QbD Assisted Systematic Review for Optimizing the Selection of PVP as a Ternary Substance in Enhancing the Complexation Efficiency of Cyclodextrins: a Pilot Study.

Inclusion complexes require higher concentration of Beta cyclodextrins (ßCD) resulting in increased formulation bulk, toxicity, and production costs. This systematic review offers a comprehensive analysis using Quality by design (QbD) as a tool to predict potential applications of Polyvinylpyrrolidone (PVP) as a ternary substance to address issues of inclusion complexes. We reviewed 623 documents from 2013 to 2023 and Eighteen (18) research papers were selected for statistical and meta-analysis using the QbD concept to identify the most critical factors for selecting drugs and effect of PVP on inclusion complexes. The QbD analysis revealed that Molecular weight (MW), Partition coefficient (Log P), and the auxiliary substance ratio directly affected complexation efficiency (CE), thermodynamic stability in terms of Gibbs free energy (ΔG), and percent drug release. However, Stability constant (Ks) remained unaffected by any of these parameters. The results showed that low MW (250), median Log P (6), and a ßCD: PVP ratio of 2:3 would result in higher CE, lower G, and improved drug release. PVP improves drug solubility, enhances delivery and therapeutic outcomes, and counteracts increased drug ionization due to decreased pH. In certain cases, its bulky nature and hydrogen bonding with CD molecules can form non-inclusion complexes. The findings of the study shows that there is potential molecular interaction between PVP and ß-cyclodextrins, which possibly enhances the stability of inclusion complexes for drug with low MW and log P values less than 9. The systematic review shows a comprehensive methodology based on QbD offers a replicable template for future investigations into drug formulation research.

African jewel fish (Hemichromis bimaculatus) distinguish individual faces based on their unique iridophore patterns.

Previous research has shown that African jewel fish (Hemichromis bimaculatus) recognize pair-bonded mates during their exchanges of egg-guarding duties. The current research examined the perceptual cues for face recognition by comparing two face models displaying anatomically realistic arrangements of blue iridophores derived from discriminant function analysis of distinct sibling groups. Four groups each consisting of 9 subadults were examined using a narrow compartment restraining lateral movement where face models were presented at eye level for eight trials. Because respiratory movement of the operculum can mechanically displace the eye thereby shifting the retinal image, jewel fish reduce their respiration rate during increased attention. When two experimental groups were presented with the same face models on four trials following initial model presentations, both groups exhibited stable respiration rates indicative of model habituation. When the habituated face models were switched to novel face models on the fifth trial, the rates of respiration decreased as measured by reliable increases in the elapsed times of opercular beats. Switching the models back to the habituated models on the sixth trial caused reliable decreases in the elapsed times of opercular beats, resembling the earlier trials for the habituated models. Switching the face models again to the formerly novel models on the seventh trial produced respiration rates that resembled those of the habituated models. The two control groups viewing the same models for all eight trials exhibited no substantial change in respiration rates. Together, these findings indicate that jewel fish can learn to recognize novel faces displaying unique arrangements of iridorphores after one trial of exposure.

Septic shock, hyperferritinemic syndrome, and multiple organ dysfunction without respiratory failure in a patient with disseminated histoplasmosis and advanced HIV disease.

AIDS-related disseminated histoplasmosis (DH) can cause septic shock and multiorgan dysfunction with mortality rates of up to 80%. A 41-year-old male presented with fever, fatigue, weight loss, disseminated skin lesions, low urine output, and mental confusion. Three weeks before admission, the patient was diagnosed with HIV infection, but antiretroviral therapy (ART) was not initiated. On day 1 of admission, sepsis with multiorgan dysfunction (acute renal failure, metabolic acidosis, hepatic failure, and coagulopathy) was identified. A chest computed tomography showed unspecific findings. Yeasts suggestive of Histoplasma spp. were observed in a routine peripheral blood smear. On day 2, the patient was transferred to the ICU, where his clinical condition progressed with reduced level of consciousness, hyperferritinemia, and refractory septic shock, requiring high doses of vasopressors, corticosteroids, mechanical ventilation, and hemodialysis. Amphotericin B deoxycholate was initiated. On day 3, yeasts suggestive of Histoplasma spp. were observed in the bone marrow. On day 10, ART was initiated. On day 28, samples of peripheral blood and bone marrow cultures revealed Histoplasma spp. The patient stayed in the ICU for 32 days, completing three weeks of intravenous antifungal therapy. After progressive clinical and laboratory improvement, the patient was discharged from the hospital on oral itraconazole, trimethoprim-sulfamethoxazole, and ART. This case highlights the inclusion of DH in the differential diagnosis of patients with advanced HIV disease, septic shock and multiorgan dysfunction but without respiratory failure. In addition, it provides early in-hospital diagnosis and treatment and comprehensive management in the ICU as determining factors for a good outcome.

Septic shock, hyperferritinemic syndrome, and multiple organ dysfunction without respiratory failure in a patient with disseminated histoplasmosis and advanced HIV disease

ABSTRACT AIDS-related disseminated histoplasmosis (DH) can cause septic shock and multiorgan dysfunction with mortality rates of up to 80%. A 41-year-old male presented with fever, fatigue, weight loss, disseminated skin lesions, low urine output, and mental confusion. Three weeks before admission, the patient was diagnosed with HIV infection, but antiretroviral therapy (ART) was not initiated. On day 1 of admission, sepsis with multiorgan dysfunction (acute renal failure, metabolic acidosis, hepatic failure, and coagulopathy) was identified. A chest computed tomography showed unspecific findings. Yeasts suggestive of Histoplasma spp. were observed in a routine peripheral blood smear. On day 2, the patient was transferred to the ICU, where his clinical condition progressed with reduced level of consciousness, hyperferritinemia, and refractory septic shock, requiring high doses of vasopressors, corticosteroids, mechanical ventilation, and hemodialysis. Amphotericin B deoxycholate was initiated. On day 3, yeasts suggestive of Histoplasma spp. were observed in the bone marrow. On day 10, ART was initiated. On day 28, samples of peripheral blood and bone marrow cultures revealed Histoplasma spp. The patient stayed in the ICU for 32 days, completing three weeks of intravenous antifungal therapy. After progressive clinical and laboratory improvement, the patient was discharged from the hospital on oral itraconazole, trimethoprim-sulfamethoxazole, and ART. This case highlights the inclusion of DH in the differential diagnosis of patients with advanced HIV disease, septic shock and multiorgan dysfunction but without respiratory failure. In addition, it provides early in-hospital diagnosis and treatment and comprehensive management in the ICU as determining factors for a good outcome.

Clinical Features of Patients Presenting to the Emergency Department With Cardiovascular Adverse Reactions After COVID-19 mRNA Vaccination

Background@#Since the implementation of the nationwide coronavirus disease 2019 (COVID-19) vaccination campaign, emergency departments (EDs) have had an increasing number of patients reporting postvaccination cardiovascular adverse effects. We investigated the clinical features of patients who visited the ED for cardiovascular adverse reactions after COVID-19 mRNA vaccination. @*Methods@#We conducted a retrospective observational study in two EDs. Patients with cardiovascular adverse reactions after COVID-19 mRNA vaccination who visited EDs between June 1, 2021, and October 15, 2021, were selected. The clinical data of these patients were collected by reviewing medical records. @*Results@#Among 683 patients, 426 (62.4%) were female. The number of patients in their 20s was the highest (38.9% of males, 28.2% of females) (P < 0.001). More patients visited the ED for adverse reactions following the first vaccine dose than following the second dose (67.6% vs. 32.2%). Chief complaints were chest pain/discomfort (74.4%), dyspnea (14.3%) and palpitation (11.3%). The final diagnosis was a nonspecific cause (63.1%), and 663 (97.1%) patients were discharged from the ED. The admission rate was higher in males than in females (3.9% vs. 1.9%). Myocarditis was diagnosed in four males, who showed mild clinical progression and were discharged within 5 hospital days. @*Conclusion@#Most patients who visited the ED with cardiovascular adverse reactions were discharged from the ED, but some were admitted for other medical diseases as well as adverse vaccine reactions. Therefore, further surveillance and a differential diagnosis of cardiovascular adverse events after COVID-19 mRNA vaccination should be considered by emergency physicians.

Cooccurrence of N501Y, P681R and other key mutations in SARS-CoV-2 Spike

Analysis of circa 4.2 million severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome sequences on Global Initiative on Sharing All Influenza Data (GISAID) shows the spike mutations N501Y (common to Alpha, Beta, Gamma, Omicron variants) and P681R (central to Delta variants spread) have cooccurred 3,678 times between 17 October 2020 and 1 November 2021. In contrast, the N501Y+P681H combination is present in Alpha and Omicron variants and circa 1.1 million entries. Two-thirds of the 3,678 cooccurrences were in France, Turkey or US (East Coast), and the rest across 62 other countries. 55.5% and 4.6% of the cooccurrences were Alphas Q.4 and Gammas P.1.8 sub-lineages acquiring P681R; 10.7% and 3.8% were Deltas B.1.617.2 lineage and AY.33 sub-lineage acquiring N501Y; remaining 10.2% were in other variants. Despite the selective advantages individually conferred by N501Y and P681R, the N501Y+P681R combination counterintuitively didnt outcompete other variants in every instance. Although a relief to worldwide public health efforts, in vitro and in vivo studies are urgently required in the absence of a strong in silico explanation for this phenomenon. This study demonstrates a pipeline to analyse combinations of key mutations from public domain information in a systematic manner and provide early warnings of spread.

But Mouse, you are not alone: On some severe acute respiratory syndrome coronavirus 2 variants infecting mice

In silico predictions combined with in vitro, in vivo and in situ observations collectively suggest that mouse adaptation of the SARS-CoV-2 virus requires an aromatic substitution in position 501 or position 498 (but not both) of the spike proteins receptor binding domain. This effect could be enhanced by mutations in positions 417, 484, and 493 (especially K417N, E484K, Q493K and Q493R), and to a lesser extent by mutations in positions 486 and 499 (such as F486L and P499T). Such enhancements due to more favourable binding interactions with residues on the complementary angiotensin-converting enzyme 2 (ACE2) interface, are however, unlikely to sustain mouse infectivity on their own based on theoretical and experimental evidence to date. Our current understanding thus points to the Alpha, Beta, Gamma, and Omicron variants of concern infecting mice, while Delta and Delta Plus lack a similar biomolecular basis to do so. This paper identifies eleven countries (Brazil, Chile, Djibouti, Haiti, Malawi, Mozambique, Reunion, Suriname, Trinidad and Tobago, Uruguay and Venezuela) where targeted local field surveillance of mice is encouraged because they may have come in contact with humans who had the virus with adaptive mutation(s). It also provides a systematic methodology to analyze the potential for other animal reservoirs and their likely locations.

Evaluation of Recruitment of Older Adults of Color into a Community-Based Chronic Disease Self-Management Wellness Pathway Program in Los Angeles County.

Background: Established relationships between researchers, stakeholders and potential participants are integral for recruitment of potential older adult participants and Evidence-Based Programs (EBPs) for chronic disease management have empirically been shown to help improve health and maintain healthy and active lives. To accelerate recruitment in EBPs and potential future research, we propose a Wellness Pathway allowing for delivery within multipurpose senior centers (MPCs) linked with medical facilities among lower-income urban older adults. The study aims were to: 1) assess the effectiveness of three MPC-delivered EBPs on disease management skills, health outcomes, and self-efficacy; and 2) assess the feasibility of the proposed Wellness Pathway for lower-income urban-dwelling older adults of color. Methods: We administered surveys and conducted a pre-post analysis among participants enrolled in any 1 of 3 MPC-based EBPs (n=53). To assess feasibility of the pathway, we analyzed survey data and interviews (EBP participants, MPC staff, physicians, n=10). Results: EBP participation was associated with greater disease management skills (increased time spent stretching and aerobic activity) but not improvements in self-efficacy or other health outcomes. Interviews revealed: 1) older adults valued EBPs and felt the Wellness Pathway feasible; 2) staff felt it feasible given adequate growth management; 3) physicians felt it feasible provided adequate medical facility integration. Conclusions: MPC-based EBPs were associated with improvements in disease management skills among older adults; a proposed Wellness Pathway shows early evidence of feasibility and warrants further investigation. Future efforts to implement this model of recruiting older adults of color into EBPs should address barriers for implementation and sustainability.

Developing a culturally tailored stroke prevention walking programme for Korean immigrant seniors: a focus group study.

OBJECTIVES: To gain better understanding of (i) beliefs and knowledge about stroke; (ii) attitudes about walking for stroke prevention; and (iii) barriers and facilitators to walking among Korean seniors for the cultural tailoring of a stroke prevention walking programme. BACKGROUND: Physical inactivity is a major risk factor for stroke. Korean immigrant seniors are one of the most sedentary ethnic groups in the United States. DESIGN: An explorative study using focus group data. Twenty-nine Korean immigrant seniors (64-90 years of age) who had been told by a doctor at least once that their blood pressure was elevated participated in 3 focus groups. Each focus group consisted of 8-11 participants. METHODS: Focus group audiotapes were transcribed and analysed using standard content analysis methods. RESULTS: Participants identified physical and psychological imbalances (e.g. too much work and stress) as the primary causes of stroke. Restoring 'balance' was identified as a powerful means of stroke prevention. A subset of participants expressed that prevention may be beyond human control. Overall, participants acknowledged the importance of walking for stroke prevention, but described barriers such as lack of personal motivation and unsafe environment. Many participants believed that providing opportunities for socialisation while walking and combining walking with health information sessions would facilitate participation in and maintenance of a walking programme. CONCLUSIONS: Korean immigrant seniors believe strongly that imbalance is a primary cause of stroke. Restoring balance as a way to prevent stroke is culturally special among Koreans and provides a conceptual base in culturally tailoring our stroke prevention walking intervention for Korean immigrant seniors. IMPLICATIONS FOR PRACTICE: A stroke prevention walking programme for Korean immigrant seniors may have greater impact by addressing beliefs about stroke causes and prevention such as physical and psychological imbalances and the importance of maintaining emotional well-being.

Treatment of multifocal motor neuropathy with intravenous immunoglobulin.

Multifocal motor neuropathy (MMN) is a rare inflammatory, chronically progressive, unremitting disorder affecting the peripheral nervous system. Although the etiology of this condition is not known, high titers of IgM Ab to GM1 may serve as a biomarker for this disease. Clinical findings of motor weakness are associated with focal conduction blocks and with time, axonal destruction. Evidence supporting an immune etiology as well as the use of intravenous immunoglobulin to limit the disease progression is reviewed.

Intravenous immunoglobulin use for neurologic diseases.

Intravenous immunoglobulin (IVIG) has been used primarily for immune deficiency patients, and its greatest expansion is seen more and more in the treatment of autoimmune disorders, especially in neurology. The benefits of IVIG treatment include its availability in all treatment centers and its ease of administration in an outpatient setting. This article gives an overview of some autoimmune neurologic diseases and explores the clinical evidence supporting the use of IVIG.

Eye fixations of deaf and hearing observers in simultaneous communication perception.

OBJECTIVES: The purpose of this study was to examine characteristics of eye gaze behavior, specifically eye fixations, during reception of simultaneous communication (SC). SC was defined as conceptually accurate and semantically based signs and fingerspelling used in conjunction with speech. Specific areas of focus were (1) the pattern of frequency, duration, and location of observers' eye fixations in relation to the critical source of disambiguating information (signs or speech) in SC, and (2) how the pattern of an observer's eye fixations was related to the source of critical information (sign or speech), expectations regarding the location of the critical information after exposure to the stimulus set, observer characteristics, and sender. DESIGN: The investigation used eye tracking technology to monitor eye fixations of observers who watched silent video clips of sentences rendered in SC by three senders. Each sentence contained one of a pair of sign-critical (e.g., "sleeves"/"leaves") or speech-critical (e.g., "invited"/"hired") contrast items designed to depend on information at the hands or mouth, respectively, to resolve its ambiguity. Observers were 20 adults: five faculty/staff with early onset deafness, five faculty/staff with normal hearing, and ten college students with early onset deafness. Faculty and staff were identified by a sign language assessment specialist to be experienced and skillful users of SC. Students, exposed to SC in classroom instruction, were recruited through paper and electronic ads. RESULTS: Generally, observers looked toward the face, regardless of whether signs or speech disambiguated the message, suggesting that eye fixations toward the hands of the sender are not necessary to apprehend essential information to accurately identify an ambiguous part of the message during SC. However, other aspects of eye behavior indicated sensitivity to type of critical contrast. In particular, fixations were shorter during sign-critical items compared to speech-critical items, even after adjusting for stimulus length. In addition, experienced, adult deaf users of SC made more, brief eye fixations than observers who had normal hearing. Finally, differences in eye fixation patterns toward different senders indicates that sender characteristics affect visual processes in SC perception. CONCLUSIONS: This study provides supportive evidence of brief, frequent eye movements by deaf perceivers over small areas of a video display during reception of visuospatial linguistic information. These movements could be used to enhance activation of brain centers responsible for processing motion, consistent with neurophysiological evidence of attentional mechanisms or visual processes unique to perception of a visual language.

JNK1 activation mediates C5b-9-induced P0 mRNA instability and P0 gene expression in Schwann cells.

The protein zero (P0) glycoprotein is an important component of compact peripheral nerve myelin produced by the glial cells of the mammalian peripheral nervous system. P0 mRNA expression is reduced following exposure of Schwann cells to sublytic C5b-9, the terminal activation complex of the complement cascade. Sublytic complement treatment decreased P0 mRNA by 81% within 6 h and required C5b-9 assembly. C5b-9 induced a threefold increase in both JNK1 activity and c-jun mRNA within 20 and 30 min, respectively, compared with cells treated with either human serum depleted of complement component C7 (C7dHS) or medium alone. Sublytic C5b-9 stimulation, in the presence of the transcription inhibitor Actinomycin D, decreased P0 mRNA expression by 52%, indicating that mRNA was selectively destabilized. This effect was prevented by pretreatment with L-JNK inhibitor 1 (L-JNKI1). To study a potential inhibition of P0 gene transcription, we transfected Schwann cells with a P0 promoter-firefly luciferase construct. Sublytic C5b-9 stimulation of the transfected cells decreased luciferase activity by 82% at 6 h, and this effect was prevented by pretreatment with L-JNKI1 inhibitor. Our results indicate that the ability of C5b-9 in vitro to affect P0 gene expression is mediated via JNK1 activation that leads to enhanced mRNA decay and transcriptional repression of P0.

Initial and long-term management of autoimmune neuropathies.

The inflammatory neuropathies (chronic inflammatory demyelinating polyradiculoneuropathy [CIDP], Guillain-Barré syndrome [GBS] and multifocal motor neuropathy [MMN]) affect only one to two individuals per 100 000 of the population, but result in major disability and impairment. Intravenous immunoglobulin (IVIg) can be used as an initial treatment for CIDP, GBS and MMN. While plasma exchange and corticosteroids can also be used initially, they are not as uniformly effective for each of these disorders as IVIg. Substituting corticosteroids, plasma exchange or immunosuppressants may be appropriate for patients not responding to initial IVIg therapy, and combination therapy may be needed in some patients. There are no data from controlled clinical trials of long-term management strategies for CIDP and MMN; however, empirical evidence suggests that a positive long-term response to IVIg can be achieved by increasing the initial dose or its frequency of administration. Corticosteroids and immunosuppressants may be appropriate in some patients with CIDP. Adverse events with IVIg are usually mild and not treatment limiting; however, patients do need to be monitored for uncommon, but serious, adverse events such as renal insufficiency, stroke and thromboembolic events. Nevertheless, the safety profile of IVIg is exceptional relative to the potential complications of other long-term treatments for CIDP and MMN, especially corticosteroids and immunosuppressants. Predictors of response have been reported for each of the neuropathies, and until controlled clinical trials provide evidence on which to base treatment strategies, effective management will require individualising therapy according to patient response.

Regulation of cytokine-induced neuron death by ovarian hormones: involvement of antiapoptotic protein expression and c-JUN N-terminal kinase-mediated proapoptotic signaling.

Mechanisms underlying the divergent effects of ovarian hormones on neuron death induced by TNFalpha were investigated in differentiated PC12 cells (dPC12). dPC12 cells were exposed to 17beta-estradiol (E, 1.0 nm), progesterone (P, 100 nm), or a combination of both hormones for 0-72 h before treatment with TNFalpha (0-150 ng) to induce cell death. Cells undergoing apoptosis were identified by a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling assay and fluorescence-activated cell sorting after 18 h. Cell death induced by TNFalpha was decreased 89% after E treatment and increased 2-fold after P treatment compared with cells treated with TNFalpha alone. Treatment with E for 24 h before TNFalpha exposure was required for maximum neuroprotection, whereas P-enhanced death was maximal after a 30-min P treatment. TNFalpha induced a 3-fold increased activity of c-JUN-N-terminal kinase (JNK) 1 in d PC12 cells within 20 min that could be increased 5- to 8-fold by P together with TNFalpha. A peptide inhibitor of JNK1 abrogated P enhancement of TNFalpha-mediated dPC12 death but had only a minimal effect on cell death by TNFalpha alone. Inhibition of caspase-8 activation reduced death induced by TNFalpha alone but was much less effective for P+TNF. P alone did not activate caspase-8. E increased estrogen receptor alpha (ERalpha) and Bcl-xL expression and all but abolished TNFalpha receptor 1 (TNFR1) expression. P decreased ERalpha and Bcl-xL expression and doubled TNFR1 expression. These data suggest that P regulates apoptosis or survival through augmentation of JNK signaling and altered TNFR1 expression, whereas E mainly affects the expression of BCL-xL, TNFR1, and ERalpha.

Nurse-managed primary care: outcomes of a faculty practice network.

PURPOSE: To describe selected outcomes of nurse-managed primary care in a large faculty practice network (FPN) and to use guidelines proposed by the National Organization of Nurse Practitioner Faculties (NONPF) to evaluate those outcomes. DATA SOURCES: Mission and goals, nursing control, fiscal stability, health care outcomes, and faculty role integration were examined. CONCLUSIONS: Outcomes show that the FPN directly supports the mission and goals of the East Tennessee State University College of Nursing and is managed by nurse faculty members. The FPN uses earned revenue, grants, and contracts to maintain fiscal stability. Patients are highly satisfied with services, and external and internal audits find the quality of care to be excellent. Students are educated in the centers. Faculty members publish and present research and other scholarly work derived from the FPN. IMPLICATIONS FOR PRACTICE: This model demonstrates that faculty practice can work, can meet the evaluation components of guidelines of a major national organization, and can contribute to the improvement of health for vulnerable populations.

Therapy of CIDP and related immune-mediated neuropathies.

This study assesses the data supporting the current use of immunotherapy for management of neuropathies with a presumed autoimmune basis. Immune or inflammatory mechanisms are implicated in an increasing number of disorders that involve damage to peripheral nerves and sensory ganglia. The most prevalent of these is chronic inflammatory demyelinating polyradiculoneuritis (CIDP). CIDP is clinically distinguishable from a series of other immune- or inflammation-mediated neuropathies. These include the following: multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy associated with conduction block; brachial or lumbar plexitis; multifocal motor neuropathy, a distal demyelinating neuropathy associated with antibodies to the myelin-associated glycoprotein (MAG); and sensory neuronopathy. We reviewed the literature of the National Library of Medicine using the above terms and their variations. The results from short-term, randomized, controlled trials support the efficacy of intravenous immunoglobulin (IVIg), plasma exchange, and corticosteroids in the treatment of CIDP, and the efficacy of IVIg in the treatment of MMN. Only anecdotal experience is available for assessing the treatment of MADSAM neuropathy, lumbar and brachial plexitis, MAG neuropathy, and sensory neuronopathy. Cytotoxic and immunosuppressive drugs are frequently used to treat patients with many of these disorders when they are refractory to standard treatments, but no controlled trials have been done to support their use. This review discusses the complications and criteria for use of these therapies. Selecting the best immunotherapy for an individual patient should be based on the proven efficacy of a given regimen in modulating the pathophysiology underlying the neuropathy, the anticipated duration of disease, and the patient's age, reproductive status, and coexisting metabolic derangement.