Early Alzheimer's disease pathology in human cortex involves transient cell states.

Cellular perturbations underlying Alzheimer's disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of AD pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes-which we refer to as the early cortical amyloid response-were prominent in neurons, wherein we identified a transitional hyperactive state preceding the loss of excitatory neurons, which we confirmed by acute slice physiology on independent biopsy specimens. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with ß-amyloid production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions.

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)-present in some but not all cells-remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e-4), with recurrent somatic deletions of exons 1-5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5' deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk.

Early Alzheimer's disease pathology in human cortex is associated with a transient phase of distinct cell states.

Cellular perturbations underlying Alzheimer's disease are primarily studied in human postmortem samples and model organisms. Here we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of Alzheimer's disease pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes-which we refer to as the Early Cortical Amyloid Response-were prominent in neurons, wherein we identified a transient state of hyperactivity preceding loss of excitatory neurons, which correlated with the selective loss of layer 1 inhibitory neurons. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathological burden increased. Lastly, both oligodendrocytes and pyramidal neurons upregulated genes associated with amyloid beta production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.

Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson's disease.

The loss of dopamine (DA) neurons within the substantia nigra pars compacta (SNpc) is a defining pathological hallmark of Parkinson's disease (PD). Nevertheless, the molecular features associated with DA neuron vulnerability have not yet been fully identified. Here, we developed a protocol to enrich and transcriptionally profile DA neurons from patients with PD and matched controls, sampling a total of 387,483 nuclei, including 22,048 DA neuron profiles. We identified ten populations and spatially localized each within the SNpc using Slide-seq. A single subtype, marked by the expression of the gene AGTR1 and spatially confined to the ventral tier of SNpc, was highly susceptible to loss in PD and showed the strongest upregulation of targets of TP53 and NR2F2, nominating molecular processes associated with degeneration. This same vulnerable population was specifically enriched for the heritable risk associated with PD, highlighting the importance of cell-intrinsic processes in determining the differential vulnerability of DA neurons to PD-associated degeneration.

3D-printed oxygen-releasing scaffolds improve bone regeneration in mice.

Low oxygen (O2) diffusion into large tissue engineered scaffolds hinders the therapeutic efficacy of transplanted cells. To overcome this, we previously studied hollow, hyperbarically-loaded microtanks (µtanks) to serve as O2 reservoirs. To adapt these for bone regeneration, we fabricated biodegradable µtanks from polyvinyl alcohol and poly (lactic-co-glycolic acid) and embedded them to form 3D-printed, porous poly-ε-caprolactone (PCL)-µtank scaffolds. PCL-µtank scaffolds were loaded with pure O2 at 300-500 psi. When placed at atmospheric pressures, the scaffolds released O2 over a period of up to 8 h. We confirmed the inhibitory effects of hypoxia on the osteogenic differentiation of human adipose-derived stem cells (hASCs and we validated that µtank-mediated transient hyperoxia had no toxic impacts on hASCs, possibly due to upregulation of endogenous antioxidant regulator genes. We assessed bone regeneration in vivo by implanting O2-loaded, hASC-seeded, PCL-µtank scaffolds into murine calvarial defects (4 mm diameters × 0.6 mm height) and subcutaneously (4 mm diameter × 8 mm height). In both cases we observed increased deposition of extracellular matrix in the O2 delivery group along with greater osteopontin coverages and higher mineral deposition. This study provides evidence that even short-term O2 delivery from PCL-µtank scaffolds may enhance hASC-mediated bone tissue regeneration.

A national physician survey on prescribing syringes as an HIV prevention measure.

BACKGROUND: Access to sterile syringes is a proven means of reducing the transmission of human immunodeficiency virus (HIV), viral hepatitis, and bacterial infections among injection drug users. In many U.S. states and territories, drug paraphernalia and syringe prescription laws are barriers to syringe access for injection drug users (IDUs): pharmacists may be reluctant to sell syringes to suspected IDUs, and police may confiscate syringes or arrest IDUs who cannot demonstrate a "legitimate" medical need for the syringes they possess. These barriers can be addressed by physician prescription of syringes. This study evaluates physicians' willingness to prescribe syringes, using the theory of planned behavior to identify key behavioral influences. METHODS: We mailed a survey to a representative sample of physicians from the American Medical Association physician database. Non-responding physicians were then called, faxed, or re-sent the survey, up to four times. RESULTS: Twenty percent responded to the survey. Although less than 1 percent of respondents had ever prescribed syringes to a known injection drug user, more than 60% of respondents reported that they would be willing to do so. Physicians' willingness to prescribe syringes was best predicted by the belief that it was a feasible and effective intervention, but individual and peer attitudes were also significant. CONCLUSION: This was the first nationwide survey of the physician willingness to prescribe syringes to IDUs. While the majority of respondents were willing to consider syringe prescription in their clinical practices, multiple challenges need to be addressed in order to improve physician knowledge and attitudes toward IDUs.

Prescribing syringes to prevent HIV: a survey of infectious disease and addiction medicine physicians in Rhode Island.

This article describes the assessment of physicians' attitudes and practices regarding prescribing syringes to injection drug users (IDUs). A brief, anonymous, self-administered questionnaire was sent to all Infectious Disease and Addiction Medicine specialists in Rhode Island. Of 49 eligible physicians, 39 responded (response rate 80%). Most (95%) indicated that there is a legitimate medical reason for IDUs to obtain sterile syringes. Many (71%) agreed that they would prescribe syringes to prevent disease in IDUs if it were clearly legal to do so. We can conclude that physician syringe prescription to IDUs may be an acceptable supplement to existing HIV prevention strategies.

Syringe prescription to prevent HIV infection in Rhode Island: a case study.

Injection drug users (IDUs) are a population at high risk for many diseases, including AIDS, and are clearly in need of medical and substance abuse treatment. Access to sterile syringes is critical for lowering the risk of transmission of HIV and other blood-borne pathogens among IDUs. Previously tried strategies include needle exchange programs and changing laws to allow the legal purchase and possession of syringes. An alternative strategy is to have physicians prescribe syringes to IDUs. To the best of our knowledge, this has previously been tried by only a few physicians in rare situations and never on a programmatic basis. This report describes the genesis of physician's syringe prescription in Rhode Island and some of the lessons learned to date. Because of the illicit nature of drug use, a tremendous amount of mistrust and fear on the part of IDUs often leads to poor interaction with the medical establishment. Prescription of syringes by a physician can serve as a tool for reaching out to a high-risk and often out-of-treatment population of drug users. It is a way for the health care community to tap into drug-using networks and bring those populations into a medical care system.

The EEOC charge priority policy and claimants with psychiatric disabilities.

OBJECTIVE: In June 1995 the U.S. Equal Employment Opportunity Commission (EEOC) instituted a new charge priority policy. Under the new policy, charges are classified as one of three priority levels during or immediately after intake. Only charges assigned a high priority receive a full investigation. This paper examines the effect of the charge priority policy on individuals with psychiatric disabilities who filed Americans With Disabilities Act (ADA) charges with the EEOC. METHODS: Using data extracted from the EEOC's charge data system, the authors analyzed all 66,298 ADA claims prioritized and closed between June 1995 and March 1998. The z test for difference in proportions and the generalized estimating equations procedure were used. The primary outcome measure was the priority assignment received by ADA claimants. RESULTS: Charges that received a high priority assignment were more likely to result in benefits for claimants. Charges filed by claimants with psychiatric disabilities were significantly less likely to be assigned a high priority than charges filed by other claimants. Claimants with psychiatric disabilities were also significantly less likely to benefit from their claims. CONCLUSIONS: The strong relationship between being assigned high priority and receiving benefits as a result of filing a charge demonstrates the importance of accurate priority categorization. The finding that people with psychiatric disabilities are less likely than others to benefit from their claims is cause for concern, particularly given the fact that the accuracy of the charge prioritization system has not been validated.

Differential response of human and bovine platelets to bovine von Willebrand factor and vascular subendothelium.

Human platelets undergo agglutination when stirred with bovine plasma (BP), but bovine platelets do not. The present study has shown that exposure of washed bovine platelets to subthreshold concentrations of adenosine diphosphate or thrombin before stirring restores their sensitivity to BP, and the cells undergo rapid agglutination. This agglutination was prevented by a monoclonal antibody, to glycoprotein GPIb. Flow cytometry studies revealed that exposure of bovine platelets to thrombin caused an increase in their ability to bind antibodies known to react with human GPIb or GPIIb-IIIa receptors. Interaction of bovine and human platelets with vascular subendothelium revealed additional differences in reactivity. Bovine platelets in citrate anticoagulant reacted poorly with subendothelium under flow conditions compared with human platelets. In contrast, bovine platelets in blood with low molecular weight heparin as anticoagulant adhered more readily than human cells. These findings suggest that different mechanisms are involved in hemostasis in human and bovine species.

Syringe laws and pharmacy regulations are structural constraints on HIV prevention in the US.

OBJECTIVE: To review the legal and regulatory barriers that restrict pharmacy sales of syringes to injection drug users (IDUs) and to discuss how reducing these barriers can facilitate access to sterile syringes for IDUs and improve HIV prevention. BACKGROUND: IDUs' access to sterile syringes from community pharmacies in the United States is limited by state laws and regulations governing syringe sales. Restricted availability of sterile syringes from pharmacies is a structural barrier that greatly impedes HIV prevention for IDUs, who often share and reuse syringes because they cannot obtain and possess sterile syringes. These high-risk behaviors contribute to the transmission of HIV and other blood-borne pathogens among IDUs, their sexual partners, and their children. STATE EXPERIENCES: In Connecticut, because of high HIV prevalence among IDUs, restrictive syringe laws were changed. After the legal changes in Connecticut, both pharmacy sales of syringes in areas of high drug use and purchases of syringes in pharmacies (reported by IDUs) increased, while syringe sharing (reported by IDUs) decreased. Maine and Minnesota have made similar changes in laws. CONCLUSIONS: Increasing access to sterile syringes through pharmacies requires the repeal or modification of legal barriers. Pharmacy sale of syringes to IDUs is an inexpensive HIV prevention intervention with the potential to substantially reduce HIV transmission. Further studies are needed to document how changes to legal barriers can influence HIV prevention for IDUs.

Physician prescribing of sterile injection equipment to prevent HIV infection: time for action.

Injection drug users, their sex partners, and their children are at high risk for acquiring HIV infection and other bloodborne diseases. The risk for disease transmission in the United States is partly the result of restricted access to sterile injection equipment. Physicians and pharmacists can play an important role in providing syringe access by prescribing and dispensing syringes to patients who use injection drugs and cannot or will not enter drug treatment Prescribing and dispensing injection equipment are ethical, clinically appropriate, and fully consistent with current public health guidelines on disease prevention. An analysis of the laws of the 50 U.S. states, the District of Columbia, and Puerto Rico finds that physicians in nearly all these jurisdictions may legally prescribe sterile injection equipment to prevent disease transmission among drug-using patients and that pharmacists in most states have a clear or reasonable legal basis for filling the prescriptions. Given these medical and legal findings, physicians may wish to take a larger role in improving access to sterile injection equipment by prescribing this equipment for their patients where this practice is legal, and by joining efforts to change the law where it poses a barrier.

A multidimensional measure of religious involvement for cancer patients: the Duke Religious Index.

Despite increasing interest in the relationship between religious involvement and health outcomes for cancer patients, research has been limited by the lack of appropriate measures. Few of the many instruments available are well suited to cancer patients. The current study examined the psychometric properties of one recently developed measure, the Duke Religious Index (DRI), which assesses several aspects of religious involvement. The DRI was evaluated in two distinct samples: 104 cancer patients receiving treatment at a bone marrow transplantation program and 175 gynecology clinic patients. The instrument demonstrated good internal consistency (coefficient alphas 0.87-0.94). Moderate to high correlations with other measures of religiosity provided support for convergent validity. Modest relationships with other measures commonly used in psychosocial oncology (e.g., optimism, social support, purpose in life) indicated that the instrument provides unique information (all rs's < 0. 42). Small relationships with social desirability response bias, negative affect, and relationship cohesion further supported the divergent validity of the instrument (all rs's < 0.22). The DRI was significantly associated with demographic characteristics but not with medical variables. Findings support the value of the DRI for use in oncology settings.

Surveillance, social risk, and symbolism: framing the analysis for research and policy.

Name-based surveillance for HIV, considered alone, is a useful public health measure; its benefits outweigh its direct costs. There is little evidence that name-based surveillance directly deters individuals at risk of HIV from being tested, or exposes them to significant social risks. Yet such surveillance is chronically controversial. Understood in a broader context of the social risks and symbolic politics of HIV, as subjectively experienced by people at risk, this opposition is both rational and instructive. Although often discussed, the social risks of HIV infection are poorly understood. To the extent these risks have been addressed by privacy and antidiscrimination laws, the solution has been less complete than many public health professionals appear to believe: developments in law and policy, including the increasing prevalence of criminal HIV transmission laws and proposed changes in HIV testing and counseling standards, are contextual factors that help explain the opposition to name-based surveillance. Rather than focusing piecemeal on specific "barriers" to testing and care, an appreciation of the surveillance debate in context suggests a positive undertaking in public health policy to provide the conditions of opportunity, information, motivation and confidence that people with HIV need to accept an effective program of early intervention.

The law and the public's health: a study of infectious disease law in the United States.

Law plays crucial roles in the field of public health, from defining the power and jurisdiction of health agencies, to influencing the social norms that shape individual behavior. Despite its importance, public health law has been neglected. Over a decade ago, the Institute of Medicine issued a report lamenting the state of public health administration, generally, and calling, in particular, for a revision of public health statutes. The Article examines the current state of public health law. To help create the conditions in which people can be healthy, public health law must reflect an understanding of how public health agencies work to promote health, as well as the political and social contexts in which these agencies operate. The authors first discuss three prevailing ways in which the determinants of health are conceptualized, and the political and social problems each model tends to create for public health efforts. The analysis then turns to the core functions of public health, emphasizing how law furthers public health work. The Article reports the results of a fifty-state survey of communicable disease control law, revealing that few states have systematically reformed their laws to reflect contemporary medical and legal developments. The Article concludes with specific guidelines for law reform.

Outcomes of employment discrimination charges filed under the Americans With Disabilities Act.

OBJECTIVE: The outcomes of employment discrimination charges filed under the Americans With Disabilities Act (ADA) by individuals with psychiatric disabilities and those with other disabilities were compared. METHODS: Data obtained from the Equal Employment Opportunity Commission (EEOC) consisted of all ADA employment claims closed as of March 31, 1998. Charges were categorized by whether they were investigated by the EEOC or by a Fair Employment Practice Agency (FEPA). RESULTS: Of the 175,226 charges filed, 83.2 percent were closed by March 31, 1998. Of these, 15.7 percent brought some kind of benefit to charging parties, although only 1.7 percent resulted in new hires or reinstatements. Of charges investigated by FEPAs, 23.3 percent led to some benefit, compared with 11.5 percent of charges investigated by the EEOC. Of charges investigated by the EEOC, the median actual monetary benefit was $5,646, compared with $2,400 for charges investigated by FEPAs. A total of 13.6 percent of charges filed by individuals with psychiatric disabilities resulted in benefits, compared with a benefit rate of 16 percent for persons with other disabilities. The median actual monetary benefit received by persons with psychiatric disabilities was $5,000, compared with $3,500 for those with nonpsychiatric disabilities. Individuals whose charges were investigated in the first three years of ADA implementation were more likely to receive benefits than individuals whose charges were investigated more recently. CONCLUSIONS: Most employment discrimination charges filed under the ADA do not result in benefits or a finding of reasonable cause. Outcomes for people with psychiatric disabilities do not differ substantially from those for people with other disabilities.