Prolonged Clinical Benefit with Futibatinib in a Patient with FGFR Inhibitor-Pretreated FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma: Case Report.

Multiple FGFR inhibitors have demonstrated significant activity in pretreated advanced FGFR2 fusion-positive intrahepatic cholangiocarcinoma. The irreversible pan-FGFR inhibitor futibatinib has the potential to overcome acquired resistance to ATP-competitive FGFR inhibitors in a subset of patients. We present a case of prolonged clinical benefit using FGFR inhibitors sequentially, initially an ATP-competitive inhibitor followed by futibatinib upon progression, for a total of 36 months of FGFR-targeting therapy. This case supports sequential FGFR-targeting therapies for FGFR2 fusion-positive cholangiocarcinoma, with futibatinib acting as rescue therapy after failure of ATP-competitive inhibitors.

Differences and similarities between the EULAR/ASAS-EULAR and national recommendations for treatment of patients with psoriatic arthritis and axial spondyloarthritis across Europe.

This is the first report comparing EULAR and national treatment recommendations for PsA patients across Europe, and the first this decade to compare ASAS-EULAR and national treatment recommendations in axSpA patients. An electronic survey was completed from October 2021-April 2022 by rheumatologists in 15 European countries. One and four countries followed all EULAR and ASAS-EULAR recommendations, respectively. Five countries had no national treatment recommendations for PsA and/or axSpA, but followed other regulations. In several countries, national treatment recommendations predated the most recent EULAR/ASAS-EULAR recommendations. Entry criteria for starting biologic/targeted synthetic disease-modifying anti-rheumatic drugs varied considerably. In several countries, for PsA patients with significant skin involvement, interleukin-17 inhibitors were not given preference. The positioning of Janus Kinase inhibitors differed and Phosphodiesterase-4 inhibitors were not in use/reimbursed in most countries. This study may motivate European countries to update their national treatment recommendations, to align them better with the latest international recommendations.

Borrelia burgdorferi Co-Localizing with Amyloid Markers in Alzheimer's Disease Brain Tissues.

BACKGROUND: Infections by bacterial or viral agents have been hypothesized to influence the etiology of neurodegenerative diseases. OBJECTIVE: This study examined the potential presence of Borrelia burgdorferi spirochete, the causative agent of Lyme disease, in brain autopsy tissue of patients diagnosed with either Alzheimer's (AD) or Parkinson's diseases. METHODS: Brain tissue sections from patients with age-matched controls were evaluated for antigen and DNA presence of B. burgdorferi using various methods. Positive Borrelia structures were evaluated for co-localization with biofilm and AD markers such as amyloid and phospho-tau (p-Tau) using immunohistochemical methods. RESULTS: The results showed the presence of B. burgdorferi antigen and DNA in patients with AD pathology and among those, one of them was previously diagnosed with Lyme disease. Interestingly, a significant number of Borrelia-positive aggregates with a known biofilm marker, alginate, were found along with the spirochetal structures. Our immunohistochemical data also showed that Borrelia-positive aggregates co-localized with amyloid and phospho-tau markers. To further prove the potential relationship of B. burgdorferi and amyloids, we infected two mammalian cell lines with B. burgdorferi which resulted in a significant increase in the expression of amyloid-ß and p-Tau proteins in both cells lines post-infection. CONCLUSION: These results indicate that B. burgdorferi can be found in AD brain tissues, not just in spirochete but a known antibiotics resistant biofilm form, and its co-localized amyloid markers. In summary, this study provides evidence for a likely association between B. burgdorferi infections and biofilm formation, AD pathology, and chronic neurodegenerative diseases.

In-situ fluorescence spectroscopy is a more rapid and resilient indicator of faecal contamination risk in drinking water than faecal indicator organisms.

Faecal indicator organisms (FIOs) are limited in their ability to protect public health from the microbial contamination of drinking water because of their transience and time required to deliver a result. We evaluated alternative rapid, and potentially more resilient, approaches against a benchmark FIO of thermotolerant coliforms (TTCs) to characterise faecal contamination over 14 months at 40 groundwater sources in a Ugandan town. Rapid approaches included: in-situ tryptophan-like fluorescence (TLF), humic-like fluorescence (HLF), turbidity; sanitary inspections; and total bacterial cells by flow cytometry. TTCs varied widely in six sampling visits: a third of sources tested both positive and negative, 50% of sources had a range of at least 720 cfu/100 mL, and a two-day heavy rainfall event increased median TTCs five-fold. Using source medians, TLF was the best predictor in logistic regression models of TTCs ≥10 cfu/100 mL (AUC 0.88) and best correlated to TTC enumeration (ρs 0.81), with HLF performing similarly. Relationships between TLF or HLF and TTCs were stronger in the wet season than the dry season, when TLF and HLF were instead more associated with total bacterial cells. Source rank-order between sampling rounds was considerably more consistent, according to cross-correlations, using TLF or HLF (min ρs 0.81) than TTCs (min ρs 0.34). Furthermore, dry season TLF and HLF cross-correlated more strongly (ρs 0.68) than dry season TTCs (ρs 0.50) with wet season TTCs, when TTCs were elevated. In-situ TLF or HLF are more rapid and resilient indicators of faecal contamination risk than TTCs.

Large-scale survey of seasonal drinking water quality in Malawi using in situ tryptophan-like fluorescence and conventional water quality indicators.

Faecally-contaminated drinking water is a risk to human health, with the greatest risks to those living in developing countries. UN Sustainable Development Goal 6 aims to address this issue. Tryptophan-like fluorescence (TLF) shows potential as a rapid method for detecting microbial contamination in drinking water, which could reduce the spread of waterborne diseases. This study is the first to investigate the effectiveness of TLF for a large-scale survey using a randomised, spot-sampling approach. The large-scale survey took place in Malawi, sub-Saharan Africa, in the dry season (n = 183). A subset of sources were revisited at the end of the following wet season (n = 41). The effectiveness of TLF was assessed by comparing TLF results to thermotolerant coliforms (TTC), humic-like fluorescence (HLF), inorganic hydrochemical data and sanitary risk scores. The most prominent differences in microbial water quality were observed between source types, with little variation between districts and seasons. TLF, TTCs, turbidity and sanitary risk scores were all elevated at alternative sources (shallow wells and tap stands) compared to hand-pumped boreholes. In the dry season, 18% of hand-pumped boreholes showed TTC contamination, which increase to 21% in the wet season. Groundwater recharge processes are likely responsible for seasonal variability of inorganic hydrochemistry at hand-pumped boreholes. TLF was able to distinguish no and low WHO risk classes (TTC 0-9 cfu/100 mL) from medium, high and very high risk classes (TTC 10 - >1000 cfu/100 mL). TLF failed to distinguish between no and low risk classes, which limits the use of TLF for assessing water quality to drinking water standards. This dataset indicates that HLF may raise baseline TLF for samples with low TLF values, increasing false positives. Therefore, TLF is better suited as a rapid high-level water quality screening tool to assess moderate and high levels of faecal contamination.

AKT/mTORC2 Inhibition Activates FOXO1 Function in CLL Cells Reducing B-Cell Receptor-Mediated Survival.

PURPOSE: To determine whether inhibition of mTOR kinase-mediated signaling represents a valid therapeutic approach for chronic lymphocytic leukemia (CLL). EXPERIMENTAL DESIGN: Stratification of mTOR activity was carried out in patients with primary CLL samples and an aggressive CLL-like mouse model. The potency of dual mTOR inhibitor AZD8055 to induce apoptosis in primary CLL cells was assessed in the presence/absence of B-cell receptor (BCR) ligation. Furthermore, we addressed the molecular and functional impact of dual mTOR inhibition in combination with BTK inhibitor ibrutinib. RESULTS: Differential regulation of basal mTORC1 activity was observed in poor prognostic CLL samples, with elevated p4EBP1T37/46 and decreased p70S6 kinase activity, suggesting that dual mTORC1/2 inhibitors may exhibit improved response in poor prognostic CLL compared with rapalogs. AZD8055 treatment of primary CLL cells significantly reduced CLL survival in vitro compared with rapamycin, preferentially targeting poor prognostic subsets and overcoming BCR-mediated survival advantages. Furthermore, AZD8055, and clinical analog AZD2014, significantly reduced CLL tumor load in mice. AKT substrate FOXO1, while overexpressed in CLL cells of poor prognostic patients in LN biopsies, peripheral CLL cells, and mouse-derived CLL-like cells, appeared to be inactive. AZD8055 treatment partially reversed FOXO1 inactivation downstream of BCR crosslinking, significantly inhibiting FOXO1T24 phosphorylation in an mTORC2-AKT-dependent manner, to promote FOXO1 nuclear localization, activity, and FOXO1-mediated gene regulation. FOXO1 activity was further significantly enhanced on combining AZD8055 with ibrutinib. CONCLUSIONS: Our studies demonstrate that dual mTOR inhibitors show promise as future CLL therapies, particularly in combination with ibrutinib.

Thermodynamic and kinetic controls on cotransport of Pantoea agglomerans cells and Zn through clean and iron oxide coated sand columns.

Recent observations that subsurface bacteria quickly adsorb metal contaminants raise concerns that they may enhance metal transport, given the high mobility of bacteria themselves. However, metal adsorption to bacteria is also reversible, suggesting that mobility within porous medium will depend on the interplay between adsorption-desorption kinetics and thermodynamic driving forces for adsorption. Till now there has been no systematic investigation of these important interactions. This study investigates the thermodynamic and kinetic controls of cotransport of Pantoea agglomerans cells and Zn in quartz and iron-oxide coated sand (IOCS) packed columns. Batch kinetic studies show that significant Zn sorption on IOCS takes place within two hours. Adsorption onto P. agglomerans surfaces reaches equilibrium within 30 min. Experiments in flow through quartz sand systems demonstrate that bacteria have negligible effect on zinc mobility, regardless of ionic strength and pH conditions. Zinc transport exhibits significant retardation in IOCS columns at high pH in the absence of cells. Yet, when mobile bacteria (non attached) are passed through simultaneously with zinc, no facilitated transport is observed. Adsorption onto cells becomes significant and plays a role in mobile metal speciation only once the IOCS is saturated with zinc. This suggests that IOCS exhibits stronger affinity for Zn than cell surfaces. However, when bacteria and Zn are preassociated on entering the column, zinc transport is initially facilitated. Subsequently, zinc partly desorbs from the cells and redistributes onto the IOCS as a result of the higher thermodynamic affinity for IOCS.

Relationship between arterial dysfunction and extra-articular features in patients with rheumatoid arthritis.

Systemic inflammation may be a common process that underpins both atherosclerosis and extra-articular features (ExRA) of rheumatoid arthritis (RA). We evaluated the relationship between ExRA and arterial dysfunction in 114 consecutive patients with RA (82% women) without overt arterial disease aged 40-65 years. A trained research nurse undertook 'SphygmoCor' pulse wave analysis (PWA) using radial applanation tonometry to measure the extent (augmentation index, AIX%) and timing (reflected wave transit time, RWT, msec) of aortic wave reflection. Assessment included fasting blood sample, patient questionnaire and medical record review. Mean differences were adjusted for age, sex, mean blood pressure, smoking pack-years, fasting cholesterol, Stanford HAQ score and erythrocyte sedimentation rate. Mean age was 54 (SD 7) and median RA duration 10 (IQR 4-17) years. There was a trend for arterial dysfunction (higher AIX%; lower RWT) to increase as the number of ExRA features rose, but no difference in AIX% (-0.5, 95%CI -2.8 to 1.8, P = 0.65) or RWT (0.3 ms, 95%CI -3.6 to 4.2, P = 0.86) between 'any ExRA' and 'no ExRA'. Arterial dysfunction was not associated with the presence of rheumatoid nodules, Sjogren's syndrome or carpal tunnel syndrome. Our study was too small to determine whether severe ('Malmo') ExRA (vasculitis, pericarditis, episcleritis) was truly associated with a higher AIX% (3.8, 95%CI -2.3 to 9.9, P = 0.22) and lower RWT (-5.5 ms 95%CI -13.1 to 2.1, P = 0.16). While arterial dysfunction may be associated with the number of ExRA features and severe ExRA, it does not appear to be associated with other ExRA features.

Relationship between arterial stiffness and Stanford Health Assessment Questionnaire disability in rheumatoid arthritis patients without overt arterial disease.

OBJECTIVE: To quantify the relationship between Stanford Health Assessment Questionnaire (HAQ) disability and arterial stiffness in patients with rheumatoid arthritis (RA). METHODS: A consecutive series of 114 patients with RA but without overt arterial disease, aged 40-65 years, were recruited from rheumatology clinics. A research nurse measured blood pressure (BP), arterial stiffness (heart rate-adjusted augmentation index), fasting lipids, glucose, erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF). A self-completed patient questionnaire included HAQ, damaged joint count, EuroQol measure of health outcome, and Godin physical activity score. Multiple linear regression (MLR) adjusted for age, sex, smoking pack-years, cholesterol, mean arterial BP, physical activity, daily fruit and vegetable consumption, arthritis duration, ESR, and RA criteria. RESULTS: Mean age was 54 years (81% women) with a median HAQ of 1.13 (interquartile range 0.50; 1.75). Median RA duration was 10 years, 83% were RF-positive, and median ESR was 16 mm/h. Mean arterial stiffness was 31.5 (SD 7.7), BP 125/82 mm Hg, cholesterol 5.3 mmol/l, and 24% were current smokers. Current therapy included RA disease-modifying agents (90%), prednisolone (11%), and antihypertensive therapy (18%). Arterial stiffness was positively correlated with HAQ (r = 0.42; 95% CI 0.25 to 0.56). On MLR, a 1-point increase in HAQ disability was associated with a 2.8 increase (95% CI 1.1 to 4.4; p = 0.001) in arterial stiffness. Each additional damaged joint was associated with a 0.17 point increase (95% CI 0.04 to 0.29; p = 0.009) in arterial stiffness. The relationship between EuroQol and arterial stiffness was not statistically significant. CONCLUSION: In patients with RA who are free of overt arterial disease, higher RA disability is associated with increased arterial stiffness independently of traditional cardiovascular risk factors and RA characteristics.

Phase III Study of Silver Leaf Nylon Dressing vs Standard Care for Reduction of Inframammary Moist Desquamation in Patients Undergoing Adjuvant Whole Breast Radiation Therapy.

AIMS: The primary objective of this study was to assess silver leaf nylon dressings as a prophylactic measure in reducing inframammary fold radiation induced dermatitis in women receiving adjuvant whole breast radiotherapy compared with standard skin care. A secondary objective was to assess if the dressing influenced breast skin-related pain, itching and burning resulting from whole breast radiotherapy. MATERIAL AND METHODS: A prospective randomized trial compared silver leaf nylon dressing worn continuously from the sixth fraction of whole breast radiotherapy until 14 days after therapy completion to standard skin care in patients deemed to be at risk of inframammary radiation induced dermatitis by virtue of a large breast volume or a significant inframammary skin fold in the treatment position. Stratification before randomization was for anthracycline chemotherapy and fractionation scheme. Digital photos of the inframammary region were taken at one week before, the last day of whole breast radiotherapy, and one week after treatment completion. Three observers blinded to treatment arm assessed the images for the presence of moist desquamation and the Radiation Therapy Oncology Group (RTOG) skin toxicity score. Patients completed questionnaires comprising visual analogue scales for pain, itching and burning sensation, and questions regarding which topical skin cream was being used, at the before-mentioned times as well as at baseline and two weeks after completing whole breast radiotherapy. RESULTS: A total of 196 patients completed the study. Moist desquamation occurred in 38% of patients. No difference in incidence or maximum size of moist desquamation or RTOG skin toxicity scores was seen between the treatment arms. However, on the last day of radiation treatment and one week after completion of treatment, patient reports of itching decreased in the experimental arm. At one week before whole breast radiotherapy completion, patients using Glaxal Base cream reported worse burning, those using aloe vera reported worse pain and burning, whereas patients who had not used a moisturizing cream reported less pain. CONCLUSION: Silver leaf nylon dressing use did not demonstrate a decrease in the incidence of inframammary moist desquamation, but did decrease itching in the last week of radiation and one week after treatment completion.

Arterial stiffness and cumulative inflammatory burden in rheumatoid arthritis: a dose-response relationship independent of established cardiovascular risk factors.

OBJECTIVE: To quantify the relationship between arterial stiffness and cumulative inflammatory burden in patients with RA. METHODS: We recruited RA patients without overt arterial disease aged 40-65 years, attending hospital rheumatology outpatient clinics. Standardized research nurse assessment included blood pressure (BP), pulse wave analysis (PWA, SphygmoCor), BMI, fasting blood sample (lipids, glucose, RF and ESR), patient questionnaire (smoking, alcohol, diet, exercise, family history of premature coronary heart disease and Stanford HAQ), current medication and medical record review. Cumulative inflammatory burden was measured as ESR area-under-the-curve (ESR-years) extracted from medical records. Arterial stiffness was measured using PWA [aortic augmentation index (AIX@75)]. Multiple linear regression was used to adjust for age, sex and nine other cardiovascular risk factors. RESULTS: We recruited 114 RA patients (mean age 54 years, female 81%, current DMARD 90%, current NSAID 70%, ACR criteria 56%) comprising 1040 RA person-years. Cholesterol, glucose and BMI were similar in women and men. Women had a longer duration of arthritis (10 vs 7 years) and were more likely to be seropositive (85 vs 71%). BP, smoking and alcohol consumption were lower for women. On fully adjusted analysis, an increase of 100 ESR-years was associated with an increase in AIX@75 of 0.51 (95% CI 0.13, 0.88). On fully adjusted analysis restricted to women the increase was 0.43 (95% CI 0.01, 0.85). CONCLUSIONS: In RA patients free of overt arterial disease, a dose-response relationship exists between cumulative inflammatory burden and arterial stiffness. This relationship is independent of established CV risk factors.

Spirochetal cyst forms in neurodegenerative disorders,...hiding in plain sight.

Here is proposed a hypothesis that a completely unsuspected biology exists for pathogenic spirochetes, namely that the cystic spirochetal forms (long thought to be static and resting or just a dormant cohort) actually are capable of killing mammalian host cells. At least two "lethal" scenarios are proposed; first, the host cell destruction from the "inside out" by small caliber cystic forms invading the host cell cytoplasm, and second host cell destruction by engulfment of entire host cells by large caliber cystic spirochetal forms. Conventional thinking about spirochetal cyst forms is divided between two polar spheres of influence; one a majority community that completely denies the existence of spirochetal cyst forms, and a second group of academically persecuted individuals who accepts the precepts of such antebellum scientists as Schaudinn, Hoffman, Dutton, Levaditi, Balfour, Fantham, Noguchi, McDonough, Hindle, Steiner, Ingraham, Coutts, Hampp, Warthin, Ovcinnikov, and Delamater. Microscopic images of cystic spirochetes are difficult to ignore, but as has been the case in this century, academic "endowments" have nearly expunged all cystic spirochetal image data from the current textbook versions of what is the truth about the spirochetaceae. If the image database from the last century is obliterated; many opportunities to diagnose will be lost. Variously sized cystic spirochetal profiles within diseased nerve cells explain the following structures: Lewy body of Parkinson's disease, Pick body, ALS spherical body, Alzheimer plaque. Borrelia infection is therefore a unifying concept to explain diverse neurodegenerative diseases, based not entirely on a corkscrew shaped profile in diseased tissue, but based on small, medium and large caliber rounded cystic profiles derived from pathogenic spirochetes which are..."hiding in plain sight".

A life cycle for Borrelia spirochetes?

Subsequent to Schaudinn and Hoffman's visualization of Treponema pallidum in 1905, many distinguished syphilologists proposed that spirochetes have a life cycle. What is the "essence" of a life cycle? Simply put, life cycles are diverse arrays of life forms, which emerge in an ordered sequence; which are "connected" to one another across primary and secondary hosts, and constitute a cycle with "circular" relationship between hosts. Fecal-oral life cycles and blood-to-blood life cycles are exemplary of host parasite relationships in this realm. The "blood-to-blood" begins and ends with an insect taking a blood "meal". In this operatic scenario, a "blood-less" insect functions simultaneously as a hypodermic needle and as an incubator for some of the infectious components. The initial phase is inside the body fluid compartment of an insect. The second phase is in the blood or body fluid of a warm-blooded mammal. Third, is the phase inside the cell of a mammalian host. And a final portion of the "life" marked by "death" of the parasitized mammalian cells and the release of infectious parasites which return to the "warm" blood where the "cold blooded" vector again takes a blood meal. The cycle then begins again. In each phase of a blood to blood life cycle, the infectious agent changes its shape. Blood phase "profiles" look different from "tissue phase" profiles. Some of the tissue phase profiles may be "invisible". Borrelia spirochetes offer an excellent example of a life cycle, by virtue of the insect vector to mammalian "piece", the blood and intracellular residence "pieces" and the morphologic diversity "piece". Stereotypes of what a spirochete "should " look like, have actually produced a state of "perseveration" in spirochetal pathobiology. We have been "stuck" like a broken record, on the corkscrew form, and have failed to see the rest of the life cycle. Cystic, granular, and cell wall deficient spirochetal profiles, which were well known in the 19th and 20th centuries by such titans as Schaudinn, Hoffman, Noguchi, Delamater, Steiner, and Mattman, have been repudiated by professional microbiologists, and by pathologists who practice and who confer the status of 21st century truths in microbiology matters. Proper microscopic study, as is required by Dr. Robert Koch's second postulate, for establishing links between microbes and disease, presupposes that the microscopist be aware of the complete array of morphologic repertoires of the alleged pathogen. (Morphologies, which are herein introduced.).

Plaques of Alzheimer's disease originate from cysts of Borrelia burgdorferi, the Lyme disease spirochete.

Here is hypothesized a truly revolutionary notion that rounded cystic forms of Borrelia burgdorferi are the root cause of the rounded structures called plaques in the Alzheimer brain. Rounded "plaques' in high density in brain tissue are emblematic of Alzheimer's disease (AD). Plaques may be conceptualized as rounded "pock mark-like" areas of brain tissue injury. In this century, in brain tissue of AD, plaques are Amyloid Plaques according to the most up to date textbooks. In the last century, however, Dr. Alois Alzheimer did not require amyloid as the pathogenesis for either the disease or for the origin of its plaques. Surely, amyloid is an event in AD, but it may not be the primal cause of AD. Indeed in plaques, amyloid is regularly represented by the "congophilic core" structure which is so named because the waxy amyloid material binds the congo red stain and is congophilic. However an accepted subset of plaques in AD is devoid of a congophilic amyloid core region (these plaques "cotton wool" type plaques, lack a central congophilic core structure). Furthermore, there is "plaque diversity" in Alzheimer's; small, medium and large plaques parallel variable cystic diameters for Borrelia burgdorferi. Perturbations of AD plaque structure (i.e. young plaques devoid of a central core and older plaques with or without a central core structure) offer room for an alternate pathway for explanation of ontogeny of the plaque structures. If amyloid is not required to initiate all of the possible plaques in Alzheimer's, is it possible that amyloid just a by product of a more fundamental primal path to dementia? If a byproduct status is assigned to amyloid in the realm of plaque formation, then is amyloid also an epiphenomenon rather than a primary pathogenesis for Alzheimer's disease. In the "anatomy is destiny" model, cysts of borrelia are always round. Why then not accept roundness as a fundamental "structure determines function" argument for the answer to the mystery of why Alzheimer plaques are always round? Parataxis causality, a concept borrowed from philosophy, is the error that comes from linking two events, which occur contemporaneously or in close proximity to one another with a cause and effect relationship. Parataxis tells us that what appears to be cause and effect in the couplet "amyloid plaque" merely by a proximity relationship may be "spurious causality" which is a cognitive dead end.