Assessing Respiratory Tract Infections' Prevalence and Microbial Profiles in Mechanically Ventilated Patients: Insights From Broncho Alveolar Lavage Examination.

Introduction Chest infections represent a significant challenge in mechanically ventilated patients, often leading to adverse outcomes despite advancements in critical care. This prospective study was conducted in the intensive care unit of tertiary referral care, with objectives to assess chest infection prevalence, microbial profiles, and outcomes in mechanically ventilated patients through broncho-alveolar lavage (BAL) examination. Methodology This prospective study involved 38 patients aged 15 to 65 years who were receiving mechanical ventilation and underwent BAL. The procedure of BAL was followed as per the guidelines and recommendations outlined by the American Thoracic Society for Bronchoscopic Lavage. Microbial analysis involves the use of microscopic examination and quantitative culture methods. Different staining techniques were utilized to identify bacteria, fungi, and mycobacteria. Complications and adverse events were monitored and recorded. Results Out of the 38 patients who underwent BAL, the majority, 30 (78.94%), were found to have chest infections, with gram-negative bacteria, including Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii, being the causative agents. The antibiotic sensitivity profiles indicated that the organisms were susceptible to carbapenems and broad-spectrum ß-lactam/ß-lactamase inhibitor combinations while showing resistance to fluoroquinolones. Despite adequate treatment, mortality remained significant in 12 (31.57%) patients. Conclusion Study findings underscore the importance of proactive surveillance, early diagnosis, and targeted management strategies to mitigate the burden of respiratory infections in critical care settings.

Rational Design and Synthesis of Isatin-Chalcone Hybrids Integrated with 1H-1,2,3-Triazole: Anti-Proliferative Profiling and Molecular Docking Insights.

In this study, a series of isatin-chalcone linked triazoles were synthesized using Cu-promoted Azide-Alkyne Cycloaddition (CuAAC) reaction and evaluated for their cytotoxicity against various cancer cell lines. The most potent compound displayed approximately 2.5 times greater activity compared to both reference compounds against ovarian cancer cell lines. These findings were supported by caspase-mediated apoptosis and molecular docking analyses. Docking revealed comparable VEGFR-2 affinities for 5 b and 5-FU but highlighted stronger interaction of 5 b with EGFR, evident from its lower docking score. Overall, these results signify the notable anti-proliferative potential of most synthesized hybrids, notably emphasizing the efficacy of compound 5 b in suppressing cancer cell growth.

Phytochemicals, Herbal Extracts, and Dietary Supplements for Metabolic Disease Management.

Comprehensive and effective care techniques have become essential due to the global epidemic dimensions of metabolic disorders, including diabetes, obesity, and cardiovascular ailments. Recent research highlights the potential of dietary supplements, herbal extracts, and phytochemicals in treating metabolic diseases. This abstract conveys the current state of the science in this field by highlighting these findings' underlying mechanisms and potential therapeutic applications. Plant-based diets contain naturally occurring bioactive molecules termed phytochemicals, which have shown promise in treating various metabolic illnesses. Examples include curcumin, flavonoids, and polyphenols' insulin-sensitizing, antioxidant, and antiinflammatory properties. Herbal extracts, derived from ancient medicinal herbs, have been used by people for years to treat a wide range of ailments. Recent studies have shown the efficacy of these strategies in improving lipid profiles, glucose metabolism, and overall cardiovascular health. Omega-3 fatty acids, vitamins, and minerals are just a few of the numerous nutritional supplements that are critical to metabolic health. These vitamins improve insulin sensitivity, regulate blood sugar, and decrease inflammation. Probiotics and prebiotics also affect the gut flora, which significantly affects metabolic function. These natural medicines' ability to treat metabolic diseases either by themselves or in combination with conventional medical interventions. However, when using it therapeutically, one must consider the differences in doses, individual responses, and bioavailability. The article concludes that phytochemicals, plant extracts, and food supplements offer a promising avenue for the management of metabolic illnesses. Comprehensive research, including clinical studies, is needed to ascertain their safety and efficacy characteristics. When added to treatment strategies, these natural therapies could be helpful supplements that improve overall health and the quality of life among individuals with metabolic diseases. Naringenin, a citrus flavonoid, can potentially prevent kidney injury in hyperuricemia by reducing uric acid, inflammation, apoptosis, DNA damage, and activating antioxidants. Further research and professional consultation are essential. Factors contributing to metabolic diseases, current approaches to management nutritional approaches for managing obesityassociated metabolic impairments in the liver and small intestine, and nutritional approaches for managing obesity-associated metabolic dysregulation are also explained briefly.

Cardiorespiratory Effects of Yogic Versus Slow Breathing in Individuals with a Spinal Cord Injury: An Exploratory Cohort Study.

Background: An intricate physiological and pathophysiological connection exists between the heart and lungs, which is especially important in individuals with spinal cord injury (SCI). While an exercise intervention may seem the best approach to leverage this relationship, the prior work has shown that, despite numerous health benefits, regular exercise training does not improve cardiorespiratory control in individuals with SCI. Breath training presents an alternative intervention that is uniquely accessible, with yogic breathing directly engaging linked fluctuations in respiration and cardiovascular control. In addition, there is evidence across a range of populations that regular yogic breathing reduces cardiovascular disease risk. It is possible that the chronic decrease in breathing frequency associated with regular yogic breathing, rather than the specific yogic breathing techniques themselves, is the primary contributor to the observed risk reduction. Methods: Therefore, in 12 individuals with traumatic SCI from C4 to T8, the authors compared Unpaced and conventional 0.083 Hz (Slow) paced breathing with various yogic breathing techniques including: (1) inspiratory-expiratory breath holds (i.e., Kumbhaka or "Box Breathing"), (2) extended exhalation (1:2 duty cycle), and (3) expiratory resistance via throat constriction (i.e., Ujjayi). Beat-to-beat heart rate and blood pressure were measured as well as end-tidal CO2 and O2 saturation were measured. Statistical analysis was performed using a one-way repeated-measures analysis of variance with post hoc pairwise t tests corrected for multiple comparisons. Results: As expected, all slow breathing patterns markedly increased respiratory sinus arrhythmia (RSA) compared with Unpaced in all (n = 12) individuals. More importantly, Ujjayi breathing appeared to improve ventilatory efficiency over Unpaced breathing in individuals with SCI by increasing O2 saturation (97.6% vs. 96.1%; p = 0.042) and tended to decrease end-tidal CO2 (32 mmHg vs. 35 mmHg; p = 0.08). While other slow breathing patterns demonstrated similar effects, only Ujjayi improved RSA while increasing heart rate and improving ventilatory efficiency. Conclusions: Hence, slow breathing per se can result in important cardiorespiratory changes, but the yogic breathing practice of Ujjayi, with glottic throat resistance, may hold the greatest promise for improving cardiorespiratory control in individuals with SCI (CTR ID No. NCT05480618).

Extended exposure to low doses of azacitidine induces differentiation of leukemic stem cells through activation of myeloperoxidase.

Oral azacitidine (oral-Aza) treatment results in longer median overall survival (OS) (24.7 vs. 14.8 months in placebo) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy. The dosing schedule of oral-Aza (14 days/28-day cycle) allows for low exposure of Aza for an extended duration thereby facilitating a sustained therapeutic effect. However, the underlying mechanisms supporting the clinical impact of oral-Aza in maintenance therapy remain to be fully understood. In this preclinical work, we explore the mechanistic basis of oral-Aza/extended exposure to Aza through in vitro and in vivo modeling. In cell lines, extended exposure to Aza results in sustained DNMT1 loss, leading to durable hypomethylation, and gene expression changes. In mouse models, extended exposure to Aza, preferentially targets immature leukemic cells. In leukemic stem cell (LSC) models, the extended dose of Aza induces differentiation and depletes CD34+CD38- LSC. Mechanistically, LSC differentiation is driven in part by increased myeloperoxidase (MPO) expression. Inhibition of MPO activity either by using an MPO-specific inhibitor or blocking oxidative stress, a known mechanism of MPO, partly reverses the differentiation of LSC. Overall, our preclinical work reveals novel mechanistic insights into oral-Aza and its ability to target LSC.

Isatin-indoloquinoxaline click adducts with a potential to overcome platinum-based drug-resistance in ovarian cancer.

Herein, a series of isatin tethered indolo[2,3-b]quinoxaline hybrids was synthesized by considering the pharmacophoric features of known DNA intercalators and topoisomerase II inhibitors. The anti-proliferative properties of the synthesized compounds were evaluated against ovarian cancer cell lines (SKOV-3 and Hey A8). Four of the compounds exhibited promising anti-proliferative activities, with one of them being 10-fold more potent than cisplatin against drug-resistant Hey A8 cells. Further investigations were carried out to determine the DNA intercalating affinities of the most active compounds as potential mechanisms for their anti-proliferative activities. ADMET in silico studies were performed to assess the physicochemical, pharmacokinetics, and toxicity parameters of active compounds. This study, to the best of our knowledge, is the first report on the potential of isatin-indoloquinoxaline hybrids as structural blueprints for the development of new DNA intercalators. Additionally, it explores their potential to circumvent platinum-based resistance in ovarian cancer.

Choosing Between Ketamine and Electroconvulsive Therapy for Outpatients With Treatment-Resistant Depression-Advantage Ketamine?

This Viewpoint examines key issues stemming from several recent reports of electroconvulsive therapy (ECT) vs ketamine for improving depressive symptoms in treatment-resistant depression (TRD).

Stereo/regio-selective access to substituted 3-hydroxy-oxindoles with anti-proliferative assessment and in silico validation.

The manuscript focuses on a highly stereo-/regioselective approach for synthesizing a diverse array of substituted-3-hydroxy-2-oxindoles. The synthesized compounds were subsequently subjected to anti-proliferative assessment against various cell lines, including colorectal carcinoma, ovarian cancer, and human metastatic melanoma cancer. The structural characterization of the synthesized scaffolds was unambiguously confirmed using X-ray diffraction analysis. Among the synthesized compounds, one compound demonstrated exceptional potency within the series. It exhibited 1.2, 2.12, and 1.55 times greater potency than cisplatin against the HCT116, OVCAR10, and 1205Lu cell lines, respectively. These results were further supported by in vitro caspase-mediated apoptosis studies. Molecular docking studies of these compounds on the target VEGFR2 protein revealed their binding capability.

Chemical Composition, Preliminary Toxicity, and Antioxidant Potential of Piper marginatum Sensu Lato Essential Oils and Molecular Modeling Study.

The essential oils (OEs) of the leaves, stems, and spikes of P. marginatum were obtained by hydrodistillation, steam distillation, and simultaneous extraction. The chemical constituents were identified and quantified by GC/MS and GC-FID. The preliminary biological activity was determined by assessing the toxicity of the samples to Artemia salina Leach larvae and calculating the mortality rate and lethal concentration (LC50). The antioxidant activity of the EOs was determined by the DPPH radical scavenging method. Molecular modeling was performed using molecular docking and molecular dynamics, with acetylcholinesterase being the molecular target. The OES yields ranged from 1.49% to 1.83%. The EOs and aromatic constituents of P. marginatum are characterized by the high contents of (E)-isoosmorhizole (19.4-32.9%), 2-methoxy-4,5-methylenedioxypropiophenone (9.0-19.9%), isoosmorhizole (1.6-24.5%), and 2-methoxy-4,5-methylenedioxypropiophenone isomer (1.6-14.3%). The antioxidant potential was significant in the OE of the leaves and stems of P. marginatum extracted by SD in November (84.9 ± 4.0 mg TE·mL-1) and the OEs of the leaves extracted by HD in March (126.8 ± 12.3 mg TE·mL-1). Regarding the preliminary toxicity, the OEs of Pm-SD-L-St-Nov and Pm-HD-L-St-Nov had mortality higher than 80% in concentrations of 25 µg·mL-1. This in silico study on essential oils elucidated the potential mechanism of interaction of the main compounds, which may serve as a basis for advances in this line of research.

The therapeutic use and efficacy of ketamine in alcohol use disorder and alcohol withdrawal syndrome: a scoping review.

Introduction: Alcohol use disorder (AUD) is the most prevalent substance use disorder (SUD) globally. In 2019, AUD affected 14.5 million Americans and contributed to 95,000 deaths, with an annual cost exceeding 250 billion dollars. Current treatment options for AUD have moderate therapeutic effects and high relapse rates. Recent investigations have demonstrated the potential efficacy of intravenous ketamine infusions to increase alcohol abstinence and may be a safe adjunct to the existing alcohol withdrawal syndrome (AWS) management strategies. Methods: We followed Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines to conduct a scoping review of two databases (PubMed and Google Scholar) for peer-reviewed manuscripts describing the use of ketamine in AUD and AWS. Studies that evaluated the use of ketamine in AUD and AWS in humans were included. We excluded studies that examined laboratory animals, described alternative uses of ketamine, or discussed other treatments of AUD and AWS. Results: We identified 204 research studies in our database search. Of these, 10 articles demonstrated the use of ketamine in AUD or AWS in humans. Seven studies investigated the use of ketamine in AUD and three studies described its use in AWS. Ketamine used in AUD was beneficial in reducing cravings, alcohol consumption and longer abstinence rates when compared to treatment as usual. In AWS, ketamine was used as an adjunct to standard benzodiazepine therapy during severe refractory AWS and at signs of delirium tremens. Adjunctive use of ketamine demonstrated earlier resolution of delirium tremens and AWS, reduced ICU stay, and lowered likelihood of intubation. Oversedation, headache, hypertension, and euphoria were the documented adverse effects after ketamine administration for AUD and AWS. Conclusion: The use of sub-dissociative doses of ketamine for the treatment of AUD and AWS is promising but more definitive evidence of its efficacy and safety is required before recommending it for broader clinical use.

Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression.

BACKGROUND: Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. METHODS: We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period. RESULTS: A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation. CONCLUSIONS: Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.).

Theoretical and Anti-Klebsiella pneumoniae Evaluations of Substituted 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide and Imidazopyridine Hydrazide Derivatives.

A series of multistep synthesis protocols was adopted to synthesize substituted imidazopyridines (IMPs) (SM-IMP-01 to SM-IMP-13, and DA-01-05). All substituted IMPs were then characterized using standard spectroscopic techniques such as 1H-NMR, 13C-NMR, elemental analyses, and mass spectrometry. Our both in vitro qualitative and quantitative results for antibacterial analysis, against Klebsiella pneumoniae ATCC 4352 and Bacillus subtilis ATCC 6051 suggested that all compounds essentially exhibited activity against selected strains of bacteria. Our DFT analyses suggested that the compounds of the SM-IMP-01-SM-IMP-13 series have HOMO/LUMO gaps within 4.43-4.69 eV, whereas the compounds of the DA-01-DA-05 series have smaller values of the HOMO/LUMO gaps, 3.24-4.17 eV. The lowest value of the global hardness and the highest value of the global softness, 2.215 and 0.226 eV, respectively, characterize the compound SM-IMP-02; thus, it is the most reactive compound in the imidazopyridine carboxamide series (except hydrazide series). This compound also depicted lesser MIC values against Klebsiella pneumoniae ATCC 4352 and Bacillus subtilis ATCC 6051 as 4.8 µg/mL, each. In terms of another series, hydrazide DA-05 depicted strong antimicrobial actions (MIC: 4.8 µg/mL against both bacterial strains) and also had the lowest energy gap (3.24 eV), higher softness (0.309 eV), and lesser hardness (1.62 eV). Overall, when we compare qualitative and quantitative antimicrobial results, it is been very clear that compounds with dibromo substitutions on imidazopyridine (IMP) rings would act as better antimicrobial agents than those with -H at the eighth position on the IMP ring. Furthermore, substituents of higher electronegativities would tend to enhance the biological activities of dibromo-IMP compounds. DFT properties were also well comparable to this trend and overall, we can say that the electronic behavior of compounds under investigation has key roles in their bioactivities.

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

A Cross-Sectional Clinicomycological Study on Dermatophytosis: A Report From a Single Tertiary Healthcare Center in Eastern India.

Background Dermatophytosis is a public health concern in tropical countries. In India, a scalable number of dermatophytosis cases from multiple states are reported. In the eastern part of India, very few studies were published assessing the clinicomycological profiles of patients. Hence, we conducted this study to ascertain the clinicomycological profile of patients suffering from dermatophytosis with special reference to associated socio-environmental factors. Materials and methods This cross-sectional observational study was conducted in a tertiary care hospital situated in Bihar state of India from January 2021 to December 2021. We included a total of 330 patients of all age groups who were clinically diagnosed with superficial mycosis from the Department of Dermatology and sent for investigations to the Department of Microbiology. The collected specimens from the lesions were prepared with wet potassium hydroxide and examined under the microscope. Then, the specimens were inoculated and incubated at 25°C for up to four weeks. Fungal isolates were identified by gross appearance and microscopy if growth was observed. Results Among the 330 patients, 186 (56.4%) were males and 144 (43.6%) were females. The majority of the patients (54.5%) were from the low socioeconomic group and living in overcrowded places. Direct microscopy was positive in 198 (60%) patients, and culture was positive in 68 (20.61%) patients. The majority of the patients who were found positive in direct microscopy were from the age group of 21-30 years (39.9%), followed by 1-10 years (25.25%). A total of 92 (46.4%) cases were of tinea capitis, followed by 68 (34.3%) patients of tinea corporis. Trichophyton was the predominant fungus isolated, and Trichophyton mentagrophytes was the most common species (52.6%). Conclusion Tinea capitis was the most common provisionally diagnosed dermatophytosis in our tertiary care hospital in Bihar, an Indian state in its eastern zone. Low socioeconomic status and poor personal hygiene were the factors associated with the high prevalence of dermatophyte infections in this region of India. A detailed analysis of all these epidemiological factors is needed to limit the prevalence of dermatophytosis in tropical regions.

Comparison of Outcomes in Unilateral and Bilateral Pediatric Cochlear Implants: Our Experience.

The aim of our study is to compare the outcomes in unilateral and bilateral cochlear implants in pediatric age and also between simultaneous and sequential cochlear implant surgery. This retrospective study was carried out with 83 children aged between 12 months to 2.5 years which included 41 children with bilateral Cochlear implants and 42 with unilateral implants. Out of these 41 children, 21 were simultaneous and 20 were sequential cochlear implant. All the children were operated at civil hospital Gandhinagar, Gujarat, India. CAP, SIR, localization, traffic noise and speech in noise scores were assessed at regular intervals over the period of 4 years. Also the drug administration time, surgical time, operating room time were assessed for simultaneous and sequential cochlear implant surgery. Children with bilateral simultaneous implants fared significantly better with CAP, SIR, localization, speech noise and traffic noise scores than sequential bilateral implants and unilateral implants with a significant difference of means t tests between the two groups. Simultaneous cochlear implant surgery is associated with reduced surgical time, operating room time, it shortens the total in patient stay. There is less of drug administration and bilateral ones are stimulated simultaneously. Bilateral cochlear implants perform better with respect to auditory perception skills and spontaneous speech when compared with unilateral implants, but simultaneous surgery is better and safe option for pediatric cochlear implantation.

A qualitative assessment of perceptions and attitudes toward postoperative pain and opioid use in patients undergoing elective knee arthroscopy.

BACKGROUND: Orthopedic surgeons routinely prescribe opioids to manage post-operative pain. In the face of an opioid epidemic, a one-size-fits-all approach to pain management is no longer appropriate. Patient-centred prescribing practices should be used by surgeons; however, little is known about what influences patient attitudes toward postoperative pain and its management to inform such practices. We sought to explore patient attitudes toward postsurgical pain management, including opioids. METHODS: We conducted qualitative, semistructured interviews of 11 opioid-naive patients (age 16-46 yr) who were scheduled to undergo arthroscopic knee surgery. Transcripts were analyzed thematically using a framework analysis that involved familiarization, developing a thematic framework, indexing, charting and mapping, and interpretation. RESULTS: Participant attitudes toward postoperative pain and opioids were influenced by perceived tolerance to pain based on personal experience, perceived predisposition to addiction based on personal assumptions regarding addictive personality traits and risk factors, and perceptions of opioid use shaped by external influences, including family, friends and the media's depiction of the opioid epidemic. Every patient expressed that preoperative counselling and education regarding postoperative pain management would be beneficial in improving their knowledge base, easing anxieties and clarifying misunderstandings. CONCLUSION: Surgeons can address the patient-reported factors identified in this study to help optimize a patient's perioperative experience without relying solely on prescribed analgesia. By improving accessibility to education and promoting safe, patient-centred prescribing practices, we may reduce reliance on opioids in orthopedic surgery.

Mid-term outcomes of the Wagner Cone Prosthesis™ stem for developmental dysplasia of the hip: minimum two year follow-up.

PURPOSE: Treatment of symptomatic developmental dysplasia of the hip (DDH) requires a technically demanding total hip arthroplasty (THA) reconstruction. In patients with DDH, prostheses can be difficult to implant and often face the risk of fracture, mismatch, and loosening. The Wagner Cone Prosthesis™ is a tapered, conical stem which can improve treatment success in this population. We look at midterm survivorship and outcomes of THA for DDH using the Wagner Cone Prosthesis™. METHODS: We retrospectively analyzed 28 patients (33 hips) with DDH undergoing THA using the Wagner Cone Prosthesis™ between January 2008 and January 2020. Ten, nine, and fourteen included patients were classified as Hartofilakidis A, B, and C, respectively. Survivorship according to Kaplan-Meier analysis was the primary outcome, with re-operation and revision as endpoints. The Oxford hip score (OHS) was used to assess clinical outcome. We used multivariate analysis to determine predictors of poor outcomes. The average follow-up was 4.6 years, with a minimum of two years. RESULTS: Kaplan-Meier survivorship over the 13-year study period was 93.9 ± 4.2% for all-cause revision as an endpoint and 96.9 ± 3.1% for stem revisions only. The overall reoperation rate was 6.1%, with periprosthetic fracture and dislocation being reasons for re-operation. No patients were revised for aseptic loosening, and no patients were revised for subsidence. OHS improved from 19.3 ± 9.6 (4-39) pre-operatively to 37.6 ± 8.4 (19-48) at latest follow-up (p < 0.05). CONCLUSION: In patients with DDH, THA with the Wagner Cone Prosthesis™ demonstrates excellent clinical, radiographic, and patient-reported functional outcomes at midterm follow-up.

Genetic and environment effects on structural neuroimaging endophenotype for bipolar disorder: a novel molecular approach.

We investigated gene-environment effects on structural brain endophenotype in bipolar disorder (BD) using a novel method of combining polygenic risk scores with epigenetic signatures since traditional methods of examining the family history and trauma effects have significant limitations. The study enrolled 119 subjects, including 55 BD spectrum (BDS) subjects diagnosed with BD or major depressive disorder (MDD) with subthreshold BD symptoms and 64 non-BDS subjects comprising 32 MDD subjects without BD symptoms and 32 healthy subjects. The blood samples underwent genome-wide genotyping and methylation quantification. We derived polygenic risk score (PRS) and methylation profile score (MPS) as weighted summations of risk single nucleotide polymorphisms and methylation probes, respectively, which were considered as molecular measures of genetic and environmental risks for BD. Linear regression was used to relate PRS, MPS, and their interaction to 44 brain structure measures quantified from magnetic resonance imaging (MRI) on 47 BDS subjects, and the results were compared with those based on family history and childhood trauma. After multiplicity corrections using false discovery rate (FDR), MPS was found to be negatively associated with the volume of the medial geniculate thalamus (FDR = 0.059, partial R2 = 0.208). Family history, trauma scale, and PRS were not associated with any brain measures. PRS and MPS show significant interactions on whole putamen (FDR = 0.09, partial R2 = 0.337). No significant gene-environment interactions were identified for the family history and trauma scale. PRS and MPS generally explained greater proportions of variances of the brain measures (range of partial R2 = [0.008, 0.337]) than the clinical risk factors (range = [0.004, 0.228]).

A comparison of the safety, feasibility, and tolerability of ECT and ketamine for treatment-resistant depression.

Treatment-resistant depression (TRD) is a problematic and prevalent public health and societal concern. Although electroconvulsive therapy (ECT) is the gold standard TRD intervention, the treatment evokes apprehension due to public perceptions, feasibility, and tolerability. Despite significant medical advancements, few medications have been approved by the U.S. Food and Drug Administration for TRD. In 2019, intranasal esketamine, the S-isomer of racemic ketamine, was approved for TRD, garnering significant excitement about the potential for the drug to act as an alternative treatment to ECT. The goal of this narrative review is to compare the safety, efficacy, and tolerability of ketamine and ECT; clarify whether ketamine is a reasonable alternative to ECT; and to facilitate improved treatment assignment for TRD. Empirical quantitative and qualitative studies and national and international guidelines for these treatments are reviewed. The field awaits the results of two ongoing large comparative effectiveness trials of ECT and IV ketamine for TRD, which should help guide clinicians and patients as to the relative risk and benefit of these interventions. Over the next five years we anticipate further innovations in neuromodulation and in drug development which broadly aim to develop more tolerable versions of ECT and ketamine, respectively.