Timothy Syndrome

Provides nationwide access to all covered entities enrolled in the 340B Prime Vendor Program KANNAPOLIS, N.C.--(BUSINESS WIRE)-- Genixus, a pharmaceutical company focused on transforming acute and critical care medicines, is pleased to announce the execution of a contract with the 340B Prime Vendor Program, managed by Apexus LLC., for KinetiX Propofol 1% ready-to-administer (RTA) syringes, designed to simplify workflow and support effective care delivery. This press release features multimedia. View the full release here: KinetiX Propofol features several key attributes: Long-term shelf stability to support a hospital’s supply chain Intuitive labeling and color-coded plunger rod support rapid identification Auto-dispensing cabinet (ADC) ready to keep product proximal to delivery site RFID-enabled with the latest technology in kit and tray management 10ml and 20ml RTA syringes offer flexibility to minimize waste Durable polymer syringe eliminates risks of glass breakage and delamination "We are excited about our agreement with Apexus and the opportunity to provide KinetiX Propofol to more hospitals and patients," said Kendall Foster, CEO of Genixus. “Propofol is a critical medication used for procedural sedation, during monitored anesthesia care, or as an induction agent for general anesthesia. With the introduction of our KinetiX RTA syringe platform, we look to support improvements in safety, speed, and satisfaction for clinicians, so they can spend more time on what they do best: patient care." The contract with Apexus is a significant milestone for Genixus, as it expands access and supports their mission of simplifying acute & critical care medicines through innovation. Ordering for KinetiX Propofol will be available to covered entities beginning June 1 at . About Genixus: Genixus, headquartered in Kannapolis, North Carolina, is a development stage pharmaceutical manufacturer and FDA-registered repackager and 503B outsourcing provider of high-quality easy-to-use ready-to-administer products for acute and critical care. Leveraging the highest-quality biopharmaceutical manufacturing standards and innovative point-of-care design, Genixus is changing care delivery and helping healthcare professionals to achieve better quality outcomes for patients. For more information, visit and follow the company on LinkedIn. About the 340B Prime Vendor Program: The 340B Prime Vendor Program, managed by Apexus™, is a contract awarded by the Health Resources and Services Administration (HRSA), which is responsible for administering the 340B Drug Pricing Program. As the Prime Vendor, Apexus contracts with manufacturers and distributors to help ensure access to discounted medications, provides 340B education to all stakeholders, and helps support program integrity through technical assistance. Propofol 1% Injectable Emulsion, USP Repackaged by Genixus, Corp. Indications and Usage Indication Approved Patient Population Initiation and maintenance of Monitored Anesthesia Care (MAC) sedation Adults only Combined sedation and regional anesthesia Adults only (see prescribing information PRECAUTIONS) Induction of General Anesthesia Patients greater than or equal to 3 years of age Maintenance of General Anesthesia Patients greater than or equal to 2 months of age Intensive Care Unit (ICU) sedation of intubated, mechanically ventilated patients Adults only Safety, effectiveness, and dosing guidelines for propofol injectable emulsion, USP have not been established for MAC Sedation in the pediatric population; therefore, it is not recommended for this use. Propofol injectable emulsion, USP is not recommended for induction of anesthesia below the age of 3 years or for maintenance of anesthesia below the age of 2 months because its safety and effectiveness have not been established in those populations. Propofol injectable emulsion, USP is not recommended for obstetrics, including Cesarean section deliveries. Propofol injectable emulsion, USP is not recommended for use in nursing mothers because propofol has been reported to be excreted in human milk, and the effects of oral absorption of small amounts of propofol, USP are not known. Important Safety Information PROPOFOL should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure. Use of PROPOFOL has been associated with both fatal and life-threatening anaphylactic and anaphylactoid reactions. PROPOFOL is contraindicated in patients with a known hypersensitivity to propofol or any of PROPOFOL components, and also in patients with allergies to eggs, egg products, soybeans or soy products. Strict aseptic technique must always be maintained during handling. PROPOFOL is a single access parenteral product (single patient ready to use syringe), which contains benzyl alcohol (10mg per mL) to inhibit the rate of growth of microorganisms, for up to 12 hours, in the event of accidental extrinsic contamination. PROPOFOL has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with PROPOFOL. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly. PROPOFOL should not be coadministered through the same IV catheter with blood or plasma because compatibility has not been established. Administer PROPOFOL with caution in patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis. Abrupt discontinuation of PROPOFOL prior to weaning or for daily evaluation of sedation levels should be avoided. For both adult and pediatric ICU sedation, PROPOFOL infusion has been associated with Propofol Infusion Syndrome, that have resulted in death. Neurosurgical Anesthesia: When PROPOFOL is used in patients with increased intracranial pressure or impaired cerebral circulation, significant decreases in mean arterial pressure should be avoided because of the resultant decrease in cerebral perfusion pressure. Cardiac Anesthesia: Slower rates of administration should be utilized in premedicated patients, geriatric patients, patients with recent fluid shifts, and patients who are hemodynamically unstable. This Important Safety Information does not include all the information needed to use PROPOFOL, Injectable Emulsion, USP safely and effectively. Please see full prescribing information for PROPOFOL, Injectable Emulsion, USP. To report SUSPECTED ADVERSE REACTIONS, contact Genixus at 1-833-436-4987, or FDA at 1-800-FDA-1088 or .

Full Year 2022 total revenues with double-digit growth of 12% at €47.5 million, in line with prior guidanceSignificant expansion of gross profit margin from 32% to 42% and ongoing cost control resulted in significant improvement of net resultsBoth Pharma and Diagnostics segments positioned for strong performance in 2023, guidance of FY2023 total revenue growth between 10% to 15% CAMBRIDGE, Mass. and ROSTOCK, Germany and BERLIN, May 16, 2023 (GLOBE NEWSWIRE) -- Centogene N.V. (Nasdaq: CNTG) (“we” or the “Company”), the essential life science partner for data-driven answers in rare and neurodegenerative diseases, today announced financial results for the fiscal year ended December 31, 2022, and provided a business update. “2022 reaffirms CENTOGENE’s focus and dedication to becoming the essential data-driven partner in rare and neurodegenerative diseases. With renewed focus on our Core Diagnostics and Pharma segments and the exit of the COVID-19 business, we have continued to deliver against our goals – recording double-digit revenue growth compared to the prior year. We expanded the CENTOGENE Biodatabank to over 750,000 patients – representing the world´s largest real-world integrated multiomic data repository in rare and neurodegenerative diseases to enable diagnostics, clinical development, and access to life-saving treatments for patients and partners around the world,” stated Kim Stratton, Chief Executive Officer at CENTOGENE. “While we continue to navigate a volatile market environment, we are proactively pursuing a number of initiatives to extend our cash runway and continue improving our cost structure. Looking ahead, we expect to see 2023 annual revenue growth between 10% to 15%.” Full Year 2022 Financial Highlights Total revenues increased by 12% to €47.5 million in FY2022, compared to €42.2 million in FY2021, reflecting growth in both the Diagnostics and Pharma segmentsDiagnostics segment revenues increased by 18% in 2022 to €31.4 million, primarily related to an increase of 34% in revenues for CentoXome® (CENTOGENE’s proprietary Whole Exome Sequencing) and CentoGenome® (CENTOGENE’s proprietary Whole Genome Sequencing). Achieved upselling 25% of CentoXome® and CentoGenome® orders to MOx (CENTOGENE’s portfolio of multiomic testing solutions) in FY2022Pharma segment revenues returned to growth after two years of decline, increasing by 3% year-over-year to €16.1 million, primarily driven by progressing observational studies for patient finding and market access in collaboration with pharma partners to support clinical development stage projects in rare and neurodegenerative disorders. Gross profit margins more than doubled to 55% in FY2022 compared to 26% in FY2021The overall gross profit margin improved by 10 percentage points to 42% of revenues or €19.8 million in FY2022, compared to a 32% gross profit margin in FY2021. The gross profit margin was mainly driven by better margins in the Pharma segment and solid margins in the Diagnostics segment due to product mix of innovative, high-end products including CentoXome®, CentoGenome®, and MOxThe Company improved its net loss position by 31% at €31.8 million in FY2022 compared to a net loss of €46.2 million in FY2021. Net loss from continuing operations showed an improvement of 33% at €38.7 million in FY2022 compared to €57.4 million in FY2021. G&A costs decreased by 25%, or €10.9 million, in FY2022. Discontinued operations reflected the contributions from the COVID-19 testing business, which was ceased end of Q1 2022 Total segment adjusted EBITDA showed a significant improvement of 69% overall at €13.2 million in FY2022 compared to €7.8 million in FY2021 from the Company’s Diagnostics and Pharma segments, representing higher adjusted EBITDA contributions from both business segments. Adjusted EBITDA from the Pharma segment increased by 42% to €6.8 million in FY2022, compared to €4.8 million in FY2021, as a result of strong revenue growth and an increase in gross margins. The Diagnostics segment recorded a notable increase in adjusted EBITDA of 112% to €6.4 million in FY2022, compared to €3.0 million in FY2021, primarily due to revenue growth and improved collections of receivablesCash and cash equivalents were €36.0 million as of December 31, 2022, compared to €17.8 million for the period ending December 31, 2021. There is uncertainty about the Company's ability to continue as a going concern. Please refer to the Company's FY2022 financial statements and related disclosures “We are very encouraged by the accelerating momentum and the performance we delivered in 2022, particularly in continuing to achieve strong segment adjusted EBITDA and optimizing operational efficiency. We have made a lot of progress towards building a sustainable business – simplifying and strengthening our organization as well as optimizing our cost structure and cost management. The results can be seen in significant improvements across gross margins, which are up 10 percentage points, corporate expenses being reduced, adjusted EBITDA improved, as well as the Company’s bottom line. In 2023, we continue to prioritize cost diligence as a key driver for profitability, while actively exploring additional transaction options to extend our cash runway. By strategically managing our expenses, we seek to enhance the stability of our balance sheet and foster sustainable financial performance,” added Miguel Coego, Chief Financial Officer at CENTOGENE. Recent Business Highlights Corporate Expanded the CENTOGENE Biodatabank to over 750,000 patients, over 70% of whom are of non- European descent, approximately 30,000 active physicians, and more than 70 million unique variants thanks to the increasing number of CentoXome® and CentoGenome® analyses, which contain significantly more variants than more targeted diagnostic testsAppointed Chief Commercial Officer & General Manager - Pharma, Ian Rentsch, and significantly strengthened Pharma Business Development by more than doubling the team size – underlining the Company’s strategic focus to better serve existing partners and significantly increase collaborations with new partnersStrengthened Diagnostics Sales team and expanded direct footprint distribution network in targeted geographic areas, such as Canada, Colombia, Italy, Spain, and PortugalAuthored 62 peer-reviewed scientific publications in FY2022, unlocking insights into Parkinson’s disease, Gaucher disease, frontotemporal dementia, Fabry disease, muscular dystrophy, Alport syndrome, mucopolysaccharidosis type VI, Suleiman-El-Hattab syndrome, Galloway-Mowat syndrome, HIDEA (hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy and eye abnormalities) syndrome, and Diets-Jongmans syndrome, as well as a range of variants associated with epilepsy, genetic cancers, metabolic disorders, developmental disorders, and other rare and neurodegenerative diseasesClosed $20 million second tranche of secured loan from Oxford Finance in December 2022, upon achieving trailing twelve-months revenue performance targetAnnounced the appointment of Mary Sheahan as Chair of the Audit Committee, as well as Ad Interim Member of the Supervisory Board, which is to be confirmed at the Company’s next General Meeting of Shareholders in June Pharma Extended Takeda partnership to April 2024 to continue providing access to genetic testing for patients with lysosomal storage disordersEntered strategic collaborations with IQVIA and Premier Research to extend strategy and expand commercialization model with pharma partners via Contract Research Organizations (CROs)Extended, alongside Denali Therapeutics, the ROPAD Study, the world’s largest observational study on Parkinson’s disease genetics with approximately 15,000 enrolled patients to date. Patients enrolled in ROPAD and identified with LRRK2 genetic variations may be eligible for participation in ongoing interventional clinical studies. Denali, in collaboration with Biogen Inc., is currently evaluating the efficacy and safety of BIIB122 (DNL151), a small molecule LRRK2 inhibitorExtended and expanded, with support from Alector, Inc., the observational EFRONT Study to advance the genetic understanding of frontotemporal dementiaLaunched the CENTOGENE Biodata Network, a portfolio of data-driven partnering solutions for biopharma and research institutions, fueled by the CENTOGENE Biodatabank and over 15 years of patient insights. These customizable partnering solutions include Insight Reports, which are tailored data analysis reports that seamlessly enable partners to answer ad hoc research questions via real-world data. Biodata Licenses are also available, which enable partners to securely access CENTOGENE's multiomic, clinical, and sociodemographic datasets via a Trusted Research Environment (TRE) Diagnostics Strong order intake of approximately 70,000 test requests for FY2022, which represents a 23% increase compared to approximately 57,000 in the prior yearLaunched CentoCloud®, one of the world’s only CE-marked Software as a Service (SaaS) under the In Vitro Diagnostics Directive (98/79/EC), as well as released CENTOGENE’s FilterTool application, one of the first applications to receive CE mark under the new In Vitro Diagnostic Regulation (IVDR). Pairing CentoCloud® and the FilterTool accelerates genetic data interpretation and helps labs and healthcare institutions around the globe to access the leading CENTOGENE Biodatabank, state-of-the-art certified dry labs, and automated bioinformatic pipelines to fully support rare and neurodegenerative patientsLaunched NEW CentoGenome®, the world's most comprehensive Whole Genome Sequencing tool for diagnosis of rare and neurodegenerative diseases, which now detects Copy Number Variations associated with spinal muscular atrophy, as well as complex disease-causing variants associated with Gaucher disease and susceptibility to GBA1-related Parkinson's diseaseLaunched MOx – CENTOGENE’s portfolio of single-step multiomic solutions that combines genomic and biochemical testing to lead to a higher diagnostic yield by up to 25%Launched together with TWIST Bioscience three Next Generation Sequencing target enrichment panels, Twist Alliance CNTG Exome, Twist Alliance CNTG Rare Disease Panel, and Twist Alliance CNTG Hereditary Oncology Panel, to support rare disease and hereditary cancer research and support diagnosticsUtilizing Illumina’s new NovaSeq X Sequencing System to further optimize throughput, scale, and cost efficiencies 2023 Revenue Guidance The Company expects revenue growth to be between 10 to 15% in FY2023 compared to FY2022. About CENTOGENE CENTOGENE’s mission is to provide data-driven, life-changing answers to patients, physicians, and pharma companies for rare and neurodegenerative diseases. We integrate multiomic technologies with the CENTOGENE Biodatabank – providing dimensional analysis to guide the next generation of precision medicine. Our unique approach enables rapid and reliable diagnosis for patients, supports a more precise physician understanding of disease states, and accelerates and de-risks targeted pharma drug discovery, development, and commercialization. Since our founding in 2006, CENTOGENE has been offering rapid and reliable diagnosis – building a network of approximately 30,000 active physicians. Our ISO, CAP, and CLIA certified multiomic reference laboratories in Germany utilize Phenomic, Genomic, Transcriptomic, Epigenomic, Proteomic, and Metabolomic datasets. This data is captured in our CENTOGENE Biodatabank, with over 750,000 patients represented from over 120 highly diverse countries, over 70% of whom are of non-European descent. To date, the CENTOGENE Biodatabank has contributed to generating novel insights for more than 275 peer- reviewed publications. By translating our data and expertise into tangible insights, we have supported over 50 collaborations with pharma partners. Together, we accelerate and de-risk drug discovery, development, and commercialization in target & drug screening, clinical development, market access and expansion, as well as offering CENTOGENE Biodata Licenses and Insight Reports to enable a world healed of all rare and neurodegenerative diseases. To discover more about our products, pipeline, and patient-driven purpose, visit www.centogene.com and follow us on LinkedIn. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the U.S. federal securities laws. Statements contained herein that are not clearly historical in nature are forward-looking, and the words “anticipate,” “believe,” “continues,” “expect,” “estimate,” “intend,” “project,” and similar expressions and future or conditional verbs such as “will,” “would,” “should,” “could,” “might,” “can,” and “may,” are generally intended to identify forward-looking statements. Such forward-looking statements involve known and unknown risks, uncertainties, and other important factors that may cause CENTOGENE’s actual results, performance, or achievements to be materially different from any future results, performance, or achievements expressed or implied by the forward- looking statements. Such risks and uncertainties include, among others, negative economic and geopolitical conditions and instability and volatility in the worldwide financial markets, possible changes in current and proposed legislation, regulations and governmental policies, pressures from increasing competition and consolidation in our industry, the expense and uncertainty of regulatory approval, including from the U.S. Food and Drug Administration, our reliance on third parties and collaboration partners, including our ability to manage growth, execute our business strategy and enter into new client relationships, our dependency on the rare disease industry, our ability to manage international expansion, our reliance on key personnel, our reliance on intellectual property protection, fluctuations of our operating results due to the effect of exchange rates, our ability to streamline cash usage, our continued ongoing compliance with covenants linked to financial instruments, our requirement for additional financing and our ability to continue as a going concern, or other factors. For further information on the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to CENTOGENE’s business in general, see CENTOGENE’s risk factors set forth in CENTOGENE’s Form 20-F filed on May 16, 2023, with the Securities and Exchange Commission (the “SEC”) and subsequent filings with the SEC. Any forward- looking statements contained in this press release speak only as of the date hereof, and CENTOGENE’s specifically disclaims any obligation to update any forward-looking statement, whether as a result of new information, future events, or otherwise. Contact: CENTOGENE Ben LeggCorporate CommunicationsPress@centogene.com Lennart StreibelInvestor RelationsIR@centogene.com Centogene N.V. Consolidated statements of comprehensive loss for the years ended December 31, 2022, 2021 and 2020 4(in EUR k) Note 2022 2021* 2020* Restated RestatedRevenue 7 47,473 42,234 38,453 Cost of sales 27,712 28,735 35,286 Gross profit 19,761 13,499 3,167 Research and development expenses 17,488 19,297 14,935 General administrative expenses 32,587 43,480 37,665 Selling expenses 9,924 9,326 7,580 Impairment of financial assets 22.2 — 827 3,636 Gain on reversal of financial asset impairment 432 — — Other operating income 8.1 3,774 2,894 2,392 Other operating expenses 8.2 741 86 182 Operating loss (36,773) (56,623) (58,439)Changes in fair value of warrants 8.3 2,574 — — Interest and similar income 512 3 6 Interest and similar expenses 4,909 802 1,381 Financial costs, net 8.3 (1,823) (799) (1,375)Loss before taxes from continuing operations (38,596) (57,422) (59,814)Income taxes expenses 10 107 (70) 224 Loss for the year from continuing operations (38,703) (57,352) (60,038)Net income from discontinued operations, net of tax 9 6,862 11,106 38,052 Loss for the period (31,841) (46,246) (21,986)Other comprehensive income/(loss), all attributable to equity holders of the parent (76) 543 (48)Total comprehensive loss (31,917) (45,703) (22,034)Attributable to: — — Equity holders of the parent (31,917) (45,801) (22,094)Non‑controlling interests from continuing operations 24 — 98 60 Non‑controlling interests from discontinued operations — — — (31,917) (45,703) (22,034)Net loss per share - Basic and diluted from (in EUR) Continuing operations 11 (1.45) (2.53) (2.87)Loss attributable to parent 11 (1.19) (2.04) (1.05) *The comparative numbers have been re-presented as a result of the discontinued operations. Refer to Note 9 – Discontinued Operations. The accompanying notes form an integral part of these consolidated financial statements Centogene N.V. Consolidated statements of financial position as of December 31, 2022 and 2021 (in EUR k) Assets Note Dec 31, 2022 Dec 31, 2021 Jan 1, 2021 Restated* Restated*Non‑current assets Intangible assets 12 7,400 9,194 12,407 Property, plant and equipment 13 6,808 9,464 16,590 Right-of-use assets 14 15,351 18,904 22,120 Derivatives assets 22 510 — — Other assets 16 2,911 2,972 1,967 32,980 40,534 53,084 Current assets Inventories 15 1,819 3,869 11,405 Trade receivables and contract assets 16 16,548 23,462 28,988 Other assets 16 5,514 5,453 8,286 Cash and cash equivalents 17 35,951 17,818 48,156 59,832 50,602 96,835 92,812 91,136 149,919 Equity and liabilities Note Dec 31, 2022 Dec 31, 2021 Jan 1, 2021 Equity Issued capital 18 3,307 2,708 2,654 Capital reserve 18 145,369 133,897 125,916 Accumulated deficit and other reserves (141,265) (109,540) (63,739)Non‑controlling interests — 193 95 7,411 27,258 64,926 Non‑current liabilities Non‑current loans 20.1 40,051 — 401 Lease liabilities 20.1 13,125 15,394 17,677 Deferred tax liabilities 35 79 207 Government grants 20.2 6,687 8,028 8,950 Derivative liabilities 22 376 — — Warrant liability 22 260 — — Other liabilities 20.2, 21 202 960 640 60,736 24,461 27,875 Current liabilities Government grants 20.2 1,263 1,368 1,342 Current loans 20.1 4,635 3,815 2,492 Lease liabilities 20.1 2,311 3,330 3,528 Liabilities from income taxes 10 89 178 58 Trade payables 20.2 6,317 11,252 31,736 Other liabilities 20.2, 21 10,050 19,474 17,962 24,665 39,417 57,118 92,812 91,136 149,919 *Property, plant and equipment and lease liabilities as of December 31, 2021, and Trade receivables and contract assets and other liabilities as of December 31, 2021, and January 1, 2021, have been restated. Refer to Note 2.4 – Restatement of selected assets and liabilities in the consolidated statements of financial position and selected income and expenses in the consolidated statements of comprehensive loss. The accompanying notes form an integral part of these consolidated financial statements Centogene N.V. Consolidated statements of cash flows for the years ended December 31, 2022, 2021 and 2020 (in EUR k) Note 2022 2021* (Restated) 2020* (Restated)Operating activities Loss before taxes from continuing operations (38,596) (57,422) (59,815)Income before taxes from discontinued operations 9 6,875 11,152 38,110 Loss before taxes (31,721) (46,270) (21,705)Adjustments to reconcile earnings to cash flow from operating activities Amortization (including impairments) and depreciation 12,13,14 10,378 19,974 15,128 Inventory write-off — 1,795 — Interest income 8.3 — (3) (6)Interest expense 8.3 4,909 851 1,400 Gain on the disposal of non‑current assets (754) (18) — Expected credit loss allowances on trade receivables and contract assets 2.4 — 631 3,804 Share‑based payment expenses 21 (16) 8,035 5,658 Tax expense (89) — — Fair value adjustments of warrants 8.3 (2,574) — — Other non‑cash items (1,430) (625) (981)Net foreign exchange differences 963 — — Changes in operating assets and liabilities: Inventories 15 2,050 5,741 (9,596)Trade receivables and contract assets 16 6,914 4,855 (16,172)Other assets 16 — 1,828 255 Trade payables 20.2 (4,935) (20,484) 23,996 Other liabilities 28 (10,182) 1,952 6,681 Thereof cash flow (used in) continuing operating activities 28 (35,497) (42,635) (30,603)Thereof cash flow from discontinued operating activities 9,009 20,897 39,065 Cash flow (used in)/from operating activities (26,488) (21,739) 8,462 Investing activities Cash paid for investments in intangible assets 12 (1,727) (2,787) (6,657)Cash paid for investments in property, plant and equipment 13 (367) (2,915) (9,890)Grants received for investment in property, plant and equipment 20.2 506 168 390 Grants refunded related to disposed property, plant and equipment 20.2 — — — Cash received from disposals of property, plant and equipment 855 171 — Interest received — 3 6 Thereof cash flow (used in) continuing investing activities (1,553) (2,494) (5,366)Thereof cash flow from/(used in) discontinued investing activities 820 (2,866) (10,785)Cash flow (used in)/from investing activities (733) (5,360) (16,151) Financing activities Cash received from the issuance of shares 18 12,140 — 22,430 Cash received from issuance of warrants 2,833 — — Cash paid for acquisition of non-wholly owned subsidiary (1) — (75)Cash received from loans 20, 22.2 40,568 1,772 438 Cash repayments of loans 20, 22.2 — (464) (2,760)Cash repayments of lease liabilities 20, 22.2 (4,314) (4,244) (5,018)Interest paid 8.3 (4,909) (267) (173) Thereof net cash flow from/(used in) continuing financing activities 46,798 (2,403) 13,561 Thereof net cash flow from/(used in) discontinued financing activities (481) (800) 1,281 Cash flow from financing activities 46,317 (3,203) 14,842 Changes in cash and cash equivalents 19,096 (30,302) 7,153 Cash and cash equivalents at the beginning of the period 17,818 48,156 41,095 Effect of movements in exchange rates on cash held (963) (36) (92)Cash and cash equivalents at the end of the period 35,951 17,818 48,156 *The comparative numbers have been re-presented as a result of the discontinued operations. Refer to Note 9- Discontinued Operations. The accompanying notes form an integral part of these consolidated financial statements

Scientists have developed a research method that allows for a much more detailed examination of the brain processes involved in some neurological and mental disorders. This is achieved by growing human cortical organoids in culture and inserting them into developing rodent brains to see how they integrate and function over time. Scientists have developed a research method that allows for a much more detailed examination of the brain processes involved in some neurological and mental disorders. This is achieved by growing human cortical organoids in culture and inserting them into developing rodent brains to see how they integrate and function over time. The study, funded by the National Institute of Mental Health (NIMH), part of the National Institutes of Health, appears in the journal Nature. "This work provides a significant advance in the ability of scientists to study the cellular and circuit underpinnings of complex human brain disorders. It allows organoids to get 'wired' in a more biologically relevant context and function in ways they can't do in a petri dish," said David Panchision, Ph.D., chief of the Developmental and Genomic Neuroscience Research Branch in the Division of Neuroscience and Basic Behavioral Science at NIMH. Researcher Sergiu Pasca, M.D., and colleagues at Stanford University, Stanford, California, demonstrated that a cortical organoid cultured from human stem cells can be transplanted onto -- and integrated into -- the developing rat brain to study certain developmental and functional processes. The findings suggest that transplanted organoids may offer a powerful tool for investigating the processes associated with disease development. Researchers sometimes use cortical organoids -- three-dimensional cultures of human stem cells that can mirror some of the developmental processes seen in typical brains -- as a model for investigating how some aspects of the human brain develops and functions. However, cortical organoids lack the connectivity seen in typical human brains, limiting their usefulness for understanding complex brain processes. Researchers have been trying to overcome some of these limitations by transplanting individual human neurons into adult rodent brains. While these transplanted neurons connect with rodent brain cells, they do not become fully integrated due to the developmental limitations of the adult rat brain. In this study, the team of researchers advanced the use of brain organoids for research by transplanting an intact human cortical organoid into a developing rat brain. This technique creates a unit of human tissue that can be examined and manipulated. The researchers used methods previously pioneered in the Pasca lab to create cortical organoids using human-induced pluripotent stem cells -- cells derived from adult skin cells that have been reprogrammed into an immature stem-cell-like state. They then implanted these organoids onto the rat primary somatosensory cortex, a part of the brain involved in processing sensation. The researchers did not detect any motor or memory abnormalities or abnormalities in brain activity in the rats that received the transplanted organoid. Blood vessels from the rat brain successfully supported the implanted tissue, which grew over time. To understand the extent to which the organoids could integrate into the rat somatosensory cortex, the researchers infected a cortical organoid with a viral tracer that spreads through brain cells as an indicator of functional connections. After transplanting the marked organoid onto the rat's primary somatosensory cortex, researchers detected the viral tracer in multiple brain areas, such as the ventrobasal nucleus and the somatosensory cortex. In addition, the researchers observed new connections between the thalamus and the transplanted area. These connections were activated using electrical stimulation and stimulation of the rat's whiskers, indicating that they were receiving meaningful sensory input. Moreover, the researchers were able to activate human neurons in the transplanted organoid to modulate the rat's reward-seeking behavior. The findings suggest functional integration of the transplanted organoid into specific brain pathways. Structurally and functionally, after seven to eight months of growth, the transplanted brain organoid resembled neurons from human brain tissue more than human organoids maintained in cell culture. The fact that the transplanted organoids mirrored the structural and functional features of human cortical neurons led the researchers to wonder if they could use transplanted organoids to examine aspects of human disease processes. "The promise of this platform is not only in identifying what molecular processes underlie the advanced maturation of human neurons in living circuits and leveraging it to improve conventional in vitro models, but also in providing behavioral readouts for human neurons," said Dr. Pasca. To examine this, the researchers generated cortical organoids with cells from three participants with a rare genetic disorder associated with autism and epilepsy called Timothy syndrome and three participants without any known diseases and implanted them onto the rat brain. Both types of organoids integrated into the rat somatosensory cortex, but organoids derived from Timothy Syndrome patients displayed structural differences. These structural differences did not appear in organoids that were created from the cells of patients with Timothy Syndrome and maintained in cell culture. "These experiments suggest that this novel approach can capture processes that go beyond what we can detect with current in vitro models," said Dr. Pasca. "This is important because many of the changes that cause psychiatric disease are likely subtle differences at the circuit level."