Breast-to-brain metastasis is exacerbated with chemotherapy through blood-cerebrospinal fluid barrier and induces Alzheimer's-like pathology.

Control of breast-to-brain metastasis remains an urgent unmet clinical need. While chemotherapies are essential in reducing systemic tumor burden, they have been shown to promote non-brain metastatic invasiveness and drug-driven neurocognitive deficits through the formation of neurofibrillary tangles (NFT), independently. Now, in this study, we investigated the effect of chemotherapy on brain metastatic progression and promoting tumor-mediated NFT. Results show chemotherapies increase brain-barrier permeability and facilitate enhanced tumor infiltration, particularly through the blood-cerebrospinal fluid barrier (BCSFB). This is attributed to increased expression of matrix metalloproteinase 9 (MMP9) which, in turn, mediates loss of Claudin-6 within the choroid plexus cells of the BCSFB. Importantly, increased MMP9 activity in the choroid epithelium following chemotherapy results in cleavage and release of Tau from breast cancer cells. This cleaved Tau forms tumor-derived NFT that further destabilize the BCSFB. Our results underline for the first time the importance of the BCSFB as a vulnerable point of entry for brain-seeking tumor cells post-chemotherapy and indicate that tumor cells themselves contribute to Alzheimer's-like tauopathy.

Admission triage tool for adult intensive care unit admission in Hong Kong during the COVID-19 outbreak.

Intensive care is expensive, and the numbers of intensive care unit (ICU) beds and trained specialist medical staff able to provide services in Hong Kong are limited. The most recent increase in coronavirus disease 2019 (COVID-19) infections over July to August 2020 resulted in more than 100 new cases per day for a prolonged period. The increased numbers of critically ill patients requiring ICU admission posed a capacity challenge to ICUs across the territory, and it may be reasonably anticipated that should a substantially larger outbreak occur, ICU services will be overwhelmed. Therefore, a transparent and fair prioritisation process for decisions regarding patient ICU admission is urgently required. This triage tool is built on the foundation of the existing guidelines and framework for admission, discharge, and triage that inform routine clinical practice in Hospital Authority ICUs, with the aim of achieving the greatest benefit for the greatest number of patients from the available ICU resources. This COVID-19 Crisis Triage Tool is expected to provide structured guidance to frontline doctors on how to make triage decisions should ICU resources become overwhelmed by patients requiring ICU care, particularly during the current COVID-19 pandemic. The triage tool takes the form of a detailed decision aid algorithm based on a combination of established prognostic scores, and it should increase objectivity and transparency in triage decision making and enhance decision-making consistency between doctors within and across ICUs in Hong Kong. However, it remains an aid rather than a complete substitute for the carefully considered judgement of an experienced intensive care clinician.

Nonclinical Characterization of the Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat, a Novel Treatment of Anemia of Chronic Kidney Disease.

Anemia of chronic kidney disease (CKD) is a multifactorial disorder caused by impaired erythropoietin (EPO) production and altered iron homeostasis associated with inflammation. Hypoxia-inducible factor (HIF) is a transcription factor that stimulates erythropoiesis via a coordinated response involving increased EPO production and enhanced iron availability for Hb synthesis. HIF degradation is regulated by HIF-prolyl hydroxylase (HIF-PH) enzymes. We hypothesized that roxadustat, an orally available small-molecule inhibitor of HIF-PH, would increase EPO production and promote erythropoiesis in animal models of anemia. In cells, roxadustat increased both HIF-1α and HIF-2α proteins, leading to an increase in EPO production, even in the presence of EPO-suppressing inflammatory cytokines. Roxadustat administered intermittently to healthy rats and cynomolgus monkeys increased circulating EPO levels, reticulocytes, blood Hb, and hematocrit in a dose-dependent manner. Roxadustat corrected anemia in a rat model of CKD after five-sixth nephrectomy and in a rat model of anemia of inflammation with impaired iron metabolism induced by peptidoglycan-polysaccharide (PG-PS). In the PG-PS model, roxadustat significantly decreased hepatic expression of hepcidin, a hormone responsible for iron sequestration and functional iron deficiency, and increased expression of two genes involved in duodenal iron absorption: divalent metal transporter 1 and duodenal cytochrome b. In conclusion, by activating the HIF pathway, roxadustat increased EPO production, elevated Hb, corrected anemia, and improved iron homeostasis. The coordinated erythropoietic response stimulated by roxadustat, involving both EPO production and mobilization of iron stores, makes this compound a promising treatment of anemia of CKD and anemia associated with functional iron deficiency. SIGNIFICANCE STATEMENT: Roxadustat is a novel orally available small-molecule inhibitor of HIF prolyl hydroxylase enzymes that reversibly stabilizes HIF-α, thus activating transcription of HIF-dependent genes, including EPO and regulators of iron homeostasis. Activation of the HIF pathway by roxadustat induces erythropoiesis in healthy rats and monkeys and corrects experimentally induced anemia in rats. The coordinated erythropoietic response that increases EPO production and mobilizes iron stores makes roxadustat a promising treatment for anemia of chronic kidney disease and anemia associated with functional iron deficiency.

Comparative efficacy, safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: Insights from the SUSTAIN 1-7 trials.

In individuals with type 2 diabetes, glycaemic control and cardiovascular risk factor management reduces the likelihood of late-stage diabetic complications. Guidelines recommend treatment goals targeting HbA1c, body weight, blood pressure, and low-density lipoprotein cholesterol. Development of new treatments for type 2 diabetes requires an understanding of their mechanism and efficacy, as well as their relative effects compared to other treatment choices, plus demonstration of cardiovascular safety. Subcutaneous semaglutide is a glucagon-like peptide-1 receptor agonist currently approved in several countries for once-weekly treatment of type 2 diabetes. Semaglutide works via the incretin pathway, stimulating insulin and inhibiting glucagon secretion from the pancreatic islets, leading to lower blood glucose levels. Semaglutide also decreases energy intake by reducing appetite and food cravings, and lowering relative preference for fatty, energy-dense foods. Semaglutide was evaluated in the SUSTAIN clinical trial programme in over 8000 patients across the spectrum of type 2 diabetes. This review details the efficacy and safety profile of semaglutide in the SUSTAIN 1-5 and 7 trials, and its cardiovascular safety profile in the SUSTAIN 6 trial. Semaglutide consistently demonstrated superior and sustained glycemic control and weight loss vs. all comparators evaluated. In SUSTAIN 6, involving patients at high risk of cardiovascular disease, semaglutide significantly decreased the occurrence of cardiovascular events compared with placebo/standard of care (hazard ratio 0.74, P < 0.001 for non-inferiority). Through a comprehensive phase 3 clinical trial program, we have a detailed understanding of semaglutide's efficacy, safety, cardiovascular effects and comparative role in the treatment of type 2 diabetes.

Guidance on the management of familial hypercholesterolaemia in Hong Kong: an expert panel consensus viewpoin.

In 2016, meetings of groups of physicians and paediatricians with a special interest in lipid disorders and familial hypercholesterolaemia were held to discuss several domains of management of familial hypercholesterolaemia in adults and children in Hong Kong. After reviewing the evidence and guidelines for the diagnosis, screening, and management of familial hypercholesterolaemia, consensus was reached on the following aspects: clinical features, diagnostic criteria, screening in adults, screening in children, management in relation to target plasma low-density lipoprotein cholesterol levels, detection of atherosclerosis, lifestyle and behaviour modification, and pharmacotherapy.

Posttraumatic Stress after Treatment in an Intensive Care Unit.

OBJECTIVE: To study posttraumatic stress in patients after treatment in an intensive care unit (ICU). METHODS: This prospective cohort study included 136 adult patients with critical medical and surgical problems who were discharged from the ICU of the Caritas Medical Centre, Hong Kong. Their occurrence of posttraumatic stress disorder (PTSD), anxiety, and depression after ICU treatment were measured using the Impact of Event Scale-Revised and Hospital Anxiety and Depression Scale. Patient ICU experience was measured using the ICU Memory Tool. Multivariable analyses were conducted to examine the predictors of PTSD symptoms, anxiety, and depression. RESULTS: Symptoms of PTSD, anxiety, and depression were reported in 10% to 17% of patients. Symptom severity was associated with less factual memory, more vivid memory of feelings about and more delusional memory of the ICU experience, low emotional support, and high perceived life threat. CONCLUSIONS: Symptoms of posttraumatic stress, anxiety, and depression may occur after ICU treatment. Early identification and appropriate intervention for PTSD are important for rehabilitation.

Radiofrequency ablation compared with laparoscopic adrenalectomy for aldosterone-producing adenoma.

BACKGROUND: Radiofrequency ablation (RFA) is an emerging treatment for primary aldosteronism owing to aldosterone-producing adenoma. Whether RFA could be an alternative treatment to laparoscopic adrenalectomy is unknown. METHODS: This was a retrospective comparative study in patients with aldosterone-producing adenoma undergoing either laparoscopic adrenalectomy or CT-guided percutaneous RFA between 2004 and 2012. Short-term outcomes and long-term resolution rates of primary aldosteronism (normalized aldosterone to renin ratio), hypokalaemia and hypertension (BP lower than 140/90 mmHg without antihypertensive medical therapy) were evaluated. RESULTS: Some 63 patients were included, 27 in the laparoscopic adrenalectomy group and 36 in the RFA group. RFA was associated with shorter duration of operation (median 12 versus 124 min; P < 0·001), shorter hospital stay (2 versus 4 days; P < 0·001), lower analgesic requirements (13 of 36 versus 23 of 27 patients; P < 0·001) and earlier resumption of work (median 4 versus 14 days; P = 0·006). Morbidity rates were similar in the two groups. With median follow-up of 5·7 (range 1·9-10·6) years, resolution of primary aldosteronism was seen in 33 of 36 patients treated with RFA and all 27 patients who had laparoscopic adrenalectomy (P = 0·180). Hypertension was resolved less frequently after treatment with RFA compared with laparoscopic adrenalectomy (13 of 36 versus 19 of 27 patients; P = 0·007). Hypokalaemia was resolved in all patients. CONCLUSION: For patients with aldosterone-producing adenoma the efficacy of resolution of primary aldosteronism and hypertension was inferior after treatment with RFA compared with laparoscopic adrenalectomy.

Analyzing the design criteria of primary settlers for small sewage treatment systems: a national survey in Taiwan.

An onsite wastewater treatment facility normally has a treatment capacity of 5-200 population equivalents. The small system is receiving increasing attention in Asia countries to make up for the shortage of public sewer system. While many countries rely on large centralized system, small systems in Taiwan have significantly contributed to the treatment of municipal wastewater (21.6%) to make up for the low sewer connection (17.0%). To resolve disputes on the design criteria of primary settlers in small systems recommended by the government, a nationwide survey of 350 permit applications were conducted. This result of the survey revealed that 53% adopted self-proven criteria to reduce the size of the primary settlers using a design flow rate (Q) of 10 m(3)/d or less. The official design criteria were thus analyzed by using two new approaches of design criteria, scale-down factor and sludge blanket height ratio, as proposed in this study. The analysis indicated that sizing of primary settlers must consider the diurnal flow fluctuation and storage of settled sludge in primary settlers for a sufficient period of time, preferably up to 6 months. The official design criteria may be too conservative for Q<5m(3)/d, but inadequate for Q>20 m(3)/d. Based on the result of this study, new measures are suggested to strengthen the onsite program.

Burden of neuroinfectious diseases on the neurology service in a tertiary care center.

BACKGROUND: Neurologic infections have the potential to cause death and suffering. These disorders often go unrecognized or are misdiagnosed. There has yet not been a census of neurologic infections conducted in a hospital setting. We aimed to determine the burden of neurologic infections on the neurology service in a tertiary care center and identify challenges in the diagnosis and treatment of these infections. METHODS: We reviewed retrospectively all inpatients diagnosed with any neuroinfectious disease evaluated at Johns Hopkins Medical Institutions between October 2004 and December 2005. We recorded information on hospital admission, clinical features, microbiologic analysis, neuroimaging, EEG, pathology, treatment, and outcome. RESULTS: A total of 116 of 4,225 patients admitted to or consulted on by the neurology service were identified. Eighty percent of patients were aged between 18 and 65 years. Fifty-two patients were immunocompromised, of which 28 patients had HIV infection. Overall, 86 microbiologic agents were identified in 80 patients. The commonest causes were viral, followed by bacterial and fungal infections. However, 31% of patients remained without an identifiable microbiologic etiology. Hospitalization periods were long, with 43% of patients staying beyond 2 weeks. There was significant morbidity: 28% of patients required rehabilitation or long-term care, and 12% died. CONCLUSIONS: Neurologic infections have a major socioeconomic impact because they result in prolonged hospitalizations, expensive diagnostic tests and treatments, and long-term debilitation or death in young patients. Though potentially curable conditions, the burden of undiagnosed infections remains high.

Monocyte chemoattractant protein-1-induced tissue inflammation is critical for the development of renal injury but not type 2 diabetes in obese db/db mice.

AIMS/HYPOTHESIS: Tissue macrophage accumulation is thought to induce insulin resistance during obesity and stimulate the progression of diabetic nephropathy. Monocyte chemoattractant protein-1 (MCP-1) is a potent stimulator of macrophage recruitment. It is increased in adipose tissue during obesity and in diabetic kidneys, suggesting that inflammation of these tissues may be MCP-1-dependent. Based on these findings, the aim of this study was to examine whether a deficiency in MCP-1 would alter the development of type 2 diabetes and its renal complications. MATERIALS AND METHODS: The role of MCP-1 in the progression of type 2 diabetes and its associated renal injury was assessed in obese db/db mice that were deficient in the gene encoding MCP-1 (Ccl2). RESULTS: The incidence and development of type 2 diabetes were similar in Ccl2(+/+) and Ccl2(-/-) db/db mice between 8 and 32 weeks of age. Body mass, hyperglycaemia, hyperinsulinaemia, glucose and insulin tolerance, plasma triacylglycerol and serum NEFA were not different between these strains. Pathological changes in epididymal adipose tissue, including increases in macrophage accumulation and Tnfa mRNA and reductions in Adipoq mRNA, were unaffected by the absence of MCP-1. In contrast, kidney macrophage accumulation and the progression of diabetic renal injury (albuminuria, histopathology, renal fibrosis) were substantially reduced in Ccl2(-/-) compared with Ccl2(+/+) db/db mice with equivalent diabetes. CONCLUSIONS/INTERPRETATION: Our study demonstrates that MCP-1 promotes type 2 diabetic renal injury but does not influence the development of obesity, insulin resistance or type 2 diabetes in db/db mice. MCP-1 plays a critical role in inflammation of the kidney, but not adipose tissue, during the progression of type 2 diabetes.

Association between sleeping hours, working hours and obesity in Hong Kong Chinese: the 'better health for better Hong Kong' health promotion campaign.

OBJECTIVE: To study the inter-relationships between sleeping hours, working hours and obesity in subjects from a working population. RESEARCH DESIGN: A cross-sectional observation study under the 'Better Health for Better Hong Kong' Campaign, which is a territory-wide health awareness and promotion program. SUBJECTS: 4793 subjects (2353 (49.1%) men and 2440 (50.9%) women). Their mean age (+/-s.d.) was 42.4+/-8.9 years (range 17-83 years, median 43.0 years). Subjects were randomly selected using computer-generated codes in accordance to the distribution of occupational groups in Hong Kong. RESULTS: The mean daily sleeping time was 7.06+/-1.03 h (women vs men: 7.14+/-1.08 h vs 6.98+/-0.96 h, P<0.001). Increasing body mass index (BMI) was associated with reducing number of sleeping hours and increasing number of working hours reaching significance in the whole group as well as among male subjects. Those with short sleeping hour (6 h or less) and long working hours (>9 h) had the highest BMI and waist in both men and women. Based on multiple regression analysis with age, smoking, alcohol drinking, systolic and diastolic blood pressure, mean daily sleeping hours and working hours as independent variables, BMI was independently associated with age, systolic and diastolic blood pressure in women, whereas waist was associated with age, smoking and blood pressure. In men, blood pressure, sleeping hours and working hours were independently associated with BMI, whereas waist was independently associated with age, smoking, blood pressure, sleeping hours and working hours in men. CONCLUSION: Obesity is associated with reduced sleeping hours and long working hours in men among Hong Kong Chinese working population. Further studies are needed to investigate the underlying mechanisms of this relationship and its potential implication on prevention and management of obesity.

Hospital waste generation during an outbreak of severe acute respiratory syndrome in Taiwan.

During the SARS outbreak in Taiwan, the number of ambulatory patients and inpatients treated at one medical center decreased by 40%-70% because of the increasing number of SARS patients. At the peak of the epidemic, the amount of hospital infectious waste had increased from a norm of 0.85 kg per patient-day to 2.7 kg per patient-day. However, the hospital was able to return the generation of waste to normal levels within 10 days.

Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice.

Diabetic nephropathy involves a renal inflammatory response induced by the diabetic milieu. Macrophages accumulate in diabetic kidneys in association with the local upregulation of monocyte chemoattractant protein-1 (MCP-1); however, the contribution of macrophages to renal injury and the importance of MCP-1 to their accrual are unclear. Therefore, we examined the progression of streptozotocin (STZ)-induced diabetic nephropathy in mice deficient in MCP-1 in order to explore the role of MCP-1-mediated macrophage accumulation in the development of diabetic kidney damage. Renal pathology was examined at 2, 8, 12 and 18 weeks after STZ treatment in MCP-1 intact (+/+) and deficient (-/-) mice with equivalent blood glucose and hemoglobin A1c levels. In MCP-1(+/+) mice, the development of diabetic nephropathy was associated with increased kidney MCP-1 production, which occurred mostly in tubules, consistent with our in vitro finding that elements of the diabetic milieu (high glucose and advanced glycation end products) directly stimulate tubular MCP-1 secretion. Diabetes of 18 weeks resulted in albuminuria and elevated plasma creatinine in MCP-1(+/+) mice, but these aspects of renal injury were largely suppressed in MCP-1(-/-) mice. Protection from nephropathy in diabetic MCP-1(-/-) mice was associated with marked reductions in glomerular and interstitial macrophage accumulation, histological damage and renal fibrosis. Diabetic MCP-1(-/-) mice also had a smaller proportion of kidney macrophages expressing markers of activation (inducible nitric oxide synthase or sialoadhesin) compared to diabetic MCP-1(+/+) mice. In conclusion, our study demonstrates that MCP-1-mediated macrophage accumulation and activation plays a critical role in the development of STZ-induced mouse diabetic nephropathy.

Memory is relevant in the symmetric phase of the minority game.

Minority game is a simple-mined econophysical model capturing the cooperative behavior among selfish players. Previous investigations, which were based on numerical simulations up to about 100 players for a certain parameter alpha in the range 0.1 < approximately alpha < approximately 1, suggested that memory is irrelevant to the cooperative behavior of the minority game in the so-called symmetric phase. Here using a large scale numerical simulation up to about 3000 players in the parameter range 0.01 < approximately alpha < approximately 1, we show that the mean variance of the attendance in the minority game actually depends on the memory in the symmetric phase. We explain such dependence in the framework of crowd-anticrowd theory. Our findings conclude that one should not overlook the feedback mechanism buried under the correlation in the history time series in the study of minority game.

Laparoscopic adjustable gastric banding for the treatment of morbidly obese patients: early outcome in a Chinese cohort.

OBJECTIVE: To evaluate the efficacy of laparoscopic adjustable gastric banding in the management of morbid obesity in a cohort of Chinese patients. DESIGN. Cohort study. SETTING: University teaching hospital, Hong Kong. PATIENTS: From August 2002 to September 2003, 10 patients (6 male, 4 female) with a median age of 34 years (range, 23-48 years) underwent laparoscopic adjustable gastric banding to treat morbid obesity. Considerable co-existing diseases were present in 90% of the cases. We instituted a team approach that allowed every patient to see our dietitian, physician, psychiatrist (if necessary), and surgeon prior to deciding on the procedure to be used. MAIN OUTCOME MEASURES: Excessive body weight loss, quality-of-life score (SF36), and co-morbidities improvement. RESULTS: The 10 patients had a median weight of 127 kg (range, 115-196 kg) and median body mass index of 47 kg/m(2) (range, 38-67 kg/m(2)). The operation was successful in all patients with a median operating time of 110 minutes (range, 75-240 minutes). The median hospital stay was 3 days (range, 3-4 days) and three of the patients required overnight observation in the intensive care unit because of severe sleep apnoea and asthma. The median follow-up period was 12 months (range, 1-18 months). The mean weight loss at 6, 12, and 18 months was 19.3, 22.4, and 25.9 kg, respectively. Mean percentage of excessive weight loss at 6, 12, and 18 months was 34.9%, 36.5%, and 40.5%, respectively. Unsatisfactory weight loss (<20 kg) occurred in three patients because of poor dietary compliance and non-follow-up. Surgery also considerably improved the patients' co-morbidities (hypertension, diabetes, and obstructive sleep apnoea) and the quality of life. CONCLUSION: In the short term, laparoscopic adjustable gastric banding is certainly an effective procedure for morbid obesity, which results in a substantial weight loss and improvement of co-existing morbidities. Longer follow-up will show whether this weight loss is maintainable.

Analyzing the uncorrected error of dilution water demand for the dilution biochemical oxygen demand method.

Dilution water demand (DWD) can cause a positive error when the dilution biochemical oxygen demand (BOD) method is used. Dilution water demand may be attributed to oxidation of organic impurities in the dilution water and nitrification of ammonia added as a nutrient. To minimize the error associated with these sources, the standard BOD method requires that DWD be less than 0.2 mg/L in 5 days and does not allow correction for DWD when calculating test results. This study derives a set of theoretical equations to analyze the uncorrected errors with and without seeding. The authors concluded that DWD can be completely corrected if seeded dilution water is used for the sample dilution. When seeding individual bottles, the uncorrected error approaches 8.3 to approximately 8.8% at a 5-day depletion of 2 mg/L for a typical secondary effluent. Tests without seeding show an almost 1% higher uncorrected error than seeded tests. The analysis also suggests that these errors can be effectively reduced to less than 3% when the 5-day depletion approaches 6 mg/L. even for 5-day biochemical oxygen demand concentrations exceeding I x 10(4) mg/L. Further analysis indicates that, if not inhibited, the ammonium added to dilution water as a nutrient may contribute additional error due to nitrification.

Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy.

AIMS/HYPOTHESIS: Inflammation and fibrosis are pathological mechanisms that are partially regulated by cell signalling through the p38 mitogen-activated protein kinase (MAPK) pathway. Elements of the diabetic milieu such as high glucose and advanced glycation end-products induce activation of this pathway in renal cells. Therefore, we examined whether p38 MAPK signalling is associated with the development of human and experimental diabetic nephropathy. METHODS: Immunostaining identified phosphorylated (active) p38 MAPK in human biopsies with no abnormality ( n=6) and with Type 2 diabetic nephropathy ( n=12). Changes in kidney levels of phosphorylated p38 were assessed by immunostaining and western blotting in mice with streptozotocin-induced Type 1 diabetes that had been killed after 0.5, 2, 3, 4 and 8 months, and in Type 2 diabetic db/db mice at 2, 4, 6 and 8 months of age. RESULTS: Phosphorylated p38 was detected in some intrinsic cells in normal human kidney, including podocytes, cortical tubules and occasional interstitial cells. Greater numbers of these phosphorylated p38+ cells were observed in diabetic patients, and phosphorylated p38 was identified in accumulating interstitial macrophages and myofibroblasts. A similar pattern of p38 activation was observed in both mouse models of diabetes. In mice, kidney levels of phosphorylated p38 increased (2-6 fold) following the onset of Type 1 and Type 2 diabetes. In both mouse models, interstitial phosphorylated p38+ cells were associated with hyperglycaemia, increased HbA(1)c levels and albuminuria. Further assessment of streptozotocin-induced diabetic nephropathy showed that interstitial phosphorylated p38+ cells correlated with interstitial fibrosis (myofibroblasts, collagen). CONCLUSIONS/INTERPRETATION: Increased p38 MAPK signalling is a feature of human and experimental diabetic nephropathy. Time course studies in mouse models suggest that phosphorylation of p38 plays a pathological role, particularly in the development of interstitial fibrosis.

Wealth inequality in the minority game.

To demonstrate the usefulness of physical approaches for the study of realistic economic systems, we investigate the inequality of players' wealth in one of the most extensively studied econophysical models, namely, the minority game (MG). We gauge the wealth inequality of players in the MG by a well-known measure in economics known as the modified Gini index. From our numerical results, we conclude that the wealth inequality in the MG is very severe near the point of maximum cooperation among players, where the diversity of the strategy space is approximately equal to the number of strategies at play. In other words, the optimal cooperation between players comes hand in hand with severe wealth inequality. We also show that our numerical results in the asymmetric phase of the MG can be reproduced semianalytically using a replica method.