The fundamental question of \"what is the transport path of electrons through proteins?\" initially introduced while studying long-range electron transfer between localized redox centers in proteins in vivo is also highly relevant to the transport properties of solid-state, dry metal-protein-metal junctions. Here, we report conductance measurements of such junctions, Au-(Azurin monolayer ensemble)-Bismuth (Bi) ones, with well-defined nanopore geometry and ~103 proteins/pore. Our results can be understood as follows. (1) Transport is via two interacting conducting channels, characterized by different spatial and time scales. The slow and spatially localized channel is associated with the Cu center of Azurin and the fast delocalized one with the protein\'s polypeptide matrix. Transport via the slow channel is by a sequential (noncoherent) process and in the second one by direct, off-resonant tunneling. (2) The two channels are capacitively coupled. Thus, with a change in charge occupation of the weakly coupled (metal center) channel, the broad energy level manifold, responsible for off-resonance tunneling, shifts, relative to the electrodes\' Fermi levels. In this process, the off-resonance (fast) channel dominates transport, and the slow (redox) channel, while contributing only negligibly directly, significantly affects transport by intramolecular gating.

UNASSIGNED: Rapamycin inhibits the mTOR protein kinase. Methioninase (rMETase), by degrading methionine, targets the methionine addiction of cancer cells and has been shown to improve the efficacy of chemotherapy drugs, reducing their effective doses. Our previous study demonstrated that rapamycin and rMETase work synergistically against colorectal-cancer cells, but not on normal cells, when administered simultaneously in vitro. In the present study, we aimed to further our previous findings by exploring whether  synergy exists between rapamycin and rMETase when used sequentially against HCT-116 colorectal-carcinoma cells, compared to simultaneous administration, in vitro.
UNASSIGNED: The half-maximal inhibitory concentrations (IC50) of rapamycin alone and rMETase alone against the HCT-116 human colorectal-cancer cell line were previously determined using the CCK-8 cell viability assay (11). We then examined the efficacy of rapamycin and rMETase, both at their IC50, administered simultaneously or sequentially on the HCT-116 cell line, with rapamycin administered before rMETase and vice versa.
UNASSIGNED: The IC50 for rapamycin and rMETase, determined from previous experiments (11), was 1.38 nM and 0.39 U/ml, respectively, of HCT-116 cells. When rMETase was administered four days before rapamycin, both at the IC50, there was a 30.46% inhibition of HCT-116 cells. When rapamycin was administered four days before rMETase, both at the IC50, there was an inhibition of 41.13%. When both rapamycin and rMETase were simultaneously administered, both at the IC50, there was a 71.03% inhibition.
UNASSIGNED: Rapamycin and rMETase have synergistic efficacy against colorectal-cancer cells in vitro when administered simultaneously, but not sequentially.

UNASSIGNED: There is no consensus on the appropriate use of mixtures of local anaesthetic drugs in various combinations for nerve blocks. We intended to compare short-acting lignocaine and long-acting ropivacaine as a mixture versus undiluted sequential injections on block characteristics of ultrasound-guided (USG) supraclavicular brachial plexus block for upper limb surgeries.
UNASSIGNED: A double-blinded randomised study was conducted on 64 adult patients scheduled for upper limb surgery who received 15 mL each of 2% lignocaine with adrenaline and 0.75% ropivacaine as a 1:1 mixture in the mixed group (Group M) or sequential injections in the sequential group (Group S) by using a USG technique. The primary outcome was the percentage of participants with complete four nerve sensory blocks at 10 minutes post block injection. Secondary outcomes were sensory and motor block characteristics till 30 minutes, total duration of analgesia, sensory and motor block, and complications.
UNASSIGNED: Demographic characteristics and time taken for the procedure were similar. The percentage of participants with a complete four-nerve sensory block at 10 minutes was higher in Group S (69%) versus Group M (41%) (P = 0.04). Complete sensory and motor block rates were similar at 30 minutes. The block procedure time, total duration of analgesia, and sensory and motor block were similar in both groups. There were no major complications.
UNASSIGNED: Sequential lignocaine-ropivacaine, compared to the mixed injection technique, has a higher initial rate of sensory and motor block onset with a similar total block duration.

BACKGROUND: A combination of fractional CO2 laser and subcision is usually employed for the treatment of post-acne atrophic scars. However, the efficacy and safety of both simultaneous and sequential combination therapies should be explored.
OBJECTIVE: To compare the efficacy and safety of simultaneous and sequential fractional CO2 laser and subcision combination therapies for post-acne atrophic scars.
METHODS: This single-blind, split-face clinical trial included 34 patients with post-acne atrophic scars at our institution. Each patient underwent three sessions of subcision combined with fractional CO2 laser, with a 1-month interval between each session. The left side of the face was treated with simultaneous combination therapy, whereas the right side was treated with sequential combination therapy. Treatment efficacy was assessed at 4, 8, and 12 weeks; and 3 and 6 months after the last session.
RESULTS: Simultaneous and sequential treatments demonstrated comparable efficacy. Regarding the adverse events, the side of the face undergoing simultaneous treatment experienced longer swelling duration, higher pain levels during laser treatment, and shorter downtime.
CONCLUSIONS: Despite the longer swelling time and higher pain levels during laser treatment in the simultaneous treatment side, the effectiveness and satisfaction level of the CO2 fractional laser and subcision for treatment of the acne scars were comparable between the two combinations, with a shorter downtime for the simultaneous than for the sequential combination therapy.

BACKGROUND:  Sequential combined spinal epidural anesthesia (CSEA) is probably the greatest advancement in the central neuraxial block in this decade for geriatric patients due to the potential advantages of both spinal and epidural anesthesia. This study was designed to compare the clinical effects of sequential CSEA versus spinal and epidural anesthesia in geriatric patients undergoing transurethral resection of the prostate (TURP).
METHODS:  Ninety patients aged 65 to 80 years were randomly allocated into three groups of 30 each. Group A (n=30) patients were administered spinal anesthesia with 2.5 ml of 0.5% hyperbaric bupivacaine, group B (n=30) received epidural anesthesia with 15 ml of 0.5% isobaric bupivacaine, and group C (n=30) received sequential CSEA with 1 ml of 0.5% hyperbaric bupivacaine and 6 ml of 0.5% isobaric bupivacaine given through epidural route to extend the block up to T10. Patients were observed for hemodynamic parameters, sensory and motor block, total dose required to establish the desired level, and patient satisfaction score.
RESULTS: None of the patients were excluded in the study. Group A patients reported rapid onset of sensory block (3.08±11.57 minutes) compared to group B (11.57±1.48 minutes), and group C (5.47±1.25 minutes). The onset of motor block was expeditious in group A (8.08±1.0 minutes) compared to group B (20.33±1.86 minutes) and group C (15.53±1.31 minutes). Patients in group B had maximum hemodynamic stability but with delayed onset and were technically more complex than group A. Patients in group C were hemodynamically more stable than group A. They had a faster onset of action with decreased doses of local anesthetic drug required compared to group B.
CONCLUSIONS: Sequential CSEA is a safe, effective, and reliable technique that combines the advantages of both spinal and epidural while minimizing their disadvantages. It has the advantage of stable hemodynamic parameters along with the provision of prolongation analgesia for geriatric patients undergoing TURP surgery.

UNASSIGNED: Keratoconus (KC) is degenerative corneal disorder, with central and paracentral thinning and corneal ectasia. For KC progressive cases, primary treatment included corneal collagen cross linking (CXL) to stabilize coning and intracorneal rings segment (ICRS) to correct visual acuity.
UNASSIGNED: The aim of the study is to assess efficacy and safety of ICRS and CXL on one session (Simultaneous) or two sessions (sequential) with maximum of 1 month apart.
UNASSIGNED: This Prospective Intervention Comparative research made at Armed forces hospital, Cairo, Egypt from January 2017 to December 2019. Forty patients (60 eyes) with mild to moderate KC were enrolled. Patients sorted into Simultaneous group includes 21 patients (30 eyes) undergo two procedures (ICRS then CXL) at the same session and Sequential group included 19 patients (30 eyes) undergo ICRS then CXL on two sessions with month apart. Patients followed up at end of 1st, 3rd, and 6th months. Assessment included changes in corrected corneal surface irregularities as minimum keratometric 1 (K1), maximum keratometric readings (K2), and mean keratometric (Km) readings.
UNASSIGNED: Improvement of K1, K2, and Km in Simulations and Sequential groups achieved at end of 1st-, 3rd-, and 6th-month postoperative versus preoperative. Maximum improvement in Simulations and Sequential groups in K1 achieved at end of 6th and 1st months, in K2 at end of 3rd and 6th months and in Km at end of 1st and 3rd months.
UNASSIGNED: Combined ICRS and CXL act safely in one or two sessions and there are no statistically significant variations between results on both methods in keratometric readings.

OBJECTIVE: To comprehensively examine the characteristics and prognosis of bilateral sudden sensorineural hearing loss (BSSHL) and its subtypes compared to unilateral sudden sensorineural hearing loss (USSHL).
METHODS: PubMed, Scopus, and CINAHL.
METHODS: Databases were searched from inception to December 5, 2023, for studies reporting patient characteristics and audiometric outcomes for BSSHL and its simultaneous (Si-BSSHL) and sequential (Se-BSSHL) subtypes. Meta-analysis of continuous measures, proportions (%), mean differences (Δ), and odds ratio (OR) were performed.
RESULTS: Eleven studies were included, consisting of 368 patients with BSSHL and 2,705 patients with USSHL. The pooled prevalence among all SSHL cases was 88.1% (95% CI: 81.2%-93.6%) for USSHL and 11.9% (95% CI: 6.4% to 18.8%) for BSSHL. PTA improvement following treatment with steroids was significantly worse in patients with BSSHL (Δ15.3 dB; 95% CI: 14.6 to 15.9; p < 0.0001) compared to patients with USSHL. There was no significant difference in post-treatment PTA improvement between the BSSHL subtypes. Patients with Si-BSSHL were significantly less likely to have an idiopathic etiology (OR: 0.4; 95% CI: 0.2 to 0.8; p = 0.01) and significantly more likely to have an autoimmune disease etiology (OR: 27.4; 95% CI: 2.2 to 336.1; p = 0.01), comorbid cardiovascular disease (OR: 2.3; 95% CI: 1.1 to 5.1; p = 0.03), and comorbid hypertension (OR: 2.5; 95% CI: 1.6 to 3.8; p < 0.0001) compared to patients with USSHL.
CONCLUSIONS: BSSHL is a considerably rarer form of SSHL with worse prognosis compared to USSHL. BSSHL, and Si-BSSHL in particular, has significantly greater associations with systemic pathologies compared to USSHL. Laryngoscope, 134:3883-3891, 2024.

BACKGROUND: A cure for Helicobacter pylori (H. pylori) remains a problem of global concern. The prevalence of antimicrobial resistance is widely rising and becoming a challenging issue worldwide. Optimizing sequential therapy seems to be one of the most attractive strategies in terms of efficacy, tolerability and cost. The most common sequential therapy consists of a dual therapy [proton-pump inhibitors (PPIs) and amoxicillin] for the first period (5 to 7 d), followed by a triple therapy for the second period (PPI, clarithromycin and metronidazole). PPIs play a key role in maintaining a gastric pH at a level that allows an optimal efficacy of antibiotics, hence the idea of using new generation molecules.
OBJECTIVE: To compare an optimized sequential therapy with the standard non-bismuth quadruple therapies of 10 and 14 d, in terms of efficacy, incidence of adverse effects (AEs) and cost.
METHODS: This open-label prospective study randomized 328 patients with confirmed H. pylori infection into three groups (1:1:1): The first group received quadruple therapy consisting of twice-daily (bid) omeprazole 20 mg, amoxicillin 1 g, clarithromycin 500 mg and metronidazole 500 mg for 10 d (QT-10), the second group received a 14 d quadruple therapy following the same regimen (QT-14), and the third group received an optimized sequential therapy consisting of bid rabeprazole 20 mg plus amoxicillin 1 g for 7 d, followed by bid rabeprazole 20 mg, clarithromycin 500 mg and metronidazole 500 mg for the next 7 d (OST-14). AEs were recorded throughout the study, and the H. pylori eradication rate was determined 4 to 6 wk after the end of treatment, using the 13C urea breath test.
RESULTS: In the intention-to-treat and per-protocol analysis, the eradication rate was higher in the OST-14 group compared to the QT-10 group: (93.5%, 85.5% P = 0.04) and (96.2%, 89.5% P = 0.03) respectively. However, there was no statistically significant difference in eradication rates between the OST-14 and QT-14 groups: (93.5%, 91.8% P = 0.34) and (96.2%, 94.4% P = 0.35), respectively. The overall incidence of AEs was significantly lower in the OST-14 group (P = 0.01). Furthermore, OST-14 was the most cost-effective among the three groups.
CONCLUSIONS: The optimized 14-d sequential therapy is a safe and effective alternative. Its eradication rate is comparable to that of the 14-d concomitant therapy while causing fewer AEs and allowing a gain in terms of cost.

UNASSIGNED: The sequential anti-osteoporotic treatment for women with postmenopausal osteoporosis (PMO) is important, but the order in which different types of drugs are used is confusing and controversial. Therefore, we performed a network meta-analysis to compare the efficacy and safety of available sequential treatments to explore the most efficacious strategy for long-term management of osteoporosis.
UNASSIGNED: In this network meta-analysis, we searched the PubMed, EMBASE, Web of Science, the Cochrane Library, and ClinicalTrials.gov from inception to September 19, 2023 to identify randomised controlled trials comparing sequential treatments for women with PMO. The identified trials were screened by reading the title and abstract, and only randomised clinical trials involving sequential anti-osteoporotic treatments and reported relevant outcomes for PMO were included. The main outcomes included vertebral fracture risk, the percentage change in bone mineral density (BMD) in different body parts, and all safety indicators in the stage after switching treatment. A frequentist network meta-analysis was performed using the multivariate random effects method and evaluated using the surface under the cumulative ranking curve (SUCRA). Certainty of evidence was assessed using the Confidence in the Network Meta-Analysis (CINeMA) framework. This study is registered with PROSPERO: CRD42022360236.
UNASSIGNED: A total of 19 trials comprising 18,416 participants were included in the study. Five different sequential treatments were investigated as the main interventions and compared to the corresponding control groups. The intervention groups in this study comprised the following treatment switch protocols: switching from an anabolic agent (AB) to an anti-resorptive agent (AR) (ABtAR), transitioning from one AR to another AR (ARtAAR), shifting from an AR to an AB (ARtAB), switching from an AB to a combined treatment of AB and AR (ABtC), and transitioning from an AR to a combined treatment (ARtC). A significant reduction in the incidence of vertebral fractures was observed in ARtC, ABtAR and ARtAB in the second stage, and ARtC had the lowest incidence with 81.5% SUCRA. ARtAAR and ABtAR were two effective strategies for preventing fractures and improving BMD in other body parts. Especially, ARtAAR could improve total hip BMD with the highest 96.1% SUCRA, and ABtAR could decrease the risk of total fractures with the highest 94.3% SUCRA. Almost no difference was observed in safety outcomes in other comparisons.
UNASSIGNED: Our findings suggested that the ARtAAR and ABtAR strategy are the effective and safe sequential treatment for preventing fracture and improving BMD for PMO. ARtC is more effective in preventing vertebral fractures.
UNASSIGNED: The National Natural Science Foundation of China (82170900, 81970762), the Hunan Administration of Traditional Chinese Medicine, and the Hunan Province High-level Health Talents \"225\" Project.

BACKGROUND: Osteoporotic-related fractures represent an increasing burden to patients, health care systems and society.
OBJECTIVE: This study estimated cost-effectiveness of sequential treatment with abaloparatide (ABL) followed by alendronate (ALN) compared to relevant alternative strategies in US men and women aged 50 to 80 years at very high fracture risk (bone mineral density T-score ≤  - 2.5 and a recent fracture).
METHODS: A lifetime Markov-based microsimulation model was used to estimate healthcare costs and quality-adjusted life years (QALYs). Comparators were sequential treatment with unbranded teriparatide (TPTD)/ALN, generic ALN monotherapy, and no treatment. Analyses were conducted based on initial fracture site (hip, vertebral, or any fracture) and treatment efficacy data (derived from clinical trials or a recent network meta-analysis).
RESULTS: From all analyses completed, sequential ABL/ALN demonstrated more QALYs for lower healthcare costs versus unbranded TPTD/ALN. No treatment was dominated (higher costs for less QALYs) versus ALN monotherapy. Sequential ABL/ALN resulted in favorable cost-effectiveness (at US threshold of $150,000/QALY) versus generic ALN monotherapy in men aged ≥ 50 years with any fracture type, women aged ≥ 65 years with any fracture type, and women aged ≥ 55 years having a hip or vertebral fracture.
CONCLUSIONS: Similar cost-effectiveness of sequential ABL/ALN versus unbranded TPTD/ALN, ALN monotherapy, and no treatment was observed in both US men and women at very high fracture risk, with a moderate improvement in cost-effectiveness in men versus women and in patients with a hip or vertebral fracture.
CONCLUSIONS: Sequential therapy with ABL/ALN was cost-effective in US men and women at very high risk of fractures.