Influence of therapeutic plasma exchange treatment on short-term mortality of critically ill adult patients with sepsis-induced organ dysfunction: a systematic review and meta-analysis.

INTRODUCTION: The impact of therapeutic plasma exchange (TPE) on short-term mortality in adult patients with sepsis-induced organ dysfunction remains uncertain. The objective of the study is to assess the effect of adjunct TPE in this setting through a comprehensive literature review. METHODS: The National Library of Medicine's Medline, Ovid (Embase), the Cochrane Library database and clinicaltrial.gov from January 01, 1966, until October 01, 2022, were searched for terms: therapeutic plasma exchange, plasmapheresis, sepsis, and septic shock. We reviewed, selected and extracted data from relevant randomized clinical trials (RCTs) and matched cohort studies (MCSs) comparing short-term mortality in critically ill adult septic patients treated with standard therapy versus those receiving adjunct TPE. Risk of bias was assessed in the RCTs using Cochrane Collaboration tool and in MCSs using ROBINS-I tool. Summary statistics, risk ratios (RRs), and confidence intervals (CIs) were calculated using random effects model. RESULTS: This systematic review included 937 adult critically ill septic patients from five RCTs (n = 367) and fifteen MCSs (n = 570). Of these total, 543 received treatment with TPE in addition to standard care. The meta-analysis includes all five RCTs and only six MCSs (n = 627). The adjunct TPE treatment (n = 300) showed a significant reduction in short-term mortality (RR 0.59, 95% CI 0.47-0.74, I2 3%) compared to standard therapy alone (n = 327). The systematic review of all 20 trials revealed that adding TPE to the standard therapy of critically ill septic patients resulted in faster clinical and/or laboratory recovery. CONCLUSIONS: Our comprehensive and up-to-date review demonstrates that adjunct TPE may provide potential survival benefits when compared to standard care for critically ill adult patients with sepsis-induced organ dysfunction. While results of this meta-analysis are encouraging, large well-designed randomized trials are required to identify the optimal patient population and TPE procedure characteristics prior to widespread adoption into practice.

Theoretical Neurobiology of Consciousness Applied to Human Cerebral Organoids.

Organoids and specifically human cerebral organoids (HCOs) are one of the most relevant novelties in the field of biomedical research. Grown either from embryonic or induced pluripotent stem cells, HCOs can be used as in vitro three-dimensional models, mimicking the developmental process and organization of the developing human brain. Based on that, and despite their current limitations, it cannot be assumed that they will never at any stage of development manifest some rudimentary form of consciousness. In the absence of behavioral indicators of consciousness, the theoretical neurobiology of consciousness being applied to unresponsive brain-injured patients can be considered with respect to HCOs. In clinical neurology, it is difficult to discern a capacity for consciousness in unresponsive brain-injured patients who provide no behavioral indicators of consciousness. In such scenarios, a validated neurobiological theory of consciousness, which tells us what the neural mechanisms of consciousness are, could be used to identify a capacity for consciousness. Like the unresponsive patients that provide a diagnostic difficulty for neurologists, HCOs provide no behavioral indicators of consciousness. Therefore, this article discusses how three prominent neurobiological theories of consciousness apply to human cerebral organoids. From the perspective of the Temporal Circuit Hypothesis, the Global Neuronal Workspace Theory, and the Integrated Information Theory, we discuss what neuronal structures and functions might indicate that cerebral organoids have a neurobiological capacity to be conscious.

Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage.

BRCA1 is a breast and ovarian tumor suppressor. Given its numerous incompletely understood functions and the possibility that more exist, we performed complementary systematic screens in search of new BRCA1 protein-interacting partners. New BRCA1 functions and/or a better understanding of existing ones were sought. Among the new interacting proteins identified, genetic interactions were detected between BRCA1 and four of the interactors: TONSL, SETX, TCEANC, and TCEA2. Genetic interactions were also detected between BRCA1 and certain interactors of TONSL, including both members of the FACT complex. From these results, a new BRCA1 function in the response to transcription-associated DNA damage was detected. Specifically, new roles for BRCA1 in the restart of transcription after UV damage and in preventing or repairing damage caused by stabilized R loops were identified. These roles are likely carried out together with some of the newly identified interactors. This new function may be important in BRCA1 tumor suppression, since the expression of several interactors, including some of the above-noted transcription proteins, is repeatedly aberrant in both breast and ovarian cancers.

The Causal Efficacy of Consciousness.

Mental causation is vitally important to the integrated information theory (IIT), which says consciousness exists since it is causally efficacious. While it might not be directly apparent, metaphysical commitments have consequential entailments concerning the causal efficacy of consciousness. Commitments regarding the ontology of consciousness and the nature of causation determine which problem(s) a view of consciousness faces with respect to mental causation. Analysis of mental causation in contemporary philosophy of mind has brought several problems to the fore: the alleged lack of psychophysical laws, the causal exclusion problem, and the causal pairing problem. This article surveys the threat each problem poses to IIT based on the different metaphysical commitments IIT theorists might make. Distinctions are made between what I call reductive IIT, non-reductive IIT, and non-physicalist IIT, each of which make differing metaphysical commitments regarding the ontology of consciousness and nature of causation. Subsequently, each problem pertaining to mental causation is presented and its threat, or lack thereof, to each version of IIT is considered. While the lack of psychophysical laws appears unthreatening for all versions, reductive IIT and non-reductive IIT are seriously threatened by the exclusion problem, and it is difficult to see how they could overcome it while maintaining a commitment to the causal closure principle. Yet, non-physicalist IIT denies the principle but is therefore threatened by the pairing problem, to which I have elsewhere provided a response that is briefly outlined here. This problem also threatens non-reductive IIT, but unlike non-physicalist IIT it lacks an evident response. The ultimate aim of this survey is to provide a roadmap for IIT theorists through the maze of mental causation, by clarifying which commitments lead to which problems, and how they might or might not be overcome. Such a survey can aid IIT theorists as they further develop and hone the metaphysical commitments of IIT.

Bone without minerals and its secondary mineralization in Atlantic salmon (Salmo salar): the recovery from phosphorus deficiency.

Calcium and phosphorus (P) are the main bone minerals, and P deficiency can cause hypomineralized bones (osteomalacia) and malformations. This study used a P-deficient salmon model to falsify three hypotheses. First, an extended period of dietary P deficiency does not cause pathologies other than osteomalacia. Second, secondary mineralization of non-mineralized bone is possible. Third, secondary mineralization can restore the bones' mineral composition and mechanical properties. For 7 weeks, post-smolt Atlantic salmon (Salmo salar) received diets with regular P content (RP) or with a 50% lowered P content (LP). For additional 9 weeks, RP animals continued on the regular diet (RP-RP). LP animals continued on the LP diet (LP-LP), on a regular P diet (LP-RP) or on a high P diet (LP-HP). After 16 weeks, animals in all groups maintained a non-deformed vertebral column. LP-LP animals continued bone formation albeit without mineralization. Nine weeks of RP diet largely restored the mineral content and mechanical properties of vertebral bodies. Mineralization resumed deep inside the bone and away from osteoblasts. The history of P deficiency was traceable in LP-RP and LP-HP animals as a ring of low-mineralized bone in the vertebral body endplates, but no tissue alterations occurred that foreshadow vertebral body compression or fusion. Large quantities of non-mineralized salmon bone have the capacity to re-mineralize. If 16 weeks of P deficiency as a single factor is not causal for typical vertebral body malformations, other factors remain to be identified. This example of functional bone without minerals may explain why some teleost species can afford to have an extremely low mineralized skeleton.

Glucocorticoids induce production of reactive oxygen species/reactive nitrogen species and DNA damage through an iNOS mediated pathway in breast cancer.

BACKGROUND: Psychological stress increases the circulating levels of the stress hormones cortisol and norepinephrine (NE). Chronic exposure to elevated stress hormones has been linked to a reduced response to chemotherapy through induction of DNA damage. We hypothesize that stress hormone signalling may induce DNA damage through the production of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and interference in DNA repair processes, promoting tumourigenesis. METHODS: Breast cancer cell lines were incubated with physiological levels of cortisol and NE in the presence and absence of receptor antagonists and inducible nitric oxide synthase (iNOS) inhibitors and DNA damage measured using phosphorylated γ-H2AX. The rate of DNA repair was measured using comet assays and electrochemical sensors were used to detect ROS/RNS in the cell lysates from cells exposed to stress hormones. A syngeneic mouse model was used to assess the presence of iNOS in mammary tumours in stressed versus control animals and expression of iNOS was examined using western blotting and qRT-PCR. RESULTS: Acute exposure to cortisol and NE significantly increased levels of ROS/RNS and DNA damage and this effect was diminished in the presence of receptor antagonists. Cortisol induced DNA damage and the production of RNS was further attenuated in the presence of an iNOS inhibitor. An increase in the expression of iNOS in response to psychological stress was observed in vivo and in cortisol-treated cells. Inhibition of glucocorticoid receptor-associated Src kinase also produced a decrease in cortisol-induced RNS. CONCLUSION: These results demonstrate that glucocorticoids may interact with iNOS in a non-genomic manner to produce damaging levels of RNS, thus allowing an insight into the potential mechanisms by which psychological stress may impact breast cancer.

Organic arsenicals as efficient and highly specific linkers for protein/peptide-polymer conjugation.

The entropy-driven affinity of trivalent (in)organic arsenicals for closely spaced dithiols has been exploited to develop a novel route to peptide/protein-polymer conjugation. A trivalent arsenous acid (As(III)) derivative (1) obtained from p-arsanilic acid (As(V)) was shown to readily undergo conjugation to the therapeutic peptide salmon calcitonin (sCT) via bridging of the Cys(1)-Cys(7) disulfide, which was verified by RP-HPLC and MALDI-ToF-MS. Conjugation was shown to proceed rapidly (t < 2 min) in situ and stoichiometrically through sequential reduction-conjugation protocols, therefore exhibiting conjugation efficiencies equivalent to those reported for the current leading disulfide-bond targeting strategies. Furthermore, using bovine serum albumin as a model protein, the trivalent organic arsenical 1 was found to demonstrate enhanced specificity for disulfide-bond bridging in the presence of free cysteine residues relative to established maleimide functional reagents. This specificity represents a shift toward potential orthogonality, by clearly distinguishing between the reactivity of mono- and disulfide-derived (vicinal or neighbors-through-space) dithiols. Finally, p-arsanilic acid was transformed into an initiator for aqueous single electron-transfer living radical polymerization, allowing the synthesis of hydrophilic arsenic-functional polymers which were shown to exhibit negligible cytotoxicity relative to a small molecule organic arsenical, and an unfunctionalized polymer control. Poly(poly[ethylene glycol] methyl ether acrylate) (PPEGA480, DPn = 10, Mn,NMR = 4900 g·mol(-1), D = 1.07) possessing a pentavalent arsenic acid (As(V)) α-chain end was transformed into trivalent As(III) post-polymerization via initial reduction by biological reducing agent glutathione (GSH), followed by binding of GSH. Conjugation of the resulting As(III)-functional polymer to sCT was realized within 35 min as indicated by RP-HPLC and verified later by thermodynamically driven release of sCT, from the conjugate, in the presence of strong chelating reagent ethanedithiol.

Asymmetric Reduction of Electron-Rich Ketones with Tethered Ru(II)/TsDPEN Catalysts Using Formic Acid/Triethylamine or Aqueous Sodium Formate.

The asymmetric transfer hydrogenation (ATH) of ketones under aqueous conditions using tethered Ru(II)/η(6)-arene/diamine catalysts is described, as is the ATH of electron-rich substrates containing amine and methoxy groups on the aromatic rings. Although such substrates are traditionally challenging ones for ATH, the tethered catalysts work very efficiently. In the case of amino-substituted ketones, aqueous conditions give excellent results; however, for methoxy-substituted substrates, the more established formic acid/triethylamine system gives superior results.

Assessment of global proteome dynamics in carp: a model for investigating environmental stress.

Fish have to respond to a range of natural and man-made environmental stressors, which can lead to molecular changes within their tissues. Many studies focused on environmental stress in fish have examined the change in protein abundance or mRNA level. However, it is well-known that there is a disconnect between mRNA and protein expression. In order to bridge this gap, protein turnover must also be considered. We have developed an experimental strategy to determine the synthesis rates of individual proteins in the tissues of fish on a proteome-wide scale. This approach has been applied to the common carp ( Cyprinus carpio ), a key model species for investigating environmentally induced physiological plasticity. We have calculated the rates of protein synthesis for over a thousand individual proteins from the skeletal muscle and liver of carp. The median synthesis rate of proteins from liver was higher than that of skeletal muscle. The analysis further revealed that the same protein can have a different rate of synthesis depending on the tissue type. Our strategy permits a full investigation of proteome dynamics in fish and will have relevance to the fields of integrative biology and ecotoxicology.

Uncovering a 70-year-old permafrost degradation induced disaster in the Arctic, the 1952 Niiortuut landslide-tsunami in central West Greenland.

On December 15th 1952, at approximately 14:00 local time a mass of 5.9 × 106 m3 of permafrozen talus deposits failed in a landslide close to the Niiortuut mountain on the south coast of the Nuussuaq peninsula, central West Greenland. Between 1.8 and 4.5 × 106 m3 of the material entered the sea and generated a tsunami that propagated through the Vaigat strait (Sullorsuaq). Here we describe this catastrophic event for the first time by analysis of historical material supplemented by recent fieldwork and discuss the implications for the state of contemporary permafrozen slopes. The tsunami killed a fisherman working on the shore of southern Nuussuaq, 10 km south-east of the landslide. In the mining town of Qullissat, 30 km south of the landslide, it had a runup height of 2.2-2.7 m and caused minor material damage. Morphological evidence show that the basal surface of rupture was 80 m inside the permafrost cemented talus slope, whose degradation was a dynamic conditioning factor for the landslide. The 1952 Niiortuut landslide is the first historically recorded event of permafrost degradation induced landslide-tsunamis in the Arctic. We infer that the landslide and its cascading consequences occurred due to the early-twentieth century warming that started in the late 1910's in the Arctic. Warming is now increasingly affecting this region, as shown by an enhanced recent landslide activity.

Early brace treatment for idiopathic scoliosis may change the paradigm to improve curves.

PURPOSE: This study evaluated whether early brace treatment of curves < 25° decreased the prevalence of curve progression and surgery. METHODS: In a retrospective review, patients with idiopathic scoliosis Risser stages 0 to 2 braced at < 25° were followed until brace discontinuation, skeletal maturity, or surgery. Patients with predominantly primary thoracolumbar/lumbar curves were prescribed nighttime braces (NTB) and thoracic curves were prescribed fulltime braces (FTB). Comparisons were made for TLSO type (NTB vs. FTB) and triradiate cartilage (TRC) status (open vs. closed) at brace prescription. RESULTS: 283 patients were included, 81% who were Risser stage 0 with curves averaging 21.8° ± 2.1° at brace prescription. The average curve change was 2.4° ± 11.2°. Curves improved ≥ 6° in 23% of patients. Patients who were not skeletally mature at brace discontinuation (n = 39) had lower Cobb angles (16.7° vs. 23.9°, p < 0.001), better curve improvement (- 4.7° vs. 2.1°, p < 0.001), and were braced for a shorter period of time (1.8 years vs. 2.3 years, p = 0.011) than those who were skeletally mature at brace discontinuation (n = 239). Only 7% of patients in NTB and 8% of patients in FTB with open TRC required surgery. The numbers needed to treat to prevent surgery in patients in FTB with open TRC was calculated to be 4. CONCLUSION: Early brace treatment (Cobb < 25° and open TRC) may not only reduce curve progression and the need for surgical treatment but may also result in curve improvement, thus challenging the paradigm that the goal of bracing is merely to stop curve progression. LEVEL OF EVIDENCE: 3-retrospective cohort study.

The Impact of Name Transformation on Match Rates Within a Large Consumer Database.

Accurate record linkage depends on the availability and quality of features such as first name and last name. Privacy preserving record linkage methods using tokenization is sensitive to perturbations in the patient features used as inputs. In this study we evaluated the impact of name transformations on the accuracy of patient matching using a large commercial dataset. We used a set of 68 million records representing 59 million unique individuals, and implemented and evaluated eight name transformation strategies, and generated precision, recall and F1 scores. Transforming names to include the most common nicknames resulted in a significant gain in recall while maintaining precision, and generated the highest F1 score compared with no name transformation (0.905 vs 0.807). Strategies tailored to transforming patient features can improve the precision and recall of patient matching, and make it possible to create high quality, linked datasets for research purposes.

Intra-articular injection of flavopiridol-loaded microparticles for treatment of post-traumatic osteoarthritis.

Rapid joint clearance of small molecule drugs is the major limitation of current clinical approaches to osteoarthritis and its subtypes, including post-traumatic osteoarthritis (PTOA). Particulate systems such as nano/microtechnology could provide a potential avenue for improved joint retention of small molecule drugs. One drug of interest for PTOA treatment is flavopiridol, which inhibits cyclin-dependent kinase 9 (CDK9). Herein, polylactide-co-glycolide microparticles encapsulating flavopiridol were formulated, characterized, and evaluated as a strategy to mitigate PTOA-associated inflammation through the inhibition of CDK9. Characterization of the microparticles, including the drug loading, hydrodynamic diameter, stability, and release profile was performed. The mean hydrodynamic diameter of flavopiridol particles was ∼15 µm, indicating good syringeability and low potential for phagocytosis. The microparticles showed no cytotoxicity in-vitro, and drug activity was maintained after encapsulation, even after prolonged exposure to high temperatures (60 °C). Flavopiridol-loaded microparticles or blank (unloaded) microparticles were administered by intraarticular injection in a rat knee injury model of PTOA. We observed significant joint retention of flavopiridol microparticles compared to the soluble flavopiridol, confirming the sustained release behavior of the particles. Matrix metalloprotease (MMP) activity, an indicator of joint inflammation, was significantly reduced by flavopiridol microparticles 3 days post-injury. Histopathological analysis showed that flavopiridol microparticles reduced PTOA severity 28 days post-injury. Taken altogether, this work demonstrates a promising biomaterial platform for sustained small molecule drug delivery to the joint space as a therapeutic measure for post-traumatic osteoarthritis. STATEMENT OF SIGNIFICANCE: Post-traumatic osteoarthritis (PTOA) begins with the deterioration of subchondral bone and cartilage after acute injuries. In spite of the prevalence of PTOA and its associated financial and psychological burdens, therapeutic measures remain elusive. A number of small molecule drugs are now under investigation to replace FDA-approved palliative measures, including cyclin-dependent kinase 9 (CDK9) inhibitors which work by targeting early inflammatory programming after injury. However, the short half-life of these drugs is a major hurdle to their success. Here, we show that biomaterial encapsulation of Flavopiridol (CDK9 inhibitor) in poly (lactic-co-glycolic acid) microparticles is a promising route for direct delivery and improved drug retention time in the knee joint. Moreover, administration of the flavopiridol microparticles reduced the severity of PTOA.

Production of Inhalable Ultra-Small Particles for Delivery of Anti-Inflammation Medicine via a Table-Top Microdevice.

A table-top microdevice was introduced in this work to produce ultrasmall particles for drug delivery via inhalation. The design and operation are similar to that of spray-drying equipment used in industry, but the device itself is much smaller and more portable in size, simpler to operate and more economical. More importantly, the device enables more accurate control over particle size. Using Flavopiridol, an anti-inflammation medication, formulations have been developed to produce inhalable particles for pulmonary delivery. A solution containing the desired components forms droplets by passing through an array of micro-apertures that vibrate via a piezo-electrical driver. High-purity nitrogen gas was introduced and flew through the designed path, which included the funnel collection and cyclone chamber, and finally was pumped away. The gas carried and dried the micronized liquid droplets along the pathway, leading to the precipitation of dry solid microparticles. The formation of the cyclone was essential to assure the sufficient travel path length of the liquid droplets to allow drying. Synthesis parameters were optimized to produce microparticles, whose morphology, size, physio-chemical properties, and release profiles met the criteria for inhalation. Bioactivity assays have revealed a high degree of anti-inflammation. The above-mentioned approach enabled the production of inhalable particles in research laboratories in general, using the simple table-top microdevice. The microparticles enable the inhalable delivery of anti-inflammation medicine to the lungs, thus providing treatment for diseases such as pulmonary fibrosis and COVID-19.

Evaluating a training intervention for improving alignment between emergency medical telephone operators and callers: a pilot study of communication behaviours.

BACKGROUND: Calls to emergency medical lines are an essential component in the chain of survival. Operators make critical decisions based on information they elicit from callers. Although smooth cooperation is necessary, the field lacks evidence-based guidelines for how to achieve it while adhering to strict parameters of index-driven questioning. We aimed to evaluate the effect of a training intervention for emergency medical operators at a call centre in Tønsberg, Norway. The course was designed to enhance operators' communication skills for smoothing cooperation with callers. METHODS: Calls were analyzed using inductively developed coding based on the course rationale and content. To evaluate whether the course generated consolidated behavioral change in everyday practice, the independent analyst evaluated 32 calls, selected randomly from eight operators, two calls before and two after course completion. To measure whether skill attainment delayed decision making, we compared the time to the first decision logged by intervention operators to eight control operators. Analysis included 3034 calls: 1375 to intervention operators (T1 = 815; T2 = 560) and 1659 to control operators (T1 = 683; T2 = 976). RESULTS: Operators demonstrated improved behaviours on how they greeted the caller (p < .001), acknowledged the caller (p < .001), and displayed empathy (p = 0.015). No change was found in the use of open-ended questions and agreeing with the caller. Contrary to expectations, operators who took the course logged first decisions more quickly than the control group (p < .001). CONCLUSIONS: This pilot study demonstrated that the training intervention generated behavioural change in these operators, providing justification for scaling up the intervention.

Stemless Humeral Implants in Total Shoulder Arthroplasty.

Through an iteration of various advancements, both short stem and stemless options for humeral fixation have been proposed and have shown clinical promise. The proposed benefits of a stemless humeral implant include greater bone preservation, less stress shielding, less risk of a diaphyseal stress riser, decreased surgical time, and less intraoperative blood loss. Potential downsides include the dependence on proximal bone quality for fixation, increased cost, the dependence on the strength of subscapularis fixation, and pending FDA approval for multiple implants. The purpose of this article is to review the evidence behind stemless implants including the biomechanical advantages and disadvantages, surgical technique, and clinical outcomes.

Prevention, Reduction, and Stabilization of Dog-Ear Deformities During Arthroscopic Rotator Cuff Repair.

Arthroscopic rotator cuff repairs (ARCRs) are common procedures that have been increasing in incidence. When performing ARCR, the surgeon often identifies an undesirable flap or fold, referred to as a "dog-ear" deformity, between sutures or knots. The height and/or thickness of a dog-ear deformity may decrease the rotator cuff-to-acromion distance, resulting in possible impingement and repair compromise. Furthermore, the goal of ARCR is to achieve complete restoration of the tendon-to-footprint relation. To restore the entire footprint, this lesion must be reduced and stabilized. We present a technique using looped sutures to augment the rotator cuff repair and prevent dog-ear formation.

Technique for Double Row Superior Capsule Reconstruction with Dermal Allograft.

Superior capsular reconstruction (SCR) is increasingly being used as a procedure for addressing irreparable rotator cuff tears. The procedure was initially described for failed rotator cuff repairs where the retears are severely retracted and when grade 3-4 fatty infiltration and atrophy exist. The SCR procedure can also be considered for irreparable rotator cuff tears in patients that are either too young or too high demand to be appropriate candidates for arthroplasty. Early short and medium term follow up studies support SCR with favorable outcomes compared with other salvage procedures.

Physically Sufficient Neural Mechanisms of Consciousness.

Neural correlates of consciousness (for brevity NCC) are foundational to the scientific study of consciousness. Chalmers (2000) has provided the most informative and influential definition of NCC, according to which neural correlates are minimally sufficient for consciousness. However, the sense of sufficiency needs further clarification since there are several relevant senses with different entailments. In section one of this article, we give an overview of the desiderata for a good definition of NCC and Chalmers's definition. The second section analyses the merit of understanding the sufficiency of neural correlates for corresponding consciousness according to three relevant types of sufficiency: logical, metaphysical, and physical. In section three, a theoretical approach to consciousness studies is suggested in light of the sense in which NCC are sufficient for consciousness. Section four addresses a concern some might have about this approach. By the end, it will become apparent that our conception of NCC has important implications for research methodology, neuroethics, and the vitality of the search for NCC.