyogenes, Porphyromonas asaccharolytica and Escherichia coli) and host genes. The host genes associated with S. pyogenes in this subnetwork were characterised by cellular response to cytokines. We further found several virulence factors including hyaluronan synthase, Sic1, Isp, SagF, SagG, ScfAB-operon, Fba and genes upstream and downstream of EndoS along with bacterial housekeeping genes interacting with the human stress and immune response in various subnetworks between host and pathogen. CONCLUSIONS: At the population level, we found aetiology-dependent responses showing the potential modes of entry and immune evasion strategies employed by S. pyogenes, congruent with general cellular processes such as differentiation and proliferation. After stratifying the patients based on the subject-specific networks to study the patient-specific response, we observed different patient groups with different collagens, cytoskeleton and actin monomers in association with virulence factors, immunogenic proteins and housekeeping genes which we utilised to postulate differing modes of entry and immune evasion for different bacteria in relationship to the patients' phenotype.

Risk Factors and Predictors of Mortality in Streptococcal Necrotizing Soft-tissue Infections: A Multicenter Prospective Study.

BACKGROUND: Necrotizing soft-tissue infections (NSTI) are life-threatening conditions often caused by ß-hemolytic streptococci, group A Streptococcus (GAS) in particular. Optimal treatment is contentious. The INFECT cohort includes the largest set of prospectively enrolled streptococcal NSTI cases to date. METHODS: From the INFECT cohort of 409 adults admitted with NSTI to 5 clinical centers in Scandinavia, patients culture-positive for GAS or Streptococcus dysgalactiae (SD) were selected. Risk factors were identified by comparison with a cohort of nonnecrotizing streptococcal cellulitis. The impact of baseline factors and treatment on 90-day mortality was explored using Lasso regression. Whole-genome sequencing of bacterial isolates was used for emm typing and virulence gene profiling. RESULTS: The 126 GAS NSTI cases and 27 cases caused by SD constituted 31% and 7% of the whole NSTI cohort, respectively. When comparing to nonnecrotizing streptococcal cellulitis, streptococcal NSTI was associated to blunt trauma, absence of preexisting skin lesions, and a lower body mass index. Septic shock was significantly more frequent in GAS (65%) compared to SD (41%) and polymicrobial, nonstreptococcal NSTI (46%). Age, male sex, septic shock, and no administration of intravenous immunoglobulin (IVIG) were among factors associated with 90-day mortality. Predominant emm types were emm1, emm3, and emm28 in GAS and stG62647 in SD. CONCLUSIONS: Streptococcal NSTI was associated with several risk factors, including blunt trauma. Septic shock was more frequent in NSTI caused by GAS than in cases due to SD. Factors associated with mortality in GAS NSTI included age, septic shock, and no administration of IVIG.

Associations between YKL-40 and markers of disease severity and death in patients with necrotizing soft-tissue infection.

BACKGROUND: Necrotizing soft-tissue infection (NSTI) is a severe and fast-progressing bacterial infection. Prognostic biomarkers may provide valuable information in treatment guidance and decision-making, but none have provided sufficient robustness to have a clinical impact. YKL-40 may reflect the ongoing pathological inflammatory processes more accurately than traditional biomarkers as it is secreted by the activated immune cells, but its prognostic yields in NSTI remains unknown. For this purpose, we investigated the association between plasma YKL-40 and 30-day mortality in patients with NSTI, and assessed its value as a marker of disease severity. METHODS: We determined plasma YKL-40 levels in patients with NSTI (n = 161) and age-sex matched controls (n = 65) upon admission and at day 1, 2 and 3. RESULTS: Baseline plasma YKL-40 was 1191 ng/mL in patients with NSTI compared with 40 ng/mL in controls (p < 0.001). YKL-40 was found to be significantly higher in patients with septic shock (1942 vs. 720 ng/mL, p < 0.001), and in patients receiving renal-replacement therapy (2382 vs. 1041 ng/mL, p < 0.001). YKL-40 correlated with Simplified Acute Physiology Score II (Rho 0.33, p < 0.001). Baseline YKL-40 above 1840 ng/mL was associated with increased risk of 30-day mortality in age-sex-comorbidity adjusted analysis (OR 3.77, 95% CI; 1.59-9.24, p = 0.003), but after further adjustment for Simplified Acute Physiology Score II no association was found between YKL-40 and early mortality. CONCLUSION: High plasma YKL-40 to be associated with disease severity, renal-replacement therapy and risk of death in patients with NSTI. However, YKL-40 is not an independent predictor of 30-day mortality.

Effect of immunoglobulin G on cytokine response in necrotising soft-tissue infection: A post hoc analysis.

BACKGROUND: A marked inflammatory response in necrotising soft-tissue infection (NSTI) may contribute to the severe clinical course. Intravenous polyspecific immunoglobulin G (IVIG) is used by some as adjuvant treatment for NSTI, but in the randomised INSTINCT trial, no effect of IVIG in NSTI patients was seen on physical quality of life. In experimental studies, IVIG may induce immunosuppressive effects by reducing the pro-inflammatory response and neutralising circulating superantigens. However, data on the potential immunomodulatory effects are sparse and remain to be investigated in a clinical setting. In this post hoc analysis of the INSTINCT trial, we aimed to assess the effect of IVIG on various inflammatory cytokines up to day 3 after randomisation. METHODS: Tumour necrosis factor (TNF), interleukin-1ß, interleukin-6, interleukin-10 and granulocyte colony-stimulating factor were measured at admission, days 1, 2 and 3. RESULTS: A total of 100 ICU patients with NSTI were included; 50 were allocated to IVIG (25 g/d for 3 days) and 50 to placebo. No difference in the overall inflammatory response was observed between groups except from TNF, which was higher in the IVIG group as compared to the placebo group (area under curve-admission to day 3, 93.6 vs 60.2, P = .02). Similarly, no differences were observed in percentage change from baseline to day 3 in any of the studied cytokines between patients allocated to IVIG group and those allocated to placebo group. CONCLUSION: In ICU patients with NSTI, IVIG did not reduce the plasma concentration of cytokines in the first 3 days.

Non-invasive monitoring of carboxyhemoglobin during hyperbaric oxygen therapy.

Introduction: This study aimed to assess the capability of a pulse CO-oximeter to continuously monitor carboxyhemoglobin (COHb) during hyperbaric oxygen (HBO2) therapy. We estimated limits of agreement (LOA) between blood gas analysis and pulse CO-oximeter for COHb during HBO2 therapy in patients suffering from acute CO poisoning. Furthermore, we did a medicotechnical evaluation of the pulse CO-oximeter in hyperbaric conditions. Methods: We conducted a prospective, non-clinical, observational study in which we included n=10 patients with acute CO poisoning referred for HBO2 therapy. We did five repeated measurements of COHb for each patient during the HBO2 therapy. Bland-Altman analysis for multiple observations per individual was used to assess the agreement. The a priori LOA was ±6% for COHb. For the medicotechnical evaluation continuous measurements were obtained throughout each complete HBO2 therapy. The measurements were visually inspected and evaluated. Results: The Bland-Altman analysis showed that the pulse CO-oximeter overestimated COHb by 2.9 % [±1.0%] and the LOA was ±7.3% [±1.8%]. The continuous measurements by pulse CO-oximetry showed fluctuating levels of COHb and summarized saturations reached levels above 100%. Measurements were not affected by changes in pressure. Conclusion: To our knowledge, this study is the first to assess LOA and demonstrate use of a non-invasive method to measure COHb during HBO2 therapy. The pulse CO-oximeter performed within the manufactures reported LOA (±6%) despite hyperbaric conditions and was unaffected by changes in pressure. However, summarized saturations reached levels above 100%.

Integrated Univariate, Multivariate, and Correlation-Based Network Analyses Reveal Metabolite-Specific Effects on Bacterial Growth and Biofilm Formation in Necrotizing Soft Tissue Infections.

Necrotizing soft-tissue infections (NSTIs) have multiple causes, risk factors, anatomical locations, and pathogenic mechanisms. In patients with NSTI, circulating metabolites may serve as a substrate having impact on bacterial adaptation at the site of infection. Metabolic signatures associated with NSTI may reveal the potential to be useful as diagnostic and prognostic markers and novel targets for therapy. This study used untargeted metabolomics analyses of plasma from NSTI patients (n = 34) and healthy (noninfected) controls (n = 24) to identify the metabolic signatures and connectivity patterns among metabolites associated with NSTI. Metabolite-metabolite association networks were employed to compare the metabolic profiles of NSTI patients and noninfected surgical controls. Out of 97 metabolites detected, the abundance of 33 was significantly altered in NSTI patients. Analysis of metabolite-metabolite association networks showed a more densely connected network: specifically, 20 metabolites differentially connected between NSTI and controls. A selected set of significantly altered metabolites was tested in vitro to investigate potential influence on NSTI group A streptococcal strain growth and biofilm formation. Using chemically defined media supplemented with the selected metabolites, ornithine, ribose, urea, and glucuronic acid, revealed metabolite-specific effects on both bacterial growth and biofilm formation. This study identifies for the first time an NSTI-specific metabolic signature with implications for optimized diagnostics and therapies.

Correlation Between Immunoglobulin Dose Administered and Plasma Neutralization of Streptococcal Superantigens in Patients With Necrotizing Soft Tissue Infections.

Analyses of plasma collected pre- and postadministration of intravenous immunoglobulin (IVIG) from patients with group A Streptococcus necrotizing soft tissue infections demonstrated a negative correlation between IVIG dose and toxin-triggered T-cell proliferation (r = -.67, P < .0001). One 25-g IVIG dose was sufficient to yield plasma-neutralizing activity against streptococcal superantigens. Clinical Trials Registration. NCT01790698 and NCT02111161.

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.

Necrotizing Soft-Tissue Infections: Clinical Features and Diagnostic Aspects.

The term necrotizing soft-tissue infection (NSTI) encompasses a heterogenous group of patients with necrotizing infections, involving any body part. NSTI is diagnosed by surgical exploration, where necrosis of the subcutaneous tissue and/or muscle tissue, undermining of the skin, thrombosis of the superficial veins, and deliquescent tissue can be seen. Patients can present with vague symptoms, and approximately half of patients experience severe pain. The clinical presentation and microbiological etiology vary according to affected body site, with NSTI located to the extremities being dominated by monomicrobial group A streptococcal infections, and NSTI located to the anogenital area dominated by polymicrobial infections. No set of diagnostic criteria exists, and suspicion of the diagnosis should come from careful clinical examination and signs of local or systemic severity. Laboratory blood values show no distinct pattern but resemble those of sepsis. Imaging can aid the diagnostic process but must not delay surgical intervention.

Radiation-induced cystitis treated with hyperbaric oxygen therapy (RICH-ART): a randomised, controlled, phase 2-3 trial.

BACKGROUND: Late radiation cystitis is an adverse effect of cancer treatment with radiotherapy in the pelvic region. Symptoms of late radiation cystitis can be assessed with the Expanded Prostate Index Composite Score (EPIC). Previous reports indicate that hyperbaric oxygen therapy reduces symptoms from late radiation cystitis, but the evidence is predominantly based on non-randomised and retrospective studies. We aimed to assess whether hyperbaric oxygen therapy would mitigate symptoms of late radiation cystitis. METHODS: We did a randomised, controlled, phase 2-3 trial (RICH-ART [Radiation Induced Cystitis treated with Hyperbaric oxygen-A Randomised controlled Trial]) at five Nordic university hospitals. All patients aged 18-80 years, with pelvic radiotherapy completed at least 6 months previously, a score of less than 80 in the urinary domain of the Expanded Prostate Index Composite Score (EPIC), and referred to participating hyperbaric clinics due to symptoms of late radiation cystitis, were eligible for inclusion. Exclusion criteria were ongoing bleeding requiring blood transfusion exceeding 500 mL in the past 4 weeks, permanent urinary catheter, bladder capacity less than 100 mL, fistula in the urinary bladder, previous treatment with hyperbaric oxygen therapy for late radiation injuries, and contraindications to hyperbaric oxygen therapy. After computer-generated 1:1 randomisation with block sizes of four for each stratification group (sex, time from radiotherapy to inclusion, and previous invasive surgery in the pelvic area), patients received hyperbaric oxygen therapy (30-40 sessions, 100% oxygen, breathed at a pressure of 240-250 kPa, for 80-90 min daily) or standard care with no restrictions for other medications or interventions. No masking was applied. The primary outcome was change in patient-perceived urinary symptoms assessed with EPIC from inclusion to follow-up at visit 4 (6-8 months later), measured as absolute change in EPIC urinary total score. RICH-ART closed enrolment on Dec 31, 2017; the last follow-up data will be compiled in 2023. RICH-ART is registered with ClinicalTrials.gov, number NCT01659723, and with the European Medicines Agency, number EudraCT 2012-001381-15. FINDINGS: Of 223 patients screened between May 9, 2012, and Dec 20, 2017, 87 patients were enrolled and randomly assigned to either hyperbaric oxygen therapy (n=42) or standard care (n=45). After excluding eight patients who withdrew consent directly after randomisation (one in the hyperbaric oxygen therapy group and seven in the standard care group), 79 were included in the intention-to-treat analyses (n=41 in the hyperbaric oxygen therapy group, n=38 in the standard care group). Median time from randomisation to visit 4 was 234 days (IQR 210-262) in the hyperbaric oxygen therapy group and 217 days (195-237) in the standard care group. The difference between change in group mean of EPIC urinary total score at visit 4 was 10·1 points (95% CI 2·2-18·1; p=0·013; 17·8 points [SD 18·4] in the hyperbaric oxygen therapy group vs 7·7 points [15·5] in the standard care group). 17 (41%) of 41 patients in the hyperbaric oxygen therapy group experienced transient grade 1-2 adverse events, related to sight and hearing, during the period of hyperbaric oxygen therapy. INTERPRETATION: Our results suggest that hyperbaric oxygen therapy relieves symptoms of late radiation cystitis. We conclude that hyperbaric oxygen therapy is a safe and well tolerated treatment. FUNDING: The regional research fund of Region Västra Götaland, Sweden, the regional Health Technology Assessment Centre at Sahlgrenska University Hospital, Sweden, and Lions Cancer Research Fund of Western Sweden.

Progressive resistance training to prevent arm lymphedema in the first year after breast cancer surgery: Results of a randomized controlled trial.

BACKGROUND: Existing research suggests that progressive resistance training (PRT) after breast cancer (BC) surgery is safe, but the preventive effect on arm lymphedema has yet to be determined. METHODS: Women aged 18 to 75 years who were undergoing BC surgery with axillary lymph node dissection were eligible for the study. Recruited on the day of surgery, participants were allocated to intervention or usual care by computer randomization. The intervention consisted of PRT 3 times per week: in the first 20 weeks as a supervised group exercise and in the last 30 weeks as a self-administered exercise. The primary outcome was arm lymphedema, which was defined as a >3% increase in the interlimb volume difference by water displacement. Measurements were made at the baseline and at a 12-month follow-up by physiotherapists blinded to group allocation. Analyses of effects included t tests and regression models; missing data were addressed by multiple imputation. RESULTS: Among the 158 randomized women, no mean group difference was found in arm volume (0.3%; 95% confidence interval, -1.7% to 2.3%) or lymphedema incidence (adjusted odds ratio, 1.2; 95% confidence interval, 0.5-2.8). None of the participants exited the program because of adverse events. CONCLUSIONS: This study provides no evidence that PRT can prevent arm lymphedema in the first year after BC, but the results corroborate the importance and safety of resistance training for patients, including women at high risk for lymphedema.

Effect of progressive resistance training on health-related quality of life in the first year after breast cancer surgery - results from a randomized controlled trial.

Aims: To examine the effect of progressive resistance training (PRT) on health related quality of life and a predefined symptom cluster of pain-sleep-fatigue. Methods: This study was a planned secondary analysis of a randomized controlled trial examining the effect of PRT on prevention of arm lymphedema in a population of women between 18 and 75 years undergoing breast cancer surgery with axillary lymph node dissection. Participants were allocated by computer randomization to usual care control or a PRT intervention in a 1:1 ratio. The intervention, initiated in the third post-operative week, consisted of three times PRT per week, supervised in groups in the first 20 weeks, and self-administered in the following 30 weeks. Questionnaire assessments were made at baseline, 20 weeks and 12 months, with the European Organization for Research and Treatment in Cancer Core questionnaire (EORTC QLQ C30) and the Functional Assessment of Chronic Illness Therapy-(FACIT) fatigue questionnaire. The symptom cluster of pain-sleep-fatigue was measured with a constructed score adding EORTC C30 subscales of insomnia, pain, and fatigue. Data were treated as repeated measurements and analyzed with mixed models. Results: Among 158 recruited participants, we found a clinically relevant increased emotional functioning with nine points at both follow-ups (p = .02), and 16 and 11 points at 20 weeks and 12 months respectively (p = .04) in social functioning. Furthermore, in the subgroup of women with the symptom cluster pain-sleep-fatigue present at baseline, a significant effect was found for global health status (p = .01) and social functioning (p = .02). Conclusion: To our knowledge, this is the first study to report clinically relevant effects of PRT on social and emotional functioning in the first postoperative year after breast cancer surgery. Furthermore, a subgroup of women with the pain-sleep-fatigue symptom cluster had particular benefit from PRT on global health status and social functioning.

Pivotal Role of Preexisting Pathogen-Specific Antibodies in the Development of Necrotizing Soft-Tissue Infections.

Background: Necrotizing soft-tissue infections (NSTI) are the most severe form of bacterial-induced tissue pathology. Their unpredictable onset and rapid development into life-threatening conditions considerably complicate patient treatment. Understanding the risk factors for NSTI in individual patients is necessary for selecting the appropriate therapeutic option. Methods: We investigated the role of pathogen-specific antibodies in the manifestation of NSTI by performing a comparative serologic approach, using plasma samples and bacterial isolates from patients with clinical NSTIs or nonnecrotizing STIs caused by Streptococcus pyogenes. We also evaluated the potential beneficial effect of intravenous immunoglobulin (IVIG) treatment. Results: We identified a hitherto overlooked state of serologic susceptibility in patients with NSTIs during the earliest stages of the infection that is potentially linked to disease progression. Thus, all patients with NSTIs included in this study exhibited a deficiency in specific antibodies directed against the causative S. pyogenes strains and the majority of their exotoxins during the initial stage of the infection. We also showed that the clinical use of IVIG during the course of infection compensates the observed antibody deficiency but is unable to halt the disease progression, once tissue necrosis has developed. Conclusion: These observations emphasize the requirement of preexisting pathogen-specific antibodies to prevent the irreversible progression of tissue infections into severely spreading NSTIs and urge further investigations on the beneficial effect of IVIG-based early phase intervention strategies to prevent the severe effects of this devastating bacterial infection.

Genetic Architecture of Group A Streptococcal Necrotizing Soft Tissue Infections in the Mouse.

Host genetic variations play an important role in several pathogenic diseases, and we have previously provided strong evidences that these genetic variations contribute significantly to differences in susceptibility and clinical outcomes of invasive Group A Streptococcus (GAS) infections, including sepsis and necrotizing soft tissue infections (NSTIs). Our initial studies with conventional mouse strains revealed that host genetic variations and sex differences play an important role in orchestrating the severity, susceptibility and outcomes of NSTIs. To understand the complex genetic architecture of NSTIs, we utilized an unbiased, forward systems genetics approach in an advanced recombinant inbred (ARI) panel of mouse strains (BXD). Through this approach, we uncovered interactions between host genetics, and other non-genetic cofactors including sex, age and body weight in determining susceptibility to NSTIs. We mapped three NSTIs-associated phenotypic traits (i.e., survival, percent weight change, and lesion size) to underlying host genetic variations by using the WebQTL tool, and identified four NSTIs-associated quantitative genetic loci (QTL) for survival on mouse chromosome (Chr) 2, for weight change on Chr 7, and for lesion size on Chr 6 and 18 respectively. These QTL harbor several polymorphic genes. Identification of multiple QTL highlighted the complexity of the host-pathogen interactions involved in NSTI pathogenesis. We then analyzed and rank-ordered host candidate genes in these QTL by using the QTLminer tool and then developed a list of 375 candidate genes on the basis of annotation data and biological relevance to NSTIs. Further differential expression analyses revealed 125 genes to be significantly differentially regulated in susceptible strains compared to their uninfected controls. Several of these genes are involved in innate immunity, inflammatory response, cell growth, development and proliferation, and apoptosis. Additional network analyses using ingenuity pathway analysis (IPA) of these 125 genes revealed interleukin-1 beta network as key network involved in modulating the differential susceptibility to GAS NSTIs.

Neuronal nitric oxide inhibition attenuates the protective effect of HBO2 during cyanide poisoning.

PURPOSE: Experiments have shown that hyperbaric oxygen (HBO2) therapy reduces cyanide-induced cerebral distress. The exact mechanism behind HBO2's neuroprotective effect is unknown, but has been proposed to be mediated by an increased neuronal nitric oxide (NO) bioavailability, which may compete with cyanide for the active site of cytochrome oxidase in the mitochondrial respiratory chain. We hypothesized that the ameliorating effect of HBO2 is caused by an increased bioavailability of NO, which can be attenuated by injection of the selective neuronal NO synthase inhibitor, 7-nitroindazole, preceding the HBO2 procedure. METHODS: A total of 41 anesthetized female Sprague-Dawley rats were allocated to four groups: 1) vehicle [1.2 ml isotonic NaCl via intra-arterial administration]; 2) cyanide [5.4 mg/kg potassium CN (KCN) intra-arterial] plus 7-nitroindazole [25 mg/kg 7-nitroindazole via intraperitoneal injection]; 3) cyanide plus 7-nitroindazole plus HBO2 [284 kPa for 90 minutes]; 4) cyanide plus 7-nitroindazole plus normobaric oxygen [101.3 kPa for 90 minutes]. Cerebral interstitial lactate, glucose, glycerol and pyruvate were evaluated by means of microdialysis. RESULTS: HBO2 during inhibition of nNOS worsened cerebral metabolism compared to both solely CN-intoxicated animals and normobaric oxygen-treated animals. This was indicated by elevated lactate (in mM; 0.85 vs. 0.63 and 0.42, P=0.006 and P ⟨ 0.001, respectively), glycerol (in mM; 46 vs. 17 and 14, both P ⟨ 0.001), glucose (in mM; 0.58 vs. 0.31 and 0.32, both P ⟨ 0.001). CONCLUSIONS: The results indicate that a specific nNOS inhibition offsets the ameliorating effect of HBO2 during cerebral CN intoxication. However, other factors might contribute to this neuroprotective effect as well.

Progressive strength training to prevent LYmphoedema in the first year after breast CAncer - the LYCA feasibility study.

BACKGROUND: Lymphoedema is a common late effect after breast cancer (BC) that has no effective cure once chronic. Accumulating evidence supports progressive strength training (PRT) as a safe exercise modality in relation to the onset and exacerbation of lymphoedema. In the 'preventive intervention against LYmphoedema after breast CAncer' (LYCA) feasibility study we examined the feasibility of a program of PRT in the first year after BC to inform a planned randomised controlled trial (RCT). MATERIAL AND METHODS: LYCA was a one-group prospective pilot trial inviting women operated with axillary lymph node dissection for unilateral primary BC. Participants exercised three times a week for 50 weeks (20 weeks supervised followed by 30 weeks home-based exercise). The program ensured slow individualised progression during the exercise program. The primary outcome was feasibility measured by eligibility and recruitment rates, as well as questionnaire-assessed satisfaction and adherence to exercise. Furthermore, we assessed arm interlimb volume difference by water displacement, muscle strength by dynamic and isometric muscle testing and range of movement in the shoulder by goniometry. RESULTS: In August 2015, eight of 11 eligible patients accepted participation. Two of them dropped out early due to other health issues. The remaining six participants had high exercise adherence through the supervised period, but only three maintained this through the home exercise period. Program satisfaction was high and no serious adverse events from testing or exercising were reported. One participant presented with lymphoedema at 50-week follow-up. Muscle strength markedly increased with supervised exercise, but was not fully maintained through the home exercise period. Range of shoulder movement was not negatively affected by the program. CONCLUSION: Recruitment, testing, and exercise in LYCA was safe and feasible. At the 50-week follow-up, there was one case of lymphoedema. The LYCA program will be further tested in a full-scale RCT.