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Purpose: The aims of the study were to evaluate the clinical performance and the complications of combined tooth-/implant-supported three-unit fixed partial dentures (FPDs) in the posterior mandible. Materials and Methods: A total of 78 partially edentulous patients in the posterior mandible were recruited for the study (n = 26/group). Group 1 served as the control group and received two dental implants to support a three-unit FPD. Groups 2 and 3 were the experimental groups in which one implant was placed in conjunction with support from an adjacent tooth to support a three-unit FPD. Standard implants (= 8 mm) were included in Group 2, while short implants (< 8 mm) were included in Group 3. Periapical radiographs were taken for evaluation of crestal bone loss (CBL). Modified plaque index (MPI), bleeding index (BI), and sulcus depth values of the abutment teeth were recorded at the time of FPD delivery, 6 months after FPD delivery, and annually thereafter. Recorded complications included abutment tooth intrusions, cementation failures of the restorations, porcelain chipping/delamination, framework fracture, abutment screw loosening, abutment and abutment screw fracture, and implant fracture. Results: Statistically significant differences were observed between Group 1 (0.06 ± 0.17) and Group 2 (0.18 ± 0.32) and between Group 1 and Group 3 (0.17 ± 0.30) in terms of MPI (P = .05). No difference was observed between Group 2 (0.11 ± 0.34) and Group 3 (0.14 ± 0.36) or between Group 1 (0.04 ± 0.22) and Group 2 in terms of BI. There were statistically significant differences in terms of CBL between Group 1 (0.259 ± 0.05 mm) and Group 3 (0.11 ± 0.03 mm) and between Group 2 (0.03 ± 0.03 mm) and Group 3 (P = .05). The mean abutment tooth sulcus depth was 1.11 ± 0.31 mm for Group 2 and 1.20 ± 0.46 mm for Group 3. Conclusions: Within the limitations of the current study, it was concluded that combined tooth/implant-supported prostheses (CTISPs) are a predictable treatment choice in the posterior mandible. When a CTISP is planned, it is more predictable to use a short implant than a standard-length implant. [ABSTRACT FROM AUTHOR]

Fecal microbial transplantation (FMT) offers promise for treating ulcerative colitis (UC), though the mechanisms underlying treatment failure are unknown. This study harnessed longitudinally collected colonic biopsies (n = 38) and fecal samples (n = 179) from 19 adults with mild-to-moderate UC undergoing serial FMT in which antimicrobial pre-treatment and delivery mode (capsules versus enema) were assessed for clinical response (≥ 3 points decrease from the pre-treatment Mayo score). Colonic biopsies underwent dual RNA-Seq; fecal samples underwent parallel 16S rRNA and shotgun metagenomic sequencing as well as untargeted metabolomic analyses. Pre-FMT, the colonic mucosa of non-responsive (NR) patients harbored an increased burden of bacteria, including Bacteroides, that expressed more antimicrobial resistance genes compared to responsive (R) patients. NR patients also exhibited muted mucosal expression of innate immune antimicrobial response genes. Post-FMT, NR and R fecal microbiomes and metabolomes exhibited significant divergence. NR metabolomes had elevated concentrations of immunostimulatory compounds including sphingomyelins, lysophospholipids and taurine. NR fecal microbiomes were enriched for Bacteroides fragilis and Bacteroides salyersiae strains that encoded genes capable of taurine production. These findings suggest that both effective mucosal microbial clearance and reintroduction of bacteria that reshape luminal metabolism associate with FMT success and that persistent mucosal and fecal colonization by antimicrobial-resistant Bacteroides species may contribute to FMT failure.

BACKGROUND: There is no systematic review on the prevalence of HIV drug resistance (HIVDR) in Iran. We aimed to estimate the prevalence of HIVDR among people living with HIV (PLHIV) in Iran. We assessed HIVDR prevalence in antiretroviral therapy (ART) naïve PLHIV (i.e., those without a history of ART) and PLHIV receiving ART. METHOD: We systematically searched Scopus, PubMed, Web of Science, Embase, Iranian databases (Iranian Medical Research Information System, Magiran, and Scientific Information Database), the references of studies, and Google Scholar until March 2023. A random-effects model was used to calculate a point estimate and 95% confidence interval (95% CI) for the prevalence of HIVDR in PLHIV. RESULTS: Among 461 potential publications, 22 studies were included in the meta-analysis. The pooled prevalence of acquired HIVDR in PLHIV receiving ART was 34% (95% CI: 19, 50) for nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), 27% (95% CI: 15, 41) for non-nucleoside reverse transcriptase inhibitors (NNRTIs), and 9% (95% CI: 3, 18) for protease inhibitors (PIs). The pooled prevalence of acquired HIVDR in treatment failure PLHIV was 50% (95% CI: 31, 69) for NRTIs, 49% (95% CI: 29, 69) for NNRTIs, 11% (95% CI: 2, 24) for PIs, and 1% (95% CI: 0, 4) for integrase inhibitors (INIs). The pooled prevalence of transmitted HIVDR in ART-naïve people was 3% (95% CI; 1, 6) for NRTIs, 5% (95% CI: 2, 9) for NNRTIs, and 0 for PIs and INIs. CONCLUSION: The prevalence of HIVDR was relatively high in both ART-naïve PLHIV and those receiving ART. Without universal pretreatment HIVDR testing and more frequent routine HIV viral load testing among PLHIV who are on ART, the HIVDR prevalence might increase in PLHIV in Iran.

Background: We concurrently developed a prospective study to assess clinical outcomes among patients receiving 9-month bedaquiline (BDQ)-containing regimens, aiming to provide valuable data on the use of this short-course regimen in China. Methods: This open-label, randomized, controlled, multicenter, non-inferiority trial was conducted at sixteen hospitals, and enrolled participants aged 18 years and older with pulmonary rifampicin/multidrug tuberculosis. Participants were randomly assigned, in a 1:1 ratio. Individuals within the standard-regimen group received 6 months of BDQ, linezolid, levofloxacin, clofazimine, and cycloserine plus 12 months of levofloxacin, and any three potentially effective drugs from clofazimine, cycloserine pyrazinamide, ethambutol and protionamide, whereas individuals within shorter-regimen group received 9 months of BDQ, linezolid, levofloxacin, clofazimine and cycloserine. The primary outcome was the percentage of participants with a composite unfavorable outcome (treatment failure, death, treatment discontinuation, or loss to follow-up) by the end of the treatment course after randomization in the modified intention-to-treat population. The noninferiority margin was 10%. This trial was registered with www.chictr.org.cn, ChiCTR2000029012. Results: Between Jan 1, 2020, and Dec 31, 2023, 264 were screened and randomly assigned, 132 of 264 participants were assigned to the standard-regimen group and 132 were assigned to the shorter-regimen. Thirty-three (12.55%) of 264 participants were excluded from the modified intention-to-treat analysis. As a result, 231 participants were included in the modified intention-to-treat analysis (116 in the standard-regimen group and 115 in the shorter-regimen group).In the modified intention-to-treat population, unfavorable outcomes were reported in 19 (16.5%) of 115 participants for whom the outcome was assessable in the shorter-regimen group and 26 (22.4%) of 116 participants in the standard care group (risk difference 5.9 percentage points (97.5% CI − 5.8 to 17.5)). One death was reported in the standard-regimen group. The incidence of QTcF prolongation in the shorter-regimen group (22.6%, 26/115) was similar to the standard-regimen group (24.1%, 28/116). Conclusions: The 9-month, all-oral regimen is safe and efficacious for the treatment of pulmonary rifampicin/multidrug-resistant tuberculosis. The high incidence of QTc prolongation associated with the use of BDQ highlights the urgent need of routine electrocardiogram monitoring under treatment with BDQ-containing regimens in the Chinese population. [ABSTRACT FROM AUTHOR]

The importance of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) remains crucial in managing chronic HCV infection among patients who have experienced treatment failure and relapse after prior use of direct-acting antivirals (DAAs), as evidenced by high SVR12. However, limited real-world data exists on safety and efficacy. Therefore, the study's goal was to conduct a qualitative systematic review to assess SOF/VEL/VOX's effectiveness and safety. Thorough searches spanned PubMed, Embase, and Scopus, from 2015 to August 1st, 2023. The outcomes assessed were SVR12 and treatment-related adverse events (AEs). We identified and analyzed 12 studies in which SVR12 of the per-protocol (PP) population was 96.7% and of the intention-to-treat (ITT) population was 92.6% showing excellent efficacy of SOF/VEL/VOX. SVR12 rates notably differed among patients: those without GT3 infection (94.20%) and without cirrhosis (97.60%) experienced higher rates compared to patients having GT3 infection (87.40%) and cirrhotic patients (94.20%). Treatment-related AEs were also recorded. To summarize, our study presents evidence that SOF/VEL/VOX serves as an extremely safe and efficacious therapy for HCV-infected patients, previously treated with DAAs. [ABSTRACT FROM AUTHOR]

Background: High-risk double-expressor diffuse large B-cell lymphoma has an inferior prognosis following standard first-line therapy. After failure of secondline therapy, treatment options are limited if accompanied by localized compressive symptoms. Chimeric Antigen Receptor T cell (CAR-T) therapy preceded by bridging radiotherapy may be an effective emerging therapy. Case presentation: We report a 66-year-old female patient diagnosed with stage IV double-expressor diffuse large B-cell lymphoma. The patient achieved progressive disease after two cycles of rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone and continued to develop cervical lymph node recurrence after second-line therapy. The patient was infused with CAR-T cells after receiving focal bridging radiotherapy and remained in complete response more than 9 months after treatment. In addition, the patients did not experience serious adverse reactions related to radiotherapy as well as CAR-T cell therapy. Conclusions: In this article, we describe a patient with double-expressor diffuse large B-cell lymphoma with localized compression symptoms after second-line treatment failure who benefited from CAR-T combined with focal bridging radiotherapy. [ABSTRACT FROM AUTHOR]

Background: Infected dentinal tubules are a possible source of bacteria that are responsible for the failure of root canal treatment. Therefore, disinfection of dentinal tubules by increasing the penetration of the irrigation solution is important for success in retreatment cases. This study utilized confocal laser scanning microscopy (CLSM) to assess and compare the impact of XPR, ultrasonic irrigation (UI) and sonic activation (SA) on NaOCl penetration into dentinal tubules following endodontic retreatment. Methods: A total of forty mandibular premolars were enrolled in this investigation. Following root canal preparation up to ProTaper X3 file (30/0.07), root canals were obturated with gutta-percha and bioceramic root canal sealer with single cone technique. The root canal filling materials were removed using ProTaper nickel-titanium rotary retreatment files until the working length was reached. The retreatment procedure was finalized using the ProTaper Next X4 (40/0.06). The teeth were divided into four groups based on the irrigation activation technique: control (conventional needle irrigation), SA, UI and XPR. During the final irrigation procedure, Rhodamine B dye was introduced to 5% NaOCl for visualization via CLSM. Subsequent to image acquisition, the maximum penetration, penetration percentage, and penetration area were calculated. Data were statistically analyzed using the Kruskal-Wallis, Friedman, and Bonferroni Dunn multiple comparison tests through R software (p < 0.05). Results: In the middle third, UI yielded a significantly higher penetration percentage than the control group (p < 0.05). The UI and XPR groups showed increased penetration percentages in the coronal and middle thirds compared with the apical third (P < 0.05). Maximum penetration was notably reduced in the apical third than in comparison with the coronal and middle thirds in all groups (p < 0.05). In the control, SA and XP groups, the penetration area was ranked in descending order as coronal, middle and apical (p < 0.05). Conversely, in the ultrasonic group, the penetration area was significantly lower in the apical third than in the middle and coronal thirds (p < 0.05). Conclusions: UI enhanced the penetration percentage in the middle third of the root compared with that in the control group. XPR and SA showed no significant effect on NaOCl penetration following retreatment. [ABSTRACT FROM AUTHOR]

Background: Noninvasive ventilation (NIV) is frequently employed as a treatment option for acute hypercapnic respiratory failure (AHRF) resulting from chronic obstructive pulmonary disease (COPD). Limited research has substantiated the claims made in recent studies regarding the feasibility of employing high flow nasal cannula (HFNC). Aim: Our study assessed the outcome of using HFNC versus NIV for COPD patients with AHRF. Patients and methods: Eighty COPD patients with AHRF were confined to the respiratory intensive care unit (RICU) at Ain-Shams University Hospitals from December 2021 to 2023 and subdivided into two groups (40/group), where the first group was placed on NIV while the second group was placed on HFNC. Data during their hospital stay as demographic data, vital data, arterial blood gases, device duration, treatment failure, and mortality were recorded. Results: The majority were males with mean age 63.75 ± 9.05 years along with treatment failure and complications 25%, 12.5.% in NIV versus 45%, and zero% in HFNC, respectively, with longer hospital stay in NIV 10–15 days to 7–10 days in HFNC, and with no difference in mortality rate in both groups. Conclusion: Both modalities NIV and HFNC were effective for treating COPD with AHRF. However, NIV group was significantly superior than HFNC along with apparently faster improvement in ventilatory and respiratory status especially in high CO2 level while less complications and duration of hospital stay in HFNC with no difference in mortality in both groups. [ABSTRACT FROM AUTHOR]

Background: Antiviral drugs show significant efficacy in non-severe COVID-19 cases, yet there remains a subset of moderate COVID-19 patients whose pneumonia continues to progress post a complete course of treatment. Plasma-activated water (PAW) possesses anti-SARS-CoV-2 properties. To explore the potential of PAW in improving pneumonia in COVID-19 patients following antiviral treatment failure, we conducted this study. Methods: This was a randomized, controlled trial. Moderate COVID-19 patients with antiviral treatment failure were randomly assigned to the experimental group or the control group. They inhaled nebulized PAW or saline respectively. This was done twice daily for four consecutive days. We assessed improvement in chest CT on day 5, the rate of symptom resolution within 10 days, and safety. Results: A total of 23 participants were included, with 11 receiving PAW and 12 receiving saline. The baseline characteristics of both groups were comparable. The experimental group showed a higher improvement rate in chest CT on day 5 (81.8% vs. 33.3%, p = 0.036). The cumulative disappearance rate of cough within 10 days was higher in the experimental group. Within 28 days, 4 patients in each group progressed to severe illness, and no patients died. No adverse reactions were reported from inhaling nebulized PAW. Conclusion: This pilot trial preliminarily confirmed that nebulized inhalation of PAW can alleviate pneumonia in moderate COVID-19 patients with antiviral treatment failure, with no adverse reactions observed. This still needs to be verified by large-scale studies. Trial registration: Chinese Clinical Trial Registry; No.: ChiCTR2300078706 (retrospectively registered, 12/15/2023); URL: www.chictr.org.cn. [ABSTRACT FROM AUTHOR]

To date, despite extensive research, the prognosis of advanced osteosarcoma has not improved significantly. Thus, patients experience a reduced survival rate, suggesting that a reevaluation of current treatment strategies is required. Recently, in addition to routine surgery, chemotherapy and radiotherapy, researchers have explored more effective and safer treatments, including targeted therapy, immunotherapy, anti-angiogenesis therapy, metabolic targets therapy, and nanomedicine therapy. The tumorigenesis and development of osteosarcoma is closely related to angiogenesis. Thus, anti-angiogenesis therapy is crucial to treat osteosarcoma; however, recent clinical trials found that it has insufficient efficacy. To solve this problem, the causes of treatment failure and improve treatment strategies should be investigated. This review focuses on summarizing the pathophysiological mechanisms of angiogenesis in osteosarcoma and recent advances in anti-angiogenesis treatment of osteosarcoma. We also discuss some clinical studies, with the aim of providing new ideas to improve treatment strategies for osteosarcoma and the prognosis of patients. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML), characterized by the presence of the BCR::ABL1 fusion gene, has undergone a transformative shift with the introduction of tyrosine kinase inhibitors (TKIs). The current availability of six different TKIs (imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and asciminib) in clinical practicemakes it important to know their efficacy and toxicity profile for treatment optimization. This review examines the latest insights regarding the use of bosutinib in CML treatment. Clinical trials have demonstrated the effectiveness of bosutinib, positioning it as a first-line treatment that can induce sustained molecular responses. Importantly, it can also be effective in patients who have experienced treatment failure or intolerance with prior TKIs, revealing the potential of bosutinib also in secondand later-line settings. Even in the advanced phase of CML, bosutinib has demonstrated its capacity to achieve molecular responses, expanding its usefulness. Real-world evidence studies echo these findings, emphasizing bosutinib's effectiveness in achieving deep molecular responses, maintaining remissions, and serving as an alternative for patients intolerant or resistant to other TKIs as a second-line therapy. Notably, one of the greatest strengths of bosutinib is its favorable safety profile, in particular the low incidence of vascular complications with its use, which is undoubtedly a comparative advantage over other TKIs. In summary, the latest research highlights the versatility of bosutinib in CML treatment and underscores its pivotal role in optimizing patient management in challenging cases. Continuing research and investigation will further establish bosutinib's place in the evolving landscape of CML therapy, offering an alternative for CML patients across different treatment stages. [ABSTRACT FROM AUTHOR]

Background: UKA is a well-established treatment option for anteromedial osteoarthritis of the knee, resulting in superior functional outcomes but also higher revision rates than TKA. This study aimed to compare the outcomes of UKA, TKA, UKA converted to TKA using identical standard implants and revised TKA to support clinical decision-making. Methods: In this study, we retrospectively examined 116 patients who underwent UKA, 77 patients who received TKA, 28 patients whose UKA was converted to TKA using identical standard implants, and 21 patients who had a one-stage revision of TKA. The mean age at operation was 66.5 years (39–90 years), with a mean BMI of 28.8 kg/m2 (17.4–58.8) and a mean follow-up period of four years (0.9–9.9 years). We assessed various PROMs, including Oxford Knee Score, UCLA score, KSS score, and a modified WOMAC-Score as well as patient satisfaction and ability to resume daily activities, work, and sports. Results: The highest patient satisfaction was seen in the UKA. All scores were significantly higher for UKA than for TKA, converted UKA, and revised TKA. None of the scores showed a significant inferiority of converted UKA to TKA. In the case of revision, two scores showed significantly better results for converted UKA than for revised TKA. Conclusions: Our results indicated that patients initially treated with UKA did not have significantly worse functional outcomes after conversion to TKA, given the use of identical standard implants. This highlights the effectiveness of UKA as a therapeutic option with outcomes superior to those of primary TKA and the importance of a bone-sparing procedure. Conversely, revision TKA is linked to poorer functional outcomes compared to both primary arthroplasties. [ABSTRACT FROM AUTHOR]

Background: In Nigeria, since 2002, Imatinib mesylate (glivec®) has been available freely to chronic myeloid leukaemia (CML) patients but only at a tertiary health care centre in the southwestern part of the country. Despite this, it is not readily accessible to many patients due to the distance and other challenges including low socioeconomic status and political problems, preventing timely access to specialist care. This study evaluated the effect of the baseline characteristics on the prognostic implication and treatment outcome of CML patients in Nigeria. Method: This study retrospectively evaluated the baseline characteristics, clinical presentations and treatment outcomes of 889 CML patients over 18 years (2002–2020). Of these, 576 (65%) patients had complete information with up-to-date BCR::ABL1 records. These 576 patients were categorized based on their responses to Imatinib therapy into three groups viz.; Optimal response (OR) defined as BCR::ABL1 ratio of < 0.1% or major molecular remission (≥ 3-log reduction of BCR::ABL1 mRNA or BCR::ABL1 ratio of < 0.1% on the International Scale), Suboptimal response (SR) with BCR::ABL ratio of 0.1–1%, and Treatment failure (TF) when MMR has not been achieved at 12 months. The variables were analyzed using descriptive and inferential statistics and a p-value < 0.05 was considered statistically significant. Results: The result revealed a median age of 37 years at diagnosis with a male-to-female ratio of 1.5:1. The majority (96.8%) of the patients presented with one or more symptoms at diagnosis with a mean symptom duration of 12 ± 10.6 months. The mean Sokal and EUTOS scores were 1.3 ± 0.8 and 73.90 ± 49.09 respectively. About half of the patients presented with high-risk Sokal (49%) and EUTOS (47%) scores. Interestingly, both the Sokal (r = 0.733, p = 0.011) and EUTOS (r = 0.102, p = 0.003) scores correlated positively and significantly with the duration of symptoms at presentation. Based on response categorization, 40.3% had OR while 27.1% and 32.6% had SR and TF respectively. Conclusion: This study observed a low optimal response rate of 40.3% and treatment failure rate of 32.6% in our CML cohort while on first-line Imatinib therapy. This treatment response is strongly attributable to the long duration of symptoms of 12 months or more and high Sokal and EUTOS scores at presentation. We advocate prompt and improved access to specialist care with optimization of tyrosine kinase inhibitor therapy in Nigeria. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to validate the main therapies used in the treatment of heart failure through a clinical consensus conducted by cardiology experts in Colombia. Methods: The Delphi technique was employed, which involves a series of consultation rounds with experts to reach a consensus. Cardiologists with experience in HF treatment were selected, and they were sent electronic questionnaires to assess the relevance of various therapeutic interventions. Consensus was defined when at least 70% of the experts agreed on the relevance of an intervention. Results: Fourteen cardiology experts participated in the study. In the first round, nine therapeutic interventions were evaluated, but insufficient agreement was reached to form a consensus. A second round was conducted, where feedback was provided to the experts, and they were asked to rate the relevance of the interventions using a Likert scale. Consensus was achieved for eight of the evaluated therapeutic interventions. The focus of the third round was on the interventions that had not reached consensus in the previous rounds. Conclusions: This study provides clinical consensus on therapeutic interventions for HF in Colombia. Nine therapeutic interventions were identified as relevant by the experts. These findings can help improve HF treatment and optimize clinical outcomes in Colombia. It is important to note that this study was conducted with local experts, and the results may not be generalizable to other populations. [ABSTRACT FROM AUTHOR]

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Background: Tubal sterilization is the most commonly used method of contraception in the United States. Because contraceptive effectiveness influences contraceptive selection, we examined typical use failure rates after tubal sterilization in the United States. Methods: We estimated rates of pregnancy after tubal sterilization using data from four waves of the National Survey of Family Growth (NSFG), representative samples of U.S. women aged 15 to 44 years, collected in 2002, 2006 to 2010, 2011 to 2013, and 2013 to 2015. Survey weighting was used in survival analysis to examine time to first pregnancy after tubal sterilization. Data from these participants were censored after a tubal reversal procedure, infertility treatment, hysterectomy, or bilateral oophorectomy. Reported pregnancy rates after tubal sterilization procedures were examined by using Kaplan-Meier curves and then multivariable Cox proportional-hazards models to examine the effects of age at tubal sterilization, race/ethnicity, education, Medicaid funding, and postpartum versus interval procedures. Results: Pregnancy after tubal sterilization was reported by 2.9 to 5.2% of participants across NSFG waves. In the most recent survey wave (2013 to 2015), the estimated percentage of participants with pregnancies within the first 12 months after a tubal sterilization procedure was 2.9%; at 120 months after tubal sterilization, the estimated percentage with a pregnancy was 8.4%. At all the time points examined, pregnancy after tubal sterilization was less common after postpartum procedures than after interval procedures; however, this difference was not evident in multivariable models. In multivariable models, chance of pregnancy decreased with age at time of tubal sterilization. Race/ethnicity, education, and Medicaid funding were not consistently associated with pregnancy after tubal sterilization. Conclusions: These data suggest that there may be nontrivial rates of pregnancy after tubal sterilization. [ABSTRACT FROM AUTHOR]

In total shoulder arthroplasty, the subscapularis tendon is routinely mobilized, by tenotomy, peel, or lesser tuberosity osteotomy, to visualize the joint and allow proper implant positioning. Careful mobilization of the subscapularis is undertaken to achieve an anatomic tension-free repair. This cadaveric study tests the biomechanical differences of 2 repair techniques of the subscapularis peel (SP) compared to the classically described technique. We hypothesize that adaptation of this SP technique using a custom-designed polyether-ether-ketone (PEEK) barrel in the bicipital groove may further stabilize suture repair of the subscapularis. Twenty paired cadaveric shoulder specimens underwent SP and repair via transosseous suture fixation. The PEEK barrel used was a laboratory prototype designed for the study (Catalyst OrthoScience, Naples, FL, USA). Five specimens were repaired using a traditional Mason-Allen suture; their paired shoulders were repaired using the PEEK barrel and a Mason-Allen suture. Five specimens were repaired using the Krackow suture; their paired shoulders were repaired using the PEEK barrel and a Krackow suture. Mechanical testing was performed using a uni-axial materials testing system with primary outcome of gap displacement and secondary outcomes of maximum load to failure and method of failure. The Krackow repair method with and without PEEK augmentation was significantly stiffer than the Mason-Allen repair method with and without PEEK augmentation (P <.001 across all groups). Adding augmentation changed the strength of the Mason-Allen repair without achieving statistical significance (P =.0925). Intergroup differences in cyclic displacement were not statistically significant. The Krackow repair methods had higher mean maximal load at failure than the Mason-Allen repairs of 534 ± 108 N and 266 ± 98 N, respectively (P <.001). Maximum load at 5 mm displacement was significantly different across groups (P =.004). Methods of failure in the Mason-Allen technique groups included knot and tendon failure, and in the Krackow technique groups included suture failure and lesser tuberosity fracture. Repairing the subscapularis with a Krackow suture is significantly stronger than a Mason-Allen repair in stiffness as well as load to failure. The results reported here compare a Krackow suture with a more common Mason-Allen suture configuration, and demonstrate the application of PEEK augmentation to subscapularis repair techniques. This study can guide surgeon selection of an ideal subscapularis repair technique for stemmed or stemless total shoulder arthroplasty. [ABSTRACT FROM AUTHOR]

Race/ethnicity and individual-level socioeconomic status (SES) may contribute to health disparities in liver transplant (LT) outcomes. The socioeconomic conditions of a neighborhood may either mitigate or exacerbate these health disparities. This retrospective study investigated the relationship between race/ethnicity, individual- and neighborhood-level SES, and LT outcomes, and whether neighborhood-level SES modified the relationship between individual factors and LT outcomes. Adult individuals who underwent LT between 2010 and 2019 (n = 55,688) were identified from the United Network for Organ Sharing database. Primary exposures were race/ethnicity, education, primary insurance type, and the Social Deprivation Index (SDI) scores. Education and primary insurance type were used as proxies for individual-level SES, while SDI scores were used as a proxy for neighborhood-level SES. The primary outcome was time to occurrence of graft failure or mortality. Cox proportional hazard models were used to examine the associations between the exposures and outcomes. LT recipients who were Black (hazard ratio [HR]: 1.27, p <.0001), completed high school or less (HR: 1.06, p =.002), and had public insurance (HR: 1.14, p <.0001) had a higher rate of graft failure or mortality than those who were White, completed more than high school, and had private insurance, respectively. The SDI scores were not significantly associated with LT outcomes when adjusting for individual factors (HR: 1.02, p =.45) and did not modify the associations between individual factors and LT outcomes. Findings of this study suggest that disparities based on individual factors were not modified by neighborhood-level SES. Tailored interventions targeting the unique needs associated with race/ethnicity and individual-level SES are needed to optimize LT outcomes. [ABSTRACT FROM AUTHOR]

Esophageal cancer is a poor prognosis cancer characterized by intrinsic or acquired resistance to chemotherapeutic agents. The primary determinants of treatment failure are unknown. Expression of an anti‐viral protein, myxovirus resistance protein A (MxA) is de‐regulated in many cancers, including esophageal cancer, and its activity has been linked to apoptosis. This study has assessed whether MxA expression can influence the response of esophageal cancer cells to the chemotherapeutic agents 5‐fluorouracil (5‐FU) or oxaliplatin. MxA protein was differentially expressed in a panel of five esophageal cancer cell lines. KYSE450 and KYSE140 cells did not express MxA and were apoptosis incompetent. FLO‐1, KYSE270, and OE21 cells expressed MxA, were more drug‐sensitive and were apoptosis competent. MxA was artificially overexpressed in cell lines with no endogenous expression (KYSE450 and KYSE140). This increased the resistance of KYSE450 but not KYSE140 cells. Both cell lines remained apoptosis incompetent. We then evaluated siRNA knockdown of MxA in FLO‐1 cells and CRISPR knockout in OE21 cells. Knockdown of MxA significantly increased drug sensitivity and caspase‐3 activation in FLO‐1 cells. OE21‐MX1KO cells were also more drug‐sensitive, but in contrast to FLO‐1 cells, caspase‐3 activation was reduced. Collectively these data indicate that MxA can promote resistance to chemotherapy, but this does not always correspond with effects on apoptosis. Effects on apoptosis are cell line specific, suggesting that other co‐operating pathways determine the overall impact of MxA. Importantly, in cancer cells that overexpress the protein, drug sensitivity can be improved by interfering with MxA. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is the most common brain tumour, with a poor prognosis of about 15 months despite intensive treatment. Many trials have tested new drugs targeting specific genes, but none have succeeded, and treatments have not changed since 2005. This review explores why clinical trials with these drugs failed. It highlights the potential of combining different drugs to overcome resistance and suggests ways to improve future trials. The goal is to understand treatment failures and find new drug combinations to improve survival for GBM patients. Glioblastoma (GBM) is the most prevalent central nervous system tumour (CNS). Patients with GBM have a dismal prognosis of 15 months, despite an intensive treatment schedule consisting of surgery, chemoradiation and concurrent chemotherapy. In the last decades, many trials have been performed investigating small molecule inhibitors, which target specific genes involved in tumorigenesis. So far, these trials have been unsuccessful, and standard of care for GBM patients has remained the same since 2005. This review gives an overview of trials investigating small molecule inhibitors on their own, combined with chemotherapy or other small molecule inhibitors. We discuss possible resistance mechanisms in GBM, focussing on intra- and intertumoral heterogeneity, bypass mechanisms and the influence of the tumour microenvironment. Moreover, we emphasise how combining inhibitors can help overcome these resistance mechanisms. We also address strategies for improving trial outcomes through modifications to their design. In summary, this review aims to elucidate different resistance mechanisms against small molecule inhibitors, highlighting their significance in the search for novel therapeutic combinations to improve the overall survival of GBM patients. [ABSTRACT FROM AUTHOR]

Background/Objectives: Vericiguat has been shown to reduce cardiovascular mortality and hospitalisation for heart failure in patients with reduced ejection fraction. While Vericiguat is considered one of the standard treatments for heart failure, it is unclear under which conditions Vericiguat would be most effective. With a focus on the prognosis and improved EF of heart failure, we aimed to investigate in which cases Vericiguat is suitable for use in addition to standard cardioprotective drugs. Methods: We prospectively compared echocardiograms taken before and after the administration of Vericiguat in 46 patients with non-dialysis and without heart failure with preserved ejection fraction (non-HFpEF) (left ventricle ejection fraction [LVEF] < 50%) who were able to continue Vericiguat in addition to other standard heart failure drugs (the "Fantastic Four") for more than 6 months at our hospital. Patients who showed an improvement of 10 points or more in LVEF were defined as improved EF+. Results: LVEF improved significantly from 38 [33–45]% at the time of administration to 46 [35–54.5]% at 6 months (p < 0.001). When comparing patients with and without improved EF, a significant difference was observed in the Hb (OR = 1.66, 95%CI = 1.12–2.83, p = 0.028), early introduction (OR = 12.5, 95%CI = 1.58–149, p = 0.025), and initiation of Vericiguat after the administration of the Fantastic Four (OR = 9.79, 95%CI = 1.71–100.2, p = 0.022). Conclusions: In this study, the early administration of Vericiguat, haemoglobin value, and initiation of Vericiguat after the introduction of the Fantastic Four were identified as independent factors for eligibility in non-dialysis, non-HFpEF patients who were able to continue GDMT treatment for more than 6 months after adding Vericiguat. [ABSTRACT FROM AUTHOR]

Objectives This study contributes to the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)'s effort to define 'difficult-to-treat' PsA (D2T-PsA), leveraging insights of healthcare professionals who are GRAPPA members. The primary objective is to inform GRAPPA's D2T PsA project, ensuring the consensus definition reflects clinical experience and expertise. Methods An online survey was conducted among GRAPPA's healthcare professionals managing PsA patients. The survey covered demographic details, structured questions, and open-ended queries to gather comprehensive insights into the experts' viewpoints. Results About 223 physicians completed the survey, comprising 179 (80.2%) rheumatologists and 40 (17.9%) dermatologists. The majority, 184 (82.5%), favoured establishing distinct definitions for D2T-PsA and complex-to-manage PsA (C2M-PsA). Furthermore, 202 (90.5%) supported a definition that includes objective inflammation signs (clinical, laboratory, imaging, among others). However, opinions varied on the criteria for prior treatment failures, with most (93, 41.7%) favouring a definition that includes at least one conventional synthetic disease-modifying anti-rheumatic drug and two or more biological- or targeted-synthetic-DMARDs with different mechanisms of action. Conclusion The survey reveals a majority opinion among GRAPPA experts favouring the differentiation between D2T-PsA and C2M-PsA, and the inclusion of objective inflammatory markers in these definitions. However, there is less than 50% agreement on the specific treatment failure criteria, particularly regarding the number of therapies needed to classify PsA as D2T. These findings suggest a need for continued discussion to reach a more unified approach in defining D2T-PsA, reflecting the complexity of the condition. [ABSTRACT FROM AUTHOR]

Methicillin resistant Staphylococcus aureus (MRSA) is a known human pathogen capable of causing community and hospital acquired infections worldwide. Treatment options available for MRSA infections are limited, with vancomycin being one of the most common drugs used. It is described in the literature that vancomycin can be ineffective against MRSA isolates with MIC values between 1-2 mg/litre. This slow and steady shift of vancomycin MIC values towards higher side over a period of time is known as "MIC creep". The present retrospective study was carried out over five year period from January 2019 to June 2023. Staphylococcus aureus isolates from all clinical samples isolated during study period were included in the study. MIC50, MIC90, geometric mean MIC values were determined and analysed using Microsoft Excel. In the present study, the prevalence of MRSA was high (79.6%) in pus and tissue samples followed by blood sample (9.7%). Most of the MRSA isolates (55.80%) in present study exhibited vancomycin MIC of 1 µg/ml, there is no increasing trend of MIC values over a five year period. MIC creep is a slow and steady process which is multifactorial in origin. Regular monitoring of vancomycin MIC trend is advisable as vancomycin is the first-line treatment for culture proven severe infection with MRSA. [ABSTRACT FROM AUTHOR]

Objectives To investigate the predictive factors for difficult-to-treat rheumatoid arthritis (D2T RA) and assess the efficacy of biologic DMARDs (bDMARDs) and Janus kinase inhibitors (JAKi). Methods Retrospective analysis was conducted on data from the ANSWER cohort comprising 3623 RA patients treated with bDMARDs or JAKi in Japan. Multivariate Cox proportional hazards modelling was used to analyse the hazard ratios (HRs) for treatment retention. Results Of the 3623 RA patients, 450 (12.4%) met the first two criteria of the EULAR D2T RA definition (defined as D2T RA in this study). Factors contributing to D2T RA included age over 75 (compared with those under 65, hazard ratio [HR] = 0.46; 95% CI: 0.31, 0.69), higher rheumatoid factor (RF) titres (HR = 1.005; 95% CI: 1.00, 1.01), higher clinical disease activity index (HR = 1.02; 95% CI: 1.01, 1.03), lower methotrexate dosage (HR = 0.97; 95% CI: 0.95, 0.99), and comorbidities like hypertension (HR = 1.53; 95% CI: 1.2, 1.95) and diabetes (HR = 1.37; 95% CI: 1.09, 1.73). Anti-IL-6 receptor antibodies (aIL-6R, HR = 0.53; 95% CI: 0.37, 0.75) and JAKi (HR = 0.64; 95% CI: 0.46, 0.90) were associated with fewer discontinuations due to ineffectiveness compared with TNF inhibitors. Oral glucocorticoid usage (HR = 1.65; 95% CI: 1.11, 2.47) was linked to increased discontinuation due to toxic adverse events. Conclusion Younger onset, higher RF titres, and comorbidities predicted D2T RA development. For managing D2T RA, aIL-6R and JAKi exhibited superior drug retention. [ABSTRACT FROM AUTHOR]

Background: Daratumumab's incorporation in the upfront treatment of light chain (AL) amyloidosis has led to daratumumab (dara) refractoriness early in disease course. Patients who experience relapse or have suboptimal response to dara-based-therapy, have limited options. Objective: This study aimed to evaluate the outcomes of venetoclax-based therapy in t(11;14) positive AL patients who previously failed dara. Methods: Thirty-one patients with AL were included in this bi-institutional retrospective analysis. Results: Dara failure was due to inadequate response in 20 (65%) patients, haematologic relapse in 7 (22%), and both haematologic plus organ relapse in 4 (13%). Overall haematologic response rate to venetoclax-based therapy was 97%, with ≥ VGPR being 91%. Of the 19 evaluable patients with cardiac involvement, 14 (74%) achieved organ response. Of the 13 evaluable patients with renal involvement, 6 (46%) achieved organ response. With a median follow-up of 22 months, median time-to-next-treatment (TTNT) and overall survival (OS) were not reached. The 12- and 24-month TTNT rates were 74% and 56%, respectively. At data-cut-off, four patients had died, all from AL-related organ complications. The 12- and 24-month OS rates were 89% and 85%, respectively. Grade ≥3 adverse events occurred in 26% of patients, with 6% due to infections. Conclusion: These findings are encouraging for the use of venetoclax as salvage therapy post-dara failure. [ABSTRACT FROM AUTHOR]

Background and Aims: Few studies have focused on the outcomes of Wilson's disease (WD) diagnosed before age of 5 years. This study aimed to summarize the clinical features of early diagnosed WD and analyse treatment outcomes and the risk factors associated with treatment failure. Methods: A total of 139 children confirmed with WD before 5 years were enrolled in this study. Only patients with follow‐up over 1 year were analysed with Kaplan–Meier survival analysis. The composite outcomes included death, progression to liver failure or acute hepatitis, development of renal or neurological symptoms and persistent elevation of alanine aminotransferase (ALT). The treatment failure was defined as occurrence of at least one of above outcomes. Results: Among 139 WD patients at diagnosis, two (1.4%) WD patients presented with symptomatic liver disease, whereas 137 (98.6%) were phenotypically asymptomatic, including 135 with elevated ALT and 2 with normal liver function. Median serum ceruloplasmin (Cp) was 3.1 mg/dL, and urinary copper excretion was 87.4 μg/24‐h. There were 71 variants identified in the the copper‐transporting ATPase beta gene, and 29 were loss of function (LOF). 51 patients with LOF variant were younger at diagnosis and had lower Cp than 88 patients without LOF. Among 93 patients with over 1 year of follow‐up, 19 (20.4%) received zinc monotherapy, and 74 (79.6%) received a zinc/D‐penicillamine combination therapy. 14 (15.1%) patients underwent treatment failure, and its occurrence was associated with poor compliance (p <.01). Conclusions: Cp is a reliable biomarker for early diagnosis, and zinc monotherapy is an effective treatment for WD during early childhood. Good treatment compliance is critical to achieve a favourable outcome. [ABSTRACT FROM AUTHOR]

Background With the increasing prevalence of antibiotic resistance, real-world data on the optimal empirical second-line therapy for Helicobacter pylori are still limited. Objectives To evaluate the real-world efficacy of various second-line therapies for H. pylori. Patients and methods This was a retrospective population-based cohort study of all H. pylori -infected patients who had received the second-line treatment after the failure of primary clarithromycin triple therapy in Hong Kong between 2003 and 2018. The retreatment success rates of different second-line therapies were evaluated. Results A total of 7591 patients who received second-line treatment were included. Notably, the most commonly prescribed regimen was still clarithromycin triple therapy, but the frequency of use had decreased from 59.5% in 2003–06 to 28.7% in 2015–18. Concomitant non-bismuth quadruple therapy had emerged as the commonest regimen (from 3.3% to 43.9%). In a validation analysis, the sensitivity and specificity of retreatment-inferred second-line treatment failure were 88.3% and 97.1%, respectively. The overall success rate of second-line therapies was 73.6%. Bismuth quadruple therapy had the highest success rate of 85.6%, while clarithromycin triple therapy had the lowest success rate of 63.5%. Specifically, bismuth/metronidazole/tetracycline quadruple, metronidazole/tetracycline triple, levofloxacin/metronidazole/tetracycline quadruple, rifabutin/amoxicillin triple and amoxicillin/levofloxacin triple therapies had relatively higher success rates over 80%. Age, treatment duration, baseline conditions and first-line treatment used were associated with success rate. Conclusions Bismuth quadruple therapy was the most effective second-line regimen for H. pylori in this real-world study. Despite a very low success rate, clarithromycin-containing triple therapies were still commonly used as second-line regimens. [ABSTRACT FROM AUTHOR]

This clinical report describes the implementation of magnetic resonance imaging (MRI) to evaluate a patient with long-standing velopharyngeal dysfunction. She was referred to the craniofacial clinic at age 10 with no prior surgical history and subsequently completed a Furlow palatoplasty due to a suspected submucous cleft palate. However, results were unfavorable with minimal improvement in speech or resonance. The clinical presentation, treatment, outcomes, and contributions from MRI for secondary surgical planning are described. Addition of MRI into the clinical workflow provided insights into the anatomy and physiology of the velopharyngeal mechanism that were unable to be obtained from nasendoscopy and speech evaluation alone. [ABSTRACT FROM AUTHOR]

Background: Per oral endoscopic myotomy (POEM) is a safe therapy for the treatment of achalasia. Long-term effects of untreated achalasia include worsening dysmotility and disruptions in esophageal anatomy, i.e., tortuosity and dilation. We hypothesize that long-standing achalasia prior to intervention will have worse outcomes following POEM than in patients with symptoms for shorter duration. Methods: We retrospectively analyzed achalasia patients who underwent POEM at our institution from 2011 to 2023, categorizing them into symptom duration cohorts (< 1 year, 1–3 years, 4–10 years, > 10 years). Inclusion criteria comprised patients with documented achalasia diagnosis who received POEM treatment at our facility. Exclusion criteria encompassed individuals lacking data pertaining to achalasia diagnosis, the time frame before intervention, or those missing pre and postoperative Eckardt scores. POEM failure was defined as symptom recurrence, necessity for repeat intervention, or high postoperative Eckardt score. We compared demographic, preoperative, and postoperative outcomes across these cohorts, and employed multivariable logistic regression to explore the link between symptom duration and POEM response. Results: During the study period, in our increased cohort 234 patients met inclusion criteria. 75 patients had symptoms for < 1 year, 78 patients had symptoms from 1 to 3 years, 47 patients had symptoms from 4 to 10 years, and 34 patients had symptoms > 10 years. Patient demographics such as age, sex, BMI, Charleson-Deyo-Comorbidity-Index, and diabetes did not differ amongst cohorts. High-resolution manometry data, including achalasia type, Median IRP, LES residual pressure, and Basal LES pressure did not differ between groups. Preoperative Eckardt scores ranged from 4 to 5 across groups (p 0.24). Patients endorsed an average of three total preoperative symptoms across groups (p 0.13). Patients with symptoms greater than 4 years had significantly more endoscopic interventions prior to POEM (37% vs, 68% p.001). There was no significant difference in post-procedure mean Eckardt scores between cohorts. All cohorts experienced the same number of post-POEM symptoms. Post-POEM manometric measurements remained consistent across cohorts. Similarly, there were no significant differences in terms of symptom recurrence, requirement for repeat interventions, or repeat POEM among the cohorts. Multivariable logistic regression analysis determined achalasia symptoms greater than a decade did not result in increased odds of having a higher postoperative Eckardt score, worse dysphagia, regurgitation, or weight loss. Conclusions: In this increased cohort, this data once again suggests that longer symptom duration is not associated with increased rates of POEM failure. [ABSTRACT FROM AUTHOR]

Objective: While sleeve gastrectomy (SG) results in sustained weight loss for the majority of patients, some will experience inadequate weight loss or weight regain requiring revision. The objective of this study was to evaluate differences in weight loss over time between patients undergoing Roux-en-Y gastric bypass (RYGB) or single anastomosis duodenoileostomy (SADI) after SG. Methods: We queried a single institution's bariatrics registry to identify patients who underwent RYGB or SADI after previous SG over a three-year period. Demographics, operative characteristics, and post-operative complications were evaluated. Interval total body weight loss (TBWL) and excess body weight loss (EBWL) were calculated from available follow-ups within 2 years. Results: We identified 124 patients who underwent conversion to RYGB (n = 61) or SADI (n = 63) following previous SG. There were no differences in sex, age, or medical comorbidities between groups. The median initial BMI was higher in the SADI group (44.9 vs. 41.9 for RYGB, p = 0.03) with greater excess body weight (56.7 vs. 64.3 kg, p = 0.04). The SADI group had a shorter median operative duration (157 vs. 182 min for RYGB, p < 0.01) and lower readmission rates (0 vs. 14.75%, p < 0.01). There was no difference in post-operative complications or need for rehydration therapy between the groups. Among 122 patients (98.4%) that had follow-up weights available, there were no differences in TBWL between groups. RYGB patients had a higher EBWL at 2, 3, and 6 months (p < 0.05 for all comparisons), but there were no differences between RYGB and SADI at 1 or 2 years. Conclusions: Both RYGB and SADI conversions proved effective for further weight loss following failed SG at our academic center. While neither demonstrated clear superiority in long-term (> 1 year) weight loss, RYGB's restrictive gastric pouch may explain its early weight loss advantage. [ABSTRACT FROM AUTHOR]

Background: Intraoperative laparoscopic ultrasonography (LUS) or intraoperative cholangiography (IOC) can be used for visualisation of the biliary tract during laparoscopic cholecystectomy. The aim of this systematic review was to compare use of LUS with IOC. Methods: PubMed, Embase, the Cochrane Library, and Web of Science were searched (last update: April 2024). PICO: P = patients undergoing intraoperative imaging of the biliary tree during laparoscopic cholecystectomy for gallstone disease; I = intervention: LUS; C = comparison: IOC; O = outcomes: mortality, bile duct injury, retained gallstone, conversion to open cholecystectomy, procedural failure, operation time including imaging time. Included articles were critically appraised using checklists. Conclusions were based on studies without major risk of bias. Meta-analyses were performed using random effects models. Certainty of evidence was assessed according to GRADE. Results: Sixteen non-randomised studies met the PICO. Two before/after studies (594 versus 807 patients) contributed to conclusions regarding mortality (no events; very low certainty evidence), bile duct injury (1 versus 0 events; very low certainty evidence), retained gallstone (2 versus 2 events; very low certainty evidence), and conversion to open cholecystectomy (6 versus 21 events; risk ratio: 0.38 (95% confidence interval: 0.15–0.95); I2 = 0%; low certainty evidence). Seven additional studies, using intra-individual comparisons, contributed to conclusions regarding procedural failure; risk ratio: 1.12 (95% confidence interval: 0.70–1.78; I2 = 83%; very low certainty evidence). No studies reported operation time. Mean imaging time for LUS and IOC, reported in 12 studies, was 4.8‒10.2 versus 10.9‒17.9 min (mean difference: − 7.8 min (95% confidence interval: − 9.3 to − 6.3); I2 = 95%; moderate certainty evidence). Conclusion: It is uncertain whether there is any difference in mortality/bile duct injury/retained gallstone using LUS compared with IOC, but LUS may be associated with fewer conversions to open cholecystectomy and is probably associated with shorter imaging time. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to determine the short- and medium-term outcomes of hip dislocation in infants who failed Pavlik harness therapy and were subsequently treated with brace, closed reduction (CR) or open reduction (OR) before 6 months of age. Methods: Fifty infants (66 hip dislocations) who failed Pavlik harness therapy between 2000 and 2018 and were treated with a rigid abduction brace or undergoing a CR or OR/cast were evaluated. All demographic data obtained from the medical system, developments and complications during the follow-up and treatment process were recorded and evaluated. Results: Fifty infants (66 hips) with dislocated hips failed Pavlik harness therapy. Of these, 9 infants (12 hips) underwent rigid abduction splint therapy: 9 hips were successful, 2 hips had CR and 1 had OR. Thirty-eight infants (51 hips) had index CR, of which 3 (3 hips) failed and had OR. Radiographs of 49 hips (44 patients) were normal at the final evaluation. Pavlik harness therapy starting after 3 weeks (P = 0.028) and unilateral dislocations (P = 0.028) increased the risk of needing operating room. There was an association between OR and avascular necrosis (P = 0.025), but not between OR and other complications—dysplasia and re-dislocation/subluxation (P = 0.257 and P = 0.508, respectively). Conclusion: Closed treatment of hip dislocation is possible in most babies who fail Pavlik treatment. Babies who are started on Pavlik therapy after 3 weeks of age may be at increased risk of needing an operating room. Level of Evidence: IV. [ABSTRACT FROM AUTHOR]

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Background: Local anesthesia (LA) during routine dental treatment in children fails in 5%–35% of first attempts. No data, however, are available on the success rates of subsequent attempts. Aim: To evaluate the effectiveness of primary, secondary, and tertiary LA attempts (P‐LA, S‐LA, and T‐LA, respectively) for anesthetizing molars during routine dental treatments in children. Design: We retrospectively analyzed dental records of all children (2–18 years) who had been administered LA for the treatment of primary or permanent molars by a single paediatric dentist, between 2011 and 2022. All LAs were delivered using a computer‐controlled local anesthetic delivery (CCLAD) system. Results: The failure rate of P‐LA in 1312 molars was 13% and correlated with age (p <.001), type of tooth (p <.001), type of treatment (p <.001), and treated arch (p <.001). The effectiveness of S‐LA for buccal infiltration, intrasulcular, inferior alveolar nerve block, greater palatine nerve block (GPNB), posterior superior alveolar nerve block (PSANB), or a combination of the last two was 50%, 87.2%, 66.7%, 63.6%, 33.3%, and 100%, respectively, and was not significantly associated with age or the type of tooth, treatment, or P‐LA. Conclusion: The optimal choice of S‐LA for anesthetizing maxillary molars was a combination of PSANB and GPNB, whereas for mandibular molars, it was IS‐CCLAD system. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We aimed to identify metabolites associated with loss of glycemic control in youth-onset type 2 diabetes. RESEARCH DESIGN AND METHODS: We measured 480 metabolites in fasting plasma samples from the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study. Participants (N = 393; age 10–17 years) were randomly assigned to metformin, metformin plus rosiglitazone, or metformin plus lifestyle intervention. Additional metabolomic measurements after 36 months were obtained in 304 participants. Cox models were used to assess baseline metabolites, interaction of metabolites and treatment group, and change in metabolites (0–36 months), with loss of glycemic control adjusted for age, sex, race, treatment group, and BMI. Metabolite prediction models of glycemic failure were generated using elastic net regression and compared with clinical risk factors. RESULTS: Loss of glycemic control (HbA1c ≥8% or insulin therapy) occurred in 179 of 393 participants (mean 12.4 months). Baseline levels of 33 metabolites were associated with loss of glycemic control (q < 0.05). Associations of hexose and xanthurenic acid with treatment failure differed by treatment randomization; youths with higher baseline levels of these two compounds had a lower risk of treatment failure with metformin alone. For three metabolites, changes from 0 to 36 months were associated with loss of glycemic control (q < 0.05). Changes in d-gluconic acid and 1,5-AG/1-deoxyglucose, but not baseline levels of measured metabolites, predicted treatment failure better than changes in HbA1c or measures of β-cell function. CONCLUSIONS: Metabolomics provides insight into circulating small molecules associated with loss of glycemic control and may highlight metabolic pathways contributing to treatment failure in youth-onset diabetes. [ABSTRACT FROM AUTHOR]

Patients with the target gene mutation frequently derive significant clinical benefits from target therapy. However, differences in the abundance level of mutations among patients resulted in varying survival benefits, even among patients with the same target gene mutations. Currently, there is a lack of rational and interpretable models to assess the risk of treatment failure. In this study, we investigated the underlying coupled factors contributing to variations in medication sensitivity and established a statistically interpretable framework, named SAFE-MIL, for risk estimation. We first constructed an effectiveness label for each patient from the perspective of exploring the optimal grouping of patients' positive judgment values and sampled patients into 600 and 1,000 groups, respectively, based on multi-instance learning (MIL). A novel and interpretable loss function was further designed based on the Hosmer-Lemeshow test for this framework. By integrating multi-instance learning with the Hosmer-Lemeshow test, SAFE-MIL is capable of accurately estimating the risk of drug treatment failure across diverse patient cohorts and providing the optimal threshold for assessing the risk stratification simultaneously. We conducted a comprehensive case study involving 457 non-small cell lung cancer patients with EGFR mutations treated with EGFR tyrosine kinase inhibitors. Results demonstrate that SAFE-MIL outperforms traditional regression methods with higher accuracy and can accurately assess patients' risk stratification. This underscores its ability to accurately capture inter-patient variability in risk while providing statistical interpretability. SAFE-MIL is able to effectively guide clinical decision-making regarding the use of drugs in targeted therapy and provides an interpretable computational framework for other patient stratification problems. The SAFE-MIL framework has proven its effectiveness in capturing inter-patient variability in risk and providing statistical interpretability. It outperforms traditional regression methods and can effectively guide clinical decision-making in the use of drugs for targeted therapy. SAFE-MIL offers a valuable interpretable computational framework that can be applied to other patient stratification problems, enhancing the precision of risk assessment in personalized medicine. The source code for SAFE-MIL is available for further exploration and application at https://github.com/Nevermore233/SAFE-MIL. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to evaluate the ability of the parasternal intercostal (PIC) thickening fraction during spontaneous breathing trial (SBT) to predict the need for reintubation within 48 h after extubation in surgical patients with sepsis. Methods: This prospective observational study included adult patients with sepsis who were mechanically ventilated and indicated for SBT. Ultrasound measurements of the PIC thickening fraction and diaphragmatic excursion (DE) were recorded 15 min after the start of the SBT. After extubation, the patients were followed up for 48 h for the need for reintubation. The study outcomes were the ability of the PIC thickening fraction (primary outcome) and DE to predict reintubation within 48 h of extubation using area under receiver characteristic curve (AUC) analysis. The accuracy of the model including the findings of right PIC thickening fraction and right DE was also assessed using the current study cut-off values. Multivariate analysis was performed to identify independent risk factors for reintubation. Results: We analyzed data from 49 patients who underwent successful SBT, and 10/49 (20%) required reintubation. The AUCs (95% confidence interval [CI]) for the ability of right and left side PIC thickening fraction to predict reintubation were 0.97 (0.88–1.00) and 0.96 (0.86–1.00), respectively; at a cutoff value of 6.5–8.3%, the PIC thickening fraction had a negative predictive value of 100%. The AUCs for the PIC thickening fraction and DE were comparable; and both measures were independent risk factors for reintubation. The AUC (95% CI) of the model including the right PIC thickening fraction > 6.5% and right DE ≤ 18 mm to predict reintubation was 0.99 (0.92–1.00), with a positive predictive value of 100% when both sonographic findings are positive and negative predictive value of 100% when both sonographic findings are negative. Conclusions: Among surgical patients with sepsis, PIC thickening fraction evaluated during the SBT is an independent risk factor for reintubation. The PIC thickening fraction has an excellent predictive value for reintubation. A PIC thickening fraction of ≤ 6.5–8.3% can exclude reintubation, with a negative predictive value of 100%. Furthermore, a combination of high PIC and low DE can also indicate a high risk of reintubation. However, larger studies that include different populations are required to replicate our findings and validate the cutoff values. [ABSTRACT FROM AUTHOR]

Objective: Patients with mild oral and maxillofacial space infection (OMSI) usually need only antimicrobial therapy. However, surgical intervention is eventually needed after using antibiotics for a period. The objective of this study was to explore the risk factors for drug therapy failure in OMSI. Subjects and methods: A retrospective case‒control study was designed. From August 2020 to September 2022, patients at Shanghai Jiao Tong University Affiliated Ninth People's Hospital who were diagnosed with OMSI were retrospectively reviewed. The outcome variable was surgical intervention after the use of antibiotics. We collected common biological factors, including demographic characteristics, routine blood test results, C-reactive protein (CRP) levels and composite indicators, such as neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR). The χ2 test and binary logistic regression were used to examine the association between biological factors and the outcome variable. Results: Forty-six patients were included in this study. Further surgical intervention was needed in 20 patients (43.5%). The NLR showed a significant association with further surgical drainage (p = 0.01). A binary logistic regression equation was found by using stepwise regression based on the Akaike information criterion (R2 = 0.443), which was associated with sex (odds ratio [OR], 0.216; p = 0.092), NLR (OR, 1.258; p = 0.045), red blood cell (RBC) count (OR, 4.372; p = 0.103) and monocyte (MONO) count (OR, 9.528, p = 0.023). Receiver operating characteristic analysis produced an area under the curve for NLR of 0.725 (p = 0.01) and for the binary logistic regression model of 0.8365 (p < 0.001). Conclusion: Surgical interventions are needed in some mild OMSI patients when antimicrobial therapy fails to stop the formation of abscesses. The binary logistic regression model shows that NLR can be used as an ideal prognostic factor to predict the outcome of antimicrobial therapy and the possibility of requiring surgical intervention. Statement of clinical relevance: Using simple, inexpensive, and easily achieved biological parameters (such as routine blood test results) and composite indicators calculated by them (such as NLR) to predict whether surgical intervention is needed in the future provides a reference for clinical doctors and enables more cost-effective and efficient diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Introduction: Psychotherapeutic failures involve situational, relational, and personal factors. Dropout refers to a patient's unilateral termination of treatment without the therapist's knowledge or approval. Premature termination occurs when therapy is discontinued before achieving a sufficient reduction in initial problems. Objective: This study explores the role of therapist's emotional response (countertransference), gender, psychotherapeutic orientation, and patient diagnosis in the context of psychotherapeutic failures. Method: A mixed-method approach was used. Fifty-nine Italian psychotherapists, practicing mostly privately with at least 5 years of experience, were recruited through Italian professional internet websites. The Therapist Response Questionnaire and the Impasse Interview were administered to each psychotherapist. Each therapist was asked to reflect on their last dropout patient. Quantitative (MANOVA) and qualitative analyses (textual content analysis) were conducted with SPSS and T-LAB, respectively. Results: The quantitative analyses revealed that the most frequent countertransference response was Helpless/Inadequate, with female therapists experiencing this more frequently than male therapists. The qualitative analyses identified two main factors explaining most of the variance in countertransference responses: Parental/Protective versus Hostile/Angry, and Positive/Satisfying versus Helpless/Inadequate, with Helpless/Inadequate central. Additionally, the qualitative analysis of treatment interruption methods revealed two factors explaining over 50% of the variance. Lack of communication was linked to negative themes, while mediated and direct communication were associated with positive terms. Direct communication was characterized as useful, while mediated communication was linked to dropout and attachment figures. Conclusion: Under pressure, psychotherapists' anxiety levels increase, often managed ambivalently or avoidantly. These results suggest that awareness of psychotherapist emotional responses is important to limit psychotherapeutic failures. These findings offer valuable insights for clinical practice. [ABSTRACT FROM AUTHOR]

Background: The injectable shorter multi-drug resistant tuberculosis (MDR-TB) regimen, has been reported to be less costly and more effective in the treatment of MDR-TB compared to the longer regimen. Ethiopia introduced the injectable shorter regimen (SR) in April 2018 following official recommendation by the World Health Organization (WHO) in 2016. While the WHO recommendation was based on evidence coming from extensive programmatic studies in some Asian and African countries, there is paucity of information on patient outcomes in the Ethiopian context. Thus, we aimed to assess the treatment outcomes and identify factors associated with the outcomes of MDR-TB patients on injectable SR. Methods: A multi-center facility-based retrospective cohort study was conducted in Ethiopia on 245 MDR-TB patients who were treated between April 2018 and March 2020. Data were collected from patients' medical records and analyzed using SPSS version 25. Descriptive statistics was used to summarize the results while inferential analysis was employed to investigate predictors of treatment outcomes and survival status. Results: A total of 245 patients were included in the study, with 129 (52.7%) of them being female. Median age of the patients was 27 (IQR: 21–33). The overall treatment success rate was 87.8%, with 156 (63.7%) cured and 59 (24.1%) patients who completed treatment. The unfavorable outcomes accounted for 12.2%, with 16 (6.5%) treatment failure, 8 (3.3%) death and 6 (2.4%) lost to follow up. Majority of the unfavorable outcomes occurred during the early phase of therapy, with median time to event of 1.8 months (95% CI: 0.99—2.69). The use of khat (a green leafy shrub abused for its stimulant like effect) and being diagnosed with MDR-TB than rifampicin resistant only, were identified as independent factors associated with unfavorable outcomes. Conclusion: The injectable SR for MDR-TB was found to have positive treatment outcomes in the context of programmatic management in Ethiopia. [ABSTRACT FROM AUTHOR]

Background: Post-cholecystectomy bile duct injuries (BDIs) represent a challenging complication, with negative impacts on clinical outcomes. Several surgical and endoscopic/interventional radiologist (IR) approaches have been proposed to manage these damages, though with high failure rates. This individual patient data (IPD) systematic review analyzes the potential risk factors for failure after treatment interventions for BDIs, both surgical and endoscopic/IR. Methods: An extensive literature search was conducted on MEDLINE and Scopus for relevant articles published in English on the management of BDIs after cholecystectomy, between 1 January 2010 and 31 December 2023. Our series of BDIs was included. BDIs were always categorized according to the Strasberg's classification. The composite primary endpoints evaluated were the failure of treatment interventions, defined as patient death or the requirement of any other procedure, whatever surgical and/or endoscopic/IR, after the primary treatment. Results: A total of 342 cases were retrieved from our literature analysis, including our series of 19 patients. Among these, three groups were identified: "upfront surgery", "upfront endoscopy and/or IR" and "no upfront treatment", consisting of 224, 109 and 9 patients, respectively. After eliminating the third group, treatment intervention failure was observed overall in 34.2% (114/333) of patients, of whom 80.7% (92/114) and 19.3% (22/114) in the "upfront surgery" and in the "upfront endoscopy/IR" groups, respectively. At multivariable analysis, injury type D and E, and repair in a non-specialized center represented independent predictors of treatment failure in both groups, whereas laparoscopic cholecystectomy (LC) converted to open and immediate attempt of surgical repair exclusively in the first group. Conclusions: Significant treatment failure rates are responsible for remarkable negative effects on immediate and longer-term clinical outcomes of post-cholecystectomy BDIs. Understanding the important risk factors for this outcome may better guide the most appropriate therapeutical approach and improve clinical decisions in case this serious complication occurs. [ABSTRACT FROM AUTHOR]

Objective: To provide a brief summary of the high incidence, symptomatology, different types, and diagnosis of adenomyosis and to explore various aspects of the disease, with the primary aim of raising awareness among gynecologists for appropriate and early detection. Background: Adenomyosis, a benign gynecological condition characterized by the infiltration of endometrial tissue into the myometrium, poses significant challenges to women's reproductive health. Methods: A narrative review was conducted by searching PubMed, Scopus, and Cochrane databases and offering a non-systematic summary and critical analysis of current knowledge on the impact of adenomyosis on women's health. Articles published in the English language up to May 2023, including original scientific papers, clinical trials, meta-analyses, and reviews focusing on various aspects of adenomyosis, were included in the synthesis of this review. Conclusions: Approximately 20% of women are affected by adenomyosis, which manifests with various subtypes, distinct epidemiological profiles, symptomatology, and treatment responses. Despite its clinical significance, adenomyosis remains understudied, resulting in a significant disparity in research and the literature compared to other gynecological conditions. The severity of adenomyosis is compounded when coexisting with endometriosis, particularly deep-infiltrating endometriosis (DIE), leading to exacerbated fertility issues and severe symptomatology. The wide range of symptoms, including adverse pregnancy outcomes such as pre-eclampsia, highlights its wider impact and emphasizes the need for increased awareness of the condition. Adenomyosis is frequently associated with treatment failure in endometriosis, contributing to dienogest resistance, elevated discontinuation rates, and persistent pain post-endometriosis surgery. Additionally, the lack of specific treatments tailored to adenomyosis poses a considerable challenge in clinical management. [ABSTRACT FROM AUTHOR]

In the healthcare field, the effective implementation of clinical protocols is crucial to ensuring patient safety and well-being. In this context, this study evaluates nurses' adherence to the maintenance and replacement protocol of peripheral venous catheters (PVCs) in a university hospital in Spain, examining the impact of compliance with the protocol on the loss of PVCs and on patient safety in addition to analyzing the related costs. A retrospective observational study was conducted with 590 patients who were admitted in 2018 and 2019. The chi-square test or Fisher's exact test, as appropriate, was used to see the association between the study variables; with the dependent variable being the loss of PVCs (including, as a dependent variable, the loss of PVCs before 48 h). The patients' electronic and physical medical records were reviewed to analyze nursing interventions related to the management of PVCs. A total of 24% of patients experienced PVC loss within the first 24 h after insertion. Failure to comply with the protocol resulted in 80% more catheter loss and increased the cost of cannulation by 46.84%. Low compliance with PVC care protocols significantly increases the risk of catheter loss, suggesting the need for increased training and strict protocol implementation. The findings emphasize the critical role of nursing in ensuring patient safety through adherence to evidence-based protocols. Continuing education and diligent protocol implementation are essential to reducing healthcare costs and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Although atezolizumab plus bevacizumab is the standard first-line treatment for patients with advanced HCC, the optimal second-line regimen remains unknown. In this meta-analysis, we examined the subsequent regimen after the failure of atezolizumab–bevacizumab and found that sequential multitargeted tyrosine kinase inhibitors, including sorafenib and lenvatinib, significantly prolonged the survival of patients, with a pooled OS of 11.45 months and a PFS of 3.78 months, respectively. Moreover, the subsequent use of sorafenib or lenvatinib has manageable toxicity. Therefore, our data indicate that sorafenib or lenvatinib treatment is a rational option for patients with advanced HCC after progression on atezolizumab–bevacizumab. Background: Although atezolizumab plus bevacizumab (hereinafter, atezolizumab–bevacizumab) is the standard first-line treatment for patients with advanced HCC, the optimal second-line regimen remains unknown. This study evaluated the efficacy and safety of sorafenib and lenvatinib in patients with advanced HCC that progressed under atezolizumab–bevacizumab treatment. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched PubMed, Embase, and the Cochrane Library for articles published before November 2023. Random-effects meta-analysis was performed to determine the pooled objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), comparing patients who received sorafenib versus lenvatinib. Results: Seven studies involving 387 patients were included. The pooled ORR, DCR, OS, and PFS for sorafenib and lenvatinib together were 26% (95% CI: 14–43%), 63% (95% CI: 47–77%), 11.45 months (95% CI: 7.12–15.77, I2 = 92%, p < 0.01), and 3.78 months (95% CI: 2.34–5.23, I2 = 67%, p = 0.02), respectively. Although lenvatinib users had a longer median OS (12.42 vs. 10.75 months) and PFS (5.15 vs. 2.58 months) than sorafenib users, the pooled ORR, DCR, median OS, and PFS for these medications were comparable. Additionally, the distributions of all-grade and grade ≥ 3 adverse events for sorafenib and lenvatinib were comparable to those for these two medications when used as first-line therapies. Conclusions: Sorafenib or lenvatinib can provide effective treatment with manageable toxicity in patients with advanced HCC after disease progression under atezolizumab–bevacizumab. [ABSTRACT FROM AUTHOR]

Background Tuberculosis is a leading cause of death worldwide, and food insecurity is known to negatively influence health outcomes through multiple pathways. Few studies have interrogated the relationship between food insecurity and tuberculosis outcomes, particularly independent of nutrition. Methods We conducted a prospective cohort study of adults initiating first-line treatment for clinically suspected or microbiologically confirmed drug-sensitive tuberculosis at a rural referral center in Haiti. We administered a baseline questionnaire, collected clinical data, and analyzed laboratory samples. We used logistic regression models to estimate the relationship between household food insecurity (Household Hunger Scale) and treatment failure or death. We accounted for exclusion of patients lost to follow-up using inverse probability of censoring weighting and adjusted for measured confounders and nutritional status using inverse probability of treatment weighting. Results We enrolled 257 participants (37% female) between May 2020 and March 2023 with a median age (interquartile range) of 35 (25–45) years. Of these, 105 (41%) had no hunger in the household, 104 (40%) had moderate hunger in the household, and 48 (19%) had severe hunger in the household. Eleven participants (4%) died, and 6 (3%) had treatment failure. After adjustment, food insecurity was significantly associated with subsequent treatment failure or death (odds ratio 5.78 [95% confidence interval, 1.20–27.8]; P =.03). Conclusions Household food insecurity at tuberculosis treatment initiation was significantly associated with death or treatment failure after accounting for loss to follow-up, measured confounders, and nutritional status. In addition to the known importance of undernutrition, our findings indicate that food insecurity independently affects tuberculosis treatment outcomes in Haiti. [ABSTRACT FROM AUTHOR]

Purpose. To investigate the efficacy and safety of orthokeratology (ortho‐k) and repeated low‐level red‐light (RLRL) therapy in treating poor responders of ortho‐k in myopic children. Methods. Study participants were 100 myopic children who completed two years of ortho‐k treatment in a retrospective study. In the first year of ortho‐k treatment (phase one), they experienced axial elongation of 0.30 mm or greater (defined as poor responders to ortho‐k). Children were divided into two groups: the orthokeratology group (OK, n = 45) continued to receive ortho‐k monotherapy and the combination group (OK‐RLRL, n = 55) received RLRL in addition to ortho‐k for the next year (phase two). Axial elongation over time between the groups was compared. Results. The mean age, male‐to‐female ratio, axial length (AL), and axial elongation in phase one were comparable between OK and OK‐RLRL groups (all P > 0.05). During phase two, significant AL shortening was observed in the OK‐RLRL group compared with children in the OK group (−0.10 ± 0.16 mm vs 0.30 ± 0.19 mm, P < 0.001). Among these 55 myopic children in the OK‐RLRL group, 35 (63.6%), 25 (45.4%), 11 (20%), 6 (10.9%), and 3 (5.4%) of them had AL shortening over 0.05 mm/year, 0.10 mm/year, and 0.20 mm/year, 0.3 mm/year, and 0.4 mm/year, respectively. Older baseline age (β = −0.02), higher treatment compliance (β = −0.462), and AL change at 1 month (β = 1.263) were significantly associated with less AL elongation (all P < 0.05). Conclusions. For poor responders of orthokeratology, RLRL could slow axial elongation in addition to the ortho‐k treatment effect. Those who respond poorly to ortho‐k with elder age might benefit more from combined therapy. [ABSTRACT FROM AUTHOR]

Challenges in classifying recurrent Plasmodium vivax infections constrain surveillance of antimalarial efficacy and transmission. Recurrent infections may arise from activation of dormant liver stages (relapse), blood-stage treatment failure (recrudescence) or reinfection. Molecular inference of familial relatedness (identity-by-descent or IBD) can help resolve the probable origin of recurrences. As whole genome sequencing of P. vivax remains challenging, targeted genotyping methods are needed for scalability. We describe a P. vivax marker discovery framework to identify and select panels of microhaplotypes (multi-allelic markers within small, amplifiable segments of the genome) that can accurately capture IBD. We evaluate panels of 50–250 microhaplotypes discovered in a global set of 615 P. vivax genomes. A candidate global 100-microhaplotype panel exhibits high marker diversity in the Asia-Pacific, Latin America and horn of Africa (median HE = 0.70–0.81) and identifies 89% of the polyclonal infections detected with genome-wide datasets. Data simulations reveal lower error in estimating pairwise IBD using microhaplotypes relative to traditional biallelic SNP barcodes. The candidate global panel also exhibits high accuracy in predicting geographic origin and captures local infection outbreak and bottlenecking events. Our framework is open-source enabling customised microhaplotype discovery and selection, with potential for porting to other species or data resources. This work describes an informatic framework to identify multi-allelic markers in the genome of the malaria-causing Plasmodium vivax parasite that can inform on familial relatedness between infections. Spatial and temporal transmission patterns are demonstrated with an example marker set. [ABSTRACT FROM AUTHOR]

Plasmodium falciparum is the main causative agent of malaria, a deadly disease that mainly affects children under five years old. Artemisinin-based combination therapies have been pivotal in controlling the disease, but resistance has arisen in various regions, increasing the risk of treatment failure. The non-mevalonate pathway is essential for the isoprenoid synthesis in Plasmodium and provides several under-explored targets to be used in the discovery of new antimalarials. 1-deoxy-D-xylulose-5-phosphate synthase (DXPS) is the first and rate-limiting enzyme of the pathway. Despite its importance, there are no structures available for any Plasmodium spp., due to the complex sequence which contains large regions of high disorder, making crystallisation a difficult task. In this manuscript, we use cryo-electron microscopy to solve the P. falciparum DXPS structure at a final resolution of 2.42 Å. Overall, the structure resembles other DXPS enzymes but includes a distinct N-terminal domain exclusive to the Plasmodium genus. Mutational studies show that destabilization of the cap domain interface negatively impacts protein stability and activity. Additionally, a density for the co-factor thiamine diphosphate is found in the active site. Our work highlights the potential of cryo-EM to obtain structures of P. falciparum proteins that are unfeasible by means of crystallography. DXPS is an important enzyme for isoprenoid synthesis in Plasmodium falciparum. Here, authors elucidate the cryo-EM structure of PfDXPS showing an N-terminal domain only present in this genus. Mutation studies show its importance in DXPS stability and activity. [ABSTRACT FROM AUTHOR]

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