A phase I dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results.

BACKGROUND: SERENA-1 (NCT03616587) is a phase I, multi-part, open-label study of camizestrant in pre- and post-menopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. PATIENTS AND METHODS: Women aged ≥18 years with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy, were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, antitumor efficacy, pharmacokinetics, and impact on mutations in the estrogen receptor gene (ESR1m) circulating tumor (ct)DNA levels were assessed. RESULTS: By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events at doses ≤150 mg. Median tmax was achieved ∼2-4 h post-dose at all doses investigated, with an estimated half-life of 20-23 h. Efficacy was observed at all doses investigated, including in patients with prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. CONCLUSIONS: Camizestrant is a next-generation oral selective ER antagonist and degrader (SERD) and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75-, 150-, and 300-mg QD doses for phase II testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).

Tumourigenic non-small-cell lung cancer mesenchymal circulating tumour cells: a clinical case study.

BACKGROUND: Over the past decade, numerous reports describe the generation and increasing utility of non-small-cell lung cancer (NSCLC) patient-derived xenografts (PDX) from tissue biopsies. While PDX have proven useful for genetic profiling and preclinical drug testing, the requirement of a tissue biopsy limits the available patient population, particularly those with advanced oligometastatic disease. Conversely, 'liquid biopsies' such as circulating tumour cells (CTCs) are minimally invasive and easier to obtain. Here, we present a clinical case study of a NSCLC patient with advanced metastatic disease, a never smoker whose primary tumour was EGFR and ALK wild-type. We demonstrate for the first time, tumorigenicity of their CTCs to generate a patient CTC-derived eXplant (CDX). PATIENTS AND METHODS: CTCs were enriched at diagnosis and again 2 months later during disease progression from 10 ml blood from a 48-year-old NSCLC patient and implanted into immunocompromised mice. Resultant tumours were morphologically, immunohistochemically, and genetically compared with the donor patient's diagnostic specimen. Mice were treated with cisplatin and pemetrexed to assess preclinical efficacy of the chemotherapy regimen given to the donor patient. RESULTS: The NSCLC CDX expressed lung lineage markers TTF1 and CK7 and was unresponsive to cisplatin and pemetrexed. Examination of blood samples matched to that used for CDX generation revealed absence of CTCs using the CellSearch EpCAM-dependent platform, whereas size-based CTC enrichment revealed abundant heterogeneous CTCs of which ∼80% were mesenchymal marker vimentin positive. Molecular analysis of the CDX, mesenchymal and epithelial CTCs revealed a common somatic mutation confirming tumour origin and showed CDX RNA and protein profiles consistent with the predominantly mesenchymal phenotype. CONCLUSIONS: This study shows that the absence of NSCLC CTCs detected by CellSearch (EpCAM(+)) does not preclude CDX generation, highlighting epithelial to mesenchymal transition and the functional importance of mesenchymal CTCs in dissemination of this disease.

Effect of a live Mycoplasma synoviae vaccine on the production of eggshell apex abnormalities induced by a M. synoviae infection preceded by an infection with infectious bronchitis virus D1466.

An experimental study was conducted to assess the effect of a live Mycoplasma synoviae vaccine (Vaxsafe MS; Bioproperties Pty Ltd, Ringwood, Victoria, Australia) on M. synoviae-induced eggshell apex abnormalities (EAA). Four experimental groups of specified-pathogen-free white laying hens were made. All groups were inoculated with infectious bronchitis virus D1466 at 18 weeks of age. One group did not receive further treatment (non-vaccinated non-challenged (NVNC)). Two groups were vaccinated at 14 weeks of age against M. synoviae, and one of these groups was also challenged with an EAA-inducing M. synoviae strain 5 days after infectious bronchitis virus challenge (vaccinated non-challenged (VNC) and vaccinated challenged group (VC), respectively). The fourth group was not vaccinated but was challenged with M. synoviae (non-vaccinated challenged (NVC)). Eggs with EAA eggs were produced only in the NVC and VC groups. However, the proportion of eggs with EAA and the mean daily production of eggs with EAA per chicken was significantly lower (P<0.05) in the VC group (88/741 (11.9%) and 0.09+/-0.01 eggs per hen) compared with the NVC group (148/646 (22.9%) and 0.14+/-0.01 eggs per hen). The mean daily egg production per chicken was significantly lower in the NVC group (0.48+/-0.03 eggs) compared with that of the NVNC group (0.60+/-0.03 eggs), but not significantly different from other groups. The eggshell strength of eggs with EAA (22.8 N) was significantly lower (P<0.05) than non-affected eggs from the other groups (33.7 to 39.5 N). Furthermore, the eggshell strength of non-affected eggs in the NVC group was significantly lower (P<0.05) compared with that of non-affected eggs from the flock of origin (33.7 versus 41.2 N), but not different from the other groups. It can be concluded from the present study that vaccination with a live M. synoviae vaccine reduces the occurrence of M. synoviae-induced EAA significantly.

Artificial insemination in deer and non-domestic bovids.

Artificial insemination technology has revolutionized the domestic cattle breeding industry and allowed for the dissemination of valuable genetics worldwide. This technology has been adapted for use in many other taxa for the conservation of threatened and endangered species, but its use for the genetic management of small populations of deer, antelope and other non-domestic bovids has met numerous challenges and limited success. In practice, adaptation of domestic bovine AI protocols to other artiodactylids for genetic management has been limited by: (1) a lack of understanding of species-specific reproductive characteristics; (2) the inability to minimize handling stress; (3) pregnancy losses; and (4) regulatory challenges in semen importation. To date, AI protocols have been developed for seven species of cervid and 14 species of non-domestic bovids; recent developments in this technology has allowed greater use of AI for dissemination of genetics in farmed deer species. However, despite decades of research in the use of assisted reproduction for the conservation of antelope and other non-domestic bovids, even this simplest technique has not been used repeatedly for genetic management.

Development and evaluation of an improved diagnostic PCR for Mycoplasma synoviae using primers located in the haemagglutinin encoding gene vlhA and its value for strain typing.

Using published primers, detection of Mycoplasma synoviae and strain identification using the vlhA gene sequence was attempted. However, of 21 M. synoviae strains examined, three could not be amplified, so a new reverse primer was designed with a target in the conserved region of the vlhA gene. This allowed all 21 M. synoviae strains, a further nine strains and also material from 11 swab samples from M. synoviae-positive birds, to produce a PCR product, suggesting that the method could also be suitable for clinical specimens. The protocol was then tested on the type strains of M. synoviae and the other 22 recognised avian Mycoplasma species, with amplification of M. synoviae only. Further testing demonstrated that this PCR was equally or more sensitive than other PCR tests used to detect M. synoviae. Subsequent DNA sequence analysis of the PCR product based on percent similarity and evolutionary relationship appeared to be a useful tool for strain differentiation.

Kinetochore localisation and phosphorylation of the mitotic checkpoint components Bub1 and BubR1 are differentially regulated by spindle events in human cells.

BUB1 is a budding yeast gene required to ensure that progression through mitosis is coupled to correct spindle assembly. Two related human protein kinases, Bub1 and BubR1, both localise to kinetochores during mitosis, suggesting that they play a role in delaying anaphase until all chromosomes achieve correct, bipolar attachment to the spindle. However, how the activities of Bub1 and BubR1 are regulated by spindle events and how their activities regulate downstream cell cycle events is not known. To investigate how spindle events regulate Bub1 and BubR1, we characterised their relative localisations during mitosis in the presence and absence of microtubule toxins. In prometaphase cells, both kinases colocalise to the same domain of the kinetochore. However, whereas the localisation of BubR1 at sister kinetochores is symmetrical, localisation of Bub1 is often asymmetrical. This asymmetry is dependent on microtubule attachment, and the kinetochore exhibiting weaker Bub1 staining is typically closer to the nearest spindle pole. In addition, a 30 minute nocodazole treatment dramatically increases the amount of Bub1 localising to kinetochores but has little effect on BubR1. Furthermore, Bub1 levels increase at metaphase kinetochores following loss of tension caused by taxol treatment. Thus, these observations suggest that Bub1 localisation is sensitive to changes in both tension and microtubule attachment. Consistent with this, we also show that Bub1 is rapidly phosphorylated following brief treatments with nocodazole or taxol. In contrast, BubR1 is phosphorylated in the absence of microtubule toxins, and spindle damage has little additional effect. Although these observations indicate that Bub1 and BubR1 respond differently to spindle dynamics, they are part of a common complex during mitosis. We suggest therefore that Bub1 and BubR1 may integrate different 'spindle assembly signals' into a single signal which can then be interpreted by downstream cell cycle regulators.

Comparing ovulation synchronization protocols for artificial insemination in the scimitar-horned oryx (Oryx dammah).

Ovarian response and pregnancy success in scimitar-horned oryx (n=28) were compared, following treatment with two synchronization protocols and fixed-time artificial insemination (AI) with frozen-thawed semen. Each oryx received two injections of 500 microg of prostaglandin-F(2alpha) analogue (PGF(2alpha)-only) 11 days apart, and half received PGF(2alpha) in combination with an intravaginal progesterone-releasing device (CIDR11+PGF(2alpha)). Semen was collected by electroejaculation from anaesthetised adult oryx and cryopreserved. Anaesthetised females were transcervically inseminated 56.0+/-1.1 h (+/-S.E.M.) after PGF(2alpha) injection and/or device withdrawal using 28.0+/-1.5x10(6) motile thawed sperm. Ovarian endocrine response was monitored in 20 females by analysing faecal oestrogen and progesterone metabolites. Periovulatory oestrogen peaks were detected in 19/20 (95%) females after synchronization. There were no between-treatment differences in oestrogen concentrations or peak characteristics (P0.05). Luteal development after synchronization was delayed in half the progesterone treated (CIDR11+PGF(2alpha)) females, and faecal progestin excretion profiles indicated that the ovulatory follicle associated with synchronization either failed to ovulate or to fully lutenise. Pregnancy was diagnosed by ultrasonography and/or rectal palpation and was monitored by faecal progestin excretion. More (P=0. 013) pregnancies resulted from the PGF(2alpha)-only treatment (37.5%, 5/14) than from the CIDR11+PGF(2alpha) treatment (0/14), and four healthy scimitar-horned oryx calves were born, three after gestation intervals of 247 days and one after 249 days.

Stag exposure advances the LH surge and behavioral estrus in Eld's deer hinds after CIDR device synchronization of estrus.

The impact of male presence or absence on the timing of the preovulatory LH surge and estrus was studied in 3 experimental groups (n = 6/group) of Eld's deer hinds pretreated with intravaginal progesterone-releasing devices (CIDR-type G) as follows: Group 1 = indirect male contact barn; Group 2 = direct male contact barn; and Group 3 = male isolation barn. For all hinds, the duration of the preovulatory LH surge averaged 2.5+/-0.5 h, whereas mean peak preovulatory and basal LH concentrations were 2.9+/-0.2 ng mL(-1) and 0.27+/-0.03 ng mL(-1), respectively. Nine of 12 male-exposed hinds exhibited a preovulatory LH surge within 24 to 32 h postCIDR device withdrawal, whereas 0 of 6 male-isolated hinds exhibited a preovulatory LH surge during the same time period. Onset of behavioral estrus (45.2+/-2.3, 52.7+/-5.7 and 66.3+/-1.8 h, respectively) was significantly advanced (P<0.05) after CIDR device withdrawal in male exposed hinds (Groups 1 and 2) compared with male isolated hinds (Group 3). These data suggest that stag exposure is important for modulating the timing of the preovulatory LH surge and behavioral estrus after synchronization of estrus with exogenous progestagens.

Ovarian activity in the scimitar-horned oryx (Oryx dammah) determined by faecal steroid analysis.

Ultrasonography and radioimmunoassay (RIA) of serum oestradiol-17beta, luteinizing hormone (LH) and progesterone, and faecal oestrogen and progestin was used to assess ovarian activity in the scimitar-horned oryx (Oryx dammah). Ovarian examination using ultrasonography revealed maximal follicle and corpus luteum (CL) diameters of 15 and 32 mm, respectively. Steroid hormone metabolite distribution among individual faecal pellets within the same defaecation was relatively homogeneous with coefficients of variation averaging 10.2+/-1.8% and 16.2+/-4.6% for oestrogens and progestins, respectively. Elevated faecal oestrogen concentrations were associated with large (> 10 mm) antral follicles detected by ultrasonography. Periovulatory peaks in faecal oestrogen excretion, coincident with nadirs in progestin excretion, were detected in three females. Faecal progestin excretion exhibited a similar temporal pattern to serum progesterone concentrations, with a time lag of approximately 16 h. Faecal progestin concentrations corresponded with the presence of functional CL and proved useful for monitoring luteal function, spontaneous and prostaglandin-F2alpha analogue-induced luteolysis and anovulation. In summary, faecal steroid monitoring is a practical, noninvasive method for characterising ovarian steroid excretion and has potential for facilitating the application of assisted reproductive technologies in scimitar-horned oryx.

Characterization of pathotype-specific epitopes of newcastle disease virus fusion glycoproteins by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and post-source decay sequencing.

Matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS) was used to characterize the F2 polypeptide of the fusion (F) protein of an avirulent isolate (VRI 82-6409) of Newcastle disease virus (NDV) that was previously identified by immunochemical screening as having a variant cleavage activation sequence in its fusion protein precursor (F0). The major glycoform of the intact F2 polypeptide of the VRI 82-6409 isolate was 89 Da smaller than the F2 polypeptide of the avirulent V4 isolate of the Queensland strain of NDV. Analysis of AspN protease digests of the F2 polypeptides by MALDI/TOF-MS, with and without high-performance liquid chromatographic (HPLC) separation, showed this mass difference to be due to a combination of differences in the extents of glycosylation and an amino acid difference in the AspN peptides derived from the C-termini of the F2 polypeptides. Accuracies achieved in analysis of the AspN peptides allowed the identification of this amino acid difference as glutamic acid in the VRI 82-6409 isolate compared with glycine in the V4 isolate. Analysis of fragments formed by post-source decay (PSD) of ions of the C-terminal AspN peptides localized the difference to the C-terminal residues of the respective F2 polypeptides. The present study demonstrated that MALDI/TOF-MS is a highly effective technique for the characterization of NDV variants identified by immunochemical screening of pathotype-specific epitopes at the C-termini of their F2 polypeptides.

Production of temperature-sensitive clones of Mycoplasma synoviae for evaluation as live vaccines.

An Australian field isolate of Mycoplasma synoviae (MS), 89079/7NS, was exposed to the mutagen N-nitro-N'-methyl-N-nitrosoguanidine. Fifteen clones from the exposed culture were characterized for temperature sensitivity. Four clones labelled B, D, G, and H were temperature sensitive and were further characterized for their ability to colonize chickens and elicit an immune response. Serum antibody responses to MS were detected 3 wk after infection, by eyedrop, in 10 of 10 birds inoculated with 86079/7NS and clones B and G and in 9 of 10 birds inoculated with clone H. No MS antibody response was observed in any bird inoculated with clone D. MS was recovered from the upper trachea of 10 of 10 birds inoculated with clones B, G, and H at 2 wk after infection. No MS was isolated from birds inoculated with clone D. Clone H, designated MS-H, was selected as a potential vaccine candidate.

Efficacy of a temperature-sensitive Mycoplasma synoviae live vaccine.

A temperature-sensitive clone of Mycoplasma synoviae (MS), MS-H, derived from the chemical mutagenesis of the Australian field isolate 86079/7NS, was investigated for efficacy as a live vaccine. Titers of MS-H vaccine ranged between 1.16 x 10(8) and 8.4 x 10(8) color changing units/ml when incubated at 33 C and were consistently > or = 10(2) lower when incubated at 39.5 C. Laboratory-produced MS-H vaccine protected 8 out of 10 specific-pathogen-free Webster white leghorn chickens against a combined experimental challenge of aerosols of the virulent wild MS strain 88064/FP and T-strain infectious bronchitis vaccine administered intratracheally. Laboratory and commercially produced vaccines were compared for efficacy against thoracic air sac challenge, with both achieving similar levels of air sac protection. Air sac lesion incidences of five air sacs with lesions out of 32 and four out of 32 were seen in groups vaccinated with laboratory and commercial vaccines, respectively, compared with 13 out of 20 in nonvaccinated specific-pathogen-free hybrid white leghorn chickens. An attempt to determine the dose response of the commercial vaccine was conducted with 0.5, 2, and 4 times the standard dose. Air sac lesion incidences of 16 air sacs with lesions out of 32 in the 0.5 times, 11 out of 32 in the 2 times, and 1 out of 32 in the 4 times dose groups were observed.

Safety of a temperature-sensitive clone of Mycoplasma synoviae as a live vaccine.

A temperature-sensitive (ts+) clone derived from the Australian Mycoplasma synoviae (MS) field isolate 86079/7NS was produced by chemical mutagenesis with N-methyl-N'-nitro-N-nitrosoguanidine and assessed for safety as a live vaccine. This clone, designated MS-H, was assessed for pathogenicity in three different models with air sac lesions as the criterion. No air sac lesions were observed when MS-H was administered to specific-pathogen-free hybrid white leghorn (HWL) chickens by eyedrop at 10 times the normal dose or directly into the thoracic air sacs or as an aerosol administered to specific-pathogen-free Webster white leghorn chickens with concurrent intratracheal T-strain infectious bronchitis virus (IBV). MS-H did not revert to virulence or lose the ts+ phenotype when passaged through five in vivo and 10 in vitro passages. No adverse effects were seen when HWL chickens were vaccinated concurrently with MS-H and combinations of Mycoplasma gallisepticum ts-11 vaccine, IBV vaccine, and infectious laryngotracheitis virus vaccine. Lateral transmission of MS-H was found to occur when vaccinated HWL chickens were mixed with unvaccinated chickens 2 wk after vaccination. At 1 wk after mixing, one out of two unvaccinated chickens had seroconverted to MS and was culture positive for MS. At 2 wk after mixing, both contact chickens were positive for MS by culture and serology.

The development and evaluation of two tissue culture-grown Marek's disease challenge viruses.

Standardized challenge viruses are essential for the evaluation of Marek's disease (MD) vaccines with many MD challenge preparations consisting of lymphocytes or whole blood from infected birds. Virus present in these preparations is difficult to quantify by tissue culture assays and, therefore, the infectious bird dose and long-term storage viability cannot be assured. We report on the properties of two low-passage virulent Australian MD viruses, the Woodlands No. 1 strain and strain MPF 57. Both strains were isolated in chicken embryo kidney cultures and adapted to grow in chicken embryo fibroblast cultures for a maximum of 14 passages. Both strains could be readily assayed in tissue culture and produced titres of 10(3) to 10(4) 50% tissue culture infectious doses per ml (TCID(50)). Birds inoculated at three different doses were observed over 10 weeks, and tissues examined for gross and histological lesions, bursarbody weight ratios and the presence of viraemia. Tissue culture-grown preparations of both strains were only slightly less virulent than the original lymphocyte challenge material and produced similar pathological responses and around 80% death or gross lesions. From bursarbody weight ratios strain MPF 57 appeared to be more virulent than the Woodlands No. 1 strain.

The development of lameness and bone deformity in the broiler following experimental infection with Mycoplasma gallisepticum or Mycoplasma synoviae.

Groups of eight 7-day-old Mycoplasma-free broiler chicks were inoculated with one of two strains of M. gallisepticum (MG/S6, MG/B31/85) or one of two strains of M. synoviae (MS/B31/88 and MS/B94/91) into the left hock joint. Controls were similarly inoculated with sterile mycoplasma broth. The birds were assessed at 2, 3, 4 and 5 weeks of age (1, 2, 3 and 4 weeks post-injection) for lameness and joint and limb lesions. At 5 weeks of age they were killed and examined for gross skeletal abnormalities and microscopic lesions of both hock joints. The in-contact controls showed no joint swelling or lameness. The mycoplasma did not apparently spread to cause gross pathology in the joints of in-contact control birds, or to other joints in a bird injected with mycoplasma. Each mycoplasma strain caused specific pathologies manifest as varying degrees of lameness, left hock joint swelling, bone deformity and differences in the severity of articular cartilage and chondrodystrophic growth plate pathology. Shortening and bowing of the right tibiotarsus in the birds injected with mycoplasma indicated unilateral increased limb loading contributing to bone deformity. Chondrodystrophy seen with three mycoplasmal strains may have contributed to bone deformity in these birds. Lameness appeared to be a consequence of either joint swelling and/or bone deformity resulting in mechanical dysfunction. The role of joint pain in the lameness was not determined.

Comparison of seasonal changes in reproductive parameters of adult male European fallow deer (Dama dama dama) and hybrid Mesopotamian x European fallow deer (D. d. mesopotamica x D. d. dama).

In a study, aimed at comparing seasonal reproductive development of European fallow deer (Dama dama dama) with Mesopotamian (D. d. mesopotamico) x European F1 hybrids, five adult males of each genotype, which had been raised together since birth, were maintained as a bachelor group. Morphometric (body weight, neck circumference and testis diameter), endocrine (plasma testosterone concentrations) and seminal (ejaculate volume, spermatozoa per ejaculate and spermatozoa motility) parameters were recorded at fortnightly or monthly intervals for a 15-month period, and antler status was noted daily during the general periods of casting and velvet stripping. In addition, two bucks of each genotype were blood sampled via indwelling jugular catheters every 30 min for 24-h periods on five occasions (2-3 months intervals) during the year, and plasma was analysed for concentrations of testosterone and LH. Parameter profiles of the two genotypes were compared by global and time series ante-dependence covariance analysis to investigate overall profile similarity and the seasonal nature of any observed differences. Plasma hormone profiles from high-frequency blood sampling were subjected to PULSAR analysis to determine pulse frequency and amplitude. Throughout the study hybrid males were approximately 30% heavier than European males. However, both genotypes exhibited dramatic but parallel patterns of body weight change (global P = 0.054). Neck circumference was correlated with body weight throughout (P < 0.05), with similar regression slopes between the genotypes at any sampling time (P > 0.10). Covariance adjustment to a common initial body weight was performed to eliminate the effects of large body weight differences on muscle hypertrophy and regression. While profiles of corrected neck circumference were significantly different at the global level (P < 0.01), analysis by time revealed differences occurring only during the latter period of muscular regression in spring. However, profiles of other parameters, including testis diameter, plasma testosterone concentrations, spermatozoa per ejaculate and percentage motile spermatozoa, exhibited significant displacement between genotypes (global P < 0.05) evident as 2-4 weeks advancement in the sexual development (late summer/autumn) and quiescence (spring) phases for hybrid males relative to European males. Furthermore, mean dates of antler casting and velvet stripping were significantly earlier by 2-3 weeks for hybrid males than European males (P < 0.05). High frequency blood sampling revealed markedly seasonal patterns of secretion of testosterone and LH, with hybrid males exhibiting an apparent earlier onset of high-amplitude testosterone 'surges' in February (late summer) compared to those occurring in April (autumn) for European males. When viewed collectively, the data indicate strongly that the Mesopotamian influence is evident in the earlier attainment of sexual development and fertility in late summer and autumn, and earlier onset of sexual quiescence in spring. This is in accord with anecdotal information on earlier reproductive patterns in purebred Mesopotamian fallow deer.

The effects of HIV on cognitive and motor development in children born to HIV-seropositive women with no reported drug use: birth to 24 months.

OBJECTIVE: This study documents delays in the mental and motor functioning of infants perinatally infected with human immunodeficiency virus (HIV) while controlling for confounding effects of prenatal drug exposure, ethnicity, socioeconomic status, and maternal separation and death. METHODS: The cognitive and motor development of 126 infants born to nondrug-using, HIV-seropositive Haitian women was assessed at 3-month intervals through 24 months of age using the Bayley Scales of Infant Development. By 18 months of age, 28 of the infants were diagnosed as HIV-infected, and the 98 uninfected infants served as a control group. The infected and uninfected infants did not differ with respect to mean gestational age, birth weight, ethnicity, or rates of maternal separation and death. RESULTS: By 3 months of age, the mean mental and motor scores of the infected infants were significantly lower than those of the uninfected controls. Furthermore, the initial differences between the two groups increased over time, as many of the infected infants became increasingly delayed. Although the infected infants tended to perform more poorly than the uninfected infants, nearly one third of the infected infants exhibited relatively normal cognitive development and half demonstrated relatively normal motor development. CONCLUSIONS: Over the first 24 months of life, the mean rate of development of HIV-infected infants is significantly slower than that of noninfected infants born to seropositive mothers. This occurs even when the effects are not confounded with those of prenatal drug exposure.