Microwave ablation combined with PD-L1 blockade synergistically promotes Cxcl9-mediated antitumor immunity.

Although microwave ablation (MWA) is an important curative therapy in colorectal cancer liver metastasis, recurrence still occurs clinically. Our previous studies have shown that the expression of programmed cell death 1 ligand 1 (PD-L1) is upregulated following MWA, suggesting that MWA combined with anti-PD-L1 treatment can serve as a promising clinical therapeutic strategy against cancer. Using MWA-treated preclinical mice models, MWA combined with αPD-L1 treatment decreased tumor growth and prolonged overall survival (OS). Furthermore, through flow cytometry and single-cell RNA sequencing analysis, we determined that the MWA plus αPD-L1 therapy significantly suppressed CD8+ T cell exhaustion and enhanced their effector function. A significant increase in γ-interferon (IFN-γ) stimulated transcription factors, specifically Irf8, was observed. This enhancement facilitated the polarization of tumor-associated macrophages (TAM1s and TAM2s) through the nuclear factor-κB/JAK-STAT1 signaling pathway. Furthermore, the combination therapy stimulated the production of CXC motif chemokine ligand (CXCL9) by TAM1s and tumor cells, potentially increasing the chemotaxis of CD8 T cells and Th1 cells. Knocking out Cxcl9 in MC38 tumor cells or using CXCL9 blockade enhanced tumor growth of untreated tumors and shortened OS. Taken together, our study showed that blocking the IFN-γ-Cxcl9-CD8+ T axis promoted tumor progression and discovered a potential involvement of IRF8-regulated TAMs in preventing T cell exhaustion. Collectively, we identified that the combination of MWA with anti-PD-L1 treatment holds promise as a therapeutic strategy to rejuvenate the immune response against tumors. This merits further exploration in clinical studies.

Two-sample inference procedures under nonproportional hazards.

We introduce a new two-sample inference procedure to assess the relative performance of two groups over time. Our model-free method does not assume proportional hazards, making it suitable for scenarios where nonproportional hazards may exist. Our procedure includes a diagnostic tau plot to identify changes in hazard timing and a formal inference procedure. The tau-based measures we develop are clinically meaningful and provide interpretable estimands to summarize the treatment effect over time. Our proposed statistic is a U-statistic and exhibits a martingale structure, allowing us to construct confidence intervals and perform hypothesis testing. Our approach is robust with respect to the censoring distribution. We also demonstrate how our method can be applied for sensitivity analysis in scenarios with missing tail information due to insufficient follow-up. Without censoring, Kendall's tau estimator we propose reduces to the Wilcoxon-Mann-Whitney statistic. We evaluate our method using simulations to compare its performance with the restricted mean survival time and log-rank statistics. We also apply our approach to data from several published oncology clinical trials where nonproportional hazards may exist.

A single centre prospective study of three device-assisted therapies for Parkinson's disease.

Comparative studies assessing outcomes with the three device-assisted therapies could help to individualise treatment for patients living with Parkinson's disease. We designed a single-centre non-randomised prospective observational study assessing the quality of life (QoL), motor and non-motor outcomes at 6 and 12-months in patients treated with subcutaneous apomorphine continuous 16-hours infusion (APO), levodopa-carbidopa intestinal gel (LCIG) or subthalamic nucleus deep brain stimulation (STN-DBS). In this study, 66 patients were included (13 APO; 19 LCIG; 34 STN-DBS). At baseline, cognitive, non-motor and motor scores were significantly less severe in the STN-DBS group, whereas the LCIG group had a longer disease duration and higher non-motor scores. In the APO group, there were no statistically significant changes in non-motor, motor and QoL scales. The LCIG group had significant changes in QoL and motor scales that were significant after multiple comparison analysis at 6 and 12-months. The STN-DBS group showed improvement in QoL scores and non-motor and motor scores at 6 and 12-months after multiple comparison analysis. In this real-life prospective study, device-assisted therapies showed differences in their effects on QoL and motor and non-motor function at 12-months. However, there were also differences in baseline characteristics of the patient groups that were not based on pre-determined selection criteria. Differences in characteristics of patients offered and/or treatment with different device-assisted therapies may reflect within-centre biases that may, in turn, influence perceptions of treatment efficacy or outcomes. Treatment centres should be aware of this potential confounder when assessing and offering device-assisted treatment options to their patients and potential baseline differences need to be taken into consideration when comparing the results of non-randomised studies.

Irritable bowel syndrome based on Rome IV diagnostic criteria associates with non-motor symptoms of Parkinson's disease.

BACKGROUND: Recent concepts suggest that the neuropathological hallmark of Parkinson's disease (PD) may in part originate from the enteric nervous system. We evaluated the frequency of functional gastrointestinal disorders in PD patients using Rome IV criteria and correlated the clinical severity of PD. METHODS: PD patients and matched controls were recruited between January 2020 and December 2021. Rome IV criteria were used to diagnose constipation and irritable bowel syndrome (IBS). Severity of PD motor symptoms was evaluated using UPDRS part III scores and non-motor symptoms using Non-motor Symptoms Scale (NMSS). RESULTS: A total of 99 PD patients and 64 controls were enrolled. The prevalence of constipation (65.7% vs. 34.3%, P < 0.001) and IBS (18.1% vs 5%, P = 0.02) were significantly higher in PD patients than controls. The prevalence of IBS was higher in early-stage PD than advanced-stage PD (14.43% vs. 8.25%, P = 0.02), whereas constipation was more common in advanced stages (71.43% vs. 18.56%, P < 0.001). PD patients with IBS had higher NMSS total scores (P < 0.01) than those without IBS. The severity of IBS correlated with NMSS scores (r = 0.71, P < 0.001), especially subscores in domain 3 assessing mood disorders (r = 0.83, P < 0.001), but not UPDRS part III scores (r = 0.06, P = 0.45). The severity of constipation correlated with the UPDRS part III scores (r = 0.59, P < 0.001) but not the domain 3 mood subscores (r = 0.15, P = 0.07). CONCLUSION: The prevalence of IBS and constipation was higher in PD patients than controls and phenotypic correlation supported the occurrence of IBS with higher non-motor symptom burden, especially mood symptoms, in PD patients.

PD-1/PD-L1 inhibitors for breast cancer: current status, problems and countermeasures / 中国肿瘤生物治疗杂志

@#[摘 要] PD-1/PD-L1抑制剂在乳腺癌免疫治疗中的应用已逐渐成为一种重要的治疗手段，然而对乳腺癌，尤其是三阴性乳腺癌（TNBC）的免疫治疗仍存在某些亟待解决的科学问题，包括PD-1/PD-L1抑制剂单药治疗的有效率欠佳，目前尚无明确的生物标志物来有效筛查治疗敏感人群，免疫相关不良反应（irAE）的发生率高。为了提高疗效和减少irAE的发生，采取以下措施是非常重要的：探讨PD-1/PD-L1抑制剂与其他药物的联合应用方案；采用纳米技术开发选择性靶向肿瘤细胞的纳米载体，降低抗肿瘤药物毒性并提高疗效；探寻开发可预测免疫治疗反应潜力的生物标志物；早期识别和诊疗irAE并建设多学科诊疗协作组（MDT）模式。随着这些措施的积极推进和问题的不断解决，PD-1/PD-L1抑制剂在乳腺癌的治疗中必将呈现出更为广阔的应用前景。

Effects of modern technology (exergame and virtual reality) assisted rehabilitation vs conventional rehabilitation in patients with Parkinson's disease: a network meta-analysis of randomised controlled trials.

BACKGROUND: Modern technological applications, including exergames and virtual technology-assisted rehabilitation (VTAR) programmes, are promising for Parkinson's disease (PD) rehabilitation. However, evidence regarding their efficacy for rehabilitation is inconclusive. OBJECTIVES: This network meta-analysis (NMA) investigated the efficacy of exergames and VTAR on gait and balance outcomes and acceptability for patients with PD. DATA SOURCES: ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect, Web of Science and ClinicalTrials.gov. STUDY SELECTION: Randomised controlled trials (RCTs) investigating changes in gait or balance parameters were included in this study. STUDY APPRAISAL AND SYNTHESIS METHODS: In the NMA, standardised mean differences with 95% confidence intervals were calculated using a frequentist model. GRADE ratings were used to evaluate the quality of evidence in this study. RESULTS: Twenty-three RCTs with 949 participants were included. Exergames and VTAR were associated with significantly better improvements in balance and gait outcomes than usual treatment and other active control interventions. However, exergames were not associated with changes in depressive symptoms. The evaluation of acceptability results indicated that all exergames and VTAR were adequately tolerated, as indicated by the low drop-out rates. LIMITATIONS: Small sample sizes and heterogeneity were the key limitations of this study. CONCLUSION AND IMPLICATIONS OF KEY FINDINGS: This NMA confirmed that exergames are associated with more favourable gait and balance outcomes in patients with PD compared with usual treatment and other active control interventions. GRADE ratings revealed that most direct, indirect and overall network evidence was of low to medium quality. Larger-scale studies with longer follow-up periods are warranted.

Neuroinflammation Upregulated Neuronal Toll-Like Receptors 2 and 4 to Drive Synucleinopathy in Neurodegeneration.

Background: Parkinson's disease (PD) is characterized by intraneuronal α-synuclein aggregation called Lewy bodies and progressive dopaminergic neurodegeneration. Toll-like receptor (TLR) signaling is a major pathway mediating inflammation. The molecular link on how neuroinflammation upregulates neuronal TLRs and induces accumulation of α-synuclein aggregates to drive synucleinopathy remains to be determined. Objective: Despite conditioned medium from microglia and TLR agonists were utilized to study their effects on neuronal cells, a Transwell coculture system, comprising lipopolysaccharide-activated microglia on top and retinoic acid-differentiated SH-SY5Y cells at the bottom more mimicking in vivo neuroinflammation, was employed to elucidate the mechanism of activated microglia on neuronal cells. Methods: Genetic variants of TLRs in PD patients were genotyped and the multiplex cytokines, sRAGE, and HMGB1were assessed. A coculture system was employed to measure α-synuclein aggregates and neurite shortening by confocal microscope. The expression of TLR2/4 and autophagy flux was detected by western blot and immunofluorescence. Results: PD patients showed higher plasma levels of proinflammatory cytokines and genetic TLR4 variant, c.896 A > G (p. D299G). Elevated proinflammatory cytokines in coculture medium was also seen. Phosphorylation and aggregation of α-synuclein, shortening of neurite, upregulation of TLR2/4 expression, activation of downstream p38 and JNK, and dampening of autophagic flux were seen in SH-SY5Y cells cocultured with activated microglia. Those were prevented by inhibiting TLR2/4 and p38/JNK signaling. Conclusion: Activated microglia-derived neuroinflammation induced neuronal TLR2/4-p38/JNK activation to perturb autophagy, causing accumulation of α-synuclein aggregates and neurite shortening. Targeting neuronal TLR2/4 pathway might be a mechanistic-based therapy for neurodegenerative disease, such as PD.

Treatment, Outcome, and Relapse of Spontaneous and Nonspontaneous Cerebrospinal Fluid Leak.

Cerebrospinal fluid (CSF) leak can be spontaneous or nonspontaneous. The management options include conservative treatments, blood patch, and surgical repairs. We compared clinical symptoms, image findings, management options, hospitalization, and relapse rates among different causes of CSF leaks. Eighty-one patients were recruited: 20 with spontaneous and 61 with nonspontaneous CSF leaks. Nonspontaneous causes included lumbar puncture, surgery, and trauma. Surgery sites comprised sphenoid, spine, skull base, and calvaria. Spontaneous CSF leak came from the sphenoid or spine. Age, gender, body mass index, initial symptoms, hospitalization, treatment courses, and recurrence rates showed no difference between the groups. The spontaneous group had higher CSF accumulations on their MRIs. MRI pachymeninge enhancement showed the highest sensitivity (78.6%) for intracranial hypotension. Meningitis occurred in 1/3 of sphenoid, skull base, and calvarian surgeries. Earlier reoperation was correlated with shorter hospitalization (r = 0.651), but the recurrence rates were similar. Longer intervals between surgery and CSF leak encouraged reoperation. Among the spontaneous spine and lumbar puncture-related CSF leaks, 57.1% of them responded to 4 days of conservative treatment. Among the trauma-related CSF leaks, 90.9% of them required surgical repair. The demographic data and symptoms were similar in various groups of CSF leak. The symptom onset durations and treatment strategies were different. However, the recurrence rates were similar.

Mild Chronic Colitis Triggers Parkinsonism in LRRK2 Mutant Mice Through Activating TNF-α Pathway.

BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) is a common risk gene for Parkinson's disease (PD) and inflammatory bowel disorders. However, the penetrance of the most prevalent LRRK2 mutation, G2019S, is <50%. Factors other than genetic mutations are needed in PD process. OBJECTIVES: To examine whether and how gut inflammation may act as an environmental trigger to neurodegeneration in PD. METHODS: A mild and chronic dextran sodium sulfate (DSS)-induced colitis mice model harboring LRRK2 G2019S mutation was established. The colitis severity, immune responses, locomotor function, dopaminergic neuron, and microglia integrity were compared between littermate controls, transgenic LRRK2 wild type (WT), and LRRK2 G2019S mice. RESULTS: The LRRK2 G2019S mice are more vulnerable to DSS-induced colitis than littermate controls or LRRK2 WT animals with increased intestinal expressions of pattern-recognition receptors, including toll-like receptors (TLRs), nuclear factor (NF)-κB activation, and pro-inflammatory cytokines secretion, especially tumor necrosis factor (TNF)-α. Notably, the colonic expression of α-synuclein was significantly increased in LRRK2 G2019S colitis mice. We subsequently observed more aggravated locomotor defect, microglia activation, and dopaminergic neuron loss in LRRK2 G2019S colitis mice than control animals. Treatment with anti-TNF-α monoclonal antibody, adalimumab, abrogated both gut and neuroinflammation, mitigated neurodegeneration, and improved locomotor function in LRRK2 G2019S colitis mice. Finally, we validated increased colonic expressions of LRRK2, TLRs, and NF-κB pathway proteins and elevated plasma TNF-α level in PD patients compared to controls, especially in those with LRRK2 risk variants. CONCLUSIONS: Our findings demonstrate that chronic colitis promotes parkinsonism in genetically susceptible mice and TNF-α plays a detrimental role in the gut-brain axis of PD. © 2021 International Parkinson and Movement Disorder Society.

Orthostatic myoclonus - A retrospective study of Asian patients.

BACKGROUND/PURPOSE: Orthostatic myoclonus (OM) is myoclonic jerks in both legs during standing. It may relate to gait unsteadiness and may be associated with various diagnoses, including neurodegenerative, systemic, and musculoskeletal diseases. Diagnosis is based on the surface electromyography (SEMG). METHODS: From January 2016 to June 2020, we retrospectively reviewed 35 patients diagnosed with OM based on the SEMG criteria and analyzed the electrophysiological data. RESULTS: The mean age was 75.3±8.9. Disease duration ranged from 2 days to several years. Genders were equally affected. The most common symptom was gait disturbance, and the next was leg tremulous sensation, followed by backward disequilibrium. 28.6% of our patients had falls. Electrophysiologically, bursting duration shorter than 100 ms supported the myoclonic origin from the cortex. The bursting activity occurred only on the upright and weight-bearing leg. The associated diagnoses included lumbosacral radiculopathy (28.6%), lumbosacral radiculopathy plus myasthenia gravis (2.9%), lumbosacral radiculopathy plus vascular parkinsonism (5.7%), diabetic polyneuropathy (5.7%), vascular parkinsonism (17.1%), Parkinson's disease (PD) (14.2%), normal pressure hydrocephalus (5.7%), medication-induced parkinsonism (2.9%), cervical myelopathy (2.9%), medication-related myoclonus (2.9%), and unknown (11.4%). In PD, OM was present before, along with, or after PD diagnosis. The myoclonic activity disrupted the parkinsonian tremor upon standing on SEMG. CONCLUSION: OM is a syndrome instead of a diagnosis. It is more prevalent in the elderly with gait disturbance and patients will not necessarily fall. It is associated with central and peripheral nerve system disorders, systemic diseases, and medication use. We hypothesize that OM is a pathological disintegration of motor circuit.

"Diabetic striatopathy": clinical presentations, controversy, pathogenesis, treatments, and outcomes.

Diabetic striatopathy (DS) is a rare medical condition with ambiguous nomenclature. We searched PubMed database from 1992 to 2018 for articles describing hyperglycemia associated with chorea/ballism and/or neuroimages of striatal abnormalities. Descriptive analysis was performed on demographic/clinical characteristics, locations of striatal abnormalities on neuroimages, pathology findings, treatment strategies, and outcomes. In total, 176 patients (male:female = 1:1.7) were identified from 72 articles with mean age 67.6 ± 15.9 (range, 8-92). Among them, 96.6% had type 2 DM with 17% being newly diagnosed. Average blood glucose and glycated hemoglobin concentrations were 414 mg/dL and 13.1%, respectively. Most patients (88.1%) presented with hemichorea/hemiballism. Isolated putamen and combined putamen-caudate nucleus involvements were most common on neuroimaging studies with discrepancies between CT and MRI findings in about one-sixth of patients. Unilateral arm-leg combination was the most frequent with bilateral chorea in 9.7% of patients. Chorea and imaging anomalies did not appear concomitantly in one-tenth of patients. Successful treatment rates of chorea with glucose-control-only and additional anti-chorea medications were 25.7% and 76.2%, respectively, with an overall recurrence rate being 18.2%. The most commonly used anti-chorea drug was haloperidol. To date, four out of six pathological studies revealed evidence of hemorrhage as a probable pathogenesis.

An overview of pain in Parkinson's disease.

Pain is a common non-motor symptom of Parkinson's disease (PD) and the prevalence of pain among PD patients varies because of the disease stage, co-morbidities, and evaluating tools. Risk factors for pain in PD include an early age of onset, long disease duration, motor complications, concomitant depressive symptoms, female gender, and associated medical conditions. In patients with PD, pain can be classified as musculoskeletal pain, chronic body pain (central or visceral), fluctuation-related pain, nocturnal pain, orofacial pain, pain with discolouration/oedema/swelling, and radicular/neuropathic pain; musculoskeletal pain as the most common type. Potential underlying mechanisms include a disruption of peripheral nociception and alterations in central pain threshold/processing. Genetic polymorphisms in genes that confer pain susceptibility might also play a role in the occurrence of pain in PD. In advanced stage of patients with PD, polyneuropathy could occur in patients using high dosage of levodopa. Pain often correlates to other non-motor symptoms of PD, including depression, sleep, and autonomic symptoms. Dopaminergic drugs, non-dopaminergic medications, botulinum toxin, deep brain stimulation, and physiotherapy have shown some benefits for certain types of PD-related pain. An increased awareness of pain as a common non-motor symptom of PD provides further insights into sensory system dysregulation in this disease. In this review, we aim to summarizes the clinical features of pain in patients with PD and emphasize the latest evidence of pain related to levodopa treatment.

Altered gut microbiota and inflammatory cytokine responses in patients with Parkinson's disease.

OBJECTIVE: Emerging evidence suggests that gut microbiome composition alterations affect neurodegeneration through neuroinflammation in the pathogenesis of Parkinson's disease (PD). Here, we evaluate gut microbiota alterations and host cytokine responses in a population of Taiwanese patients with PD. METHODS: Fecal microbiota communities from 80 patients with PD and 77 age and gender-matched controls were assessed by sequencing the V3-V4 region of the 16S ribosomal RNA gene. Diet and comorbidities were controlled in the analyses. Plasma concentrations of IL-1ß, IL-2, IL-4, IL-6, IL-13, IL-18, GM-CSF, IFNγ, and TNFα were measured by a multiplex immunoassay and relationships between microbiota, clinical characteristics, and cytokine levels were analyzed in the PD group. We further examined the cytokine changes associated with the altered gut microbiota seen in patients with PD in another independent cohort of 120 PD patients and 120 controls. RESULTS: Microbiota from patients with PD was altered relative to controls and dominated by Verrucomicrobia, Mucispirillum, Porphyromonas, Lactobacillus, and Parabacteroides. In contrast, Prevotella was more abundant in controls. The abundances of Bacteroides were more increased in patients with non-tremor PD subtype than patients with tremor subtype. Bacteroides abundance was correlated with motor symptom severity defined by UPDRS part III motor scores (rho = 0.637 [95% confidence interval 0.474 to 0.758], P < 0.01). Altered microbiota was correlated with plasma concentrations of IFNγ and TNFα. There was a correlation between Bacteroides and plasma level of TNFα (rho = 0.638 [95% CI: 0.102-0.887], P = 0.02); and a correlation between Verrucomicrobia abundance and plasma concentrations of IFNγ (rho = 0.545 [95% CI - 0.043-0.852], P = 0.05). The elevated plasma cytokine responses were confirmed in an additional independent 120 patients with PD and 120 controls (TNFα: PD vs. control 8.51 ± 4.63 pg/ml vs. 4.82 ± 2.23 pg/ml, P < 0.01; and IFNγ: PD vs. control: 38.45 ± 7.12 pg/ml vs. 32.79 ± 8.03 pg/ml, P = 0.03). CONCLUSIONS: This study reveals altered gut microbiota in PD and its correlation with clinical phenotypes and severity in our population. The altered plasma cytokine profiles associated with gut microbiome composition alterations suggest aberrant immune responses may contribute to inflammatory processes in PD.

Is traumatic brain injury a risk factor for neurodegeneration? A meta-analysis of population-based studies.

BACKGROUND: To determine the association of prior traumatic brain injury (TBI) with subsequent diagnosis of neurodegeneration disease. METHODS: All studies from 1980 to 2016 reporting TBI as a risk factor for diagnoses of interest were identified by searching PubMed, Embase, study references, and review articles. The data and study design were assessed by 2 investigators independently. A meta-analysis was performed by RevMan 5.3. RESULTS: There were 18 studies comprising 3,263,207 patients. Meta-analysis revealed a significant association of prior TBI with subsequent dementia. The pooled odds ratio (OR) for TBI on development of dementia, FTD and TDP-43 associated disease were 1.93 (95% CI 1.47-2.55, p < 0.001), 4.44 (95% CI 3.86-5.10, p < 0.001), and 2.97 (95% CI 1.35-6.53, p < 0.001). However, analyses of individual diagnoses found no evidence that the risk of Alzheimer's disease, and Parkinson's disease in individuals with previous TBI compared to those without TBI. CONCLUSIONS: History of TBI is not associated with the development of subsequent neurodegeneration disease. Care must be taken in extrapolating from these results because no suitable criteria define post TBI neurodegenerative processes. Therefore, further research in this area is needed to confirm these questions and uncover the link between TBI and neurodegeneration disease.

Population-based study suggests an increased risk of Alzheimer'sdisease in Sjögren's syndrome.

This population-based study was designed to estimate and compare the risk of Alzheimer's disease (AD) between patients with primary Sjögren's syndrome (SS) and non-SS patients during a 10-year follow-up period. This is a retrospective cohort study. Data were obtained from the Taiwan's National Health Insurance Research Database. We identified 4463 primary SS patients and 22,315 non-SS patients; patients were matched by sex, age, and the year of index use of health care. Each patient was studied to identify the subsequent manifestation of AD. Cox proportional hazard regression was used to study the subsequent manifestation of AD, and Kaplan-Meier survival curves were used to compare survival probability. During the 10-year follow-up period, 7 primary SS and 13 non-SS patients developed AD. During the 10-year follow-up period, the risk of AD was 2.68-fold higher in the primary SS cohort with an overall adjusted hazard ratio (HR) of 2.69 (95% CI 1.07-6.76), after adjusting for demographics and comorbidities. Within the 10-year period, patients with primary SS showed a 2.69-fold increased risk of developing AD. This risk increases with time, and the relative risk of AD is higher in older patients with primary SS.

Neurophysiological Features Of Hemiballism.

Hemiballism is a rare hyperkinetic movement disorder. The pathophysiology of hemiballism is poorly understood, and there have been few reports of neurophysiological recordings. The authors report three cases of hemiballism with associated radiological and neurophysiological findings. In patients 1 and 2, who were studied in the acute phase 4 and 14 days after presentation, irregularly timed and predominantly long-duration electromyographic (EMG) bursts were observed typically ranging from 200 to 1500 milliseconds in duration and occurring asynchronously or alternating in antagonist muscles. In patient 3, who was studied 6 weeks after presentation when the involuntary movements had become choreiform, the EMG bursts were still from 200 to 1000 milliseconds in duration but were more synchronous or co-contracting. The flailing movements of hemiballism appear to occur as a result of prolonged bursts of EMG activity generated in individual muscles unopposed by EMG bursting in the antagonist. During the subacute phase when the movements become more choreiform, the results indicate that EMG activity becomes more synchronous or co-contracting.