The Quality of Reports on Cervical Arterial Dissection following Cervical Spinal Manipulation

BackgroundCervical artery dissection (CAD) and stroke are serious harms that are sometimes associated with cervical spinal manipulation therapy (cSMT). Because of the relative rarity of these adverse events, studying them prospectively is challenging. As a result, systematic review of reports describing these events offers an important opportunity to better understand the relation between adverse events and cSMT. Of note, the quality of the case report literature in this area has not yet been assessed.Purpose1) To systematically collect and synthesize available reports of CAD that have been associated with cSMT in the literature and 2) assess the quality of these reports.MethodsA systematic review of the literature was conducted using several databases. All clinical study designs involving CADs associated with cSMT were eligible for inclusion. Included studies were screened by two independent reviewers for the presence/absence of 11 factors considered to be important in understanding the relation between CAD and cSMT.ResultsOverall, 43 articles reported 901 cases of CAD and 707 incidents of stroke reported to be associated with cSMT. The most common type of stroke reported was ischemic stroke (92%). Time-to-onset of symptoms was reported most frequently (95%). No single case included all 11 factors.ConclusionsThis study has demonstrated that the literature infrequently reports useful data toward understanding the association between cSMT, CADs and stroke. Improving the quality, completeness, and consistency of reporting adverse events may improve our understanding of this important relation.     

Germline DNA Copy Number Aberrations Identified as Potential Prognostic Factors for Breast Cancer Recurrence

Breast cancer recurrence (BCR) is a common treatment outcome despite curative-intent primary treatment of non-metastatic breast cancer. Currently used prognostic and predictive factors utilize tumor-based markers, and are not optimal determinants of risk of BCR. Germline-based copy number aberrations (CNAs) have not been evaluated as determinants of predisposition to experience BCR. In this study, we accessed germline DNA from 369 female breast cancer subjects who received curative-intent primary treatment following diagnosis. Of these, 155 experienced BCR and 214 did not, after a median duration of follow up after breast cancer diagnosis of 6.35 years (range = 0.60–21.78) and 8.60 years (range = 3.08–13.57), respectively. Whole genome CNA genotyping was performed on the Affymetrix SNP array 6.0 platform. CNAs were identified using the SNP-Fast Adaptive States Segmentation Technique 2 algorithm implemented in Nexus Copy Number 6.0. Six samples were removed due to poor quality scores, leaving 363 samples for further analysis. We identified 18,561 CNAs with ≥1 kb as a predefined cut-off for observed aberrations. Univariate survival analyses (log-rank tests) identified seven CNAs (two copy number gains and five copy neutral-loss of heterozygosities, CN-LOHs) showing significant differences (P<2.01×10⁻⁵) in recurrence-free survival (RFS) probabilities with and without CNAs.We also observed three additional but distinct CN-LOHs showing significant differences in RFS probabilities (P<2.86×10⁻⁵) when analyses were restricted to stratified cases (luminal A, n = 208) only. After adjusting for tumor stage and grade in multivariate analyses (Cox proportional hazards models), all the CNAs remained strongly associated with the phenotype of BCR. Of these, we confirmed three CNAs at 17q11.2, 11q13.1 and 6q24.1 in representative samples using independent genotyping platforms. Our results suggest further investigations on the potential use of germline DNA variations as prognostic markers in cancer-associated phenotypes.     

Cost Effectiveness of Implementing Integrated Management of Neonatal and Childhood Illnesses Program in District Faridabad,India

Introduction

Despite the evidence for preventing childhood morbidity and mortality, financial resources are cited as a constraint for Governments to scale up the key health interventions in some countries. We evaluate the cost effectiveness of implementing IMNCI program in India from a health system and societal perspective.

Methods

We parameterized a decision analytic model to assess incremental cost effectiveness of IMNCI program as against routine child health services for infant population at district level in India. Using a 15-years time horizon from 2007 to 2022, we populated the model using data on costs and effects as found from a cluster-randomized trial to assess effectiveness of IMNCI program in Haryana state. Effectiveness was estimated as reduction in infant illness episodes, deaths and disability adjusted life years (DALY). Incremental cost per DALY averted was used to estimate cost effectiveness of IMNCI. Future costs and effects were discounted at a rate of 3%. Probabilistic sensitivity analysis was undertaken to estimate the probability of IMNCI to be cost effective at varying willingness to pay thresholds.

Results

Implementation of IMNCI results in a cumulative reduction of 57384 illness episodes, 2369 deaths and 76158 DALYs among infants at district level from 2007 to 2022. Overall, from a health system perspective, IMNCI program incurs an incremental cost of USD 34.5 (INR 1554) per DALY averted, USD 34.5 (INR 1554) per life year gained, USD 1110 (INR 49963) per infant death averted. There is 90% probability for ICER to be cost effective at INR 2300 willingness to pay, which is 5.5% of India’s GDP per capita. From a societal perspective, IMNCI program incurs an additional cost of USD 24.1 (INR 1082) per DALY averted, USD 773 (INR 34799) per infant death averted and USD 26.3 (INR 1183) per illness averted in during infancy.

Conclusion

IMNCI program in Indian context is very cost effective and should be scaled-up as a major child survival strategy.     

Low‐Overpotential Electrocatalytic Water Splitting with Noble‐Metal‐Free Nanoparticles Supported in a sp3 N‐Rich Flexible COF

Covalent organic frameworks (COFs) are crystalline organic polymers with tunable structures. Here, a COF is prepared using building units with highly flexible tetrahedral sp³ nitrogens. This flexibility gives rise to structural changes which generate mesopores capable of confining very small (<2 nm sized) non‐noble‐metal‐based nanoparticles (NPs). This nanocomposite shows exceptional activity toward the oxygen‐evolution reaction from alkaline water with an overpotential of 258 mV at a current density of 10 mA cm^?2. The overpotential observed in the COF‐nanoparticle system is the best in class, and is close to the current record of ≈200 mV for any noble‐metal‐free electrocatalytic water splitting system—the Fe–Co–Ni metal‐oxide‐film system. Also, it possesses outstanding kinetics (Tafel slope of 38.9 mV dec^?1) for the reaction. The COF is able to stabilize such small‐sized NP in the absence of any capping agent because of the COF–Ni(OH)₂ interactions arising from the N‐rich backbone of the COF. Density‐functional‐theory modeling of the interaction between the hexagonal Ni(OH)₂ nanosheets and the COF shows that in the most favorable configuration the Ni(OH)₂ nanosheets are sandwiched between the sp³ nitrogens of the adjacent COF layers and this can be crucial to maximizing their synergistic interactions.     

B Cell,Th17, and Neutrophil Related Cerebrospinal Fluid Cytokine/Chemokines Are Elevated in MOG Antibody Associated Demyelination

Background

Myelin oligodendrocyte glycoprotein antibody (MOG Ab) associated demyelination represents a subgroup of autoimmune demyelination that is separate from multiple sclerosis and aquaporin 4 IgG-positive NMO, and can have a relapsing course. Unlike NMO and MS, there is a paucity of literature on immunopathology and CSF cytokine/chemokines in MOG Ab associated demyelination.

Aim

To study the differences in immunopathogenesis based on cytokine/chemokine profile in MOG Ab-positive (POS) and -negative (NEG) groups.

Methods

We measured 34 cytokines/chemokines using multiplex immunoassay in CSF collected from paediatric patients with serum MOG Ab POS [acute disseminated encephalomyelitis (ADEM = 8), transverse myelitis (TM = 2) n = 10] and serum MOG Ab NEG (ADEM = 5, TM = 4, n = 9) demyelination. We generated normative data using CSF from 20 non-inflammatory neurological controls.

Results

The CSF cytokine and chemokine levels were higher in both MOG Ab POS and MOG Ab NEG demyelination groups compared to controls. The CSF in MOG Ab POS patients showed predominant elevation of B cell related cytokines/chemokines (CXCL13, APRIL, BAFF and CCL19) as well as some of Th17 related cytokines (IL-6 AND G-CSF) compared to MOG Ab NEG group (all p<0.01). In addition, patients with elevated CSF MOG antibodies had higher CSF CXCL13, CXCL12, CCL19, IL-17A and G-CSF than patients without CSF MOG antibodies.

Conclusion

Our findings suggest that MOG Ab POS patients have a more pronounced CNS inflammatory response with elevation of predominant humoral associated cytokines/chemokines, as well as some Th 17 and neutrophil related cytokines/chemokines suggesting a differential inflammatory pathogenesis associated with MOG antibody seropositivity. This cytokine/chemokine profiling provides new insight into disease pathogenesis, and improves our ability to monitor inflammation and response to treatment. In addition, some of these molecules may represent potential immunomodulatory targets.     

Alirocumab,a Therapeutic Human Antibody to PCSK9, Does Not Affect CD81 Levels or Hepatitis C Virus Entry and Replication into Hepatocytes

BackgroundProprotein convertase subtilisin/kexin type 9 (PSCK9) is secreted mainly from the liver and binds to the low-density lipoprotein receptor (LDLR), reducing LDLR availability and thus resulting in an increase in LDL-cholesterol. While the LDLR has been implicated in the cell entry process of the hepatitis C virus (HCV), overexpression of an artificial non-secreted, cell membrane-bound form of PCSK9 has also been shown to reduce surface expression of CD81, a major component of the HCV entry complex, leading to concerns that pharmacological inhibition of PCSK9 may increase susceptibility to HCV infection by increasing either CD81 or LDLR availability. Here, we evaluated effects of PCSK9 and PCSK9 blockade on CD81 levels and HCV entry with a physiologically relevant model using native secreted PCSK9 and a monoclonal antibody to PCSK9, alirocumab.ConclusionThese results suggest that inhibition of PCSK9 with alirocumab has no effect on CD81 and does not result in increased susceptibility to HCV entry.     

Development and Two-Year Follow-Up Evaluation of a Training Workshop for the Large Preventive Positive Psychology Happy Family Kitchen Project in Hong Kong

Evidence-based practice and capacity-building approaches are essential for large-scale health promotion interventions. However, there are few models in the literature to guide and evaluate training of social service workers in community settings. This paper presents the development and evaluation of the “train-the-trainer” workshop (TTT) for the first large scale, community-based, family intervention projects, entitled “Happy Family Kitchen Project” (HFK) under the FAMILY project, a Hong Kong Jockey Club Initiative for a Harmonious Society. The workshop aimed to enhance social workers’ competence and performance in applying positive psychology constructs in their family interventions under HFK to improve family well-being of the community they served. The two-day TTT was developed and implemented by a multidisciplinary team in partnership with community agencies to 50 social workers (64% women). It focused on the enhancement of knowledge, attitude, and practice of five specific positive psychology themes, which were the basis for the subsequent development of the 23 family interventions for 1419 participants. Acceptability and applicability were enhanced by completing a needs assessment prior to the training. The TTT was evaluated by trainees’ reactions to the training content and design, changes in learners (trainees) and benefits to the service organizations. Focus group interviews to evaluate the workshop at three months after the training, and questionnaire survey at pre-training, immediately after, six months, one year and two years after training were conducted. There were statistically significant increases with large to moderate effect size in perceived knowledge, self-efficacy and practice after training, which sustained to 2-year follow-up. Furthermore, there were statistically significant improvements in family communication and well-being of the participants in the HFK interventions they implemented after training. This paper offers a practical example of development, implementation and model-based evaluation of training programs, which may be helpful to others seeking to develop such programs in diverse communities.     

Case report of whole genome sequencing in the XY female: identification of a novel <Emphasis Type="Italic">SRY</Emphasis> mutation and revision of a misdiagnosis of androgen insensitivity syndrome

Background

The 46,XY female is characterised by a male karyotype and female phenotype arising due to any interruption in the sexual development pathways in utero. The cause is usually genetic and various genes are implicated.

Case presentation

Herein we describe a 46,XY woman who was first diagnosed with androgen insensitivity syndrome (testicular feminisation) at 18 years; however, this was later questioned due to the presence of intact Müllerian structures. The clinical phenotype suggested several susceptibility genes including SRY, DHH, NR5A1, NR0B1, AR, AMH, and AMHR2. To study candidate genes simultaneously, we performed whole genome sequencing. This revealed a novel and likely pathogenic missense variant (p.Arg130Pro, c.389G>C) in SRY, one of the major genes implicated in complete gonadal dysgenesis, hence securing this condition over androgen insensitivity syndrome as the cause of the patient’s disorder of sexual development.

Conclusion

This case highlights the emerging clinical utility of whole genome sequencing as a tool in differentiating disorders of sexual development.

     

A 12-Crown-4 Ether Containing Dipeptide Boc-12-Crown-4-<Emphasis Type="SmallCaps">l</Emphasis>-DOPA-Gly-OMe Induces Cell Cycle Arrest and Apoptosis in Rat Eggs Cultured In Vitro

The study was designed to investigate whether crown ether containing dipeptide Boc-12-crown-4-l-DOPA-Gly-OMe has potential to induce meiotic cell cycle arrest and apoptosis in rat eggs cultured in vitro. The immature female rats were subjected to superovulation induction protocol and ovulated eggs were collected from ampulla of the fallopian tube. Ovulated eggs arrested at metaphase-II (M-II) stage of meiotic cell cycle were cultured in media-199 with or without various concentrations (0.0, 0.025, 0.050, 0.10, and 0.20 mM) of dipeptide for 3 h in vitro. Morphological apoptotic changes, hydrogen peroxide (H₂O₂) concentration, cytochrome c level, caspase-3 level as well as activity and DNA fragmentation were analysed in eggs cultured in vitro. Culture of M-II arrested eggs in plain medium for 3 h in vitro induced meiotic exit from M-II arrest in majority of eggs as evidenced by initiation of extrusion of second polar body (II PB). The dipeptide induced maintenance of M-II arrest and morphological apoptotic features in a concentration-dependent manner prior to degeneration. The dipeptide-induced morphological features were associated with increased H₂O₂ and cytochrome c levels in treated eggs. The increased cytochrome c induced caspase-3 level and activity and thereby DNA fragmentation as evidenced by DAB positive staining in treated eggs. Our results suggest that dipeptide Boc-12-C-4-l-DOPA-Gly-OMe induces cell cycle arrest at M-II stage and apoptosis in rat eggs cultured in vitro.