Sesquiterpenoids and Xanthones from the Kiwifruit-Associated Fungus Bipolaris sp. and Their Anti-Pathogenic Microorganism Activity

Nine previously undescribed sesquiterpenoids, bipolarisorokins A–I (1–9); two new xanthones, bipolarithones A and B (10 and 11); two novel sativene-xanthone adducts, bipolarithones C and D (12 and 13); as well as five known compounds (14–18) were characterized from the kiwifruit-associated fungus Bipolaris sp. Their structures were elucidated by extensive spectroscopic methods, electronic circular dichroism (ECD), 13C NMR calculations, DP4+ probability analyses, and single crystal X-ray diffractions. Many compounds exhibited anti-pathogenic microorganism activity against the bacterium Pseudomonas syringae pv. actinidiae and four pathogenic microorganisms.

Prevalence and severity of differing dimensions of breathlessness among elderly males in the population

Breathlessness is common in the general population. Existing data were obtained primarily with the uni-dimensional modified Medical Research Council (mMRC) breathlessness scale that does not assess intensities of unpleasantness nor physical, emotional, and affective dimensions. The aim of this research was to determine the prevalence and intensity of these dimensions of breathlessness in elderly males and any associations with their duration, change over time, and mMRC grade. We conducted a population-based, cross-sectional study of 73-year-old males in a county in southern Sweden. Breathlessness was self-reported at one time-point using a postal survey including the Dyspnoea-12 (D-12), the Multidimensional Dyspnoea profile (MDP), and the mMRC. Presence of an increased dimension score was defined as a score≥minimal clinically important difference for each dimension scale. Association with mMRC, recalled change since age 65, and duration of breathlessness were analysed with linear regression. Among 907 men, an increased dimension score was present in 17% (D-12 total score), 33% (MDP A1 unpleasantness), 19% (D-12 physical), 17% (MDP immediate perception), 10% (D-12 affective), and 17% (MDP emotional response). The unpleasantness and affective dimensions were strongly associated with mMRC ≥3. Higher MDP and D-12 scores were associated with worsening of breathlessness since age 65, and higher MDP A1 unpleasantness was associated with breathlessness of less than one year duration. Increased scores of several dimensions of breathlessness are prevalent in 73-year-old males and are positively correlated with mMRC scores, worsening of breathlessness after age 65, and duration of less than one year.

HUBUNGAN PENGETAHUAN KELUARGA DENGAN PENCEGAHAN OSTEOPOROSIS PADA LANSIA

Kejadian osteoporosis dipengaruhi berbagai faktor seperti gaya hidup tidak sehat seperti merokok, minum alkohol, minum kopi, kurang gerak atau tidak berolahraga serta pengetahuan mencegah osteoporosis yang kurang tentang mengkonsumsi kalsium dan vitamin D. Keluarga juga mempunyai peranan penting untuk mencegah terjadinya osteoporosis pada lansia yaitu pada fungsi keluarga sebagai pemeliharaan kesehatan meliputi: mengenal masalah kesehatan keluarga. Tujuan penelitian untuk mengetahui hubungan pengetahuan keluarga dengan pencegahan osteoporosis pada lansia. Desain penelitian ini bersifat analitik, dengan pendekatan cross sectional. Populasi dalam penelitian ini adalah seluruh keluarga yang tinggal bersama lansia sebanyak 48 keluarga. Jumlah sampel sebanyak 48 responden ditentukan dengan menggunakan teknik total sampling. Penelitian ini dilaksanakan pada tanggal 05 s/d 12 Agustus 2021.Analisa dilakukan dengan proses komputerisasi melalui uji chi-square. Hasil penelitian didapatkan bahwa pengetahuan keluarga berada pada kategori tinggi sebesar 43.8%. Pencegahan osteoporosis pada lansia berada pada kategori dilakukan sebesar 58.3%. Hasil uji statistik didapatkan p-value=0.000<α=0.05, hal ini membuktikan bahwa ada hubungan pengetahuan keluarga dengan pencegahan osteoporosis pada lansia. Berdasarkan hasil penelitian dapat disimpulkan bahwa hubungan pengetahuan keluarga dengan pencegahan osteoporosis pada lansia.

Effect of Daratumumab-Containing Induction on CD34+ Hematopoietic Stem Cells before Autologous Stem Cell Transplantation in Multiple Myeloma

Introduction: Daratumumab (Dara) is an anti-CD38 monoclonal antibody representing a novel treatment agent for multiple myeloma (MM). Nonetheless, several studies have reported a Dara-related impairment of CD34+ hematopoietic stem cell (HSC) mobilization and post-autologous stem cell transplantation (ASCT) complications, including low yields of mobilized HSCs and delayed neutrophil engraftment. Impact of Dara on the mobilization process and HSCs remains poorly understood even though sufficient yields of CD34+ cells are necessary for a successful ASCT and subsequent patient recovery. Aims: To compare the effect of the Dara-containing (Dara-Bortezomib-Dexamethasone [D-VCd]) and conventional (Bortezomib-Thalidomide-Dexamethasone [VTd]) therapy on CD34+ HSCs. Methods: Transplant eligible MM patients were treated with D-VCd or VTd induction regimen followed by a cyclophosphamide + G-CSF mobilization and a high-dose melphalan D -1 before ASCT. Flow cytometry (FCM) screening of CD34+ subsets was performed in the bone marrow (BM) or apheresis product (AP) at three consecutive time points: 1) diagnostic BM (DG), 2) mobilization AP (MOB), 3) a day prior ASCT BM (D-1). Furthermore, RNA sequencing (RNAseq) of sorted CD34+ cells was performed on total RNA with ribo-depletion protocol in AP after the induction. D-VCd samples had lower RNA yields thus the D-VCd or VTd groups were processed as independent batches. Results: Clinical data revealed no significant differences in mobilization (p &gt;0.050) likely due to a small cohort sizes (D-VCd n=5 vs VTd n=9), though a trend towards worse performance in D-VCd was observed. Median CD34+ cell yield was 3.08 vs 10.56 x 10 6/kg. Platelet recovery of &gt;20x10 9/L was D+14 vs D+12 (range: 11-18 vs 10-16). Neutrophil recovery of &gt;0.5x10 9/L was D+12 in both groups (range: 11-17 vs 11-12). In FCM analysis, DG (n=14), MOB D-VCd (n=5) vs VTd (n=9), D-1 D-VCd (n=7) vs VTd (n=15) were compared. CD34+ frequency (Fig. 1A) difference in MOB D-VCd vs VTd was insignificant (median: 1.15% vs 1.89%), whereas CD34+ fraction dropped in D-1 D-VCd (median: 0.52% vs 0.72%, p=0.027), albeit there was no significant reduction in D-1 D-VCd vs initial DG (median: 0.52% vs 0.45%). Differences in the distribution of certain HSC subsets were detected in the CD34+ pool (Fig. 1B-E). Frequency of multipotent progenitors (MPPs) (Fig. 1B) was increased in MOB D-VCd (median: 82.1% vs 66.2%, p=0.004). Frequency of lympho-myeloid-primed progenitor + granulocyte-monocyte progenitor (LMPP+GMP) (Fig. 1C) subset was reduced in D-VCd in both MOB (median: 1.7% vs 16.9%, p=0.042) and D-1 (median: 5.3% vs 14.0%; p=0.026). Erythro-myeloid progenitors (EMPs) (Fig. 1D) were reduced in MOB D-VCd (median: 10.7% vs 19.5%, p=0.042), while the frequency of EMPs increased in D-1 D-VCd (median: 20.8% vs 12.4%, p=0.045). No considerable differences were found in the expression of adhesion molecules CD44/HCAM or CD184/CXCR4. CD38 was strongly diminished in the whole D-VCd CD34+ fraction of MOB and D-1. To understand whether the differences in the mobilization efficacy after D-VCd induction were reflected in the expression profile of mobilized CD34+ cells, differential expression analysis was performed. Overall 133 significantly deregulated genes (p&lt;0.05; log fold change &gt;(-)1) between cohorts (D-VCd n=5 vs VTd n=5) were revealed (Fig. 2). Pathway analysis showed cellular response and localization as the most deregulated categories. The list of deregulated genes contained 25% of non-coding RNAs, some of which were linked to a protein localization in the cell (RN7SL1/2). The expression of adhesion molecules was inspected independently. Out of 59 HSC hallmark genes, only 8 were significantly altered in D-VCd. Interestingly, the main homing molecule CXCR4 seemed to be downregulated in D-VCd, while integrins A3 and B4 were upregulated. Conclusions: Despite the limited cohort sizes, a prospective trend of delayed neutrophil and platelet recovery was observed after D-VCd therapy. FCM analysis revealed a significant reduction of CD34+ subsets responsible, among others, for a reconstitution of neutrophils and megakaryocytes. A strong signal in transcriptome data which would potentially explain differential mobilization in D-VCd cohort was not detected, nevertheless, several genes with adhesive/homing and stem cell differentiation function were indeed altered. The results warrant further investigation. Figure 1 Figure 1. Disclosures Hajek: BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

TEM-GBM: An Open-Label, Phase I/IIa Dose-Escalation Study Evaluating the Safety and Efficacy of Genetically Modified Tie-2 Expressing Monocytes to Deliver IFN-α within Glioblastoma Tumor Microenvironment

Background: We developed a macrophage-based treatment relying on ex vivo transduction of autologous hematopoietic stem and progenitor cells (HSPC) to express immune-payloads within the TME. Our ATMP (Temferon) targets IFN-a, an immune-modulatory molecule counteracting also neo-angiogenesis and tumor growth, to a subset of Tie2-expressing, tumor-infiltrating macrophages known as TEMs. Materials and Methods: TEM-GBM is an open-label, Phase I/IIa dose-escalation study evaluating safety and efficacy of Temferon in up to 21 newly diagnosed glioblastoma patients with unmethylated MGMT promoter. Key eligibility criteria include age 18-70 years, ECOG 0-1 and KPS &gt;70%, and adequate cardiac, renal, hepatic and pulmonary function. Important exclusion criteria include the presence of active autoimmune disease or receipt of any oral or parenteral chemotherapy or immunotherapy within 2 years of screening. Autologous CD34+ HSPC are mobilized with lenograstim and plerixafor, collected by apheresis, purified and transduced ex vivo with a 3 rd generation lentiviral vector encoding for IFN-a2. Transgene expression is confined to TEMs by the Tie2 promoter and post-transcriptional regulation by microRNA-126 thus achieving tumor specificity. The study evaluates safety and biological activity of Temferon in 7 cohorts of three patients each, where escalating doses of Temferon are co-administered with a fixed CD34+ cell dose of non-manipulated supporter cells following a sub-myeloablative conditioning regimen (Thiotepa + BCNU or + Busulfan). The primary endpoints for this study are: Engraftment of Temferon over the first 90 DaysThe proportion of patients achieving hematologic recovery by Day +30 from ASCTShort-term tolerability of Temferon; stable blood counts and absence of cytopenias, absence of significant organ toxicities (&gt; grade 2); absence of Replication Competent Lentivirus The figure below reports the TEM-GBM study design. Results: As of 28th June 2021, 18 patients have been enrolled; 15 received Temferon (D+0) with follow-up of 30 - 697 days. There was rapid engraftment and hematological recovery after the conditioning regimen. Median neutrophil and platelet engraftment occurred at D+13 and D+12 for patients in cohort 1-3 and D+16 and D+15 for patients assigned to cohort 4 and 5, respectively. Temferon-derived differentiated cells, as determined by the presence of vector genomes in the DNA of peripheral blood and bone marrow cells, were found within 14 days post treatment and persisted subsequently, albeit at lower levels (up to 18 months). Very low concentrations of IFNa were detected in the plasma (average 7.8 pg/ml at D+30; baseline &lt; LLOQ) and in the cerebrospinal fluid (average 1.6 pg/ml at D+30; baseline &lt; LLOQ), suggesting tight regulation of transgene expression. Seven deaths occurred: six at D+241, +322, +340, +402, +478, +646 after Temferon administration due to disease progression, and one at D+60 due to complications following the conditioning regimen. Nine patients had progressive disease (PD; range D-12 to +239). SAEs include infections, venous thromboembolism, brain abscess, hemiparesis, GGT elevation and poor performance status compatible with autologous stem cell transplantation, concomitant medications and PD. Four patients underwent second surgery. These recurrent tumors had gene-marked cells present and increased expression of IFN-responsive gene signatures compared to diagnosis, indicative of local IFNa release by TEMs. In one patient, a stable lesion (as defined by MRI) had a higher proportion of T cells and TEMs within the myeloid infiltrate and an increased IFN-response signature than in a progressing lesion. The T-cell immune repertoire changed with evidence for expansion of tumor-associated clones. Tumor microenvironment characterization by scRNA and TCR sequencing is ongoing. Conclusion: These interim results show that Temferon is generally well tolerated by patients, with no dose limiting toxicities identified to date. The results provide initial evidence of Temferon's potential to activate the immune system and reprogram the tumor microenvironment (TME), as predicted by preclinical studies. Figure 1 Figure 1. Disclosures Naldini: Genenta Science: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: Founder.

Breathlessness dimensions association with physical and mental quality of life: the population based VASCOL study of elderly men

BackgroundBreathlessness is a multidimensional symptom prevalent in elderly affecting many aspects of life. We aimed to determine how different dimensions of breathlessness are associated with physical and mental quality of life (QoL) in elderly men.MethodsThis was a cross-sectional, population-based analysis of 672 men aged 73 years in a Swedish county. Breathlessness was assessed using Dyspnoea-12 (D-12) and Multidimensional Dyspnoea Profile (MDP), and QoL using the Short Form 12 physical and mental scores. Scores were compared as z-scores across scales and analysed using multivariable linear regression, adjusted for smoking, body mass index and the presence of respiratory and cardiovascular disease.ResultsWorse breathlessness was related to worse physical and mental QoL across all the D-12 and MDP dimension scores. Physical QoL was most strongly associated with perceptional breathlessness scores, D-12 total and physical scores (95% CI −0.45 to −0.30). Mental QoL was more strongly influenced by affective responses, MDP emotional response score (95% CI −0.61 to −0.48). Head-to-head comparison of the instruments confirmed that D-12 total and physical scores most influenced physical QoL, while mental QoL was mostly influenced by the emotional responses captured by the MDP.ConclusionBreathlessness dimensions and QoL measures are associated differently. Physical QoL was most closely associated with sensory and perceptual breathlessness dimensions, while emotional responses were most strongly associated with mental QoL in elderly men. D-12 and MDP contribute complimentary information, where affective and emotional responses may be related to function, deconditioning and QoL.

Feasibility of completing Multidimensional Dyspnea Profile and Dyspnea-12 over the telephone in patients with oxygen-dependent disease

BackgroundBreathlessness is prevalent in severe disease and consists of different dimensions that can be measured using the Multidimensional Dyspnea Profile (MDP) and Dyspnea-12 (D-12). We aimed to evaluate the feasibility of MDP and D-12 over telephone interviews in oxygen-dependent patients, compared with other patient-reported outcomes (modified Medical Research Council (mMRC) and Chronic Obstructive Pulmonary Disease Assessment Test (CAT)) and with completion by hand.MethodsCross-sectional, telephone study of 50 patients with home oxygen therapy. Feasibility was assessed as completion time (self-reported by patients and measured), difficulty (self-reported) and help required to complete the instruments (staff). Completion time was compared with mMRC and CAT, and feasibility was compared with completion by hand in cardiopulmonary outpatients (n=182). Feasibility by age and gender was analysed using logistic regression.ResultsOf 136 patients approached, 50 (37%) participated (mean age: 72±10 years, 66% women). Completion times (in minutes) were relatively short for MDP (self-reported 6 (IQR 5–10), measured 8 (IQR 6–10)) and D-12 (self-reported 5 (IQR 3–8), measured 3 (IQR 3–4)), and slightly longer than mMRC (median 1 (IQR 1–1)) and CAT (median 3 (IQR 2–5)). Even though the majority of patients required no help, more assistance was required by older patients. Compared with patients reporting by hand, completion over the telephone required somewhat longer time and more assistance.ConclusionMany patients with severe oxygen-dependent disease were unable or unwilling to assess symptoms over the telephone. However, among those able to participate, MDP and D-12 are feasible to measure multiple dimensions of breathlessness over the telephone.

220 Effects of Actisaf HR+ SC47 Live Yeast Probiotic Fed at Two Levels to Sows on Offspring Performance Before and After Weaning

750 sows (PIC line 42) were used to evaluate the effects of ActiSaf HR+ SC47 live yeast probiotic (AS) on sow and litter performance when fed to sows and their weaned piglets (PIC line 42 x 359). 250 multiparous sows per treatment (average parity 3.6) were fed the control diet without a live yeast probiotic (NC) or a diet with 250 mg/kg AS from breeding through lactation (LY1) or 250 mg/kg AS during gestation and 500 mg/kg AS during lactation. Weaned pigs from these sows were subsequently fed 4-phase nursery diets containing 0 (wNC) or 1 g/kg AS from d 0–10 after weaning followed by 500 mg/kg AS (wLY) from d 10–42 after weaning. This provided a 3x2 nursery trial design. During lactation, number of pigs born; born live varied by treatment (P &lt; 0.05). After weaning, wLY fed pigs had lower BW on d 12, 23; d 0–12 ADG, ADFI, lower d 0–42 ADFI and $/kg gained (P &lt; 0.05). Pigs fed wLY after weaning also tended towards lower d 42 BW and d 0–42 ADG (P &lt; 0.06; Table 1). Conversely, weaned pigs from sows fed LY1 or LY2 had higher ADG and ADFI from d 0–12 and d 0–42 after weaning (P &lt; 0.05) versus pigs from sows fed NC. Pigs from sows fed LY1 or LY2 also had higher BW at d 12, 23, and 42 after weaning than pigs from sows fed NC. Pigs from sows fed LY1 and LY2 tended to have lower nursery $/kg gain (P &lt; 0.06) than pigs from sows fed NC. No significant interactions were observed. Feeding ActiSaf HR+ SC47 live yeast probiotic to gestating and lactating sows improved their weaned pigs’ growth performance and tended to improve piglet cost of production after weaning.

Do Maternal Stress and Depressive Symptoms in Perinatal Period Predict the Lactation Mastitis Occurrence? A Retrospective Longitudinal Study in Greek Women

Background: The aim of this study is to investigate whether symptoms of anxiety and depression disorders in women during the perinatal period predict the occurrence of lactation mastitis. Methods: This is a retrospective longitudinal study of 622 Greek women who were monitored from pregnancy until the first year postpartum (during the period January 2015–May 2018). The Edinburgh Postnatal Depression Scale (EPDS) and the Perinatal Anxiety Screening Scale (PASS) were administered at four time points: (a) 24th–28th gestation week, (b) 34th–38th gestation week, (c) 6 weeks postpartum, and (d) 12 months postpartum. Multivariate binary logistic regression analyses were performed. Results: Results showed that (a) increased EPDS (p < 0.02) and PASS (p < 0.05) scores during the last period before birth, (b) increased EPDS score at 6 weeks postpartum (p < 0.02), (c) PMS symptoms (p < 0.03), (d) traumatic life events during the last year (p < 0.03), and (e) the existence of a history of psychotherapy (before pregnancy) (p = 0.050) appear to be the psycho-emotional factors that can predict the possible occurrence of lactation mastitis in a breastfeeding mother. Conclusions: The association between women’s poor mental health and the occurrence of a physical health problem, such as lactation mastitis, is recognized. This study highlights the important role of early and timely detection of perinatal mental health disorders.

Effect of short-term high tryptophan diet fed to sows on their subsequent piglet behavior

Housing sows in groups creates the challenge of decreasing fighting amongst sows. One proposed method to do so is to feed a high tryptophan diet, but the effect on the fetus is unkown. To investigate this, 66 sows were fed 1 of 3 diets: Control (0.14 % SID tryptophan), Medium (0.28 % SID tryptophan), or High (0.4 2% SID tryptophan), from d 28 to 35 of gestation. Sows gestated in standard gestation stalls. Blood samples were taken on d 27 prior to and on d 35 after tryptophan supplementation. On d 1 and d 2, 3 nursing bouts were observed so as to record disputes and displacements from teat competition. The piglets’ activity and fighting were recorded on d 3, 7, and 11 from 0700 h to 1700 h. On d 12, 4 piglets per litter were blood sampled, 2 to be used in later behavior tests and 2 to act as controls for blood cortisol levels. On d 14, the 2 behavior test piglets from each litter were subjected to a 10-min Isolation Test and 5-min Human Approach Test. On d 15, the behavior test piglets were paired by sex and treatment (for example, a male Medium piglet paired with another male Medium piglet from a different crate) and each pair was subjected to a 10-min Social Challenge Test and immediately blood sampled. Piglet cortisol and serotonin did not differ among treatments (P &gt; 0.10). There were no differences (P &gt; 0.10) for number born (12.7 ± 0.4), born alive (11.7 ± 0.4), or mortality (1.1 ± 0.2). Behavior during nursing bouts was similar, with no treatment differences in number of disputes or displacements, and similar bout lengths among treatments (199.5 ± 4.6 s, P &gt; 0.10). No differences were detected for any of the variables for Isolation or the Human Approach Tests (P &gt; 0.10). During the Social Challenge Test, High piglets had more contacts approaching the head of the companion piglet than did either Medium or Control piglets (14.3 ± 1.1, 10.7 ± 1.1, and 9.69 ± 0.8 respectively, P &lt; 0.02). Total number of aggressive interactions during the test tended to be greater for Medium piglets compared to High piglets (9.3 ± 1.5 vs 5.1 ± 0.9, P &lt; 0.07). Time budget data of the litter indicate that piglets from all 3 treatments spent equal amounts of time active and inactive (P &gt; 0.10). Aggression was low with 0.3 ± 0.04 % of piglets displaying aggressive behavior. Feeding high concentrations of tryptophan for a short duration early in gestation does not have a negative impact on sows’ subsequent offspring.