Dynamic tuning of lymphocytes: physiological basis, mechanisms, and function.

Dynamic tuning of cellular responsiveness as a result of repeated stimuli improves the ability of cells to distinguish physiologically meaningful signals from each other and from noise. In particular, lymphocyte activation thresholds are subject to tuning, which contributes to maintaining tolerance to self-antigens and persisting foreign antigens, averting autoimmunity and immune pathogenesis, but allowing responses to strong, structured perturbations that are typically associated with acute infection. Such tuning is also implicated in conferring flexibility to positive selection in the thymus, in controlling the magnitude of the immune response, and in generating memory cells. Additional functional properties are dynamically and differentially tuned in parallel via subthreshold contact interactions between developing or mature lymphocytes and self-antigen-presenting cells. These interactions facilitate and regulate lymphocyte viability, maintain their functional integrity, and influence their responses to foreign antigens and accessory signals, qualitatively and quantitatively. Bidirectional tuning of T cells and antigen-presenting cells leads to the definition of homeostatic set points, thus maximizing clonal diversity.

Neural mechanisms of social comparison in subthreshold depression.

Social comparison is a common phenomenon in our daily life, through which people get to know themselves, and plays an important role in depression. In this study, event-related potential (ERP) was used to explore the temporal course of social comparison processing in the subthreshold depression group. Electrophysiological recordings were acquired from 30 subthreshold depressed individuals and 31 healthy individuals while they conducted the adapted dot estimation task. The ERP results revealed that there was a significant difference of feedback-related negativity (FRN) in the process of social comparison. Especially only in the subthreshold depression, the FRN amplitudes of worse off than some, better off than many comparisons were larger than those of upward comparisons and downward comparisons. Our results suggested that the abnormal reward sensitivity for worse off than some, better off than many comparisons might be prodromal symptoms in the subthreshold depression.

Ultrasteep Slope Cryogenic FETs Based on Bilayer Graphene.

Cryogenic field-effect transistors (FETs) offer great potential for applications, the most notable example being classical control electronics for quantum information processors. For the latter, on-chip FETs with low power consumption are crucial. This requires operating voltages in the millivolt range, which are only achievable in devices with ultrasteep subthreshold slopes. However, in conventional cryogenic metal-oxide-semiconductor (MOS)FETs based on bulk material, the experimentally achieved inverse subthreshold slopes saturate around a few mV/dec due to disorder and charged defects at the MOS interface. FETs based on two-dimensional materials offer a promising alternative. Here, we show that FETs based on Bernal stacked bilayer graphene encapsulated in hexagonal boron nitride and graphite gates exhibit inverse subthreshold slopes of down to 250 µV/dec at 0.1 K, approaching the Boltzmann limit. This result indicates an effective suppression of band tailing in van der Waals heterostructures without bulk interfaces, leading to superior device performance at cryogenic temperature.

Structural and functional brain alterations in subthreshold depression: A multimodal coordinate-based meta-analysis.

Imaging studies of subthreshold depression (StD) have reported structural and functional abnormalities in a variety of spatially diverse brain regions. However, there is no consensus among different studies. In the present study, we applied a multimodal meta-analytic approach, the Activation Likelihood Estimation (ALE), to test the hypothesis that StD exhibits spatially convergent structural and functional brain abnormalities compared to healthy controls. A total of 31 articles with 25 experiments were included, collectively representing 1001 subjects with StD. We found consistent differences between StD and healthy controls mainly in the left insula across studies with various neuroimaging methods. Further exploratory analyses found structural atrophy and decreased functional activities in the right pallidum and thalamus in StD, and abnormal spontaneous activity converged to the middle frontal gyrus. Coordinate-based meta-analysis found spatially convergent structural and functional impairments in StD. These findings provide novel insights for understanding the neural underpinnings of subthreshold depression and enlighten the potential targets for its early screening and therapeutic interventions in the future.

Normalization of increasing shocking coil impedance with full output synchronized shock.

INTRODUCTION: Impedance is a crucial parameter in cardiovascular implantable electronic devices (CIEDs). Clinically, most CIEDs measure impedance using low voltage sub-threshold measurement (LVSM). Although the LVSM of shock impedance (LVSM-SI) is generally comparable with high voltage shock impedance (HVSI), LVSM-SI might be inaccurate if peri-lead tissue degeneration occurs. METHODS AND RESULTS: We present a case of elevated LVSM-SI occurring 8 years post-lead implantation, possibly attributed to encapsulation of the right ventricular lead coil. After 0.1 J shock was delivered, a full output synchronized shock was administered to measure HVSI, revealing a normal value. Furthermore, LVSM-SI was normalized and maintained within the normal range during long-term follow-up. CONCLUSION: Our findings suggest conducting a full-output synchronized shock test to assess HVSI when abnormal LVSM-SI is detected in the remote phase post-ICD implantation, which may be considered to help normalize LVSM shock impedance.

Mapping 15-year depressive symptom transitions in late life: population-based cohort study.

BACKGROUND: The longitudinal course of late-life depression remains under-studied. AIMS: To describe transitions along the depression continuum in old age and to identify factors associated with specific transition patterns. METHOD: We analysed 15-year longitudinal data on 2745 dementia-free persons aged 60+ from the population-based Swedish National Study on Aging and Care in Kungsholmen. Depression (minor and major) was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; subsyndromal depression (SSD) was operationalised as the presence of ≥2 symptoms without depression. Multistate survival models were used to map depression transitions, including death, and to examine the association of psychosocial (social network, connection and support), lifestyle (smoking, alcohol consumption and physical activity) and clinical (somatic disease count) factors with transition patterns. RESULTS: Over the follow-up, 19.1% had ≥1 transitions across depressive states, while 6.5% had ≥2. Each additional somatic disease was associated with a higher hazard of progression from no depression (No Dep) to SSD (hazard ratio 1.09; 1.07-1.10) and depression (Dep) (hazard ratio 1.06; 1.04-1.08), but also with a lower recovery (HRSSD-No Dep 0.95; 0.93-0.97 [where 'HR' refers to 'hazard ratio']; HRDep-No Dep 0.96; 0.93-0.99). Physical activity was associated with an increased hazard of recovery to no depression from SSD (hazard ratio 1.49; 1.28-1.73) and depression (hazard ratio 1.20; 1.00-1.44), while a richer social network was associated with both higher recovery from (HRSSD-No Dep 1.44; 1.26-1.66; HRDep-No Dep 1.51; 1.34-1.71) and lower progression hazards to a worse depressive state (HRNo Dep-SSD 0.81; 0.70-0.94; HRNo Dep-Dep 0.58; 0.46-0.73; HRSSD-Dep 0.66; 0.44-0.98). CONCLUSIONS: Older people may present with heterogeneous depressive trajectories. Targeting the accumulation of somatic diseases and enhancing social interactions may be appropriate for both depression prevention and burden reduction, while promoting physical activity may primarily benefit recovery from depressive disorders.

Cellular resolution contributions to ictal population signals.

OBJECTIVE: The increased amplitude of ictal activity is a common feature of epileptic seizures, but the determinants of this amplitude have not been identified. Clinically, ictal amplitudes are measured electrographically (using, e.g., electroencephalography, electrocorticography, and depth electrodes), but these methods do not enable the assessment of the activity of individual neurons. Population signal may increase from three potential sources: (1) increased synchrony (i.e., more coactive neurons); (2) altered active state, from bursts of action potentials and/or paroxysmal depolarizing shifts in membrane potential; and (3) altered subthreshold state, which includes all lower levels of activity. Here, we quantify the fraction of ictal signal from each source. METHODS: To identify the cellular determinants of the ictal signal, we measured single cell and population electrical activity and neuronal calcium levels via optical imaging of the genetically encoded calcium indicator (GECI) GCaMP. Spontaneous seizure activity was assessed with microendoscopy in an APP/PS1 mouse with focal cortical injury and via widefield imaging in the organotypic hippocampal slice cultures (OHSCs) model of posttraumatic epilepsy. Single cell calcium signals were linked to a range of electrical activities by performing simultaneous GECI-based calcium imaging and whole-cell patch-clamp recordings in spontaneously seizing OHSCs. Neuronal resolution calcium imaging of spontaneous seizures was then used to quantify the cellular contributions to population-level ictal signal. RESULTS: The seizure onset signal was primarily driven by increased subthreshold activity, consistent with either barrages of excitatory postsynaptic potentials or sustained membrane depolarization. Unsurprisingly, more neurons entered the active state as seizure activity progressed. However, the increasing fraction of active cells was primarily driven by synchronous reactivation and not from continued recruitment of new populations of neurons into the seizure. SIGNIFICANCE: This work provides a critical link between single neuron activity and population measures of seizure activity.

Efficacy of an Internet- and Mobile-Based Intervention for Subclinical Anxiety and Depression (ICare Prevent) with Two Guidance Formats: Results from a Three-Armed Randomized Controlled Trial.

INTRODUCTION: Limited research exists on intervention efficacy for comorbid subclinical anxiety and depressive disorders, despite their common co-occurrence. Internet- and mobile-based interventions (IMIs) are promising to reach individuals facing subclinical symptoms. OBJECTIVE: This study aimed to evaluate the efficacy of a transdiagnostic and self-tailored IMI in reducing subclinical anxiety and depressive symptom severity with either individualized (IG-IMI) or automated (AG-IMI) guidance compared to a waitlist control group with care-as-usual access (WLC). METHODS: Participants included 566 adults with subclinical anxiety (GAD-7 ≥ 5) and/or depressive (CES-D ≥16) symptoms, who did not meet criteria for a full-syndrome depressive or anxiety disorder. In a three-arm randomized clinical trial, participants were randomized to a cognitive behavioral 7-session IMI plus booster session with IG-IMI (n = 186) or AG-IMI (n = 189) or WLC (n = 191). Primary outcomes included observer-rated anxiety (HAM-A) and depressive (QIDS) symptom severity 8 weeks after randomization assessed by blinded raters via telephone. Follow-up outcomes at 6 and 12 months are reported. RESULTS: Symptom severity was significantly lower with small to medium effects in IG-IMI (anxiety: d = 0.45, depression: d = 0.43) and AG-IMI (anxiety: d = 0.31, depression: d = 0.32) compared to WLC. No significant differences emerged between guidance formats in primary outcomes. There was a significant effect in HAM-A after 6 months favoring AG-IMI. On average, participants completed 85.38% of IG-IMI and 77.38% of AG-IMI. CONCLUSIONS: A transdiagnostic, self-tailored IMI can reduce subclinical anxiety and depressive symptom severity, but 12-month long-term effects were absent. Automated guidance holds promise for enhancing the scalability of IMIs in broad prevention initiatives.

Reduction in motor error by presenting subthreshold somatosensory information during visuomotor tracking tasks.

Weak sensory noise acts on the nervous system and promotes sensory and motor functions. This phenomenon is called stochastic resonance and is expected to be applied for improving biological functions. This study investigated the effect of electrical stimulation on grip force adjustment ability. The coefficient of variation and absolute motor error in grip force was measured during a visuomotor tracking task under different intensities of somatosensory noise. Depending on the style of force exertion, the grip movement used in the visuomotor tracking task consisted of force generation (FG), force relaxation (FR), and constant contraction (Constant) phases. The subthreshold condition resulted in significantly lower coefficient of variation in the Constant phase and motor errors in the FG and Constant phases than the no-noise condition. However, the differences among the other conditions were insignificant. Additionally, we examined the correlation between the motor error in the condition without electrical stimulation and the change in motor error induced by subthreshold electrical stimulation. Significant negative correlations were observed in all FG, FR, and Constant phases. These results indicated that somatosensory noise had a strong effect on subjects with large motor errors and enhanced the grip force adjustment ability. By contrast, subjects with small motor errors had weak improvement in motor control. Although the effect of subthreshold noise varies depending on the individual differences, stochastic resonance is effective in improving motor control ability.

Subthreshold slope below 60 mV/decade in graphene transistors induced by channel geometry at the wafer-scale.

In this paper, we demonstrate experimentally that field-effect transistors with nanoconstricted graphene monolayer channels have a subthreshold swing (SS) below 60 mV/dec, which is slightly dependent on temperature. Two shapes of nanoconstricted graphene monolayers are considered: (i) a bow-tie shape, representative for a symmetric channel, and (ii) a trapezoidal shape, which illustrates an asymmetric channel. While both types of nonuniform channels are opening a bandgap in graphene, thus showing an on/off ratio of 105, the SS in the graphene bow-tie channel is below 60 mV/dec in the temperature range 25 °C-44 °C.

Time Is Ripe for Targeting Per- and Polyfluoroalkyl Substances-Induced Hormesis: Global Aquatic Hotspots and Implications for Ecological Risk Assessment.

Globally implemented ecological risk assessment (ERA) guidelines marginalize hormesis, a biphasic dose-response relationship characterized by low-dose stimulation and high-dose inhibition. The present study illuminated the promise of hormesis as a scientific dose-response model for ERA of per- and polyfluoroalkyl substances (PFAS) represented by perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS). A total of 266 hormetic dose-response relationships were recompiled from 1237 observations, covering 30 species from nine representative taxonomic groups. The standardized hormetic amplitudes followed the log-normal probability distribution, being subject to the limits of biological plasticity but independent of stress inducers. The SHapley Additive exPlanations algorithm revealed that the target endpoint was the most important variable explaining the hormetic amplitudes. Subsequently, quantitative frameworks were established to incorporate hormesis into the predicted no-effect concentration levels, with a lower induction dose and a zero-equivalent point but a broader hormetic zone for PFOS. Realistically, 10,117 observed concentrations of PFOA and PFOS were gathered worldwide, 4% of which fell within hormetic zones, highlighting the environmental relevance of hormesis. Additionally, the hormesis induction potential was identified in other legacy and emerging PFAS as well as their alternatives and mixtures. Collectively, it is time to incorporate the hormesis concept into PFAS studies to facilitate more realistic risk characterizations.

Altered EEG Microstates Dynamics in Individuals with Subthreshold Depression When Generating Negative Future Events.

Negative bias in prospection may play a crucial role in driving and maintaining depression. Recent research suggests abnormal activation and functional connectivity in regions of the default mode network (DMN) during future event generation in depressed individuals. However, the neural dynamics during prospection in these individuals remain unknown. To capture network dynamics at high temporal resolution, we employed electroencephalogram (EEG) microstate analysis. We examined microstate properties during both positive and negative prospection in 35 individuals with subthreshold depression (SD) and 35 controls. We identified similar sets of four canonical microstates (A-D) across groups and conditions. Source analysis indicated that each microstate map partially overlapped with a subsystem of the DMN (A: verbal; B: visual-spatial; C: self-referential; and D: modulation). Notably, alterations in EEG microstates were primarily observed in negative prospection of individuals with SD. Specifically, when generating negative future events, the coverage, occurrence, and duration of microstate A increased, while the coverage and duration of microstates B and D decreased in the SD group compared to controls. Furthermore, we observed altered transitions, particularly involving microstate C, during negative prospection in the SD group. These altered dynamics suggest dysconnectivity between subsystems of the DMN during negative prospection in individuals with SD. In conclusion, we provide novel insights into the neural mechanisms of negative bias in depression. These alterations could serve as specific markers for depression and potential targets for future interventions.

Association of white matter hyperintensities and clinical vascular burden with depressive symptoms in Black older adults.

OBJECTIVES: Black older adults have a higher vascular burden compared to non-Hispanic White (NHW) older adults, which may put them at risk for a form of depression known as vascular depression (VaDep). The literature examining VaDep in Black older adults is sparse. The current study addressed this important gap by examining whether vascular burden was associated with depressive symptoms in Black older adults. METHODS: Participants included 113 Black older adults from the Healthy Brain Project, a substudy of the Health, Aging, and Body Composition Study. In multiple regression analyses, clinical vascular burden (sum of vascular conditions) and white matter hyperintensity (WMH) volume predicted depressive symptoms as measured by the Center for Epidemiologic Studies Depression Scale, controlling for demographic variables. Follow-up analyses compared the associations in the Black subsample and in 179 NHW older adults. RESULTS: Higher total WMH volume, but not clinically-defined vascular burden, predicted higher concurrent depressive symptoms and higher average depressive symptoms over 4 years. Similar associations were found between uncinate fasciculus (UF) WMHs and concurrent depressive symptoms and between superior longitudinal fasciculus WMHs and average depressive symptoms. The association between depressive symptoms and UF WMH was stronger in Black compared to NHW individuals. CONCLUSION: This research is consistent with the VaDep hypothesis and extends it to Black older adults, a group that has historically been underrepresented in the literature. Results highlight WMH in the UF as particularly relevant to depressive symptoms in Black older adults and suggest this group may be particularly vulnerable to the negative effects of WMH.

Neural coding of space by time.

The intertwining of space and time poses a significant scientific challenge, transcending disciplines from philosophy and physics to neuroscience. Deciphering neural coding, marked by its inherent spatial and temporal dimensions, has proven to be a complex task. In this paper, we present insights into temporal and spatial modes of neural coding and their intricate interplay, drawn from neuroscientific findings. We illustrate the conversion of a purely spatial input into the temporal form of a singular spike train, demonstrating storage, transmission to remote locations, and recall through spike bursts corresponding to Sharp Wave Ripples. Moreover, the converted temporal representation can be transformed back into a spatiotemporal pattern. The principles of the transformation process are illustrated using a simple feed-forward spiking neural network. The frequencies and phases of Subthreshold Membrane potential Oscillations play a pivotal role in this framework. The model offers insights into information multiplexing and phenomena such as stretching or compressing time of spike patterns.

Altered static and dynamic functional network connectivity in individuals with subthreshold depression: a large-scale resting-state fMRI study.

Dynamic functional network connectivity (dFNC) is an expansion of static FNC (sFNC) that reflects connectivity variations among brain networks. This study aimed to investigate changes in sFNC and dFNC strength and temporal properties in individuals with subthreshold depression (StD). Forty-two individuals with subthreshold depression and 38 healthy controls (HCs) were included in this study. Group independent component analysis (GICA) was used to determine target resting-state networks, namely, executive control network (ECN), default mode network (DMN), sensorimotor network (SMN) and dorsal attentional network (DAN). Sliding window and k-means clustering analyses were used to identify dFNC patterns and temporal properties in each subject. We compared sFNC and dFNC differences between the StD and HCs groups. Relationships between changes in FNC strength, temporal properties, and neurophysiological score were evaluated by Spearman's correlation analysis. The sFNC analysis revealed decreased FNC strength in StD individuals, including the DMN-CEN, DMN-SMN, SMN-CEN, and SMN-DAN. In the dFNC analysis, 4 reoccurring FNC patterns were identified. Compared to HCs, individuals with StD had increased mean dwell time and fraction time in a weakly connected state (state 4), which is associated with self-focused thinking status. In addition, the StD group demonstrated decreased dFNC strength between the DMN-DAN in state 2. sFNC strength (DMN-ECN) and temporal properties were correlated with HAMD-17 score in StD individuals (all p < 0.01). Our study provides new evidence on aberrant time-varying brain activity and large-scale network interaction disruptions in StD individuals, which may provide novel insight to better understand the underlying neuropathological mechanisms.

Brain-gut axis mechanism of subthreshold nonsuicidal self-injury addictive features in adolescents.

Nonsuicidal self-injury (NSSI) is associated with an increased risk of suicide. As the diagnostic criteria outlined in DSM-5 and other related clinical studies, a patient must have engaged in self-injurious behavior at least 5 times within the past year. However, patients with fewer than 5 self-injury behaviors should not be ignored. Our study included 46 adolescents aged 10-19 years with subthreshold NSSI (sNSSI), along with a control group of 50 healthy adolescents matched for age and other factors. We collected resting-state functional magnetic resonance imaging data and stool samples. The Ottawa Self-Injury Inventory and Deliberate Self-Harm Inventory were used to evaluate self-harm behaviors and addictive features. Local brain activity was assessed using fractional amplitude of low-frequency fluctuations (fALFF), and brain regions with abnormal fALFF were selected as seeds for whole-brain functional connectivity analysis. Stool samples were identified using 16S rDNA amplicon sequencing, and the LDA Effect Size method was used to explore significant differences between grouped samples. Mediation analysis was performed to investigate the brain-gut axis mechanisms of addictive features in sNSSI. We found that compared with healthy controls, sNSSI patients have abnormal fALFF in left thalamus and posterior cingulate cortex, dysconnectivities of left thalamus, and decreased Prevotellaceae. Our results suggested that addictive features of sNSSI may have a brain-gut mechanism. Furtherly, patients with 1-4 NSSI behaviors in the past year should have separate name for identification, such as "subthreshold NSSI".

Effects of a single subanesthetic dose of esketamine on postoperative subthreshold depressive symptoms in patients undergoing unilateral modified radical mastectomy: a randomised, controlled, double-blind trial.

BACKGROUND: Breast cancer is the most common malignant tumor in females worldwide. During disease development, breast cancer patients suffer anxious and depressed, which may lead to worse quality of life or even higher mortality. Esketamine has been regarded as an antidepressant in breast cancer patients with mild or moderate depression. Here, we wonder whether the administration of esketamine could reduce the postoperative depressive symptom score of breast cancer patients who have no preoperative depression. METHODS: A total of 64 patients treated with unilateral modified radical mastectomy were randomly divided into an experimental group (esketamine group, Group E) and a control group (Group C), with 32 cases in each one. After anesthesia induction, Group C received 0.2 ml/kg of normal saline intravenously and Group E was administered 0.2 mg/kg intravenous esketamine. The primary outcome was the Patient Health Questionnaire-9 (PHQ-9) scores. The secondary outcomes included the Visual Analogue Scale (VAS) scores for pain, inflammatory markers, perioperative-related indicators, and the incidence of postoperative delirium, nausea and vomiting. RESULTS: The PHQ-9 score on postoperative day (POD) 1 in Group E declined from the preoperative level, while the score in Group C was higher than before, and the former was far lower than the latter (P = 0.047). There is no statistically significant difference in PHQ-9 scores between Group E and Group C on POD 3, 7, and 30. Moreover, the postoperative leukocyte level of Group E was higher than that of Group C, and the difference was statistically significant (P = 0.030). CONCLUSIONS: A single subanesthetic dose of esketamine can result in lower postoperative score on subthreshold depressive symptoms compared to the Group C on POD 1, without increasing the occurrence of postoperative adverse reactions. TRIAL REGISTRATION: Registration number: Chinese Clinical Trial Registry ChiCTR2200057028. Date of registration: 26/02/2022.

The effect of nondamaging subthreshold laser therapy in patients with chronic central serous chorioretinopathy.

PURPOSE: To evaluate the efficacy of nondamaging subthreshold laser therapy in Korean patients with chronic central serous chorioretinopathy (cCSC). METHODS: This retrospective interventional case series included 31 patients (31 eyes) with cCSC who underwent nondamaging laser therapy using Endpoint Management (EpM) software. Since a barely visible burn of the test spot was defined as 100% pulse energy, 30% pulse energy with a 200-µm spot was titrated to treat the macular area based on EpM settings. A 30% pulse laser with a spacing of 0.25-beam diameter was applied to cover the macular area where hyperfluorescent leaks were observed on fluorescein angiography. Changes in central macular thickness (CMT), subretinal fluid (SRF) height, subfoveal choroidal thickness (SCT), and logarithm of the minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA) were measured at baseline and after 3 and 6 months. If the subretinal fluid persisted for 3 months, retreatment was performed. RESULTS: At 6 months post-treatment, the complete SRF resolution rate was 48.39% (15/31 eyes), and the partial SRF resolution rate was 12.90% (4/31 eyes). The change in mean BCVA (logMAR) was not significant (0.31 ± 0.29 at the baseline and 0.31 ± 0.40 at month 6) (p = 0.943). At the baseline, the mean CMT (µm) decreased from 350.74 ± 112.76 at baseline to 239.71 ± 130.25 at month 6 (p < 0.001), and the mean SRF height (µm) decreased from 193.16 ± 90.69 at baseline to 70.58 ± 100.00 at month 6 (p < 0.001). However, the change in SCT was not statistically significant (p = 0.516). In 15 patients who were retreated at month 3, the mean SRF height (µm) decreased significantly from 144.67 ± 74.01 at month 3 to 77.13 ± 63.77 at month 6 (p = 0.002). No side effects associated with laser therapy were observed during the 6-month follow-up. CONCLUSIONS: Nondamaging laser therapy with a modified macular treatment was effective in reducing CMT and SRF and showed favorable visual and anatomical outcomes in patients with cCSC.

Subthreshold micropulse laser combined with anti-vascular endothelial growth factor therapy for diabetic macular edema: a systematic review and meta-analysis.

PURPOSE: To evaluate the effects of subthreshold micropulse laser (SML) in addition to anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME). METHODS: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were systematically searched for studies that compared anti-VEGF with SML and anti-VEGF monotherapy for DME. Outcome measures were best-corrected visual acuity (BCVA), central macular thickness (CMT), and the number of anti-VEGF injections. RESULTS: Eight studies including 493 eyes were selected. Four studies were randomized controlled, and the other four were retrospective. Meta-analysis showed that there was no significant difference in BCVA (mean difference [MD] -0.04; 95%CI -0.09 to 0.01 logMAR; P = 0.13;). CMT was thinner in the group of anti-VEGF with SML (MD -11.08; 95%CI -21.04 to -1.12 µm; P = 0.03); however, it was due to a single study that weighed higher, and the sensitivity and subcategory analyses did not support the finding. The number of anti-VEGF injections was significantly decreased in the group of anti-VEGF with SML (MD -2.22; 95%CI -3.02 to -1.42; P < 0.0001). CONCLUSION: Current evidence indicates that adding SML to anti-VEGF therapy could significantly reduce the number of anti-VEGF injections compared to anti-VEGF monotherapy, while achieve similar BCVA and CMT.

Subthreshold laser treatment in retinal diseases: a mini review.

PURPOSE: To summarize the mechanism and the clinical applications of subthreshold laser (STL) in retinal practice. Subthreshold or "non-destructive" laser includes all types of laser treatments that produce minimal or no damage to the tissues and no visible signs after application. METHODS: A descriptive review of articles from literature databases (PubMed, Medline, Embase, Cochrane, Web of Science) published before August 2023, which discuss current STL treatments of retinal diseases. RESULTS: This review provides evidence for STL as a treatment option for central serous chorioretinopathy, diabetic retinopathy, age-related macular degeneration, macular edema due to retinal vein occlusion, and other maculopathies. In most published reports, STL has shown a therapeutic effect without damage to the underlying tissue. CONCLUSION: Subthreshold laser treatment has shown safety and efficacy in the management of some retinal and macular diseases. Stimulation of the retinal pigment epithelium without destroying adjacent neuroretina has been shown to be sufficient in inducing retinal repair in many clinical cases. Recent research and clinical studies continue to explore the mechanisms and improving therapeutic benefits of this technology as well as extend the range of retinal disorders treatable by this modality.