Time Points Research Articles

Experience from a single-center study on multimodal medication therapy for patients with complex regional pain syndrome.

Despite the application of various therapeutic methods, pain caused by complex regional pain syndrome (CRPS) is not sufficiently managed and often progresses to a chronic stage. For the systematic and effective treatment of CRPS, we developed an algorithm for multimodal medication therapy based on the established pathophysiology of CRPS to control CRPS-related pain. In this study, we present the outcomes of our novel algorithm for multimodal medication therapy for patients with CRPS, consisting of three major components: multimodal oral medication, intravenous ketamine, and intravenous lidocaine therapy. We retrospectively investigated patients with CRPS who received multimodal therapy. Pain severity scores were evaluated using a numerical rating scale at four time points (P1, pain at initial consultation; P2, pain after oral medication; P3, pain after ketamine treatment; and P4, pain after lidocaine treatment). The effect of the multimodal medication therapy algorithm on pain management was evaluated at each time point. In patients with CRPS, multimodal oral medication, intravenous ketamine, and intravenous lidocaine therapies led to significantly improved pain control (p< 0.05). Additionally, the combination of these three therapies (through the multimodal medication therapy algorithm) resulted in significant pain relief in patients with CRPS (p< 0.05). Our multimodal medication therapy algorithm effectively controlled pain in patients with CRPS. However, further prospective studies with large sample sizes and randomized controlled trials are needed for more accurate generalization.

Different doses of hyaluronic acid injections in patients with knee osteoarthritis: A multicenter, randomized, prospective, single-blind, clinical study.

Many formulations and dosing regimens are available for hyaluronic acid (HA). To compare different doses of linear, high-molecular weight (HMW) HA injections among patients with knee osteoarthritis (OA). Hundred patients were included in this randomized, single-blinded trial and randomly divided into three HA injection groups. The first group received five weekly 20mg HA injections, the second group received three weekly 32mg HA injections, and the third group received a single 48mg HA injection. Patients were evaluated at baseline, 1, 3, and 6months after the last injection for pain, stiffness, and function using the visual analog scale (VAS) and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire. Quality of life, patient's global assessment, and Timed Up and Go (TUG) test scores were also evaluated. There was significant improvement in the WOMAC, VAS-pain, quality of life, patient's global assessment, and TUG test mean scores at all follow-up time points (p< 0.001). However, the groups showed no significant differences in WOMAC, VAS-activity pain, and patient global scores at any follow-up point. Intra-articular injections of different doses of linear HMW HA can improve pain, stiffness, function, and quality of life in patients suffering from knee OA over a six-month period.

Intraoperative pain prediction of percutaneous kyphoplasty under local anesthesia by preoperative experimental pain assessment.

Percutaneous kyphoplasty (PKP) is the preferred treatment for osteoporotic vertebral compression fractures (OVCF) Currently, the preoperative anesthesia methods for PKP are mainly local anesthesia and tracheal intubation general anesthesia. To assess whether patient sensitivity to pain measured preoperatively could predict the patients' pain response during PKP treatment under local anesthesia, to facilitate the development of an optimal preoperative anesthesia plan for patients. Fifty-five female patients diagnosed with osteoporotic single vertebral fracture who were treated with PKP under local anesthesia were selected. The patients' pain sensitivities, including pain threshold and pain tolerance threshold, were evaluated with a pain test device on the day before the operation in the ward. Heart rate (HR), mean arterial pressure (MAP), and blood oxygen saturation (SpO2) were recorded before anesthesia, post-anesthesia, after needle puncture, and after balloon dilatation. At the same time, blood was drawn at the above time points to determine the level of norepinephrine (NA) as an indicator of intraoperative pain stress response. The numerical rating scale (NRS) during surgery was recorded at the end of the surgery. The preoperative pain tolerance threshold of 55surgical patients was correlated with the intraoperative NRS score (r=-0.768, P< 0.001), as well as with the preoperative and intraoperative changes in HR (r=-0.791, P< 0.001), MAP (r=-0.819, P< 0.001), and NA (r=-0.553, P< 0.001). Thus, the lower the preoperative pain tolerance threshold, the more severe the patient's response to pain during PKP treatment under local anesthesia, and the greater the hemodynamic changes. Consequently, the intraoperative experience becomes worse. However, there was no correlation between preoperative pain threshold and NRS scores (r=-0.069, P= 0.616) nor between the preoperative and intraoperative changes in HR (r= 0.103, P= 0.453), MAP (r= 0.086, P= 0.535), and NA (r=-0.058, P= 0.674). The results indicated that preoperative pain assessment could predict the level of pain response in OVCF patients during PKP surgery under local anesthesia.

Nuclear Localization Signal Enhances the Targeting and Therapeutic Efficacy of a Porphyrin-Based Molecular Cargo: A Systemic In Vitro and Ex Vivo Evaluation.

The objective of the present work was to evaluate the potential of a nuclear localization signal (NLS) toward facilitating intracellular delivery and enhancement in the therapeutic efficacy of the molecular cargo. Toward this, an in-house synthesized porphyrin derivative, namely, 5-carboxymethyelene-oxyphenyl-10,15,20-tris(4-methoxyphenyl) porphyrin (UTriMA), was utilized for conjugation with the NLS sequence [PKKKRKV]. The three compounds synthesized during the course of the present work, namely DOTA-Lys-NLS, DOTA-UTriMA-Lys-NLS, and DOTA-Lys-UTriMA, were evaluated for cellular toxicity in cancer cell lines (HT1080), wherein all exhibited minimal dark toxicity. However, during photocytotoxicity studies with DOTA-Lys-UTriMA and DOTA-UTriMA-Lys-NLS conjugates in the same cell line, the latter exhibited significantly higher light-dependent toxicity compared to the former. Furthermore, the photocytotoxicity for DOTA-UTriMA-Lys-NLS in a healthy cell line (WI26VA4) was found to be significantly lower than that observed in the cancer cells. Fluorescence cell imaging studies carried out in HT1080 cancer cells revealed intracellular accumulation for the NLS-conjugated porphyrin (DOTA-UTriMA-Lys-NLS), whereas unconjugated porphyrin (DOTA-Lys-UTriMA) failed to do so. To evaluate the radiotherapeutic effects of the synthesized conjugates, all three compounds were radiolabeled with 177Lu, a well-known therapeutic radionuclide with high radiochemical purity (>95%). During in vitro studies, the [177Lu]Lu-DOTA-UTriMA-Lys-NLS complex exhibited the highest cell binding as well as internalization among the three radiolabeled complexes. Biological distribution studies for the radiolabeled compounds were performed in a fibrosarcoma-bearing small animal model, wherein significantly higher accumulation and prolonged retention of [177Lu]Lu-DOTA-UTriMA-Lys-NLS (9.32 ± 1.27% IA/g at 24 h p.i.) in the tumorous lesion compared to [177Lu]Lu-UTriMA-Lys-DOTA (2.3 ± 0.13% IA/g at 24 h p.i.) and [177Lu]Lu-DOTA-Lys-NLS complexes (0.26 ± 0.17% IA/g at 24 h p.i.) were observed. The results of the biodistribution studies were further corroborated by recording serial SPECT-CT images of fibrosarcoma-bearing Swiss mice administered with [177Lu]Lu-DOTA-UTriMA-Lys-NLS at different time points. Tumor regression studies performed with [177Lu]Lu-DOTA-UTriMA-Lys-NLS in the same animal model with two different doses [250 μCi (9.25 MBq) and 500 μCi (18.5 MBq)] resulted in a significant reduction in tumor mass in the treated group of animals. The above results revealed a definite enhancement in the targeting ability of molecular cargo upon conjugation with NLS and hence indicated that this strategy may be helpful for the preparation of drug-NLS conjugates as multimodal agents.

Postsurgical utility of copeptin for the prediction of postoperative arginine vasopressin deficiency.

Arginine vasopressin deficiency (AVD) following neurosurgical procedures for pituitary disorders is common and can delay discharge. Copeptin, a stable surrogate marker of arginine vasopressin, may predict postoperative AVD. The authors' aim was to assess the optimal postoperative sampling time and cut-point concentration of copeptin to predict the development of postsurgical AVD. Adults without preexisting AVD who were undergoing surgery for a pituitary lesion between February 2020 and April 2022 were eligible for study inclusion. Two samples were drawn from each patient postoperatively to assess the copeptin concentration using an immunofluorescent assay. Samples were denoted as "early" (within 6 hours of extubation) or "postoperative day 1" (POD1; within 10-30 hours of extubation). Patients were evaluated for the development of AVD. One hundred ninety-two patients (54.2% female) with a median age of 54.5 years (IQR 39.8-67.0 years) were included in the study. The median copeptin concentration at both time points was significantly lower in those with AVD (transient or permanent; n = 22, 11.5%) than in those without (early: 4.9 vs 18.7 pmol/L, p < 0.001; POD1: 3.4 vs 4.9 pmol/L, p < 0.001) but did not differ in those who developed transient versus permanent AVD. The optimal copeptin cut point for the prediction of AVD was < 8.5 pmol/L for early samples (sensitivity 0.70, specificity 0.80, positive predictive value [PPV] 0.29, negative predictive value [NPV] 0.96) and < 4.3 pmol/L for POD1 samples (sensitivity 0.82, specificity 0.63, PPV 0.22, NPV 0.96). In early samples, a copeptin cutoff of 22.9 pmol/L increased the sensitivity for the detection of AVD to 95% with an NPV of 99%. The proportion of patients who had AVD was higher (60.0% vs 8.8%, p < 0.001) and the copeptin concentration lower (early: 4.3 vs 17.0 pmol/L, p < 0.001; POD1: 2.7 vs 4.9 pmol/L, p < 0.001) among those who had undergone surgery for a craniopharyngeal duct pathology versus a pituitary adenoma. Although copeptin was lower in patients with persistent Cushing's disease than in those in remission, the difference did not reach statistical significance (early p = 0.11, POD1 p = 0.52). Furthermore, the copeptin concentration could not predict the development of syndrome of inappropriate secretion of antidiuretic hormone. Patients without AVD who had received stress dose steroids intraoperatively had lower median early copeptin (11.7 vs 19.1 pmol/L, p = 0.027). In early postoperative copeptin samples, the optimal copeptin cut point for AVD diagnosis was < 8.5 pmol/L, and a level > 22.9 pmol/L had predicative utility in excluding AVD. Caution should be used when interpreting copeptin results, as patients administered glucocorticoids intraoperatively without AVD had lower median copeptin concentrations.

Use of mindfulness training to improve BAC self-estimation during a drinking episode.

Individuals are often inaccurate at estimating levels of intoxication following doses of alcohol. Previous research has shown that when required to estimate (BAC) at different time points, participants often underestimate their BACs and amounts of alcohol consumed. The present study aimed to increase drinkers' BAC estimation accuracy after drinking alcohol using mindfulness-based feedback to increase their awareness of the interoceptive cues associated with alcohol intoxication. Thirty-three adults were given 0.65 g/kg of alcohol and received one of three training conditions: BAC feedback only, body scan exercise + BAC feedback and no treatment control. Those in the BAC feedback group received feedback concerning their observed BAC during dose exposure. Participants in the body scan group received BAC feedback and underwent a mindfulness exercise to enhance their perception of the acute subjective effects of alcohol. The control group received no BAC estimation training. Participants attended four study sessions: Two training sessions where participants underwent structured training based on their condition and two retention sessions to test for the lasting effects of the training exercises. Retention tests showed that participants in both treatment groups were most accurate in estimating their BACs. There were no differences among the groups in their perceived levels of intoxication at posttraining. The findings suggest that BAC feedback, alone and in combination with, mindfulness training can improve accuracy in estimating BACs. The findings provide preliminary support for the efficacy of mindfulness training in combination with BAC feedback to improve BAC estimation accuracy. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The Acquisition of Static and Dynamic Intervention Skills by Graduate Speech-Language Pathology Students.

Speech-language pathology programs use simulated learning experiences (SLEs) to teach graduate student clinicians about fidelity to therapeutic interventions, including static skills (clinical actions that are delivered in a prespecified way regardless of the client's behavior) and dynamic skills (contingent responses formulated in response to a client's behavior). The purpose of this study was to explore student learning of static and dynamic skills throughout SLEs and live clinical practice. Thirty-three speech-language pathology graduate students participated in this study. Students were first trained to deliver an intervention before having their treatment fidelity measured at three time points: an initial SLE, actual clinical practice, and a final SLE. Treatment fidelity was first summarized using an overall accuracy score and then separated by static and dynamic skills. We hypothesized that (a) overall accuracy would increase from the initial simulation to treatment but remain steady from treatment to the final simulation and that (b) students would acquire dynamic skills more slowly than static skills. In line with our hypotheses, students' overall accuracy improved over time. Although accuracy for static skills was mostly established after the first simulation, dynamic skills remained less accurate, with a slower acquisition timeline. These results demonstrate that SLEs are efficacious in teaching students the clinical skills needed for actual clinical practice. Furthermore, we show that dynamic skills are more difficult for students to learn and implement than static skills, which suggests the need for greater attention to dynamic skill acquisition during clinical education.

Cordyceps militaris: A Comprehensive Study on Laboratory Cultivation and Anticancer Potential in Dalton's Ascites Lymphoma Tumor Model.

Cancer, a predominant cause of mortality, poses a formidable challenge in our pursuit of elevating life expectancy. Throughout history, individuals have sought natural remedies with minimal side effects as an appealing substitute for chemotherapeutic drugs. One such remedy is Cordyceps militaris, a renowned medicinal mushroom deeply entrenched in Asian ethnomedicine. Revered for its rejuvenating and curative attributes, it relied upon for ages. The mushroom's soaring demand outpaced natural availability, necessitating controlled laboratory cultivation as the core focus and exploring the potential of methanolic extracts from harvested Cordyceps militaris fruiting bodies against Dalton's Lymphoma Ascites (DLA) cells in vitro, with a specific emphasis on its anticancer traits. For cultivation, we employed a diverse range of rice substrates, among which bora rice showed promising growth of C. militaris fruiting bodies. To assess DLA cell cytotoxicity, several assays, including trypan blue exclusion assay, MTT assay, and LDH assay, were employed at different time points (24-96 h), which provided valuable insights on DLA cell viability and proliferation, shedding light on its therapeutic potential against cancer. Our studies unveiled that methanolic extract prompts apoptosis in DLA cells via AO/EB dual staining, manifesting consistent apoptosis indicators such as membrane blebbing, chromatin condensation, nuclei fragmentation, and cellular shrinkage at 48-96 h of treatment. Furthermore, these striking repercussions of apoptosis were comprehended by an in silico approach having molecular docking simulation against antiapoptotic proteins like BCL-2, BCL-XL, MCL-1, BFL-1 HSP100. Methanolic C. militaris extracts exhibited cytotoxicity and apoptotic alterations in DLA cells.

Neural Mechanisms Determining the Duration of Task-free, Self-paced Visual Perception.

Humans spend hours each day spontaneously engaging with visual content, free from specific tasks and at their own pace. Currently, the brain mechanisms determining the duration of self-paced perceptual behavior remain largely unknown. Here, participants viewed naturalistic images under task-free settings and self-paced each image's viewing duration while undergoing EEG and pupillometry recordings. Across two independent data sets, we observed large inter- and intra-individual variability in viewing duration. However, beyond an image's presentation order and category, specific image content had no consistent effects on spontaneous viewing duration across participants. Overall, longer viewing durations were associated with sustained enhanced posterior positivity and anterior negativity in the ERPs. Individual-specific variations in the spontaneous viewing duration were consistently correlated with evoked EEG activity amplitudes and pupil size changes. By contrast, presentation order was selectively correlated with baseline alpha power and baseline pupil size. Critically, spontaneous viewing duration was strongly predicted by the temporal stability in neural activity patterns starting as early as 350msec after image onset, suggesting that early neural stability is a key predictor for sustained perceptual engagement. Interestingly, neither bottom-up nor top-down predictions about image category influenced spontaneous viewing duration. Overall, these results suggest that individual-specific factors can influence perceptual processing at a surprisingly early time point and influence the multifaceted ebb and flow of spontaneous human perceptual behavior in naturalistic settings.

Submission to Special Issue to Explainable Representation Learning-Based Intelligent Inspection and Maintenance of Complex Systems: Synchronization of Inertial Neural Networks With Unbounded Delays via Sampled-Data Control.

This article addresses the synchronization issue for inertial neural networks (INNs) with heterogeneous time-varying delays and unbounded distributed delays, in which the state quantization is considered. First, by fully considering the delay and sampling time point information, a modified looped-functional is proposed for the synchronization error system. Compared with the existing Lyapunov-Krasovskii functional (LKF), the proposed functional contains the sawtooth structure term V8(t) and the time-varying terms ex(t-βħ (t)) and ey(t-βħ (t)) . Then, the obtained constraints may be further relaxed. Based on the functional and integral inequality, less conservative synchronization criteria are derived as the basis of controller design. In addition, the required quantized sampled-data controller is proposed by solving a set of linear matrix inequalities. Finally, two numerical examples are given to show the effectiveness and superiority of the proposed scheme in this article.

Expectation Modulates Repetition Suppression at Later But Not Early Stages during Visual Word Recognition: Evidence from Event-related Potentials.

Visual word recognition is commonly rapid and efficient, incorporating top-down predictive processing mechanisms. Neuroimaging studies with face stimuli suggest that repetition suppression (RS) reflects predictive processing at the neural level, as this effect is larger when repetitions are more frequent, that is, more expected. It remains unclear, however, at the temporal level whether and how RS and its modulation by expectation occur in visual word recognition. To address this gap, the present study aimed to investigate the presence and time course of these effects during visual word recognition using EEG. Thirty-six native Cantonese speakers were presented with pairs of Chinese written words and performed a nonlinguistic oddball task. The second word of a pair was either a repetition of the first or a different word (alternation). In repetition blocks, 75% of trials were repetitions and 25% were alternations, whereas the reverse was true in alternation blocks. Topographic analysis of variance of EEG at each time point showed robust RS effects in three time windows (141-227 msec, 242-445 msec, and 467-513 msec) reflecting facilitation of visual word recognition. Importantly, the modulation of RS by expectation was observed at the late rather than early intervals (334-387 msec, 465-550 msec, and 559-632 msec) and more than 100 msec after the first RS effects. In the predictive coding view of RS, only late repetition effects are modulated by expectation, whereas early RS effects may be mediated by lower-level predictions. Taken together, our findings provide the first EEG evidence revealing distinct temporal dynamics of RS effects and P(rep) effects in visual processing of Chinese words.

Subcutaneous administration of ceftazidime at 20 and 40 mg/kg produces theoretically therapeutic plasma concentrations for at least 120 hours in red-eared sliders (Trachemys scripta elegans).

To evaluate and compare the pharmacokinetic parameters of SC ceftazidime administered at 20 and 40 mg/kg to red-eared sliders. 8 adult red-eared sliders (Trachemys scripta elegans). In a sequential, 2-period study with a 3-week washout period between treatments, ceftazidime was administered SC to turtles at 20 and 40 mg/kg. Blood samples were collected from the subcarapacial sinus at 0, 24, 48, 72, 96, and 120 hours after ceftazidime administration. Plasma ceftazidime concentrations were quantified using reversed-phase HPLC. Mean plasma half-life after 20- and 40-mg/kg dosing was 39.75 ± 8.0 hours and 33.03 ± 6.56 hours, respectively. Mean maximum plasma concentration after 20- and 40-mg/kg dosing was 71.0 ± 15.93 µg/mL and 120.0 ± 30.62 µg/mL, respectively. Mean plasma ceftazidime concentrations remained ≥ 8 µg/mL, the theoretical MIC for various reptile pathogens for all time points. Results indicate that ceftazidime dosed at either 20 or 40 mg/kg produces plasma concentrations exceeding the theoretical MIC of various reptile pathogens for at least 120 hours. An ideal dosing interval could not be determined, as all plasma concentrations remained above the threshold of interest for all time points. Follow-up studies should focus on establishing a dosing interval and more rigorous monitoring for potential adverse effects.

Timing of Worsening Renal Function in Patients Hospitalized for Heart Failure Exacerbation Who Were Being Treated With Intravenous Diuretic Therapy.

This retrospective observational study investigated the incidence of worsening renal function (WRF) in patients hospitalized for heart failure (HF) and treated with intravenous diuretics in Japan.Methods and Results: Associations between WRF at any point and HF treatments, and the effects of WRF on outcomes were evaluated (Diagnosis Procedure Combination database). Of 1,788 patients analyzed (mean [±SD] age 80.5±10.2 years; 54.4% male), 641 (35.9%) had WRF during a course of hospitalization for worsening HF: 208 (32.4%) presented with WRF before admission (BA-WRF; estimated glomerular filtration rate decreased by ≥25% from baseline at least once between 30 days prior to admission and admission); 44 (6.9%) had WRF that persisted before and after admission (P-WRF); and 389 (60.7%) had WRF develop after admission (AA-WRF). Delayed initial diuretic administration, higher maximum doses of intravenous diuretics during hospitalization, and diuretic readministration during hospitalization were associated with a significantly higher incidence of AA-WRF. Patients with WRF at any time point were at higher risk of death during hospitalization compared with patients without WRF, with adjusted hazard ratios of 3.56 (95% confidence interval [CI] 2.23-5.69) for BA-WRF, 3.23 (95% CI 2.21-4.71) for AA-WRF, and 13.16 (95% CI 8.19-21.15) for P-WRF (all P<0.0001). Forty percent of WRF occurred before admission for acute HF; there was no difference in mortality between patients with BA-WRF and AA-WRF.

Dry needling combined with exercise therapy: Effects on wrist flexors spasticity in post-stroke patients - A randomized controlled trial.

The positive contribution of dry needling (DN) in conjunction with exercise therapy for patients with stroke and spasticity remains uncertain. To examine the effects of DN combined with exercise therapy on wrist flexor spasticity and motor function in patients with stroke. Twenty-four participants with stroke were randomly assigned to either the DN and exercise therapy group or the DN alone group. Assessments were conducted at baseline, after the 4th treatment session, and 3 weeks post-treatment. A significant Group×Time interaction was observed for wrist active range of motion (ROM) (P = 0.046), favoring the DN with exercise therapy group (∼10° at baseline, ∼15° immediately after the 4th session, and 15.4° at follow-up). The improvements in spasticity, passive ROM, and H-reflex latency were sustained during follow-up. However, there were no significant between-group differences in any outcome at any measurement time point. The combined DN and exercise therapy did not exhibit superiority over DN alone concerning spasticity severity and motor function. However, it demonstrated additional advantages, particularly in improving motor neuron excitability and wrist passive extension.

Work for them or myself: a motivational approach to study the influences of supervisor bottom-line mentality on employee exhaustion

ABSTRACT Extending current bottom-line mentality research, this paper provides a new theoretical perspective for examining the how and when supervisor bottom-line mentality (i.e., supervisors who solely focus on bottom-line attainments at the expense of other priorities) is related to employee exhaustion. Drawing on self-determination theory, it is proposed that supervisor bottom-line mentality is positively related to external regulation and negatively related to intrinsic motivation, both of which can further predict employee exhaustion. Leader-member exchange is also proposed as a boundary condition that prevents the negative relationship between supervisor bottom-line mentality and intrinsic motivation but enhances the positive relationship with external regulation. Data collected at three time points from 251 employees in China provide support for most hypotheses, except the relationship between supervisor bottom-line mentality and intrinsic motivation. The proposed negative relationship was only significant after including control variables. Theoretical and practical implications are discussed and directions for future research are provided.

Skeletal stem cells in bone development, homeostasis and disease.

Tissue-resident stem cells are essential for development and repair, and in the skeleton this function is fulfilled by recently identified skeletal stem cells (SSCs). However, recent work has identified that SSCs are not monolithic, with long bones, craniofacial sites, and the spine being formed by distinct stem cells. Recent studies have utilized techniques such as fluorescence-activated cell sorting (FACS), lineage tracing and single-cell sequencing to investigate the involvement of SSCs in bone development, homeostasis and disease. These investigations have allowed researchers to map the lineage commitment trajectory of SSCs in different parts of the body and at different time points. Furthermore, recent studies have shed light on the characteristics of SSCs in both physiological and pathological conditions. This review focuses on discussing the spatiotemporal distribution of SSCs and enhancing our understanding of the diversity and plasticity of SSCs by summarizing recent discoveries.

Monitoring the Long-Term Effectiveness of Miltefosine in Indian Post-Kala-Azar Dermal Leishmaniasis.

Post-kala-azar dermal leishmaniasis (PKDL), the dermal sequel to visceral leishmaniasis (VL), is characterized by hypopigmented macules (macular) and/or papules and nodules (polymorphic). Post-kala-azar dermal leishmaniasis plays a significant role in disease transmission, emphasizing the need for monitoring chemotherapeutic effectiveness. Accordingly, this study aimed to quantify the parasite burden in PKDL patients after treatment with miltefosine by a quantitative polymerase chain reaction (qPCR). A Leishmania kinetoplastid gene-targeted qPCR was undertaken using DNA from skin biopsy specimens of patients with PKDL at three time points, i.e., at disease presentation (week 0, n = 157, group 1), upon completion of treatment (week 12, n = 39, group 2), and at any time point 6 months after completion of treatment (week ≥36, n = 54, group 3). A cycle threshold (Ct) <30 was considered the cutoff for positivity, and load was quantified as the number of parasites/µg genomic DNA (gDNA); cure was considered when samples had a Ct >30. The parasite load at disease presentation (group 1) was 10,769 (1,339-80,441)/µg gDNA (median [interquartile range]). In groups 2 and 3, qPCR results were negative in 35/39 cases (89.7%) and 48/54 cases (88.8%), respectively. In the 10/93 (10.8%) qPCR-positive cases, the parasite burdens in groups 2 and 3 were 2,420 (1,205-5,661)/µg gDNA and 22,195 (5,524-100,106)/µg gDNA, respectively. Serial monitoring was undertaken in 45 randomly selected cases that had completed treatment; all cases in groups 2 or 3 had a Ct >30, indicating cure. Overall, qPCR confirmed an 89.2% cure (as 83/93 cases showed parasite clearance), and the persistent qPCR positivity was attributed to nonadherence to treatment or unresponsiveness to miltefosine and remains to be investigated.

Mass Drug Administration to Reduce Malaria Transmission: A Systematic Review and Meta-Analysis.

Malaria remains a significant cause of morbidity and mortality, even in low-transmission settings. With the advent of longer acting, more effective, and well-tolerated antimalarials, there is renewed interest in the efficacy of mass drug administration (MDA) to accelerate to elimination. We conducted a systematic review and meta-analysis to assess the efficacy of MDA to reduce the incidence and prevalence of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) infection. From 1,044 articles screened, 14 articles, including 10 randomized controlled trials (RCTs), were identified. Five included data on Pf only; five included Pf and Pv. Two of the Pf studies were conducted in areas of high-moderate transmission, the remainder were in areas of low-very low transmission. In higher transmission areas, MDA reduced incidence of Pf parasitemia (rate ratio = 0.61, 95% CI: 0.40-0.92; moderate certainty) 1 to 3 months after drug administration; no significant effect of MDA on Pf parasitemia prevalence was detected 1 to 3 months post-MDA (risk ratio [RR] = 1.76, 95% CI: 0.58-5.36; low certainty). In lower transmission settings, both incidence and prevalence of Pf parasitemia were reduced 1 to 3 months post-MDA (rate ratio = 0.37, 95% CI: 0.21-0.66; RR = 0.25, 95% CI: 0.15-0.41, respectively). Pv prevalence was reduced 1 to 3 months post-MDA (RR = 0.15, 95% CI: 0.10-0.24); there were no RCTs providing data on incidence of Pv. There was no significant effect of MDA at later time points. MDA may have short-term benefits; however, there was no evidence for longer term impact, although none of the trials assessed prolonged interventions.

Redefining Classical Theory of Humours (Akhlat) with Emphasis on Khilt-e-Sauda (Black Bile) Through its Physiological Role

Background: According to Hippocrates, Akhlat is of four types, i.e., Dam (Blood), Balgham (Phlegm), Safra (Yellow Bile), and Sauda (Black Bile). The correct proportion of these fluids in the body, in terms of quality and quantity, leads to health, while their irregular distribution leads to diseases. The argument presented in this paper will encompass both Tabayi and Ghair Tabayi Sauda. Objective: However, in light of recent advances in the area of molecular biology and biochemistry of the human body, we aim to discuss Sauda as a Khilt in the context of human physiology. We propose that the chemico-biological / physiological role of the molecule rather than its structure will define its placement in Khilt-e-Sauda. Conclusion: Chemico/biological role of the molecule may change with the physiological context, and hence the placement of the molecule previously included in the Khilt-e-Sauda, may or may not remain in that categorization at that point in time in that physiological state.

Association between early lactate-related variables and 6-month neurological outcome in out-of-hospital cardiac arrest patients

IntroductionThe role of lactate measurement in out-of-hospital cardiac arrest (OHCA) survivors remains controversial. We assessed the association between early lactate-related variables, OHCA characteristics, and long-term neurological outcome. MethodsIn OHCA patients who received targeted temperature management, lactate levels were measured at 0, 12, and 24 h after the return of spontaneous circulation. We calculated lactate clearance and time-weighted cumulative lactate (TWCL), which represent the area under the time-lactate curve. The area under the receiver operating characteristic curve (AUC) and the adjusted odds ratios (AORs) of lactate-related variables for predicting 6-month poor outcome (Cerebral Performance Category 3–5) were evaluated. Interactions between lactate variables and characteristics of OHCA were evaluated by a multivariable logistic model with interaction terms and subgroup analysis. ResultsA total of 347 OHCA patients were included. After adjustment, higher lactate levels at the three time points were associated with a poor outcome (AOR 1.10 [95% CI, 1.03–1.18], AOR 1.15 [95% CI, 1.02–1.29], and AOR 1.36 [95% CI, 1.15–1.60], respectively), while TWCL was the only lactate kinetics variable associated with a poor outcome (AOR 1.29 [95% CI, 1.12–1.49]). We identified several interactions between lactate-related variables and OHCA characteristics. In particular, the AUC of TWCL was excellent in cases of noncardiac etiology (AUC 0.92 [95% CI, 0.86–0.96] but only moderate in cardiac etiology (AUC 0.69 [95% CI, 0.62–0.75]). ConclusionsEarly lactate levels, especially at 24 h, and TWCL were independent predictors of neurologic outcome in these patients, whereas lactate clearance was not. The prognostic ability of lactate-related variables varied depending on the OHCA characteristics.