Residual Axillary Metastases in Node-Positive Breast Cancer Patients After Neoadjuvant Treatment: A Register-Based Study.

BACKGROUND: Lymph node (LN) metastasis after neoadjuvant chemotherapy (NACT) generally warrants axillary lymph node dissection, which opposes guidelines of upfront surgery in many cases. We investigated the risk of having additional metastases in the axilla when the LNs removed by targeted axillary dissection (TAD) harbored metastases after NACT. We aimed to identify subgroups suitable for de-escalated axillary treatment. METHODS: This register-based study used data from the Danish Breast Cancer Cooperative Group database. Data were analyzed with logistic regression models. The primary outcome was the metastatic burden in non-TAD LNs in patients with positive TAD LNs after NACT. RESULTS: Among 383 patients, < 66.6% positive TAD LNs (adjusted odds ratio [OR] 0.34, 95% confidence interval [CI] 0.17-0.62), only isolated tumor cells (ITCs) [OR 0.11, 95% CI < 0.01-0.82], and breast pathological complete response (pCR) [OR 0.07, 95% CI < 0.01-0.56] were associated with a low risk of having more than three positive non-TAD LNs. In 315 patients with fewer than three positive non-TAD LNs, the proportion of positive TAD LNs (OR 0.45, 95% CI 0.27-0.76 for 33.3-66.6% vs. > 66.6%), size of the TAD LN metastasis (OR 0.14, 95% CI 0.04-0.54 for ITC vs. macrometastasis), tumor size at diagnosis (OR 0.30, 95% CI 0.15-0.64 for 20-49 mm vs. ≥ 50 mm) and breast pCR (OR 0.38, 95% CI 0.15-0.96) were associated with residual LN metastases in the axilla. CONCLUSIONS: Breast pCR or ITC only in TAD LNs can, with reasonable certainty, preclude more than three positive non-TAD LNs. Additionally, patients with only ITCs in the TAD LN had a low risk of having any non-TAD LN metastases after NACT. De-escalated axillary treatment may be considered in both subgroups.

Nationwide lung function monitoring from infancy in newborn-screened children with cystic fibrosis.

Background: Cystic fibrosis (CF) lung disease starts in infancy and can be assessed for structural lung abnormalities using computed tomography or magnetic resonance scans, or for lung function impairment using multiple breath washout (MBW). However, in infancy these two methods are not well correlated. Trajectories of CF lung disease assessed by MBW in infants and toddlers remain poorly described, which is why we aimed to 1) describe the trajectory of lung function, 2) explore risk factors for progression and 3) explore the real-life effect of lumacaftor/ivacaftor. Methods: This was a nationwide observational cohort study (2018-2021) using data collected as part of the routine clinical surveillance programme (including MBW and monthly endo-laryngeal suction sampling for bacterial pathogens) in children born after implementation of newborn screening for CF (May 2016). Lumacaftor/ivacaftor commenced from age 2 years in children homozygous for F508del. Ventilation distribution efficiency (VDE), recently described to have advantages over lung clearance index (LCI), was reported as the primary MBW outcome after z-score calculations based on published reference data. Mixed effect linear regression models were the main statistical analyses performed in this study. Results: 59 children, aged 2-45 months, contributed with 211 MBW occasions (median (interquartile range (IQR)) 3 (2-5) MBW occasions per child) with a median (IQR) follow-up time of 10.8 (5.2-22.3) months. An overall mean annual deterioration rate of -0.50 (95% CI -0.78- -0.22) z-VDE was observed, starting from an estimated mean z-VDE of -1.68 (95% CI -2.15- -1.22) at age 0.0 years (intercept). Pseudomonas aeruginosa "ever" (n=14, MBWs 50) had a significantly worse z-VDE trajectory versus P. aeruginosa "never" (mean difference 0.53 (95% CI 0.16-0.89) per year; p=0.0047) and lumacaftor/ivacaftor treatment (n=22, MBWs 46) significantly improved the trajectory of z-VDE (mean difference 1.72 (95% CI 0.79-2.66) per year; p=0.0004), leading to a stable mean z-VDE trajectory after start of treatment. Conclusions: Infants and toddlers with CF demonstrated progressive deterioration in z-VDE over the first years of life. P. aeruginosa isolation "ever" was associated with an accelerated deterioration in lung function, while lumacaftor/ivacaftor therapy significantly improved and stabilised the trajectory.

Treating brain metastases in metastatic breast cancer: outcomes after stereotactic radiosurgery examined in a retrospective, single-center cohort analysis.

INTRODUCTION: We examined the role of receptor profiles and other prognostic factors in survival outcomes after stereotactic radiosurgery (SRS) for brain metastases in breast cancer patients, to help improve selection of candidates for SRS. MATERIAL AND METHODS: We included 149 consecutive patients who received SRS between 2012 and 2019 at the University Hospital of Copenhagen, Rigshospitalet, Denmark. Overall survival (OS) following SRS was determined through the Kaplan-Meier method, while CNS progression-free survival (CNS-PFS) was determined through competing risk analysis. Prognostic factors for both OS and CNS-PFS were evaluated through uni- and multivariate Cox regression and Fine-Gray models, respectively. The proportional hazards assumptions were tested through Schoenfeld residuals, and non-proportionality was accounted for by the inclusion of time-dependent variables. RESULTS: Median OS was 14.8 months for the entire cohort and was as follows for the four receptor profiles: 33.3 months for ER+/HER2+ (ER: estrogen receptor, HER2: human epidermal growth factor receptor 2), 11.0 months for ER+/HER2-, 17.7 months for ER-/HER2+, and 5.3 months for ER-/HER2-. In the multivariate model, the ER-/HER2- receptor profile (hazard ratio (HR): 2.00, 95% confidence interval (CI): 1.09-3.67) and the presence of extracranial visceral metastases (HR: 2.90, 95% CI: 1.53-5.50) were associated with worse OS. The ER+/HER2+ receptor profile (HR: 0.43, 95% CI: 0.19-0.96) and 5+ lines of treatment (HR: 0.40, 95% CI: 0.20-0.82) were both associated with improved OS. For CNS-PFS, 5+ lines of treatment (sub-distributional hazard ratio (SHR): 2.88, 95% CI: 1.06-7.81) was associated with worse CNS-PFS, while extracranial visceral metastases (SHR: 0.54, 95% CI: 0.30-0.97) was associated with reduced risk of CNS progression - which is primarily due to patients with extracranial metastases dying before developing new CNS progression. CONCLUSION: Extracranial visceral disease and the ER-/HER2- receptor profile were associated with poor survival outcomes following SRS.

The effect of comprehensive geriatric assessment on care received, treatment completion, toxicity, cancer-related and geriatric assessment outcomes, and quality of life for older adults receiving systemic anti-cancer treatment: A systematic review.

INTRODUCTION: This systematic review aims to summarise the available literature on the effect of geriatric assessment (multidimensional health assessment across medical, social, and functional domains; "GA") or comprehensive geriatric assessment (geriatric assessment with intervention or management recommendations; "CGA") compared to usual care for older adults with cancer on care received, treatment completion, adverse treatment effects, survival and health-related quality of life. MATERIALS AND METHODS: A systematic search of MEDLINE, EMBASE, CINAHL, and PubMed was conducted to identify randomised controlled trials or prospective cohort comparison studies on the effect of GA/CGA on care received, treatment, and cancer outcomes for older adults with cancer. RESULTS: Ten studies were included: seven randomised controlled trials (RCTs), two phase II randomised pilot studies, and one prospective cohort comparison study. All studies included older adults receiving systemic therapy, mostly chemotherapy, for mixed cancer types (eight studies), colorectal cancer (one study), and non-small cell lung cancer (one study). Integrating GA/CGA into oncological care increased treatment completion (three of nine studies), reduced grade 3+ chemotherapy toxicity (two of five studies), and improved quality of life scores (four of five studies). No studies found significant differences in survival between GA/CGA and usual care. GA/CGA incorporated into care decisions prompted less intensive treatment and greater non-oncological interventions, including supportive care strategies. DISCUSSION: GA/CGA integrated into the care of an older adult with cancer has the potential to optimise care decisions, which may lead to reduced treatment toxicity, increased treatment completion, and improved health-related quality of life scores.

Circadian desynchrony disturbs the function of rat spermatozoa.

Decreased male fertility is a growing health problem that requires a better understanding of molecular events regulating reproductive competence. Here the effects of circadian desynchrony on the rat spermatozoa functionality were studied. Circadian desynchrony was induced in rats that lived for 2 months under disturbed light conditions designed to mimic shiftwork in humans (two days of constant light, two days of continual dark, and three days of 14:10 h light:dark schedule). Such a condition abolished circadian oscillations in the rats' voluntary activity, followed by a flattened transcriptional pattern of the pituitary gene encoding follicle stimulating hormone subunit (Fshb), and genes important for germ cell maturation (Tnp1 and Prm2) as well as the clock in seminiferous tubules. However, the number of spermatozoa isolated from the epididymis of the rats suffering from circadian desynchrony did not deviate from the controls. Nevertheless, spermatozoa functionality, estimated by motility and progesterone-induced acrosome reaction, was reduced compared to the control. These changes were associated with the altered level of main markers of mitochondrial biogenesis (Pprgc1a/PGC1A, Nrf1/NRF1, Tfam, Cytc), decreased mitochondrial DNA copy number, ATP content, and clock genes (Bmal1/BMAL1, Clock, Cry1/2, and Reverba). The principal-component-analysis (PCA) points to a positive association of the clock and mitochondrial biogenesis-related genes in spermatozoa from rats suffering circadian desynchrony. Altogether, the results show the harmful effect of circadian desynchrony on spermatozoa functionality, targeting energetic homeostasis.

Proton linear energy transfer and variable relative biological effectiveness for adolescent patients with Hodgkin lymphoma.

Objectives: Proton therapy has a theoretical dosimetric advantage due to the Bragg peak, but the linear energy transfer (LET), and therefore the relative biological effectiveness (RBE), increase at the end of range. For patients with Hodgkin lymphoma, the distal edge of beam is often located within or close to the heart, where elevated RBE would be of potential concern. The purpose of this study was to investigate the impact of RBE and the choice of beam arrangement for adolescent patients with mediastinal Hodgkin lymphoma. Methods: For three previously treated adolescent patients, proton plans with 1-3 fields were created to a prescribed dose of 19.8 Gy (RBE) in 11 fractions (Varian Eclipse v13.7), assuming an RBE of 1.1. Plans were recalculated using Monte-Carlo (Geant4 v10.3.3/Gate v8.1) to calculate dose-averaged LET. Variable RBE-weighted dose was calculated using the McNamara model, assuming an α/ß ratio of 2 Gy for organs-at-risk. Results: Although the LET decreased as the number of fields increased, the difference in RBE-weighted dose (Δdose) to organs-at-risk did not consistently decrease. Δdose values varied by patient and organ and were mostly of the order of 0-3 Gy (RBE), with a worst-case of 4.75 Gy (RBE) in near-maximum dose to the left atrium for one plan. Conclusions: RBE-weighted doses to organs-at-risk are sensitive to the choice of RBE model, which is of particular concern for the heart. Advances in knowledge: There is a need to remain cautious when evaluating proton plans for Hodgkin lymphoma, especially when near-maximum doses to organs-at-risk are considered.

Work and education interruption in long-term Hodgkin lymphoma survivors: an analysis among patients from nine EORTC-LYSA trials.

BACKGROUND: Disease-specific studies on the impact of Hodgkin lymphoma (HL) on education or work interruption and resumption are lacking. MATERIAL AND METHODS: In a cross-sectional study conducted among long-term HL survivors enrolled from 1964 to 2004 in nine randomised EORTC-LYSA trials, the interruption and resumption of education/work was investigated. Survivors alive 5-44 years after diagnosis who were studying or working at time of diagnosis were included (n = 1646). Patient and treatment characteristics were obtained from trial records. Education and work outcomes were collected using the Life Situation Questionnaire. Logistic regression was used to model education or work interruption; Cox regression was used to study resumption rates. RESULTS: Among survivors studying at time of diagnosis (n = 323), 52% (95% CI: 46-57%) interrupted their education; however, it was resumed within 24 months by 92% (95% CI: 87-96%). The probability of interruption decreased with time: the more recent the treatment era, the lower the risk (OR 0.70 per 10 years, 95% CI: 0.49-1.01). Treatment with radiotherapy (yes vs. no) was associated with a higher education resumption rate (HR 2.01, 95% CI 1.07-3.78) whereas age, sex, stage, radiotherapy field and chemotherapy were not.Among survivors working at time of diagnosis (n = 1323), 77% (95% CI: 75-79%) interrupted their work. However, it was resumed within 24 months by 86% (95% CI: 84%-88%). Women were more likely to interrupt their work as compared to men (OR 1.90, 95% CI: 1.44-2.51) and, when interrupted, less likely to resume work (HR 0.70, 95% CI: 0.61-0.80). Survivors with a higher educational level were less likely to interrupt their work (OR 0.68 for university vs. no high school, 95% CI: 0.46-1.03); and when interrupted, more likely to resume work (HR 1.50 for university vs. no high school, 95% CI: 1.21-1.86). Increasing age was also associated with lower resumption rates (HR 0.62 for age ≥50 vs. 18-29 years, 95% CI: 0.41-0.94). CONCLUSION: An interruption in education/work was common among long-term HL survivors. However, most of the survivors who interrupted their studies or work had resumed their activities within 24 months. In this study, no associations between survivors' characteristics and failure to resume education were observed. Female sex, age ≥50 years, and a lower level of education were found to be associated with not resuming work after treatment for HL.

Isolation and Characterization of the First Zobellviridae Family Bacteriophage Infecting Klebsiella pneumoniae.

In order to address the upcoming crisis in the treatment of Klebsiella pneumoniae infections, caused by an increasing proportion of resistant isolates, new approaches to antimicrobial therapy must be developed. One approach would be to use (bacterio)phages and/or phage derivatives for therapy. In this study, we present a description of the first K. pneumoniae phage from the Zobellviridae family. The vB_KpnP_Klyazma podovirus, which forms translucent halos around the plaques, was isolated from river water. The phage genome is composed of 82 open reading frames, which are divided into two clusters located on opposite strands. Phylogenetic analysis revealed that the phage belongs to the Zobellviridae family, although its identity with the closest member of this family was not higher than 5%. The bacteriophage demonstrated lytic activity against all (n = 11) K. pneumoniae strains with the KL20 capsule type, but only the host strain was lysed effectively. The receptor-binding protein of the phage was identified as a polysaccharide depolymerase with a pectate lyase domain. The recombinant depolymerase protein showed concentration-dependent activity against all strains with the KL20 capsule type. The ability of a recombinant depolymerase to cleave bacterial capsular polysaccharides regardless of a phage's ability to successfully infect a particular strain holds promise for the possibility of using depolymerases in antimicrobial therapy, even though they only make bacteria sensitive to environmental factors, rather than killing them directly.

Comparison of outcomes between Hodgkin's lymphoma patients treated in and outside clinical trials: A study based on the EORTC-Dutch late effects cohort-linked data.

Studies have shown higher survival rates for patients with Hodgkin lymphoma (HL) treated within clinical trials compared to patients treated outside clinical trials. However, endpoints are often limited to overall survival (OS). In this retrospective cohort study, we investigated the effect of trial participation on OS, the incidence of relapse, second cancer, and cardiovascular disease (CVD). The study population consisted of patients with HL, aged between 14 and 51 years at diagnosis, who started their treatment between 1962 and 2002 at three Dutch cancer centres. Patients were either included in the EORTC Lymphoma Group trials (H1-H9) or treated according to standard guidelines at the time. After adjusting for differences in baseline characteristics, trial participation was associated with longer OS (median OS: 29.4 years [95%CI: 27.0-31.6] for treatment inside trials versus 27.4 years [95%CI: 26.0-28.5] for treatment outside trials, p = .046), a lower incidence of relapse (HR = 0.79, 95%CI: 0.63-0.98, p = .036) and a higher incidence of CVD (HR = 1.49, 95%CI: 1.23-1.79, p < .001). The trial effect for CVD was present only for patients treated before 1983. No evidence of differences in the incidence of second cancer was found. Consequently, essential results from clinical trials should be implemented into standard practice without undue delay.

Employment situation among long-term Hodgkin lymphoma survivors in Europe: an analysis of patients from nine consecutive EORTC-LYSA trials.

PURPOSE: Little is known about the employment situation of long-term Hodgkin lymphoma (HL) survivors despite their young age at diagnosis and the favorable prognosis of the disease. In this cross-sectional study, we aim to describe the employment situation in a cohort of long-term HL survivors compared to the general population and investigate the associations with disease characteristics and treatment exposure. METHODS: HL survivors > 25 years (n = 1961) were matched 1:25 to controls (n = 49,025) from the European Union Labour Force Survey. Individual treatment information was obtained from trial records. Employment and socio-demographic characteristics were collected using the Life Situation Questionnaire. Logistic regression models were used to estimate associations between disease and treatment characteristics with employment status and work-related attitudes. RESULTS: At employment assessment, 69.7% of survivors (95% CI: 67.6-71.7%) were working; of these, 68.9% (95% CI: 66.3-71.3%) worked full-time, a figure comparable to that of controls (p value 0.17). The risk of not working was associated with increasing age at diagnosis, increasing age at survey, female sex, lower educational level, and relapse history. Of those who were at work during treatment, 16.8% (95% CI: 14.5-19.3%) stated their income had subsequently decreased, which was attributed to their HL by 65.4% (95% CI: 57.5-72.8). Among those not at work, 25.1% (95% CI: 20.7-29.8) survivors were disabled compared to only 14.5% (95% CI: 13.8-15.3%) of controls. CONCLUSIONS: In this cohort of HL survivors, employment status was comparable to that of the general population. However, increasing age at follow-up, female sex, lower educational level, and relapse history are risk factors for unemployment, a perceived decrease in income, and disability. IMPLICATIONS FOR CANCER SURVIVORS: To further improve follow-up care, special attention should be paid to these vulnerable subgroups.

The cost of the circadian desynchrony on the Leydig cell function.

The increased frequency of different lifestyles that disrupts circadian rhythms, together with a trend in the accretion of male idiopathic infertility, imposes the necessity to understand the contribution of circadian rhythms disruption to fertility regulation. In this study, the effects of circadian desynchrony (CD) on the steroidogenic capacity of adult Leydig cells were studied. Adult rats were housed under a disturbing light regime (2 days of constant light, 2 days of continual dark, and 3 days of 12:12 h light:dark schedule) designed to mimic shiftwork in humans. CD was characterized by changed and decreased rhythmic locomotor activity and reduced blood testosterone. In the Leydig cells changed transcription of the clock genes (Bmal1, Clock, Cry1 and Reverba/b increased while Per1/2 reversed phase) was detected. This was followed by reduced transcription of genes (Star, Cyp11a1, and Hsd3b1/2) primarily involved in mitosteroidogenesis. In parallel, mitochondrial membrane potential (Δψi) and ATP production declined losing their characteristic oscillatory pattern. Also, the main markers of mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam, Cytc), fusion (Mfn2), and mitophagy (Pink1 and Tfeb) were disturbed. Collectively, CD targets mitochondria in Leydig cells by reducing mitosteroidogenesis, mitoenergetics, and disturbing mitochondrial dynamics. These changes contribute to testosterone decline compromising androgen-dependent functions, including reproduction.

Streptocinnamides A and B, Depsipeptides from Streptomyces sp. KMM 9044.

The bacterium Streptomyces sp. KMM 9044 from a sample of marine sediment collected in the northwestern part of the Sea of Japan produces highly chlorinated depsiheptapeptides streptocinnamides A (1) and B (2), representatives of a new structural group of antibiotics. The structures of 1 and 2 were determined using nuclear magnetic resonance and mass spectrometry studies and confirmed by a series of chemical transformations. Streptocinnamide A potently inhibits Micrococcus sp. KMM 1467, Arthrobacter sp. ATCC 21022, and Mycobacterium smegmatis MC2 155.

An integrated approach to cardioprotection in lymphomas.

In potentially curable cancers, long-term survival depends not only on the successful treatment of the malignancy but also on the risks associated with treatment-related toxicity, especially cardiotoxicity. Malignant lymphomas affect patients at any age, with acute and late toxicity risks that could have a severe effect on morbidity, mortality, and quality of life. Although our understanding of chemotherapy-associated and radiotherapy-associated cardiovascular disease has advanced considerably, new drugs with potential cardiotoxicity have been introduced for the treatment of lymphomas. In this Review, we summarise the mechanisms of treatment-related cardiac injury, available clinical data, and protocols for optimising cardioprotection in lymphomas. We discuss ongoing research strategies to advance our knowledge of the molecular basis of drug-induced and radiation-induced toxicity. Additionally, we emphasise the potential for personalised follow-up and early detection, including the role of biomarkers and novel diagnostic tests, highlighting the role of the cardio-oncology team.

Investigating the benefits and harms of hypodermoclysis of patients in palliative care: A consecutive cohort study.

BACKGROUND: Palliative populations are at risk for dehydration which can cause discomfort, distress and cognitive symptoms. Subcutaneous hydration ('hypodermoclysis') has been used as an alternative administration route to the more invasive intravenous route, but research is lacking on its net clinical effects (harms and benefits) for palliative populations, particularly in real world settings. AIM: To quantify prospectively the net clinical effects of hypodermoclysis in palliative patients with advanced disease who required supplementary fluids. DESIGN: Multisite, multinational consecutive cohort study. SETTING/PARTICIPANTS: Patients receiving hypodermoclysis in an inpatient palliative care setting. RESULTS: Twenty sites contributed data for 99 patients, of which 88 had complete benefits and harms data. The most common primary target symptom for infusion was generalised weakness (18.2%), and the most common non-symptom indication was supplemental hydration (31.8%). Benefits were experienced in 33% of patients in their primary target symptom, and in any symptom in 56.8%. Harms were experienced in 38.7% of patients (42% at Grade 1). Benefits increased with higher performance status, while harms were more frequent in patients with lower performance status (Australia-modified Karnofsky performance status ⩽40). Patients in the terminal phase of their illness experienced the least benefit (15.4% in any indication only) and had more frequent harms (38%). CONCLUSIONS: Hypodermoclysis may improve certain symptoms in patients in palliative care but frequency of harms and benefits may differ at certain timepoints in the illness trajectory. Further research is needed to better delineate which patients will derive the most net clinical benefit from hypodermoclysis.

Deep Functional Profiling of Wild Animal Microbiomes Reveals Probiotic Bacillus pumilus Strains with a Common Biosynthetic Fingerprint.

The biodiversity of microorganisms is maintained by intricate nets of interactions between competing species. Impaired functionality of human microbiomes correlates with their reduced biodiversity originating from aseptic environmental conditions and antibiotic use. Microbiomes of wild animals are free of these selective pressures. Microbiota provides a protecting shield from invasion by pathogens in the wild, outcompeting their growth in specific ecological niches. We applied ultrahigh-throughput microfluidic technologies for functional profiling of microbiomes of wild animals, including the skin beetle, Siberian lynx, common raccoon dog, and East Siberian brown bear. Single-cell screening of the most efficient killers of the common human pathogen Staphylococcus aureus resulted in repeated isolation of Bacillus pumilus strains. While isolated strains had different phenotypes, all of them displayed a similar set of biosynthetic gene clusters (BGCs) encoding antibiotic amicoumacin, siderophore bacillibactin, and putative analogs of antimicrobials including bacilysin, surfactin, desferrioxamine, and class IId cyclical bacteriocin. Amicoumacin A (Ami) was identified as a major antibacterial metabolite of these strains mediating their antagonistic activity. Genome mining indicates that Ami BGCs with this architecture subdivide into three distinct families, characteristic of the B. pumilus, B. subtilis, and Paenibacillus species. While Ami itself displays mediocre activity against the majority of Gram-negative bacteria, isolated B. pumilus strains efficiently inhibit the growth of both Gram-positive S. aureus and Gram-negative E. coli in coculture. We believe that the expanded antagonistic activity spectrum of Ami-producing B. pumilus can be attributed to the metabolomic profile predetermined by their biosynthetic fingerprint. Ultrahigh-throughput isolation of natural probiotic strains from wild animal microbiomes, as well as their metabolic reprogramming, opens up a new avenue for pathogen control and microbiome remodeling in the food industry, agriculture, and healthcare.

Novel Klebsiella pneumoniae K23-Specific Bacteriophages From Different Families: Similarity of Depolymerases and Their Therapeutic Potential.

Antibiotic resistance is a major public health concern in many countries worldwide. The rapid spread of multidrug-resistant (MDR) bacteria is the main driving force for the development of novel non-antibiotic antimicrobials as a therapeutic alternative. Here, we isolated and characterized three virulent bacteriophages that specifically infect and lyse MDR Klebsiella pneumoniae with K23 capsule type. The phages belonged to the Autographiviridae (vB_KpnP_Dlv622) and Myoviridae (vB_KpnM_Seu621, KpS8) families and contained highly similar receptor-binding proteins (RBPs) with polysaccharide depolymerase enzymatic activity. Based on phylogenetic analysis, a similar pattern was also noted for five other groups of depolymerases, specific against capsule types K1, K30/K69, K57, K63, and KN2. The resulting recombinant depolymerases Dep622 (phage vB_KpnP_Dlv622) and DepS8 (phage KpS8) demonstrated narrow specificity against K. pneumoniae with capsule type K23 and were able to protect Galleria mellonella larvae in a model infection with a K. pneumoniae multidrug-resistant strain. These findings expand our knowledge of the diversity of phage depolymerases and provide further evidence that bacteriophages and phage polysaccharide depolymerases represent a promising tool for antimicrobial therapy.

Perspectives on palliative oxygen for breathlessness: systematic review and meta-synthesis.

Oxygen therapy is frequently prescribed for the palliation of breathlessness, despite lack of evidence for its effectiveness in people who are not hypoxaemic. This study aimed to compare and contrast patients', caregivers' and clinicians' experiences of palliative oxygen use for the relief of chronic breathlessness in people with advanced life-limiting illnesses, and how this shapes prescribing.A systematic review and meta-synthesis of qualitative data was conducted. MEDLINE, CINAHL and PsycINFO were searched for peer-reviewed studies in English (2000-April 2019) reporting perspectives on palliative oxygen use for reducing breathlessness in people with advanced illnesses in any healthcare setting. After data extraction, thematic synthesis used line-by-line coding of raw data (quotes) to generate descriptive and analytical themes.Of 457 articles identified, 22 met the inclusion criteria by reporting perspectives of patients (n=337), caregivers (n=91) or clinicians (n=616). Themes common to these perspectives were: 1) benefits and burdens of palliative oxygen use, 2) knowledge and perceptions of palliative oxygen use beyond the guidelines, and 3) longitudinal trajectories of palliative oxygen use.There are differing perceptions regarding the benefits and burdens of using palliative oxygen. Clinicians should be aware that oxygen use may generate differing goals of therapy for patients and caregivers. These perceptions should be taken into consideration when prescribing oxygen for the symptomatic relief of chronic breathlessness in patients who do not quality for long-term oxygen therapy.

Screening Tools for Identifying Older Adults With Cancer Who May Benefit From a Geriatric Assessment: A Systematic Review.

IMPORTANCE: Older adults with cancer are at risk of overtreatment or undertreatment when decision-making is based solely on chronological age. Although a geriatric assessment is recommended to inform care, the time and expertise required limit its feasibility for all patients. Screening tools offer the potential to identify those who will benefit most from a geriatric assessment. Consensus about the optimal tool to use is lacking. OBJECTIVE: To appraise the evidence on screening tools used for older adults with cancer and identify an optimal screening tool for older adults with cancer who may benefit from geriatric assessment. EVIDENCE REVIEW: Systematic review of 4 databases (MEDLINE, Embase, CINAHL [Cumulative Index to Nursing and Allied Health Literature], and PubMed) with narrative synthesis from January 1, 2000, to March 14, 2019. Studies reporting on the diagnostic accuracy and use of validated screening tools to identify older adults with cancer who need a geriatric assessment were eligible for inclusion. Data were analyzed from March 14, 2019, to March 23, 2020. FINDINGS: Seventeen unique studies were included, reporting on the use of 12 screening tools. Most studies were prospective cohort studies (n = 11) with only 1 randomized clinical trial. Not all studies reported time taken to administer the screening tools. The Geriatric-8 (G8) (n = 12) and the Vulnerable Elders Survey-13 (VES-13) (n = 9) were the most frequently evaluated screening tools. The G8 scored better in sensitivity and the VES-13 in specificity. Other screening tools evaluated include the Groningen Frailty Index, abbreviated comprehensive geriatric assessment, and Physical Performance Test in 2 studies each. All other screening tools were evaluated in 1 study each. CONCLUSIONS AND RELEVANCE: To date, the G8 and VES-13 have the most evidence to recommend their use to inform the need for geriatric assessment. When choosing a screening tool, clinicians will need to weigh the tradeoffs between sensitivity and specificity. Future research needs to further validate or improve current screening tools and explore other factors that can influence their use, such as ease of use and resourcing.

Dose-response relationships for radiation-related heart disease: Impact of uncertainties in cardiac dose reconstruction.

BACKGROUND AND PURPOSE: Radiation-related heart disease (RRHD) can occur many decades after thoracic radiotherapy for Hodgkin lymphoma (HL) or childhood cancer (CC). To quantify the likely risk of RRHD for patients treated today, dose-response relationships derived from patients treated in previous decades are used. Publications presenting these dose-response relationships usually include estimates of uncertainties in the risks but ignore the effect of uncertainties in the reconstructed cardiac doses. MATERIALS/METHODS: We assessed the systematic and random uncertainties in the reconstructed doses for published dose-response relationships for RRHD risk in survivors of HL or CC. Using the same reconstruction methods as were used in the original publications, we reconstructed mean heart doses and, wherever possible, mean left-ventricular doses for an independent case-series of test patients. These patients had known, CT-based, cardiac doses which were compared with the reconstructed doses to estimate the magnitude of the uncertainties and their effect on the dose-response relationships. RESULTS: For all five reconstruction methods the relationship between reconstructed and CT-based doses was linear. For all but the simplest reconstruction method, the dose uncertainties were moderate, the effect of the systematic uncertainty on the dose-response relationships was less than 10%, and the effects of random uncertainty were small except at the highest doses. CONCLUSIONS: These results increase confidence in the published dose-response relationships for the risk of RRHD in HL and CC survivors. This may encourage doctors to use these dose-response relationships when estimating individualised risks for patients-an important aspect of personalising radiotherapy treatments today.