Alternative Treatment Strategies Research Articles

Prolonged sitafloxacin and doxycycline combination regimen for treating infections by highly resistant Mycoplasma genitalium.

Mycoplasma genitalium, which causes sexually transmitted diseases, is increasingly resistant to key antibiotics such as macrolides and quinolones, posing a challenge for treatment. To assess the effectiveness of prolonged sitafloxacin and doxycycline combination therapy as a new alternative treatment strategy for highly drug-resistant M. genitalium strains. A prospective cohort study was conducted at the National Center for Global Health and Medicine, Tokyo, Japan, from 1 January 2020 to 31 October 2022. Patients with M. genitalium urogenital or rectal infections and those who did not receive the initial sitafloxacin monotherapy were included. Patients were administered sitafloxacin and doxycycline for 21 days as salvage therapy. M. genitalium isolates were tested for parC, gyrA and 23S rRNA resistance-associated mutations. Twenty-seven patients received the combination therapy. All M. genitalium strains available for resistance analysis had parC (24/24) and macrolide resistance-associated (25/25) mutations, and 68% (17/25) had gyrA mutations. The overall cure rate was 77.8%. For strains with concurrent parC and gyrA mutations, the cure rate was 68.8% (P = 0.053) compared with that for monotherapy (37.5%). Prolonged combination therapy is highly effective against M. genitalium strains with concurrent parC and gyrA mutations. Future research should focus on establishing the optimal treatment duration and monitoring the risk of resistance.

Bacterial isolates and antibiotic sensitivity in canine bacterial keratitis in Korea.

To analyze bacterial isolates associated with canine bacterial keratitis and their antibiotic susceptibility patterns in Korea, focusing on multidrug resistance (MDR) and identifying effective antibiotic combinations for clinical treatment. A total of 146 dogs diagnosed with suspected bacterial keratitis between October 2022 and October 2023 in Korea, with 157 eye samples collected for analysis. Eye samples were cultured to isolate bacteria, and antibiotic susceptibility testing was performed using the minimum inhibitory concentration (MIC) method. Bacterial identification was conducted using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF). The study assessed the efficacy of individual antibiotics and combination therapies. Bacteria were isolated in 55.4% of the samples. The most common genera were Staphylococcus species (48.5%, 48/99), Streptococcus species (13.1%, 13/99), Pseudomonas species (9.1%, 9/99), and Escherichia coli (9.1%, 9/99). Amikacin (84.8%) showed the highest antibiotic susceptibility, while doxycycline exhibited the lowest (17.2%). The most effective antibiotic combinations were amikacin-moxifloxacin (93%). MDR isolates accounted for 52.5% (52/99) of the total bacterial samples. Staphylococcus species were the most common isolates, with 52.5% showing MDR, underscoring the need to curb antibiotic misuse. While antibiotics like amikacin demonstrated high susceptibility rates, their use should be reserved for resistant infections to prevent further resistance development. Rather than focusing solely on finding effective combinations of antibiotics, it is crucial to consider alternative treatment strategies that offer more sustainable solutions. Rather than relying on antibiotic combinations, attention should shift to sustainable alternatives to treat bacterial keratitis and reduce antibiotic dependence in clinical practice.

A recent update on the antibacterial effects ofdistinct bioactive molecules derived from theCannabis plant.

The number of human infections with multidrug-resistant (MDR) bacteria is increasing worldwide and constitutes a serious threat to human health. Given the lack of novel antibiotic compounds worsening this dilemma, alternative antibiotic-independent treatment and prevention strategies of infectious diseases applying natural compounds appear highly appreciable. Given the long-known health-beneficial and disease-alleviating properties of Cannabis, we performed a literature search summarizing current knowledge regarding the antibacterial effects of extracts from different parts of the Cannabis sativa plant and of defined Cannabis-derived molecules and their potential mode of action. Theincluded studies revealed that various extracts and essential oils of C. sativa as well as major cannabinoids exerted potent activities against a broad spectrum of Gram-positive bacteria and against some Gram-negative bacterial species including MDR strains. Particularly the disruption of the bacterial cytoplasmic membrane by some cannabinoids resulted in potent antibacterial effects against Gram-positivebacteria including methicillin-resistant Staphylococcus aureus. Furthermore, defined cannabinoids inhibited the formation of and eradicated existing bacterial biofilms. In conclusion, given their antibacterial properties distinct Cannabis-derived molecules expand the repertoire of antibiotics-independent treatment options in the combat of bacterial infectious diseases which should be further addressed in future studies including clinical trials.

Application of Artificial Intelligence Models to Predict the Onset or Recurrence of Neovascular Age-Related Macular Degeneration

Neovascular age-related macular degeneration (nAMD) is one of the major causes of vision impairment that affect millions of people worldwide. Early detection of nAMD is crucial because, if untreated, it can lead to blindness. Software and algorithms that utilize artificial intelligence (AI) have become valuable tools for early detection, assisting doctors in diagnosing and facilitating differential diagnosis. AI is particularly important for remote or isolated communities, as it allows patients to endure tests and receive rapid initial diagnoses without the necessity of extensive travel and long wait times for medical consultations. Similarly, AI is notable also in big hubs because cutting-edge technologies and networking help and speed processes such as detection, diagnosis, and follow-up times. The automatic detection of retinal changes might be optimized by AI, allowing one to choose the most effective treatment for nAMD. The complex retinal tissue is well-suited for scanning and easily accessible by modern AI-assisted multi-imaging techniques. AI enables us to enhance patient management by effectively evaluating extensive data, facilitating timely diagnosis and long-term prognosis. Novel applications of AI to nAMD have focused on image analysis, specifically for the automated segmentation, extraction, and quantification of imaging-based features included within optical coherence tomography (OCT) pictures. To date, we cannot state that AI could accurately forecast the therapy that would be necessary for a single patient to achieve the best visual outcome. A small number of large datasets with high-quality OCT, lack of data about alternative treatment strategies, and absence of OCT standards are the challenges for the development of AI models for nAMD.

Challenges in diagnosing and treating Liddle syndrome in resource-limited settings: A case report from Indonesia

Liddle syndrome, a rare form of monogenic hypertension, poses significant diagnostic and therapeutic challenges due to its phenotypic variability and the need for genetic testing. The rarity of the condition, coupled with the limited availability of first-line treatments such as epithelial sodium channel (ENaC) blockers, makes this case report particularly urgent and novel, highlighting alternative management strategies in resource-limited settings. The aim of this case report was to present the diagnostic challenges, therapeutic strategies, and clinical outcomes of a patient with Liddle syndrome who did not have access to ENaC blockers, emphasizing the importance of early recognition and personalized treatment. A 35-year-old female presented with resistant hypertension (190/100 mmHg) and bilateral limb weakness. Laboratory results revealed persistent hypokalemia, hypernatremia, and metabolic alkalosis. Low aldosterone levels, alongside clinical and family history, led to the diagnosis of Liddle syndrome. Genetic testing was not conducted due to resource limitations, and ENaC blockers were unavailable. The patients were managed with a combination of alternative antihypertensive agents, potassium supplementation, and a low-sodium diet. Although this approach led to modest improvements in blood pressure and motor strength, persistent hypokalemia and hypernatremia underscored the suboptimal control of the syndrome's underlying pathophysiology in the absence of ENaC blockers. This case highlights the challenges faced in resource-limited settings and the need for innovative strategies to manage rare conditions like Liddle syndrome. Liddle syndrome's diagnostic and therapeutic challenges underscore the critical importance of early recognition and access to targeted therapies. In the absence of ENaC blockers, alternative treatment strategies can provide some benefit, but they often fall short of optimal management. This case emphasizes the need for enhanced clinical awareness, improved access to genetic testing, and the development of personalized treatment approaches to achieve better patient outcomes.

Enhanced Antitumor Efficacy of Oncolytic Vaccinia Virus Therapy Through Keratin-Mediated Delivery in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) represents an aggressive subtype characterized by high rates of recurrence and metastasis, necessitating the exploration of alternative treatment strategies. Oncolytic vaccinia virus (OVV) therapy has emerged as a promising approach, selectively infecting and destroying tumor cells. However, its efficacy is often hampered by inadequate viral distribution within the tumor microenvironment. Here, we investigate the potential of keratin (KTN) as a carrier for OVV delivery to enhance viral distribution and antitumor efficacy. In vitro assays revealed that KTN significantly improves OVV stability, leading to increased tumor cell apoptosis and necrosis. Furthermore, KTN effectively inhibits cancer cell migration by suppressing the epithelial–mesenchymal transition (EMT) process and downregulating metastasis-related proteins. These findings are corroborated in a syngeneic TNBC mouse model, where KTN-mediated OVV delivery enhances cytotoxic T cell-mediated antitumor immune responses without compromising the anti-angiogenic effects of the virus. Notably, KTN alone exhibits antitumor effects by suppressing tumor growth and metastasis, underscoring its potential as a standalone therapeutic agent. In conclusion, our study underscores the promise of KTN-mediated OVV delivery as a promising therapeutic strategy for TNBC. By improving viral distribution, suppressing EMT, and enhancing antitumor immunity, this approach holds significant potential for enhancing patient outcomes in TNBC treatment. Further investigation is warranted to explore the broader utility of KTN in various cancer therapy approaches.

Connexin43 Contributes to Alzheimer's Disease by Promoting the Mitochondria-Associated Membrane-Related Autophagy Inhibition.

The perturbed structure and function of mitochondria-associated membranes (MAM), instead of the amyloid cascade, have been gradually proposed to play a basic role in the pathogenesis of Alzheimer's disease (AD). Notably, autophagy inhibition is one of the main mechanisms of MAM dysfunction and plays an important role in neuronal injury. However, the upstream molecular mechanism underlying the MAM dysfunctions remains elusive. Here, we defined an unexpected and critical role of connexin43 (Cx43) in regulating the MAM structure. The expression levels of Cx43 and mitofusin-2 (MFN2, the MAM biomarker) increase significantly in 9-month-old APPswe/PS1dE9 double-transgenic AD model mice, and there is an obvious colocalization relationship. Moreover, both AD mice and cells lacking Cx43 exhibit an evident reduction in the MAM contact sites, which subsequently promotes the conversion from microtubule-associated protein 1 light-chain 3B I (LC3B-I) to LC3B-II via inhibition mTOR-dependent pathway and then initiates the generation of autophagosomes. Autophagosome formation ultimately promotes β-amyloid (Aβ) clearance and attenuates Aβ-associated pathological changes in AD, mainly including astrogliosis and neuronal apoptosis. Our findings not only reveal a previously unrecognized effect of Cx43 on MAM upregulation but also highlight the major player of MAM-induced autophagy inhibition in Cx43-facilitated AD pathogenesis, providing a novel insight into the alternative therapeutic strategies for the early treatment of AD.

Feasibility of neoadjuvant chemotherapy for bulky early stage to stage IIIB cervical cancer in Uganda

IntroductionExternal beam radiotherapy (EBRT) became unavailable in Uganda from February 2016 to November 2017. Following resource stratification guidelines, an alternative treatment strategy was developed. MethodsBulky early stage to Stage IIIB patients received at least 3 cycles of neoadjuvant chemotherapy (NAC). Surgery was performed if adequate response was achieved and adjuvant therapy given for high risk factors. Chemotherapy versus supportive care was advised in unresectable disease. NAC protocol completion was defined as receiving at least 3 cycles of NAC followed by either surgery, chemotherapy and/or radiation, or best supportive care. The purpose of this study was to determine the completion rate of NAC and assess the adverse events associated with treatment. Data were collected through retrospective chart review. ResultsFrom February 2016 to November 2018, 53 evaluable patients were identified. 86.8% (46/53) of patients presented in Stage IIB or higher. The completion rate of the NAC protocol was 75.5% (40/53). 94.3% (50/53) received platinum-taxane combination. 7.6% (4/52) grade 3 adverse events occurred related to chemotherapy, all hematologic. 18.8% (10/53) patients underwent surgery with 2 aborted cases due to metastatic or inoperable disease. No adverse events related to surgery were reported. 5 patients underwent adjuvant therapy after surgery due to high risk factors or incomplete pathology findings. 26 patients received adjuvant radiation (3 brachytherapy, 23 EBRT after it became available). Reported side effects related to radiation included vaginal fibrosis and skin reactions. ConclusionIn this limited-resource setting, majority of patients completed a NAC treatment strategy for cervical cancer with acceptable toxicities.

Outcomes of Radiofrequency Ablation for Autonomously Functioning Thyroid Adenomas-Mayo Clinic Experience.

Autonomously functioning thyroid nodules (AFTNs) constitute 5% to 7% of thyroid nodules and represent the second most common cause of hyperthyroidism following Graves' disease. Currently, radioactive iodine (RAI) and surgery are the standard treatment options, and both incur a risk of postprocedural hypothyroidism and other surgery and radiation-related complications. This work aimed at assessing the efficacy of radiofrequency ablation (RFA) as an alternative treatment option for resolving hyperthyroidism and the nodule volume rate reduction (VRR) and its associated adverse events. A total of 22 patients underwent RFA for a solitary AFTN. Seventy-two percent (n = 16) had subclinical hyperthyroidism, 9% (n = 2) had overt hyperthyroidism, and 18% (n = 4) were biochemically euthyroid on antithyroid medication. Average pretreatment TSH was 0.41 mIU/L (SD = 0.98) and free T4 1.29 ng/dL (SD = 0.33). Following a single RFA session, hyperthyroidism resolved in 90.9% (n = 20) and average VRR (61.13%) was achieved within 3 to 6 months following the ablation. Except for 1 nodule, none of the nodules grew during the follow-up period (16.5 months). Two patients (9%) developed transient tachycardia requiring short-term beta-blocker therapy, and 2 developed mild hypothyroidism requiring levothyroxine therapy. Two patients developed recurrent hyperthyroidism and elected to undergo lobectomy and repeat RFA respectively. No serious adverse effects were noted in this cohort. RAI and/or surgery represent the standard of care for toxic adenomas, but RFA shows excellent efficacy and safety profile. Therefore, at centers with RFA expertise, it should be considered an alternative treatment strategy, avoiding radiation and surgery-related complications.

Current State of Therapeutics for HTLV-1

Human T cell leukaemia virus type-1 (HTLV-1) is an oncogenic retrovirus that causes lifelong infection in ~5–10 million individuals globally. It is endemic to certain First Nations populations of Northern and Central Australia, Japan, South and Central America, Africa, and the Caribbean region. HTLV-1 preferentially infects CD4+ T cells and remains in a state of reduced transcription, often being asymptomatic in the beginning of infection, with symptoms developing later in life. HTLV-1 infection is implicated in the development of adult T cell leukaemia/lymphoma (ATL) and HTLV-1-associated myelopathies (HAM), amongst other immune-related disorders. With no preventive or curative interventions, infected individuals have limited treatment options, most of which manage symptoms. The clinical burden and lack of treatment options directs the need for alternative treatment strategies for HTLV-1 infection. Recent advances have been made in the development of RNA-based antiviral therapeutics for Human Immunodeficiency Virus Type-1 (HIV-1), an analogous retrovirus that shares modes of transmission with HTLV-1. This review highlights past and ongoing efforts in the development of HTLV-1 therapeutics and vaccines, with a focus on the potential for gene therapy as a new treatment modality in light of its successes in HIV-1, as well as animal models that may help the advancement of novel antiviral and anticancer interventions.

Correction of Griscelli Syndrome Type 2 causing mutations in the RAB27A gene with CRISPR/Cas9.

Griscelli Syndrome Type 2 (GS-2) is a rare, inherited immune deficiency caused by a mutation in the RAB27A gene. The current treatment consists of hematopoietic stem cell transplantation, but a lack of suitable donors warrants the development of alternative treatment strategies, including gene therapy. The development of mutation-specific clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 gene editing technology has opened the way for custom-designed gene correction of patient-derived stem cells. In this study, we aimed to custom design CRISPR/Cas9 constructs and test their efficiency on homology-directed repair (HDR) on the correction of exon 3 and exon 7 mutations in the RAB27A gene of GS-2 patient-derived mesenchymal stem cells (MSCs) and induced pluripotent stem cells. We assessed RAB27A gene and protein expression using qRT-PCR, Western Blot, and immune fluorescence in GS-2 patient-derived MSCs and induced pluripotent stem cells (iPSCs). Guide RNAs (gRNAs) and donor DNAs were designed based on patient mutations in exon 3 and exon 7 using the CHOPCHOP online tool and transfected into GS-2 MSCs and iPSCs by electroporation. The cells were cultured for 2 days and then used for mutation analysis using DNA sequencing. MSCs and iPSCs from the GS-2 patients lacked RAB27A gene and protein expression. After gRNA and donor DNAs were designed and optimized, we found HDR efficiency with gRNA3.3 (10% efficiency) and gRNA7.3 (27% efficiency) for MSCs but lower efficiency in iPSCs (<5%). However, transfection of both MSCs and iPSCs resulted in massive cell death, loss of colony formation, and spontaneous differentiation. The use of CRISPR/Cas9 to genetically correct MSCs and iPSCs from GS-2 patients with different mutations through HDR is feasible but requires optimization of the procedure to reduce cell death and improve stem cell function before clinical application.

Investigating In Vivo Tumor Biomolecular Changes Following Radiation Therapy Using Raman Spectroscopy.

Treatment resistance is a major bottleneck in the success of cancer therapy. Early identification of the treatment response or lack thereof in patients can enable an earlier switch to alternative treatment strategies that can enhance response rates. Here, Raman spectroscopy was applied to monitor early tumor biomolecular changes in sensitive (UM-SCC-22B) and resistant (UM-SCC-47) head and neck tumor xenografts for the first time in in vivo murine tumor models in response to radiation therapy. We used a validated multivariate curve resolution-alternating least-squares (MCR-ALS) model to resolve complex multicomponent Raman spectra into individual pure spectra and their respective contributions. We observed a significant radiation-induced increase in the contributions of lipid-like species (p = 0.0291) in the radiation-sensitive UM-SCC-22B tumors at 48 h following radiation compared to the nonradiated baseline (prior to commencing treatment). We also observed an increase in the contribution of collagen-like species in the radiation-resistant UM-SCC-47 tumors at 24 h following radiation compared to the nonradiated baseline (p = 0.0125). In addition to the in vivo analysis, we performed ex vivo confocal Raman microscopic imaging of frozen sections derived from the same tumors. A comparison of all control and treated tumors revealed similar trends in the contributions of lipid-like and collagen-like species in both in vivo and ex vivo measurements; however, when evaluated as a function of time, longitudinal trends in the scores of collagen-like and lipid-like components were not consistent between the two data sets, likely due to sample numbers and differences in sampling depth at which information is obtained. Nevertheless, this study demonstrates the potential of fiber-based Raman spectroscopy for identifying early tumor microenvironmental changes in response to clinical doses of radiation therapy.

Molecular and clinical heterogeneity within MYC-family amplified medulloblastoma is associated with survival outcomes: A multicenter cohort study.

MYC/MYCN are the most frequent oncogene amplifications in medulloblastoma (MB) and its primary biomarkers of high-risk (HR) disease. However, while many patients' MYC(N)-amplified tumors are treatment-refractory, some achieve long-term survival. We therefore investigated clinicobiological heterogeneity within MYC(N)-amplified MB and determined its relevance for improved disease management. We characterized the clinical and molecular correlates of MYC- (MYC-MB; n = 64) and MYCN-amplified MBs (MYCN-MB; n = 95), drawn from >1600 diagnostic cases. Most MYC-MBs were molecular group 3 (46/58; 79% assessable) and aged ≥3 years at diagnosis (44/64 [69%]). We identified a "canonical" very high-risk (VHR) MYC-amplified group (n = 51/62; 82%) with dismal survival irrespective of treatment (11% 5-year progression-free survival [PFS]), defined by co-occurrence with ≥1 additional established risk factor(s) (subtotal surgical-resection [STR], metastatic disease, LCA pathology), and commonly group 3/4 subgroup 2 with a high proportion of amplified cells. The majority of remaining noncanonical MYC-MBs survived (i.e. non-group 3/group 3 without other risk features; 11/62 (18%); 61% 5-year PFS). MYCN survival was primarily related to molecular group; MYCN-amplified SHH MB, and group 3/4 MB with additional risk factors, respectively defined VHR and HR groups (VHR, 39% [35/89]; 20% 5-year PFS/HR, 33% [29/89]; 46% 5-year PFS). Twenty-two out of 35 assessable MYCN-amplified SHH tumors harbored TP53 mutations; 9/12 (75%) with data were germline. MYCN-amplified group 3/4 MB with no other risk factors (28%; 25/89) had 70% 5-year PFS. MYC(N)-amplified MB displays significant clinicobiological heterogeneity. Diagnostics incorporating molecular groups, subgroups, and clinical factors enable their risk assessment. VHR "canonical" MYC tumors are essentially incurable and SHH-MYCN-amplified MBs fare extremely poorly (20% survival at 5 years); both require urgent development of alternative treatment strategies. Conventional risk-adapted therapies are appropriate for more responsive groups, such as noncanonical MYC and non-SHH-MYCN MB.

Bridging the gaps: prioritizing research strategies for enhanced malaria control and elimination.

Malaria continues to be a significant global health challenge, with millions of cases and hundreds of thousands of deaths reported annually. To combat this disease effectively, it is imperative to identify and address significant research gaps in malaria control and elimination efforts. This review synthesizes current knowledge and highlights critical gaps in several crucial areas of malaria research. Firstly, we discuss the complexities of vector biology and control, emphasizing the need for a deeper understanding of vector behavior, particularly in urban settings. Secondly, the study examines the challenges posed by drug resistance and the urgent need for alternative treatment strategies and novel drug targets. Thirdly, the review explores the ongoing quest for an effective malaria vaccine, underscoring the importance of understanding immunological correlates of protection. The study also explores medication resistance genes and genomic epidemiology, highlighting the need for more investigation into potential targets for drugs and vaccine candidates. Furthermore, it addresses the socioeconomic and environmental determinants of malaria transmission, highlighting the importance of integrating multidisciplinary approaches to address transmission dynamics. The study concludes with a discussion of how malaria transmission is impacted by climate change and the necessity of research to guide adaptation measures.

6430 SAT-534 Evaluating the Effectiveness of Combined T4 and T3 Therapy or Desiccated Thyroid Versus T4 Monotherapy in Hypothyroidism: A Systematic Review and Meta-Analysis

Abstract Disclosure: M. Nassar: None. A. Hassan: None. M.T. Desouki: None. S. Ramadan: None. M.A. Hassan: None. A. Chaudhuri: None. Background: Many patients with hypothyroidism experience persistent symptoms despite normalized TSH levels, which highlights the need for alternative treatment strategies. This study aims to evaluate the effectiveness of combined T4 and T3 therapy or desiccated thyroid (DTE) compared to T4 monotherapy, with a focus on thyroid profile, lipid profile, and quality of life metrics, including the 36-point thyroid symptom questionnaire (TSQ-36), Beck Depression Inventory (BDI) scores, and General Health Questionnaire (GHQ)-28 scores. Methods: A systematic literature search was conducted using a Boolean strategy on the following databases: Embase, Medline/PubMed, and Web of Science. The search included results from the inception of each database until 11/23/2023. We used the following keywords: "Armour Thyroid," OR "Thyroid Extract," OR "Natural Desiccated Thyroid," OR "Nature-Throid," "Desiccated Thyroid," OR "NP Thyroid," OR "Synthroid," OR "Levothyroxine," OR "Liothyronine," "Cytomel," OR "Thyroid USP," OR "Unithroid." AND "hypothyroidism. " We only included RCTs. We excluded non-English articles. Results: Initially, 6,394 records were identified. After removing 477 duplicate records, 5,917 records underwent title and abstract screening, excluding 5,874 records. The full texts of the remaining 43 articles were examined for eligibility, excluding 27 articles. Ultimately, 16 studies met the inclusion criteria and were incorporated into our analysis. We included two studies on desiccated thyroid and 15 studies on combined therapy. In this meta-analysis, combination therapy with T4+T3 revealed a significant reduction in free T4 levels (mean difference (MD): -0.34; 95% CI: -0.47, -0.20), total T4 levels (mean difference: -2.20; 95% CI: -3.03, -1.37), and GHQ-28 scores (MD: -2.89; 95% CI: -3.16, -2.63) compared to T4 monotherapy. Total T3 levels increased significantly in combined therapy (MD: 29.82; 95% CI: 22.40, 37.25). The analyses demonstrated moderate to high heterogeneity. There was no significant difference in heart rate, SHBG, TSH, lipid profile, TSQ-36, or BDI score. DTE significantly increased serum total T3 levels (MD: 50.90; 95% CI: 42.39, 59.42) and significantly decreased serum total T4 (MD: -3.11; 95% CI: -3.64, -2.58) and free T4 levels (MD: -0.50; 95% CI: -0.57, -0.43) compared to T4 monotherapy. Moreover, DTE treatment showed a modest increase in TSH levels (MD: 0.49; 95% CI: 0.17, 0.80). The analyses indicated low heterogeneity. There was no significant difference in heart rate, SHBG, lipid profile, TSQ-36, GHQ-28, or BDI score. Conclusions: Our study revealed that combined therapy and DTE lead to higher T3 and lower T4 levels compared to T4 monotherapy in hypothyroidism. However, no significant effects on heart rate, lipid profile, or quality of life were noted. Given the heterogeneity of results, personalized treatment approaches are recommended. Presentation: 6/1/2024

Hepatitis B virus (HBV) viremia despite tenofovir disoproxil fumarate-containing antiretroviral therapy in persons with HBV/HIV coinfection

BackgroundThe goal of treatment of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection is suppression of both viruses; yet incomplete HBV suppression on tenofovir (TFV) disoproxil fumarate (TDF)-based antiretroviral therapy (ART) is common. This study investigated TFV resistance-associated mutations (RAMs) in individuals with HBV/HIV coinfection with viremia on TDF/lamivudine (3TC)-containing ART. MethodsSamples from individuals with HBV DNA levels ≥20 IU/mL in a cross-sectional study of 138 persons with HBV/HIV coinfection in Ghana were analyzed in the present study. HBV was sequenced for RAM analysis. TFV-diphosphate (TFV-DP) concentration in peripheral blood mononuclear cells (PBMCs) was used to assess ART adherence level. ResultsNine of 138 participants (6.5 %) had detectable HBV DNA levels ≥20 IU/mL while on ART. Seven of the nine participants had TFV-DP concentrations commensurate with 7 doses per week, and six had suppressed HIV RNA. Phylogenetic analysis revealed that eight sequences were HBV genotype E, with one genotype E/A recombinant. Ten previously-reported TFV RAMs were present in the study samples; eight were wild-type for HBV genotype E. The non-genotype-E-wild-type point mutations M267L and K333Q were found in two and one patients, respectively. No 3TC RAMs were found. ConclusionHBV viremia despite high adherence to TDF/3TC-based ART may be associated with the presence of TFV RAMs. These findings highlight the need for enhanced resistance monitoring and further research to examine the clinical significance of reported TFV RAMs. Individuals with HBV/HIV coinfection and TFV resistance on TDF-based ART may need alternative treatment strategies.

Interferon-induced factor 16 is essential in metastatic melanoma to maintain STING levels and the immune responses upon IFN-γ response pathway activation

BackgroundImmune checkpoint inhibitor (ICIs)-based therapies are the standard of care treatment for patients with metastatic melanoma (MM). The stimulator of interferon genes (STING) signaling pathway is critical in controlling immune...

First-Line Tyrosine Kinase Inhibitors in Soft-Tissue Sarcomas: A Role for Anlotinib?

The optimal medical treatment of chemotherapy-ineligible patients affected by advanced soft-tissue sarcomas is unclear. In this population, tyrosine kinase inhibitors represent an appealing alternative treatment strategy. First-line use of the tyrosine kinase inhibitor anlotinib in chemotherapy-ineligible patients with soft-tissue sarcoma showed promising activity across multiple histologies. See related article by Li et al., p. 4310.

Antimicrobial efficacy of 2% chlorhexidine gel, triphala, and Azadirachta indica as intracanal medicaments against Enterococcus faecalis: A randomized clinical trial

Abstract Context: Concerns about adverse reactions and the development of antibiotic resistance have prompted an alternative treatment strategy that utilizes traditional medicinal herbs. Aim: This randomized control trial assessed the antimicrobial efficacy of 2% chlorhexidine (CHX) gel, Triphala, and Azadirachta indica as intracanal medicaments against Enterococcus faecalis. Materials and Methods: Forty patients with nonvital teeth and single root canals were selected (n = 10). Following the initial access opening, the first microbial samples (S1) were collected using paper points. Second microbial samples (S2) were collected following the chemo-mechanical preparation and 1 week after introducing the intracanal medicaments. Group I: 2% CHX, Group II: A. indica, Group III: Triphala, and Group IV: Calcium hydroxide (Ca(OH)2). S1 and S2 samples were collected, and bacterial growth was observed using the colony-forming unit (CFU) count. Statistical Analysis: Comparison of the difference in CFU count among four groups was performed using one-way ANOVA test (P &lt; 0.05) followed by post hoc Tukey test. Results: Reduction in CFU count postmedication S2 from S1 in each group was statistically significant. Percentage reduction in CFU count was highest in Triphala group followed by A. indica and 2% CHX group. Percentage reduction in CFU count was least in Ca(OH)2 group. The post hoc pairwise comparison of % reduction in CFU count among four groups showed that the percent reduction was highest in Triphala group. Conclusion: Triphala has considerable antimicrobial efficacy against E. faecalis.

Effective Treatment of Refractory Oral Ulcers Using a Compound Chinese Herbal Mouthwash: A Report of Two Cases

Oral ulcers are a prevalent oral mucosal disorder, characterized by benignancy and self-limiting progression. However, a subset of these ulcers exhibits resistance to conventional therapeutic interventions, necessitating alternative treatment strategies. In this study, we present two cases of refractory oral ulcers that demonstrated limited responsiveness to standard treatments but achieved significant therapeutic benefits following the application of a compound Chinese herbal mouthwash. Case 1 involved a 60-year-old female patient diagnosed with Behçet's syndrome. Initial treatment with glucocorticoids and immunosuppressants yielded limited improvement in her oral ulcers; however, combination therapy involving the Chinese herbal mouthwash resulted in significant improvement and complete healing after a 2-week period. Case 2 presented a 48-year-old female patient with chronic tongue ulceration pain persisting for one year without any detectable systemic etiology. Despite receiving oral vitamin supplementation and local analgesic jelly, her symptoms remained unalleviated. A 3-week treatment regimen involving the administration of the Chinese herbal mouthwash in conjunction with thalidomide led to the complete resolution of her oral ulcers. The findings from this study suggest that the compound Chinese herbal mouthwash may serve as an adjuvant therapeutic approach for managing chronic oral ulcers that are resistant to conventional treatment.