Interleukin-10 suppression enhances T-cell antitumor immunity and responses to checkpoint blockade in chronic lymphocytic leukemia.

T-cell dysfunction is a hallmark of B-cell Chronic Lymphocytic Leukemia (CLL), where CLL cells downregulate T-cell responses through regulatory molecules including programmed death ligand-1 (PD-L1) and Interleukin-10 (IL-10). Immune checkpoint blockade (ICB) aims to restore T-cell function by preventing the ligation of inhibitory receptors like PD-1. However, most CLL patients do not respond well to this therapy. Thus, we investigated whether IL-10 suppression could enhance antitumor T-cell activity and responses to ICB. Since CLL IL-10 expression depends on Sp1, we utilized a novel, better tolerated analogue of the Sp1 inhibitor mithramycin (MTMox32E) to suppress CLL IL-10. MTMox32E treatment inhibited mouse and human CLL IL-10 production and maintained T-cell effector function in vitro. In the Eµ-Tcl1 mouse model, treatment reduced plasma IL-10 and CLL burden and increased CD8+ T-cell proliferation, effector and memory cell prevalence, and interferon-γ production. When combined with ICB, suppression of IL-10 improved responses to anti-PD-L1 as shown by a 4.5-fold decrease in CLL cell burden compared to anti-PD-L1 alone. Combination therapy also produced more interferon-γ+, cytotoxic effector KLRG1+, and memory CD8+ T-cells, and fewer exhausted T-cells. Since current therapies for CLL do not target IL-10, this provides a novel strategy to improve immunotherapies.

Child maltreatment and the early onset of problem behaviors: can a program of nurse home visitation break the link?

This study investigated the relationship between child maltreatment and the early onset of problem behaviors in the Elmira Nurse Home Visitation Program. Participants were predominantly low-income and unmarried mothers and their first-born children who were randomized either to receive over 2 years of home-visitation services by nurses or to be placed in a comparison group. Data were drawn from a follow-up study that took place when the children were 15 years of age. Results demonstrated that, in the comparison group. child maltreatment was associated with significant increases in the number of early onset problem behaviors reported by the youth. For the youth in the nurse-visited group there was no relationship between maltreatment and early onset problem behaviors. We suggest that this finding was due to the effects of the intervention in reducing the number as well as the developmental timing of the maltreatment incidents. Results suggest that prenatal and infancy home visiting by nurses can moderate the risk of child maltreatment as a predictor of conduct problems and antisocial behavior among children and youth born into at-risk families.

Preventing child abuse and neglect with a program of nurse home visitation: the limiting effects of domestic violence.

CONTEXT: Home visitation to families with young children has been promoted as an effective way to prevent child maltreatment, but few studies have examined the conditions under which such programs meet this goal. OBJECTIVE: To investigate whether the presence of domestic violence limits the effects of nurse home visitation interventions in reducing substantiated reports of child abuse and neglect. DESIGN: Fifteen-year follow-up study of a randomized trial. SETTING: Semirural community in upstate New York. PARTICIPANTS: Of 400 socially disadvantaged pregnant women with no previous live births enrolled consecutively between April 1978 and September 1980, 324 mothers and their children participated in the follow-up study. INTERVENTIONS: Families were randomly assigned to receive routine perinatal care (control group; n = 184 participated in follow-up), routine care plus nurse home visits during pregnancy only (n = 100), or routine care plus nurse home visits during pregnancy and through the child's second birthday (n = 116). MAIN OUTCOME MEASURES: Number of substantiated reports over the entire 15-year period involving the study child as subject regardless of the identity of the perpetrator or involving the mother as perpetrator regardless of the identity of the child abstracted from state records and analyzed by treatment group and level of domestic violence in the home as measured by the Conflict Tactics Scale. RESULTS: Families receiving home visitation during pregnancy and infancy had significantly fewer child maltreatment reports involving the mother as perpetrator (P =. 01) or the study child as subject (P =.04) than families not receiving home visitation. The number of maltreatment reports for mothers who received home visitation during pregnancy only was not different from the control group. For mothers who received visits through the child's second birthday, the treatment effect decreased as the level of domestic violence increased. Of women who reported 28 or fewer incidents of domestic violence (79% of sample), home-visited mothers had significantly fewer child maltreatment reports during the 15-year period than mothers not receiving the longer-term intervention (P =.01). However, this intervention did not significantly reduce child maltreatment among mothers reporting more than 28 incidents of domestic violence (21% of sample). CONCLUSIONS: The presence of domestic violence may limit the effectiveness of interventions to reduce incidence of child abuse and neglect. JAMA. 2000;284:1385-1391.

The timing of academic difficulties among maltreated and nonmaltreated children.

OBJECTIVE: In this study we examined the relationship between child maltreatment and the timing of academic difficulties. METHOD: This study uses survival analysis to investigate the timing of risk of experiencing an academic difficulty for the first time. Three types of academic difficulties were examined-grade repetitions, poor English grades, and poor math grades. The sample included approximately 300 maltreated and 300 nonmaltreated children aged 5-18. RESULTS: Maltreated children displayed greater risk than nonmaltreated children of repeating a grade and receiving a poor English and mathematics grade for the first time across most elementary years. Maltreated and nonmaltreated children share the same peaks in risk: first grade for their first grade repetitions and kindergarten for their first poor English and math grade. The best-fitting discrete time hazards models suggested underlying temporal patterns of risk vary according to the type of academic difficulty. For instance, maltreated children were at substantially higher risk than nonmaltreated children of repeating kindergarten and first grade. From second through sixth grade, maltreated and nonmaltreated children were indistinguishable in their risk of repeating a grade for the first time. In contrast, discrete-time hazards modeling showed that while the absolute risk of receiving a poor English or mathematics grade changes across the elementary years, the relative risk by maltreatment status does not. CONCLUSIONS: While maltreated and nonmaltreated children share the same peaks in risk, the relative risk changes across time for grade repetitions but not for the first occurrence of a poor English or mathematics grade. In summary, this study highlights the importance of time in understanding the relationship between child maltreatment and academic difficulties.

Prenatal and infancy home visitation by nurses: recent findings.

This article describes a 20-year program of research on the Nurse Home Visitation Program, a model in which nurses visit mothers beginning during pregnancy and continuing through their children's second birthdays to improve pregnancy outcomes, to promote children's health and development, and to strengthen families' economic self-sufficiency. The results of two randomized trials (one in Elmira, New York, and the second in Memphis, Tennessee) are summarized, and an ongoing trial in Denver, Colorado, is briefly described. Results of the Elmira and Memphis trials suggest the following: The program benefits the neediest families (low-income unmarried women) but provides little benefit for the broader population. Among low-income unmarried women, the program helps reduce rates of childhood injuries and ingestions that may be associated with child abuse and neglect, and helps mothers defer subsequent pregnancies and move into the workforce. Long-term follow-up of families in Elmira indicates that nurse-visited mothers were less likely to abuse or neglect their children or to have rapid successive pregnancies. Having fewer children enabled women to find work, become economically self-sufficient, and eventually avoid substance abuse and criminal behavior. Their children benefitted too. By the time the children were 15 years of age, they had had fewer arrests and convictions, smoked and drank less, and had had fewer sexual partners. The program produced few effects on children's development or on birth outcomes, except for children born to women who smoked cigarettes when they registered during pregnancy. The positive effects of the program on child abuse and injuries to children were most pronounced among mothers who, at registration, had the lowest psychological resources (defined as high levels of mental health symptoms, limited intellectual functioning, and little belief in their control of their lives). Generally, effects in Elmira were of greater magnitude and covered a broader range of outcomes than in Memphis, perhaps because of differences between the populations studied, community contexts, or a higher rate of turnover among home visitors in Memphis than in Elmira. The article concludes that the use of nurses as home visitors is key; that services should be targeted to the neediest populations, rather than being offered on a universal basis; that clinically tested methods of changing health and behavioral risks should be incorporated into program protocols; and that services must be implemented with fidelity to the model tested if program benefits found in scientifically controlled studies are to be reproduced as the program is replicated in new communities.

Long-term effects of nurse home visitation on children's criminal and antisocial behavior: 15-year follow-up of a randomized controlled trial.

CONTEXT: A program of home visitation by nurses has been shown to affect the rates of maternal welfare dependence, criminality, problems due to use of substances, and child abuse and neglect. However, the long-term effects of this program on children's antisocial behavior have not been examined. OBJECTIVE: To examine the long-term effects of a program of prenatal and early childhood home visitation by nurses on children's antisocial behavior. DESIGN: Fifteen-year follow-up of a randomized trial. Interviews were conducted with the adolescents and their biological mothers or custodial parents. SETTING: Semirural community in New York. PARTICIPANTS: Between April 1978 and September 1980, 500 consecutive pregnant women with no previous live births were recruited, and 400 were enrolled. A total of 315 adolescent offspring participated in a follow-up study when they were 15 years old; 280 (89%) were born to white mothers, 195 (62%) to unmarried mothers, 151 (48%) to mothers younger than 19 years, and 186 (59%) to mothers from households of low socioeconomic status at the time of registration during pregnancy. INTERVENTION: Families in the groups that received home visits had an average of 9 (range, 0-16) home visits during pregnancy and 23 (range, 0-59) home visits from birth through the child's second birthday. The control groups received standard prenatal and well-child care in a clinic. MAIN OUTCOME MEASURES: Children's self-reports of running away, arrests, convictions, being sentenced to youth corrections, initiation of sexual intercourse, number of sex partners, and use of illegal substances; school records of suspensions; teachers' reports of children's disruptive behavior in school; and parents' reports of the children's arrests and behavioral problems related to the children's use of alcohol and other drugs. RESULTS: Adolescents born to women who received nurse visits during pregnancy and postnatally and who were unmarried and from households of low socioeconomic status (risk factors for antisocial behavior), in contrast with those in the comparison groups, reported fewer instances (incidence) of running away (0.24 vs 0.60; P = .003), fewer arrests (0.20 vs 0.45; P = .03), fewer convictions and violations of probation (0.09 vs 0.47; P<.001), fewer lifetime sex partners (0.92 vs 2.48; P= .003), fewer cigarettes smoked per day (1.50 vs 2.50; P= .10), and fewer days having consumed alcohol in the last 6 months (1.09 vs 2.49; P = .03). Parents of nurse-visited children reported that their children had fewer behavioral problems related to use of alcohol and other drugs (0.15 vs 0.34; P = .08). There were no program effects on other behavioral problems. CONCLUSIONS: This program of prenatal and early childhood home visitation by nurses can reduce reported serious antisocial behavior and emergent use of substances on the part of adolescents born into high-risk families.

Long-term effects of home visitation on maternal life course and child abuse and neglect. Fifteen-year follow-up of a randomized trial.

CONTEXT: Home-visitation services have been promoted as a means of improving maternal and child health and functioning. However, long-term effects have not been examined. OBJECTIVE: To examine the long-term effects of a program of prenatal and early childhood home visitation by nurses on women's life course and child abuse and neglect. DESIGN: Randomized trial. SETTING: Semirural community in New York. PARTICIPANTS: Of 400 consecutive pregnant women with no previous live births enrolled, 324 participated in a follow-up study when their children were 15 years old. INTERVENTION: Families received a mean of 9 home visits during pregnancy and 23 home visits from the child's birth through the second birthday. DATA SOURCES AND MEASURES: Women's use of welfare and number of subsequent children were based on self-report; their arrests and convictions were based on self-report and archived data from New York State. Verified reports of child abuse and neglect were abstracted from state records. MAIN RESULTS: During the 15-year period after the birth of their first child, in contrast to women in the comparison group, women who were visited by nurses during pregnancy and infancy were identified as perpetrators of child abuse and neglect in 0.29 vs 0.54 verified reports (P<.001). Among women who were unmarried and from households of low socioeconomic status at initial enrollment, in contrast to those in the comparison group, nurse-visited women had 1.3 vs 1.6 subsequent births (P=.02), 65 vs 37 months between the birth of the first and a second child (P=.001), 60 vs 90 months' receiving Aid to Families With Dependent Children (P=.005), 0.41 vs 0.73 behavioral impairments due to use of alcohol and other drugs (P=.03), 0.18 vs 0.58 arrests by self-report (P<.001), and 0.16 vs 0.90 arrests disclosed by New York State records (P<.001). CONCLUSIONS: This program of prenatal and early childhood home visitation by nurses can reduce the number of subsequent pregnancies, the use of welfare, child abuse and neglect, and criminal behavior on the part of low-income, unmarried mothers for up to 15 years after the birth of the first child.

The effects of neglect on academic achievement and disciplinary problems: a developmental perspective.

The present study examines the effect of child neglect, alone and in combination with abuse, on academic achievement and school disciplinary problems for elementary, junior high, and senior high students. The sample included 324 neglected children and adolescents, and a matched nonmaltreated sample of 420 children and adolescents. All subjects were in grades K through 12 in a small city in New York state. The results revealed that neglected children did perform more poorly than their nonmaltreated counterparts, having lower grades, more suspensions, more disciplinary referrals, and more grade repetitions, even when controlling for gender of child and SES. Neglect alone and neglect in combination with physical or sexual abuse was related to lower grades and more suspensions. The combination of abuse and neglect had a particularly strong effect on the number of disciplinary referrals and grade repetitions. Abused/neglected students in junior high had the highest number of grade repetitions. The number of disciplinary referrals continued to increase through senior high for both neglected and abused/neglected students. Interestingly, the academic performance of all subjects dropped during junior high. Neglect and neglect in combination with abuse appeared to exacerbate a decline in academic performance that occurs as children enter junior high school.

The role of work identity in women's adjustment to divorce.

A study of the role of employment in the divorce adjustment of 40 women found work identity to be associated with higher self-esteem and lower distress. Four established components of work identity--meaningfulness, social interaction/support, productivity, and positive distraction--were assessed via qualitative analyses; links among various life contexts were examined; and postdivorce changes explored. Results support the role of work identity in divorced women's adjustment.

Mobility as a mediator of the effects of child maltreatment on academic performance.

This study examined the role of residential and school mobility as a mediator between child maltreatment and academic outcomes. Using a sample of 711 maltreated and nonmaltreated children ranging from 5 to 15 years old matched on gender, grade, school, and socioeconomic status, path analytic techniques were employed to assess direct and indirect effects of maltreatment on recent achievement test scores, current grades, and grade repetitions. The results indicated that mobility did help account for the effects of maltreatment on each of the outcomes. For grades in English/reading, 32.7% of the effect of maltreatment was accounted for by amount of mobility, while for test scores and grade repetitions the numbers were 14.6% and 19.1%, respectively.

The epidemiology of child abuse: findings from the Second National Incidence and Prevalence Study of Child Abuse and Neglect.

The epidemiology of child abuse was investigated with data from the Second National Incidence and Prevalence Study of Child Abuse and Neglect. A statistical comparison of incidence rates suggested that age, family income, and ethnicity were risk factors for both sexual abuse and physical abuse, but county metrostatus was not. Gender was a risk factor for sexual abuse but not for physical abuse. A logistic regression analysis showed that ethnicity, county metrostatus, and a gender-by-income interaction distinguished sexual abuse from physical abuse.

Protective personality characteristics among adolescent victims of maltreatment.

The purpose of this research was to examine whether personality characteristics, locus of control orientation, and self-esteem were protective against depression among female adolescent victims of maltreatment and to examine whether the presence of these characteristics was related to the age of the victim when maltreatment began. Thirty-three maltreated adolescent females and a comparison group of 112 nonmaltreated female adolescents were administered a questionnaire containing scales measuring locus of control orientation, self-esteem, and depression. Results revealed that personality characteristics interacted with maltreatment status in predicting depression, suggesting that they are protective factors. Results also revealed that adolescents who first experienced maltreatment during childhood were significantly less likely than those who first experienced maltreatment during adolescence to have these protective personality characteristics.

Tendon suspension sling arthroplasty for thumb trapeziometacarpal arthritis.

Forty consecutive tendon suspension sling arthroplasties for relief of pantrapezial osteoarthritis in 38 patients were reviewed. The procedure consists of excision of the trapezium and reconstitution of the tethering action of the first intermetacarpal and the palmar oblique carpometacarpal ligaments; 50% of the distally based flexor carpi radialis tendon is used. A double figure-eight sling suspends the first metacarpal securely, followed by distal advancement of the abductor pollicis longus to tighten the sling and palmarly abduct the thumb ray. The technique resulted in relief of pain, preservation of strength, maintenance of a normally contoured first web space, and functional carpometacarpal range of motion. Procedures were performed over a 4-year period (1986 to 1990), with an average follow-up of 21 months. At final follow-up, 85% of the patients had minimal symptoms; key pinch and grip strengths measured 76% and 81% of the contralateral uninvolved side, respectively. The logic of the mechanical design of the procedure and encouraging subjective and objective follow-up at 4 years make the technique of tendon suspension sling arthroplasty an attractive alternative to existing procedures for the surgical management of recalcitrant and disabling osteoarthritis of the basilar thumb joint.

Social relationships, personality, and anxiety during a major stressful event.

Although it is commonly believed that social relationships buffer the effects of stress on mental health, these apparent buffering effects may be spurious reflections of personality or prior mental health. This possibility was investigated in a prospective study of a medical school entrance examination. Five weeks before the examination, Ss (N = 56) rated their personality (extraversion and neuroticism) and social relationships (number of social contacts and perceived support). They then rated their anxiety for 35 days surrounding the examination. Controlling for personality and prior anxiety, social contacts buffered against increases in anxiety, whereas perceived support did not. Further analyses revealed that discretionary social contacts were beneficial whereas obligatory contacts were not.

Maltreatment among runaway and homeless youth.

A sample of 223 adolescents who sought services from runaway and homeless youth programs in New York State during 1986-1987 was identified as having a history of maltreatment. A demographic profile is presented and the nature of their maltreatment described. The majority of these youth were female and between 15-16 years of age. Less than 25% came from intact families and one-third were born to single mothers. Of the sample, 60% had allegedly experienced physical abuse, 42% emotional abuse, 48% neglect, and 21% sexual abuse. Over one-third were "pushed out" of their homes by their families. Biological mothers were the most frequently cited perpetrators of maltreatment (63%), followed by biological fathers (45%). The sample of maltreated runaways is compared to both statewide and national samples of runaway and homeless youth with regard to their demographic characteristics and the problems they present to staff at intake (e.g., depression, substance abuse, etc.). Youth in the maltreated sample were more likely to be female and were more likely to have engaged in suicidal behavior. Otherwise, the maltreated runaways were not readily distinguished from the runaway and homeless youth population at large.

Phase II trial of methylglyoxal bis-guanylhydrazone (MGBG) in refractory small cell lung cancer.

Methylglyoxal bis-guanylhydrazone (MGBG), a potent inhibitor of polyamine synthesis, has demonstrated single agent activity against a number of tumor types including malignant lymphomas and head and neck, esophageal and non-small cell lung cancers. The growth of small cell lung cancer (SCLC) cell lines can be arrested by polyamine inhibition. Therefore a phase II trial was conducted in twenty-four patients with refractory SCLC. MGBG was administered by intravenous infusion at a dose of 500 mg/m2 per week for four cycles and then every two weeks thereafter. The dose was escalated by 100 mg/m2 every two weeks in the absence of toxicity greater than or equal to grade 2. One patient achieved a partial response of objectively measurable lung disease and supraclavicular adenopathy. Three patients had stable disease. Dose limiting toxicity consisted primarily of mild to moderate nausea, vomiting, stomatitis and/or diarrhea. Myelosuppression was uncommon and rarely dose limiting. We conclude that MGBG in the dose and schedule used does not have significant activity as a single agent in previously treated small cell lung cancer.

Silicone wrist implant: long-term follow-up study.

Nineteen patients with 20 silicone rubber wrist implants of the Swanson design were followed for an average of 6 years. Sixty-five percent of the patients experienced little or no wrist pain after the operation. There was an average of 24 degrees of wrist flexion and 21 degrees of extension. Implant fracture occurred in 65% of the patients. This was not necessarily correlated with clinical symptoms. Subsidence of the implant occurred 100% of the time. Revision procedures were done after six (30%) of the procedures. There was no evidence of radiographic change suggesting silicone synovitis. There is a progressive deterioration in the radiographic appearance and the clinical result after use of this implant. Salvage by means of radiocarpal arthrodesis, or a soft tissue arthroplasty, has been successful in our patients.

The nature and substantiation of official sexual abuse reports.

A representative sample of 796 sexual abuse reports from New York State in 1985 was studied to explore factors associated with the decision to substantiate or unsubstantiate these reports. This study focused on the age, sex, and ethnicity of the subject child, and the source of the report as predictors of case substantiation. Substantiation rates tended to increase with the age of the child although this was more characteristic of reports involving female than male victims. Overall, reports involving female children were more likely to be substantiated than those involving male children. Ethnicity of the child showed no significant relationship to substantiation. Source of report, however, showed a strong relationship to case determination, with mandated reports found to be substantiated at a rate 13% higher than reports from non-mandated sources.

The maltreatment of adolescents.

Official reports of maltreatment involving adolescent victims were compared to those involving younger children in a representative sample of protective services' reports drawn from New York State in 1985. Specific case characteristics, including age, gender, ethnicity of the victim, and source of report, are described and their relation to case substantiation is examined. Analyses revealed that adolescents represent a substantial proportion of all victims of official child maltreatment reports. The impact of age on substantiation varied as a function of the type of maltreatment, where for adolescents sexual abuse reports were more likely to be substantiated, while neglect and physical abuse reports were less likely to be substantiated. Reports involving adolescents were significantly more likely to involve a female victim. Significant gender differences in substantiation rate were found only for sexual abuse reports involving adolescents. White children were also found to be under-represented in this sample, while blacks were over-represented relative to their numbers in the population. The impact of minority status on substantiation was significant for neglect and physical abuse reports involving children. The majority of adolescent reports came from mandated sources, which had a significantly higher substantiation rate than reports from non-mandated sources.