The Role of Complement in Kidney Disease: Conclusions From a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Uncontrolled complement activation can cause or contribute to glomerular injury in multiple kidney diseases. While complement activation plays a causal role in atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G), over the past decade a rapidly accumulating body of evidence has shown a role for complement activation in multiple other kidney diseases, including diabetic nephropathy and several glomerulonephritides. The number of available complement inhibitor therapies has also increased during the same period. In 2022 KDIGO convened a Controversies Conference, The Role of Complement in Kidney Disease, to address the expanding role of complement dysregulation in the pathophysiology, diagnosis, and management of various glomerular diseases, diabetic nephropathy, and other forms of HUS. Conference participants reviewed the evidence for complement playing a primary causal or secondary role in progression for several disease states and considered how evidence of complement involvement might inform management. Participating patients with various complement-mediated diseases and caregivers described concerns related to life planning, implications surrounding genetic testing, and the need for inclusive implementation of effective novel therapies into clinical practice. The value of biomarkers in monitoring disease course and the role of the glomerular microenvironment in complement response were examined, and key gaps in knowledge and research priorities were identified.

Controlling posture to see the world: The integration of visual task demands and postural sway in sitting and standing infants.

Our ability to integrate posture with visually demanding tasks is a critical aspect of motor behavior flexibility. When looking at a small object, excessive body movements impair an individual's ability to visually attend to the object. To overcome this problem, we adjust our postural sway to successfully focus on the object. The goal of the current study was to assess whether infants also adjust postural sway when engaged in a challenging visual task. The participants, 19 independently sitting infants (Sitters) and 21 newly independently standing infants (Standers), sat or stood on a force plate while viewing differently sized images displayed on a monitor (smaller images: 8 × 6.5 cm or 3 × 3 cm; larger images: 13 × 16 cm or 13 × 13 cm). Regardless of image size, Standers were less stable than Sitters with larger sway areas and faster sway velocities. Both Sitters and Standers adjusted sway area but not sway velocity, based on image size. Sitters and Standers differed in how they controlled sway dynamics. Standers but not Sitters altered sway dynamics based on image size. Overall, infants used posture-specific adaptive control strategies to make fine-grained adjustments based on image size. The development of the ability to integrate posture with a visually demanding task further emphasizes the capability of advanced complex motor behaviors during infancy, enabling infants to flexibly attend to important aspects of their environment at different postural positions.

Risk of residual cancer after complete response following first-line chemotherapy in men with metastatic non-seminomatous germ cell tumour and International Germ Cell Cancer Cooperative Group intermediate/poor prognosis: A multi-institutional retrospective cohort study.

INTRODUCTION: Current guidelines recommend surveillance in metastatic non-seminomatous germ cell tumour patients treated with first-line-chemotherapy and a complete clinical response (normalisation of serum tumour markers and residual masses <1 cm). However, this recommendation is based on a series including patients with good prognosis according to International Germ Cell Cancer Cooperative Group prognostic group (IGCCCG-PG). The aim of this study was to analyse the proportion of residual teratoma and survival among patients with intermediate/poor IGCCCG-PG and a complete clinical response after first-line-chemotherapy. MATERIAL & METHODS: This is a retrospective study of men with intermediate/poor IGCCCG-PG, who had a complete clinical response after first-line chemotherapy. Patients were either followed by surveillance or treated with post-chemotherapy retroperitoneal lymph node dissection (pcRPLND). RESULTS: Between 2009 and 2018, 143 men with intermediate (n = 83) or poor (n = 60) IGCCCG-PG were treated at 11 international centres. Among 33 patients treated with pcRPLND, the specimen showed teratoma and viable cancer in 16 (48%) and 4 (12%). During a median a 7-year follow-up, 20/110 (18%) patients managed with surveillance relapsed, of whom seven (6%) had a retroperitoneal-only relapse versus 2/33 patients managed with pcRPLND relapsed. No difference was observed regarding overall survival (OS) among men treated with pcRPLND or surveillance (5-year OS, 93% and 89%, p-value = 0.35). The median time-to-recurrence among men on surveillance was 1.3 years (range: 0.3-9.1), and the most common sites of relapses included retroperitoneum (11%), chest (5%), and bones (4%). CONCLUSIONS: While most men with intermediate/poor IGCCCG-PG harbour teratoma/cancer in the retroperitoneum despite a complete response to first-line-chemotherapy, only 6% managed with surveillance relapsed in the retroperitoneum. There was no significant difference in OS between the two groups.

Management of Residual Nonretroperitoneal Disease in Postchemotherapy Nonseminomatous Germ-Cell Tumors.

PURPOSE: The majority of patients with advanced nonseminomatous germ-cell tumor are cured with combination chemotherapy and surgical resection of residual disease when appropriate. In patients with both retroperitoneal (RP) and non-RP postchemotherapy residual disease, management of the non-RP disease is typically guided by pathologic findings at the time of RP resection. There are limited data to help guide management decisions in patients with non-RP postchemotherapy residual disease alone. MATERIALS AND METHODS: The prospectively maintained Indiana University testicular cancer database was queried for patients with metastatic nonseminomatous germ-cell tumor treated between 1990 and 2021 who had residual non-RP disease in the absence of residual RP disease after completing either first-line or salvage chemotherapy. RESULTS: One hundred twenty-nine patients met eligibility and were included in this analysis. Seventy-five patients had teratoma in the primary tumor site, while 54 did not. Of those with teratoma in the primary, 55% had at least one postchemotherapy non-RP surgical specimen with teratomatous elements compared with 17% of those without teratoma in the primary (P < .001). Of those without teratoma in the primary site, 56% had at least one postchemotherapy non-RP surgical specimen with active germ-cell tumor compared with 31% of those with teratoma in the primary (P = .0046). CONCLUSION: The presence of teratoma in the primary tumor site is associated with a higher rate of teratoma in postchemotherapy residual non-RP disease. Patients without teratoma in the primary tumor should still be considered for resection of residual postchemotherapy disease that could harbor teratoma or active germ-cell tumor.

Surveillance after Complete Response to First-Line Chemotherapy in Patients with Metastatic Nonseminomatous Germ Cell Tumor.

PURPOSE: The optimal management of patients with metastatic germ cell tumors who achieve a complete response (CR) after first-line chemotherapy remains unsettled. This study reports long-term outcomes of patients with metastatic germ cell tumor managed with surveillance after achieving a CR to first-line chemotherapy. MATERIALS AND METHODS: Patients with metastatic nonseminomatous germ cell tumor treated at Indiana University between 1990 and 2017 who achieved a CR after first-line chemotherapy and were monitored with surveillance were retrospectively analyzed. CR was defined as normalization of tumor markers AFP and hCG, and no residual mass >1 cm in long axis. Kaplan-Meier methods were used to analyze progression-free survival (PFS) and overall survival (OS). RESULTS: Three hundred sixty-seven patients achieved a CR and were managed with surveillance. After a median followup of 4.97 years, 34 patients had disease progression. At most recent followup, 346 (94%) patients were alive with no evidence of disease, 10 patients (2.7%) died of their disease, 5 (1.4%) died of other causes and 6 (1.6%) were lost to followup. The estimated 2-year PFS was 91% (95% CI: 87%-94%) and 2-year OS was 98% (95% CI: 96%-99%). The estimated 2-year PFS by International Germ Cell Cancer Collaborative Group risk category was 92% for good vs 90% for intermediate vs 87% for poor risk (p=0.15), and the estimated 2-year OS was 99% for good vs 96% for intermediate vs 93% for poor risk disease (p=0.001). CONCLUSIONS: Patients with metastatic nonseminomatous germ cell tumor who achieve a CR after first-line chemotherapy can be observed. Most patients who relapse can be salvaged with surgery and/or chemotherapy.

Innovation in Resident Core Oncology Education: Switching from an Inpatient Ward Rotation to a Hybrid Model of Inpatient Consultations and Outpatient Clinics.

Interest in an oncology career has decreased among internal medicine residents completing an inpatient hematology-oncology rotation. Over years, our institutional data at Indiana University School of Medicine reflected lower satisfaction with the oncology inpatient ward rotation as compared to other rotations. We hypothesized that a switch from an inpatient ward rotation to a hybrid model of inpatient consultations and outpatient clinics would improve resident satisfaction with their educational experience in oncology. Over the 6-month periods preceding and following the change in rotation format, residents were asked to complete anonymous rotation evaluations and rate their experiences on a 5-point Likert scale (poor 1 to excellent 5). Areas assessed included patient load, educational value of patient mix, quality of didactics and teaching, quality of patient care delivery, adequacy of time for reading, and overall rotation quality. The hybrid oncology rotation was rated as significantly superior to the traditional ward format in six out of eight areas including patient load, educational value of patient mix, time for study, teaching quality, relevance of material, and overall rating. Improvements in the perceived quality of patient care delivery (p = 0.139) and quality of didactics (p = 0.058) were also observed without reaching statistical significance. The balance of inpatient and outpatient experiences with the hybrid rotation was highly rated (4.5 ± 0.5). The implementation of a hybrid oncology rotation was associated with perceived improvement in educational value, patient mix, and time for reflection and study without apparent compromise in the quality of patient care delivery.

Participant evaluation of teleconference support for African American women with breast cancer.

BACKGROUND: African American women with breast cancer face obstacles such as transportation and family obligations when attending standard support groups. Teleconference support circumvents barriers such as transportation to participation, but few evaluations have been reported about teleconference support. OBJECTIVE: The purpose of this article was to describe the format of a teleconference group and to provide a descriptive account of the participants' feedback about a teleconference group intervention. METHODS: A descriptive design was used. Participants completed the Overall Support Group Evaluation tool at the end of the 10th group session. RESULTS: Teleconference group participants' feedback indicated that they perceived they had gained knowledge about breast cancer and coping. The participants expressed that the group helped them to reach out and ask for support and improved family and work relationships. Also, participants rated the group highly for the presence of therapeutic factors. On a scale of 1 to 4, with 4 being the highest, mean scores ranged from 3.97 to 3.56. CONCLUSIONS: The participants gave high ratings of satisfaction in terms of knowledge gained, leadership style, and benefits. The participants perceived that the group increased their knowledge about cancer, improved family connections, and increased their ability to deal with their cancer. IMPLICATIONS FOR PRACTICE: Using teleconferencing technology to deliver a support group to African American breast cancer patients is a beneficial method to reach a disadvantaged population that may be unable to attend face-to-face groups.

L-Dihydroxyphenylalanine modulates the steady-state expression of mouse striatal tyrosine hydroxylase, aromatic L-amino acid decarboxylase, dopamine and its metabolites in an MPTP mouse model of Parkinson's disease.

AIMS: l-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective symptomatic treatment for Parkinson's disease (PD), but PD patients usually experience a successful response to L-DOPA therapy followed by a progressive loss of response. L-DOPA efficacy relies on its decarboxylation by aromatic l-amino acid decarboxylase (AAAD) to form dopamine (DA). So exogenous L-DOPA drives the reaction and AAAD becomes the rate limiting enzyme in the supply of DA. In turn, exogenous L-DOPA regulates the expression and activity of AAAD as well as the synthesis of DA and its metabolites, changes that may be linked to the efficacy and side-effects of L-DOPA. MAIN METHODS: One-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD model was utilized to study the effects of L-DOPA on the steady-state level and activity of AAAD, tyrosine hydroxylase (TH), DA and the metabolites of DA. The MPTP and control mice were treated twice daily with PBS or with 100mg/kg of L-DOPA for 14days and the expression and activity of AAAD, the expression of TH and the levels of DA and its metabolites were determined 24h after L-DOPA or PBS treatment, when exogenous L-DOPA is eliminated. KEY FINDINGS: In the MPTP model, L-DOPA reduced the steady-state expression and the activity of striatal AAAD by 52% and 50%, respectively, DA and metabolites were also significantly decreased. SIGNIFICANCE: The outcome shows that while L-DOPA replenishes striatal DA it also down-regulates AAAD and the steady-state synthesis and metabolic capability of the dopaminergic system. These findings are important in the precipitation of L-DOPA induced side effects and the management of L-DOPA therapy.

Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab.

PURPOSE: To investigate whether there is an association between complement factor H (CFH) or LOC387715 genotypes with response to treatment with intravitreal bevacizumab for exudative age-related macular degeneration (AMD). DESIGN: Retrospective cohort study. PARTICIPANTS: The study cohort consisted of 86 patients being treated for neovascular AMD with bevacizumab alone. METHODS: Genotype determination for the CFH Y402H and LOC387715 A69S polymorphisms was performed by allele-specific digestion of polymerase chain reaction products. All patients were treated with 1.25 mg intravitreal bevacizumab at 6-week intervals until choroidal neovascularization was no longer active. MAIN OUTCOME MEASURES: CFH Y402H and LOC387715 A69S polymorphisms. Choroidal neovascular lesion characteristics were ascertained by fluorescein angiography. Snellen visual acuity (VA) was measured before and after treatment. RESULTS: For the CFH Y402H polymorphism, patients with the CFH TT genotype had the largest choroidal neovascular lesions (P = 0.02). With treatment, VA improved from 20/248 to 20/166 for the CFH TT genotype and from 20/206 to 20/170 for the TC genotype, but fell from 20/206 to 20/341 for the CFH CC genotype (P = 0.016). Only 10.5% of patients with the CFH CC genotype demonstrated improved VA with treatment, compared with 53.7% of CFH TT and TC genotypes (P = 0.004). For the LOC387715 A69S variant, patients with the TT genotype had the largest choroidal neovascular lesions (P = 0.012). There was no significant difference in response to bevacizumab treatment according to LOC387715 genotype. CONCLUSIONS: The AMD-associated CFH Y402H and LOC387715 A69S variants were associated with differences in choroidal neovascular lesion size in this study. Patients with the CFH CC genotype fared significantly worse with intravitreal bevacizumab than did those with the CFH TC and TT genotypes, suggesting a potential pharmacogenetic relationship. Prospective studies to confirm or refute this observation should be considered.

Clinical phenotypes associated with the complement factor H Y402H variant in age-related macular degeneration.

PURPOSE: To determine whether the complement factor H (CFH) Y402H variant is associated with specific age-related macular degeneration (AMD) clinical phenotypes. DESIGN: Retrospective, case-control study. METHODS: One hundred and eighty-eight white subjects with AMD and 189 control subjects were genotyped for the T-to-C polymorphism in exon 9 of the CFH gene by restriction-fragment length analysis and deoxyribonucleic acid (DNA) sequencing using genomic DNA from mouthwash samples. AMD phenotypes were characterized by clinical examination, fundus photography, and fluorescein angiography. RESULTS: Heterozygosity for the at-risk genotype (TC) increased the likelihood for AMD 2.1-fold (95% confidence interval [CI], 1.3 to 3.3), whereas homozygosity for the genotype (CC) increased the likelihood for AMD 6.5-fold (95% CI, 3.4 to 12.5) in our population. The C allele was associated significantly with predominantly classic choroidal neovascularization (odds ratio [OR], 2.01; 95% CI, 1.34 to 3.30). Neovascular lesion size was similar among the three genotypes (P = .67). CONCLUSIONS: The Y402H CFH variant carried a significantly increased risk for developing AMD in our population. Genotype and phenotype correlations regarding choroidal neovascular lesion type were observed.

Refractive defects and cataracts in mice lacking lens intrinsic membrane protein-2.

PURPOSE: To characterize the optical properties of lenses from mice deficient in the gene for lens intrinsic membrane protein-2 (Lim2), which encodes the second most abundant integral protein (Lim2) of lens fiber cell plasma membranes. METHODS: Lim2-deficient mice were derived from a library of gene-trap embryo stem cells. Genotyping was performed by polymerase chain reaction (PCR) amplification of tail genomic DNA and resequencing. Lim2 expression was analyzed by reverse transcription (RT)-PCR and Northern blotting of lens total RNA, immunoblotting of lens membrane extracts, and immunofluorescence confocal microscopy of lens sections. Lens morphology was assessed by light microscopy, and lens refractive properties were quantified with a laser imaging system. RESULTS: Genomic PCR amplification and resequencing indicated that the gene-trap vector had disrupted intron 3 of Lim2, effectively resulting in a null allele (Lim2(Gt)), as verified by RT-PCR amplification and sequencing, RNA blotting, immunoblotting, and immunofluorescence confocal microscopy. Heterozygous Lim2 gene-trap lenses (Lim2(Gt/+)) were morphologically indistinguishable from wild type, whereas homozygous Lim2 gene-trap lenses (Lim2(Gt/Gt)) consistently developed faint, central pulverulent cataracts. Laser imaging analysis indicated that rays passing through the peripheral cortex of the Lim2(Gt/Gt) lens were more strongly refracted than normal, suggesting that the internal gradient refractive index of the lens was disturbed. CONCLUSIONS: These data show that heterozygous loss of Lim2 is insufficient to trigger cataracts in mice, and they provide the first direct evidence that Lim2 plays a critical role in establishing the correct internal refractive properties of the crystalline lens.